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DRUGS 2007, Vol 67, No.

Drugs
2007, Volume 67, Issue 1 Page # Article/Title

Current Opinion 1 Inhibiting Costimulatory Activation of T Cells: A Viable Treatment Option For Rheumatoid Arthritis? Louise C Pollard

Leading Article 11 Squalene Synthase Inhibitors: Clinical Pharmacology and Cholesterol-Lowering Potential. Valentine Charlton-Menys; Paul N Durrington

Therapy In Practice 17 Practical Issues and Challenges in the Diagnosis and Treatment of Pulmonary Sarcoidosis. Surinder K Jindal

Review Article 27 57 75 Serotonergic Drugs: Effects on Appetite Expression and Use for the Treatment of Obesity. Jason C G Halford; Joanne A Harrold; Emma J Boyland; Clare L Lawton; John E Blundell Therapeutic Applications of Sildenafil Citrate in the Management of Paediatric Pulmonary Hypertension. Leah Leibovitch; Ilan Matok; Gideon Paret Ocular Adverse Effects Associated with Systemic Medications: Recognition and Management. Ricardo M Santaella; Frederick W Fraunfelder

Adis Drug Profile 95 Fixed-Dose Combination Lercanidipine/Enalapril. Philip I Hair; Lesley J Scott; Caroline M Perry

Guest Commentaries 107 107 Fixed-Dose Combination Lercanidipine/Enalapril: A Viewpoint by Nicolas R. Robles. Nicols R Robles Fixed-Dose Combination Lercanidipine/Enalapril: A Viewpoint by Roland Asmar. Roland Asmar

Adis Drug Profile 109 Limaprost. Tracy Swainston Harrison; Greg L Plosker

Guest Commentaries

119 119

Limaprost: A Viewpoint by Akira Dezawa. Akira Dezawa Limaprost: A Viewpoint by Shin-Ichi Konno. Shin-ichi Konno

Adis Drug Evaluation 121 Fenofibrate: A Review of its Use in Primary Dyslipidaemia, the Metabolic Syndrome and Type 2 Diabetes Mellitus. Gillian M Keating; Katherine F Croom

CURRENT OPINION

Drugs 2007; 67 (1): 1-9 0012-6667/07/0001-0001/$49.95/0 2007 Adis Data Information BV. All rights reserved.

Inhibiting Costimulatory Activation of T Cells


A Viable Treatment Option For Rheumatoid Arthritis?
Louise C. Pollard
Academic Department of Rheumatology, Kings College London, London, UK

Abstract

There is now good evidence that T cells play a central role in the inflammatory pathway that leads to the persistent synovitis that causes joint damage in rheumatoid arthritis (RA). T cells require two signals to become activated. The second step in the activation of T cells involves costimulatory pathways, the best described pathway being the binding of CD28 on T cells to CD80/86 on antigen-presenting cells. This observation has led to the development of a new category of biological response modifier. Abatacept is a fusion protein (cytotoxic T-lymphocyte-associated antigen-4 immunoglobulin [CTLA4Ig]); which blocks the binding of CD28 by avidly binding CD80/86. Without this costimulatory activation, the T cell becomes anergic. Abatacept has consistently been shown to improve the signs and symptoms of RA in phase II and phase III trials in patients with an inadequate response to methotrexate and anti-tumour necrosis factor (TNF) therapy. Onset of action is rapid and efficacy is maintained during the period of treatment. Recent trials have also provided evidence of improvement in quality-of-life measures and radiographic progression. The safety profile to date has also been favourable and supports the theory that targeting naive T cells early in the inflammatory pathway will lead to immunomodulation rather than immunosuppression. The evidence produced so far suggests that abatacept will be a useful addition to the available therapies for patients with RA.

Rheumatoid arthritis (RA) is the most common chronic polyarthritis, and continuing inflammation leads to an increase in morbidity and mortality. RA causes disability through persistent synovitis, joint damage and high levels of pain and fatigue. RA has traditionally been treated with disease-modifying antirheumatic drugs (DMARDs); however, the treatment of RA has been revolutionised over the last 2 decades with the introduction of biological therapies. This stemmed from advances in the understanding of the pathogenesis of RA and the inflam-

matory pathways involved. Although these drugs have undoubtedly made a significant difference to RA treatment, they have not been without problems. Currently there are three anti-tumour necrosis factor (TNF) agents available; and as a class of drugs the predominant adverse effects are the increased risk of infection and, in particular, the reactivation of latent tuberculosis (TB). Anti-TNF therapy can also worsen heart failure and not all patients respond to antiTNF therapy. The other currently available biological therapy is anakinra (anti-interleukin [IL]-1-re-

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ceptor-antagonist). While anakinra has been shown to improve the signs and symptoms of RA, it has not proven as efficacious as anti-TNF therapy. There is ongoing research investigating other potential targets in the inflammatory pathway. Abatacept targets the costimulatory pathways which are needed to activate T cells. This review describes the rationale and evidence for the use of costimulation inhibitors of T cells (abatacept) in the treatment of RA. To identify articles for this review a MEDLINE search was undertaken for publications since 1990 using the key words abatacept, CD28 costimulation and BMS-188667. In addition, articles presented at annual scientific meetings were included; although I acknowledge that these have not been the subject of rigorous peer review. 1. The Role of T Cells in the Pathogenesis of Rheumatoid Arthritis There is now a wealth of evidence showing that T cells play a central role in the pathogenesis of RA. The Sakaguchi (SKG) mouse model supports this concept; a point mutation in the gene encoding ZAP-70, a key signal transduction molecule in T cells, leads to the development of a chronic inflammatory arthritis in mice that is clinically and histologically similar to RA.[1] The point mutation leads to a positive selection of autoreactive T cells in the thymus that would otherwise have been deleted. Other supporting data include the ability to transfer RA into immunodeficient mice using T cells taken from the synovium of patients with RA.[2] Clinical observations also add to the weight of evidence, as activated T cells are seen in abundance in the synovium of RA patients.[3] T cells are dependent on activation; once activated they differentiate, proliferate and migrate into the affected tissues where they produce cytokines and regulate other immune responses. In RA, activated T cells produce a number of proinflammatory cytokines such as TNF and IL-1, as well as activating B cells to produce immunoglobulins, including rheumatoid factor. Activated T cells lead to bone loss and joint damage through a
2007 Adis Data Information BV. All rights reserved.

combination of release of matrix metalloproteinases and activation of osteoclasts.[4] Rather than a simple one-ligand activation pathway, T cells require two distinct but simultaneous signals to become activated. The first signal is the presentation of a major histocompatibility complexantigen complex on an antigen-presenting cell (APC), binding to an antigen-specific receptor on the T-cell surface.[5] The second signal is via a costimulatory pathway, without this signal the T cell becomes anergic.[6] The costimulatory pathway consists of a ligand on the APC binding with the reciprocal receptor on the T-cell surface.[7] Several different costimulatory pathways have been identified, some lead to the initial activation of T cells and some attenuate the T-cell response. One of the best described costimulatory pathways is the binding of CD28 ligand on T cells with the CD80/CD86 ligand on the APC.[8] This pathway is also felt to be one of the more important pathways and acts by initial activation of the T cell. It is this pathway that is the target for the drug abatacept. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) is a T cell surface protein which has a similar structure to CD28 on T cells, and CTLA4 is quickly upregulated once a T cell is activated.[9,10] CTLA4 binds to CD80/ CD86, the same binding sites as CD28, and has a greater affinity for CD80/CD86, thus competing with CD28. The binding of CTLA4 with CD80/ CD86 leads to down-regulation of the immune response and can prevent CD28-dependent T-cell activation.[11] Polymorphisms of CTLA4 can cause loss of self-tolerance[12] and, therefore, targeting costimulation using CTLA4 may help regulate the immune response in RA. 2. Abatacept Abatacept (CTLA4Ig) is a soluble fusion protein that consists of the extracellular domain of the CTLA4 linked to the Fc domain of human immunoglobulin G1 (IgG1).[13] Like the naturally occurring CTLA4, abatacept binds to CD80/86 on APCs. However, it differs from naturally occurring CTLA4, as abatacept is soluble rather than membrane bound and so does not produce a signal to the
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T cell but blocks the binding of CD28 to CD80/ CD86, thus preventing full activation of the T cell by interfering with the costimulatory signal. In vitro studies have shown a reduction in T-cell proliferation and inhibition of cytokines TNF, interferon- and IL-2.[14] Abatacept is administered by a 30 minute intravenous infusion given at baseline then at weeks 2 and 4, and 4-weekly thereafter. Abatacept has been licensed for use in the US as monotherapy or in combination with other DMARDs (except anti-TNF therapy).
2.1 Clinical Trial Data
2.1.1 Pilot Study

In the first pilot study published in 2002,[15] the primary goal was to assess the safety, tolerability and preliminary efficacy of pharmacological blockade of CD80 and CD86 in patients with RA. Two drugs were studied: abatacept and belatacept (LEA29Y). Belatacept is a second generation molecule based on abatacept, which has greater avidity for CD86 via the mutation of the residues of two amino acids on the parent molecule. The study was multicentre, randomised, double-blind and placebocontrolled, with seven treatment groups: abatacept or belatacept at 0.5 mg/kg, 2 mg/kg or 10 mg/kg, or placebo, with approximately 30 patients in each group. Study medication was given on days 1, 15, 29 and 57, with follow-up continued to day 169. Patients had active RA diagnosed within the last 7 years and had not responded to at least one DMARD. One hundred and seventy-four patients (81%) completed the treatment period and 160 (75%) completed to study end at day 169. Of the 40 patients who discontinued the study within the treatment period, 12 were in the placebo group, 20 in the abatacept group and 8 in the belatacept group. The most common reason for discontinuation was worsening of disease activity. The study medication seemed well tolerated and generally safe. There were no notable renal, hepatic or haematological adverse events during the study. The incidence of adverse events was similar in all
2007 Adis Data Information BV. All rights reserved.

groups, including the placebo group. Fifteen serious adverse events were reported during the treatment period, this comprised 4% in the active treatment groups compared with 13% in the placebo group. In most cases, the event was worsening of RA requiring hospitalisation. There was one episode of septic arthritis in the abatacept group diagnosed 88 days after the last infusion, although the patient had also had an intra-articular injection of corticosteroids. There were five withdrawals; two patients from the abatacept 0.5 mg/kg group (one due to worsening of RA and one patient had breast cancer diagnosed at day 57), two patients withdrew from the abatacept 2 mg/kg group (one due to worsening of RA and one due to probable anxiety attack after the second infusion) and one patient withdrew from the belatacept 10 mg/kg group (due to viral upper respiratory infection). With regard to efficacy with both agents, a dose response was noted for the primary outcome, American College of Rheumatology 20% improvement criteria (ACR)20.[16] Both active treatments, particularly the higher doses, were associated with numeric improvements in ACR relative to placebo. The study was not powered to demonstrate efficacy; however, the difference between the ACR20 response of the belatacept 10 mg/kg group and the placebo group reached clinical significance as did the ACR70 response of the abatacept 2 mg/kg group compared with the placebo group.
2.1.2 Phase II Studies

Two papers have been published with phase II data for abatacept in RA. The first was a 6-month, randomised, double-blind, placebo-controlled study comparing the safety, efficacy and immunogenicity of abatacept 2 mg/kg or 10 mg/kg with placebo in patients with active RA who had an inadequate response to methotrexate.[17] The second publication reported the results from the 6-month extension of the previous study.[18] In the first study, patients had established active RA and had been receiving methotrexate for at least 6 months; no other DMARD was allowed. Abatacept or placebo was administered by infusion on days 1, 15 and 30 and monthly thereafter. A total of 544 patients were
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recruited and 339 patients were randomised. Baseline characteristics were similar across all groups with mean disease duration of 8.99.7 years. A total of 259 patients completed the first 6 months of treatment. Significantly more patients discontinued treatment because of lack of efficacy in the placebo group compared with both treatment arms. The results for clinical efficacy showed that at 6 months the percentage of patients who achieved an ACR20 response was significantly higher in the abatacept 10 mg/kg group than placebo, and this was evident from month 2 through to month 6. There was no significant difference between the group receiving 2 mg/kg and the placebo group. The rates of ACR50 (from day 90) and ACR70 (from day 30) responses were significantly higher in both abatacept groups compared with placebo at 6 months. At 12 months, there was still a significant difference in ACR20 response in the abatacept 10 mg/kg group compared with placebo. Again, at 12 months there was no significant difference in ACR20 responses in the abatacept 2mg/kg group compared with placebo, suggesting that the lower dose is not sufficient. ACR50 and ACR70 responses continued to be significantly higher in the abatacept 10 mg/kg group compared with placebo at 12 months. At 12 months, statistically significant differences were noted in all the components of the ACR core set (tender joint count, swollen joint count, pain, acute phase reactants, patients and physicians global assessments and health assessment questionnaire) in the abatacept 10 mg/kg group compared with placebo. In the 6-month analysis, patients were also assessed using the SF-36 (short form 36-item quality of life questionnaire)[19] score and patients in the abatacept 10 mg/kg group had clinically and statistically significant improvements in all eight subscales of the SF-36 compared with placebo; there were non-significant improvements in the 2 mg/kg group. Health-related quality of life (HR-QOL) data from the 12-month study were published in April 2006.[20] This study examined the effect of abatacept therapy (10 mg/kg) in combination therapy with
2007 Adis Data Information BV. All rights reserved.

methotrexate on a broad range of HR-QOL domains. General health status was measured using the SF-36 and a health utility index (SF-6D) was also derived from 11 items of the SF-36.[21] Changes in the SF-36 scale and summary measure scores and the SF-6D from baseline to 12 months were evaluated and compared between placebo and treatment groups. Overall, the changes in SF-36 scales and summary measure scores differed between the abatacept 10 mg/kg and placebo group (multivariate analysis of variance [MANOVA] F = 4.7, p < 0.0001). Statistically significant improvements in mean score were observed in all eight scales of the SF-36 and both summary measures, with outcomes favouring the abatacept group. A statistically significant difference in mean score change on the SF-6D was also observed in the abatacept group. Throughout the 12-month period that the two studies cover, abatacept was well tolerated. No deaths or opportunistic infections were reported in any of the patients who received abatacept over 12 months. The number of malignancies was similar in the abatacept group compared with placebo. The safety profile for both dosages of abatacept was similar to placebo over 12 months. Patients in the 10 mg/kg group who completed the 12-month study were eligible for enrolment in an open-label extension study for a further 12 months.[22] Of the 115 patients eligible, 73% entered the extension study and 89% of these patients completed 2 years of treatment. Nearly 50% of the abatacept group achieved a Disease Activity Score for 28 joints (DAS28) remission at 12 months, which was sustained at 2 years (figure 1).
2.1.3 Phase III Studies

The results from the first phase III trial evaluating the efficacy and safety of abatacept were published in September 2005.[23] In this randomised, doubleblind study, abatacept was given to patients with active RA and an inadequate response to anti-TNF therapy (ATTAIN trial [Abatacept Trial in Treatment of Anti-TNF Inadequate Responders]). Two groups of patients were enroled: those receiving anti-TNF therapy at the time of screening (current users) and those who had previously received antiDrugs 2007; 67 (1)

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Abatacept 10 mg/kg (n = 84) Placebo (n = 67) Remission rates (DAS28 <2.6) [%] 60 50 40 30 20 10 0 1 90 180 270 360 450 540 630 720 Visit (days) Fig. 1. Remission rates (Disease Activity Score for 28 joints [DAS28] <2.6) for patients receiving abatacept at 12 months (blinded phase) and at 2 years (open-label, long-term extension [LTE]) based on as-observed data (reproduced from Dougados et al.,[22] with permission). Blinded phase LTE phase

period. More patients in the abatacept group achieved remission (as defined by a DAS28 of <2.6) than in the placebo group (10% vs 0.8%, p < 0.001) and 17.1% of patients in the abatacept group had low levels of disease (DAS28 3.2) compared with 3.1% of patients in the placebo group (p < 0.001). Improvements in physical function (improvement from baseline in HAQ of 0.3) were seen in 47.3% of patients in the abatacept group compared with 23.3% in the placebo group (p < 0.001) at 6 months. Improvements in HR-QOL measures (SF-36) were also observed. Improvements in scores for all subscales were seen in the abatacept group. There were significant improvements in the physical-component and mental-component summary scores compared with the placebo group. The rates of adverse events and serious adverse events were similar in both groups, but a higher number of infections were seen in the abatacept group (37.6% vs 32.3%, p = 0.3), but no unusual or opportunistic infections were observed. One patient in the abatacept group died from a myocardial infarction and congestive cardiac failure. Further HR-QOL data from the ATTAIN study has recently been published.[25] In this study, HRQOL was measured using the SF-36 (using both the scales and composite measures), HAQ and a visual analogue scale. The SF-36 was measured at baseline and at 1, 3 and 6 months (end-point) and the HAQ was measured at multiple points throughout the study. At the end-point (6 months), the abatacept group had statistically significant improvements from baseline in all SF-36 subscales and composite scores, the HAQ and the fatigue measure, compared with the placebo group. QOL was also examined for patients with different severity levels at baseline. Those receiving abatacept with a lower DAS28 level at baseline (<7.59) improved significantly more in most QOL measures (excluding role emotional [RE] in the SF-36) compared with those receiving placebo. Among those patients with a higher DAS28 at baseline, all of the mental SF-36 scales, HAQ and fatigue scores showed similar improvements in both groups. Lastly, the study looked at change in QOL over time. The results showed that the abatacept
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TNF therapy (former users). All users had to stop therapy before commencing the trial. Patients were randomly assigned in a 2 : 1 ratio to receive abatacept or placebo and stratified according to use of anti-TNF therapy at the time of enrolment. Abatacept was given at a dose of 10 mg/kg, as a 30 minute infusion on days 1, 15 and 29 and every 28 days thereafter for 6 months. The two primary endpoints were the proportion of patients with an ACR20 response at 6 months and also the proportion of patients with at least a 0.3 improvement from baseline in the Health Assessment Questionnaire (HAQ)[24] score. Secondary objectives included ACR50 and ACR70 response rates at 6 months, changes in DAS28 scores and changes from baseline in the SF-36 score at 6 months. A total of 738 patients were screened, 393 underwent randomisation and a total of 322 patients completed the study: 86.4% in the abatacept group and 74.4% in the placebo group. Lack of efficacy was the predominant reason for withdrawal from both groups. At 6 months, the rate of ACR20 (50.4% vs 19.5%, p < 0.001), ACR50 (20.3% vs 3.8%, p < 0.001) and ACR70 (10.2% vs 1.5%, p = 0.003) responses was significantly higher in the abatacept group compared with placebo. The improvement over placebo was evident from day 15 onward and progressively increased during the 6-month study
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group had significantly larger rates of change for all QOL outcomes (except for RE) compared with the placebo group. Most of the results indicated a significant difference between treatment and placebo occurred by the 12th week. The results from the phase III AIM (Abatacept in Inadequate responders to Methotrexate) study have also recently been published.[26] This 1-year, randomised, double-blind, placebo-controlled trial aimed to compare the efficacy and safety of abatacept versus placebo in combination with methotrexate in patients with RA and an inadequate response to methotrexate. Patients were randomly assigned in a 2 : 1 ratio to receive either a fixed dose of abatacept or placebo. The infusion regimen for abatacept was the same as in the ATTAIN study. All patients received methotrexate 15mg per week, although 10mg per week was allowed if there was a history of toxicity. No adjustment of methotrexate was allowed in the first 6 months but after that time increases of methotrexate were permitted, as was an addition of a further DMARD or an increase in corticosteroid if deemed necessary by the blinded investigator. The three primary endpoints were the proportion of patients achieving an ACR20 at 6 months, the proportion of patients with a clinically significant improvement (0.3) in HAQ score at 1 year, and the radiographic progression of joint erosions (assessed by comparing changes from baseline in the Genant-modified Sharp score[27]) at 1 year. Secondary objectives included assessing ACR50 and ACR70 responses at 6 months and all ACR responses at 1 year. Changes in DAS28 were also assessed, as were changes in HR-QOL by use of the SF-36. A total of 1250 patients were enrolled and 652 underwent randomisation with 452 assigned abatacept and 219 assigned placebo. Lack of efficacy was the most common reason for discontinuation in the placebo group (18% vs 3%). Adverse events were the most common reason for discontinuation in the abatacept group (4% vs 2%). At 6 months the rate of ACR20 (67.9% vs 39.7%; p < 0.001), ACR50 (39.9% vs 16.8%; p < 0.001) and ACR70 (19.8% vs 6.5%; p < 0.001) were significantly
2007 Adis Data Information BV. All rights reserved.

higher in the abatacept group compared with placebo (figure 2a2c). Between 6 and 12 months, all the ACR responses continued to improve in patients receiving abatacept. At 1 year, ACR20 responses had significantly increased to 73.1%, ACR50 responses were 48.3% and ACR70 responses were 28.8% (figure 2a2c). At 1 year, physical function (HAQ) had improved statistically significantly more in the abatacept group compared with placebo (63.7% vs 39.3%; p < 0.001) [figure 2d]. Radiographic data were collected for 92% of randomised patients. At 1 year, patients who received abatacept demonstrated statistically significant slowing of structural progression compared with placebo, with an approximately 50% reduction in change from baseline in Genant-modified Sharp scores compared with placebo. The median change from baseline in erosion, joint-space and total score are shown in figure 3. At 6 and 12 months, 30.1% and 42.5% of the abatacept group achieved a DAS28 of 3.2, compared with 10% and 9.9% of the placebo group, respectively (p < 0.001). At 1 year, DAS28 remission (DAS28 2.6) was seen in 14.8% of abatacept recipients compared with 1.9% of patients receiving placebo (p < 0.001). The HR-QOL measures also showed improvement in the abatacept group. At 6 months, significant improvements from baseline in both physical (p < 0.001) and mental components (p = 0.009) were seen compared with placebo, and they remained significant at 1 year. The overall incidence of adverse events was similar in both abatacept and placebo groups. The incidence of serious adverse events increased with abatacept treatment, but rates of discontinuation due to serious adverse events were similar between groups. The incidence of infection reported as a serious adverse event was higher with abatacept than with placebo and an increase in pneumonia with abatacept treatment was observed. One possible case of TB was observed in each group and the incidence of neoplasms (benign or malignant) was similar in both groups. No major autoimmune disorders such as multiple sclerosis or lupus were reported. More infusion reactions were observed in the
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T-Cell Activation Inhibitors in Rheumatoid Arthritis

a 80 80 70 60 50 40 30 20 10 0
85 11 3 14 1 16 3 1 0 15 29 5 5 57 28 36 22

b 70 60 50 40 30 20 10 0
85 11 3 14 1 16 3 0 15 29 1 57 5 28 22 36
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Abatacept + MTX (n = 424) Placebo + MTX (n = 214)2

ACR20 responses (%)1

ACR50 responses (%)1

c 80 80

ACR70 responses (%)1

HAQDI responses (%)1

70 60 50 40 30 20 10 0
3 14 1 16 3 1 0 15 29 5 57 85 5 28 11

70 60 50 40 30 20 10 0
3 14 1 16 3 0 15 29 1 57 85 5 11 28

Visit day

22

36

Visit day

Fig. 2. Improvement in American College of Rheumatology % improvement criteria (ACR)20 (a), ACR50 (b) and ACR70 (c) responses over 1 year in all patients who received at least one dose of the study medication; and (d) the percentage of patients who achieved a Health Assessment Questionnaire Disability Index (HAQ-DI) response (0.3-unit improvement from baseline in HAQ-DI) determined over 1 year (reproduced from Kremer et al.,[26] with permission). 1 = intention-to-treat population where all patients who withdrew from the study were considered to be ACR nonresponders subsequent to their withdrawal; 2 = because of adherence issues identified during the study, patients from one site were excluded from all efficacy analyses before unblinding but were included in the analysis of safety; MTX = methotrexate.

abatacept group; two patients had to withdraw because of severe acute infusion reactions.
2.2 Safety

With the advent of the new biological therapies an important consideration is the safety of these new drugs, especially with the observed increased risk of infection, in particular reactivation of TB[28] and opportunistic infections. Two abstracts have been published specifically looking at the safety profile of abatacept.[29,30] Moreland et al.[29] looked at the safety of abatacept from five randomised, double-blind, placebo-controlled trials. In this large population (1955 patients who received abatacept vs 989 patients given placebo), abatacept seems generally
2007 Adis Data Information BV. All rights reserved.

safe and well tolerated. However, a slight increase in infection rate was observed in the patients who received abatacept. The incidence of death and serious adverse events was similar in both groups. The most commonly reported adverse effects were headache, upper respiratory tract infections, nausea and nasopharyngitis. The ASSURE (Abatacept Study of Safety in Use with other Rheumatoid Arthritis Therapies) trial was designed to evaluate the safety profile of abatacept in routine clinic practice and, therefore, looked at the safety of abatacept as an add-on treatment in RA patients who were already taking one or more DMARD and/or biological therapy.[30] Patient-reported outcomes were also assessed (HAQ, patient

22

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Score change from baseline

12 10 8 6 4 2 0 2 Erosion score

Abatacept + MTX (n = 391) Placebo + MTX (n = 195) Median interquartile

JSN score

Total score

Fig. 3. Slowing of radiographic structural damage progression at 1 year. Interquartile range changes from baseline in Genant-modified Sharp erosion, joint space narrowing (JSN) and total scores were evaluated at 1 year or at early termination (if applicable). The dotted line indicates the 10th and 90th percentiles. Data shown are from randomly assigned and treated patients with baseline and follow-up radiography (reproduced from Kremer et al.,[26] with permission). MTX = methotrexate.

global assessment and pain). This 1-year study randomised and treated 1441 patients (959 received abatacept and 482 received placebo), most of whom were receiving combination non-biological therapies. Improvements were seen in all patient-reported outcomes in those patients treated with abatacept, with the greatest benefit seen in those patients on background non-biological therapies. With regards to safety, no difference was seen in the incidence of neoplasms and serious infections between the treatment groups in those patients receiving background non-biological DMARDs; however, in the smaller group of patients on background biological therapies there was an increase in serious adverse events and infections observed. This suggests that the safety profile for patients receiving background DMARDs appears favourable over 1 year, but given the less favourable profile in those patients on background biological therapies, this would not support the use of abatacept in combination with other biological therapies at present. 3. Conclusions Abatacept is the first drug in a new category of biological response modifiers; the CTLA4Ig fusion protein modulates the CD80/86-CD28 costimulatory pathway and provides further evidence that T cells play a central role in the pathogenesis of RA. The way in which abatacept modulates the immune
2007 Adis Data Information BV. All rights reserved.

system means that it is less likely to be immunosuppressive as it targets naive T cells and spares the innate immune system responses. Phase II and phase III trials have provided good evidence of the efficacy of abatacept in the treatment of RA. Abatacept therapy is associated with rapid and sustained improvements in both clinical and patient-reported outcomes, including QOL measures. As abatacept has a different mechanism of action to anti-TNF therapy, it would be reasonable to assume that abatacept would be effective in patients resistant to ant-TNF therapy and indeed the improvements seen in clinical outcomes were also seen in non-TNF responders. Abatacept treatment also resulted in a reduction in radiographic progression and in significant rates of remission. The combination of the favourable safety profile so far documented and the clinical benefits suggest that abatacept will certainly be an important addition to the available therapies for patients with RA. Abatacept is the first costimulatory blocker to be licensed in RA, but there is potential for other drugs in this class since new forms of CD28-CD80/86 blockade are currently being developed, as are agents that block other costimulatory pathways such as CD40 and CD154. Acknowledgements
No sources of funding were used to assist in the preparation of this review. The author has no conflicts of interest that are directly relevant to the content of this review.

References
1. Sakaguchi N, Takahashi T, Hata H, et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 2003; 426 (6965): 454-60 2. Mima T, Saeki Y, Ohshima S, et al. Transfer of rheumatoid arthritis into severe combined immunodeficient mice: the pathogenetic implications of T cell populations oligoclonally expanding in the rheumatoid joints. J Clin Invest 1995; 96 (4): 1746-58 3. Steiner G, Tohidast-Akrad M, Witzmann G, et al. Cytokine production by synovial T cells in rheumatoid arthritis. Rheumatology 1999; 38 (3): 202-13 4. Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001; 344 (12): 907-16 5. VanderBorght A, Geusens P, Raus J, et al. The autoimmune pathogenesis of rheumatoid arthritis: role of autoreactive T cells and new immunotherapies. Semin Arthritis Rheum 2001; 31 (3): 160-75

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T-Cell Activation Inhibitors in Rheumatoid Arthritis

6. Schwartz RH. T cell anergy. Annu Rev Immunol 2003; 21: 305-34 7. Janeway Jr CA, Bottomly K. Signals and signs for lymphocyte responses. Cell 1994; 76 (2): 275-85 8. Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Annu Rev Immunol 1996; 14: 233-58 9. Walunas TL, Lenschow DJ, Bakker CY, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994; 1 (5): 405-13 10. Wang XB, Zheng CY, Giscombe R, et al. Regulation of surface and intracellular expression of CTLA-4 on human peripheral T cells. Scand J Immunol 2001; 54 (5): 453-8 11. Walunas TL, Bakker CY, Bluestone JA. CTLA-4 ligation blocks CD28-dependent T cell activation. J Exp Med 1996; 183 (6): 2541-50 12. Simmonds MJ, Gough SC. Genetic insights into disease mechanisms of autoimmunity. Br Med Bull 2005; 71: 93-113 13. Linsley PS, Brady W, Urnes M, et al. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 1991; 174: 561-9 14. Nadler S, Townsend R, Mikesell G, et al. Abatacept (CTLA4Ig; BMS-188667) significantly inhibits T-cell proliferation in vitro at clinically relevant concentrations [abstract no. THU0103]. Ann Rheum Dis 2004; 63 Suppl. 1: 142 15. Moreland LW, Alten R, Van den Bosch F, et al. Costimulatory blockade in patients with rheumatoid arthritis: a pilot, dosefinding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days after the first infusion. Arthritis Rheum 2002; 46 (6): 1470-9 16. Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995; 38: 727-35 17. Kremer JM, Westhovens R, Leon M, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 2003; 349 (20): 1907-15 18. Kremer JM, Dougados M, Emery P, et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase IIb, double-blind, randomized, placebo-controlled trial [published erratum appears in Arthritis Rheum 2005 Oct; 52 (10): 3321]. Arthritis Rheum 2005; 52 (8): 2263-71 19. Ware JE. The SF-36 health survey. In: Spilker B, editor. Quality of life and pharmacoeconomics in clinical trials. 2nd ed. Lippincott-Raven: Philadelphia, 1996 20. Emery P, Kosinski M, Li T, et al. Treatment of rheumatoid arthritis patients with abatacept and methotrexate significantly improved health-related quality of life. J Rheumatol 2006 Apr; 33 (4): 681-9

21. Brazier J, Roberts J, Deverill M. The estimation of a preferencebased measure of health from the SF-36. J Health Econ 2002 Mar; 21 (2): 271-92 22. Dougados M, Westhovens R, St Clair E, et al. Sustained remission and major clinical response at 2 years shown with abatacept (CTLA4Ig) in combination with methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate [abstract no. 359]. Arthritis Rheum 2004; 50: S185 23. Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 2005; 353 (11): 1114-23 24. Fries JF, Spitz PW, Kraines RG, et al. Measurement of patient outcome in arthritis. Arthritis Rheum 1980; 23: 137-45 25. Westhovens R, Cole JC, Li T, et al. Improved health-related quality of life for rheumatoid arthritis patients treated with abatacept who have inadequate response to anti-TNF therapy in a double-blind, placebo-controlled, multicentre randomized clinical trial. Rheumatology (Oxford) 2006 Oct; 45 (10): 1238-46 26. Kremer JM, Genant HK, Moreland LW, et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2006 Jun 20; 144 (12): 865-76 27. Genant HK, Jiang Y, Peterfy C, et al. Assessment of rheumatoid arthritis using a modified scoring method on digitized and original radiographs. Arthritis Rheum 1998 Sep; 41 (9): 1583-90 28. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor -neutralizing agent. N Engl J Med 2001; 345: 1098-104 29. Moreland L, Kaine J, Espinoza L, et al. Safety of abatacept in rheumatoid arthritis patients in five double-blind, placebocontrolled trials [abstract no. 886]. Arthritis Rheum 2005; 52: S350 30. Combe B, Weinblatt M, Birbara C, et al. Safety and patientreported outcomes associated with abatacept in the treatment of rheumatoid arthritis patients receiving background disease modifying anti-rheumatic drugs (DMARDs): the ASSURE trial [abstract no. 1918]. Arthritis Rheum 2005; 52: S709

Correspondence and offprints: Dr Louise C. Pollard, Academic Department of Rheumatology, Kings College London, Weston Education Centre, 10 Cutcombe Road, London, SE5 9RJ, UK. E-mail: louise.pollard@kcl.ac.uk

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Drugs 2007; 67 (1)

LEADING ARTICLE

Drugs 2007; 67 (1): 11-16 0012-6667/07/0001-0011/$49.95/0 2007 Adis Data Information BV. All rights reserved.

Squalene Synthase Inhibitors


Clinical Pharmacology and Cholesterol-Lowering Potential
Valentine Charlton-Menys and Paul N. Durrington
Division of Cardiovascular and Endocrine Sciences, Cardiovascular Research Group, Core Technology Facility, University of Manchester, Manchester, UK

Abstract

HMG-CoA reductase inhibitors (statins) reduce cardiovascular disease morbidity and mortality with a high level of safety. Nonetheless, there are substantial numbers of people who either do not tolerate statins or whose low-density lipoprotein (LDL) levels are not lowered adequately. For these reasons, there is a need to develop other cholesterol-lowering drugs. A target for these new agents is provided by the enzymes distal to HMG-CoA reductase in the cholesterol biosynthesis pathway. Two classes of drugs have been developed: (i) squalene synthase inhibitors, which act at the first committed step in cholesterol biosynthesis, distal to the mevalonate-farnesyl diphosphate pathway; and (ii) oxidosqualene cyclase inhibitors, which act distal to the squalene intermediate. Of these, squalene synthase inhibitors have received more attention and are the subject of this review. Squalene synthase inhibitors decrease circulating LDL-cholesterol by the induction of hepatic LDL receptors in a similar manner to statins. They have fewer secondary effects mediated by a decrease in non-cholesterol products of mevalonate metabolism distal to HMG-CoA reductase, but have the potential to increase intermediates proximal to squalene. Squalene synthase inhibitors are just now entering clinical trials and data on how effectively they lower LDL-cholesterol and how they compliment the actions of statins and other agents is awaited with considerable interest.

The serum cholesterol level of an individual is one of the most important factors in predicting[1,2] and preventing[3] coronary heart disease (CHD). Statin drugs are competitive inhibitors of HMG-CoA reductase (figure 1), the primary rate-limiting enzyme in the hepatic biosynthesis of cholesterol. The resulting statin-induced decrease in intrahepatic cholesterol concentrations leads to the upregulation of hepatic receptors for low-density lipoprotein (LDL), an effect mediated by the transcription factor SREBP (sterol response element binding protein). The increase in LDL receptor expression enhances the fractional catabolic rate of circulating LDL, thus

lowering its concentration. Despite the upregulation of HMG-CoA reductase that ensues,[4] the more potent statins can lower LDL by 50%.[5] Statins have been consistently shown to reduce both CHDand stroke-related morbidity and mortality,[6] and with the exception of cerivastatin, do so with a wide margin of safety.[7] 1. Statins The main problems with the use of statins relate to dose and response. There is considerable interindividual variation in the magnitude of the effect of statins on LDL-cholesterol. There is evidence that

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Charlton-Menys & Durrington

Acetyl CoA + H2O + Acetoacetyl CoA

3-HMG-CoA HMG-CoA reductase Mevalonate

Isopentanyl PP Geranyl PP

Dimethylallyl PP Prenylation of proteins

Farnesyl PP Squalene synthase

Dolichols Protein glycosylation Geranylgeranyl PP SMC proliferation Tumour cell growth Electron transport

Squalene Squalene monooxygenase 2,3 oxidosqualene

Ubiquinone (CoQ)

Lipid antioxidant

Oxidosqualene cyclase Lanosterol synthase Lanosterol 2,3;22,23 Diepoxysqualene

Cholesterol

24,25 Epoxylanosterol

Oxysterols

HMG CoA reductase

Fig. 1. The sites of action of HMG-CoA reductase inhibitors, squalene synthase inhibitors and oxidosqualene cyclase inhibitors in the hepatic biosynthesis of cholesterol. The putative functions of intermediates and derivatives of intermediates up to the first branch point in the biosynthetic pathway for cholesterol synthesis are shown by the dashed arrows, and the stages involving multiple reactions are shown by the green lines. CoQ = coenzyme Q (ubidecarenone); PP = pyrophosphate; SMC = smooth muscle cell.

people with low rates of cholesterol synthesis,[8] perhaps due to increased absorption of dietary cholesterol,[9] may be most resistant. Accordingly, an individual whose LDL-cholesterol is insufficiently lowered with any one statin at a given dose may not benefit from an increased dose of that statin or from treatment with a different statin. Even in people whose initial response to statin therapy is good, the
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dose response remains relatively flat,[10] with further decreases of LDL-cholesterol of only approximately 6% resulting from doubling doses.[5,11]
1.1 Safety of Statins

Although the margin of safety for most statins approved for clinical use is very wide,[7,12-14] elevation of liver aminotransferases (ALT and AST) and
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myositis or myopathy can occur. Their likelihood, although low, relates to the statin dose rather than to the degree of reduction in LDL-cholesterol.[14] Studies on rat and human myotube cultures showed that statin-induced myopathy is probably due to decreased geranylgeranylation of proteins secondary to decreased mevalonate synthesis.[15,16] Potentially, statins could have other effects downstream of HMG-CoA reductase (figure 1). Their consequences might prove favourable, enhancing the protection of statins against cardiovascular disease by mechanisms other than LDLcholesterol lowering (pleiotropic effect), or unfavourable, leading to adverse events as in the case of myositis. An example of a potentially favourable statin effect, as yet unexplained, is the decrease in Creactive protein associated with their use. [17] Important effects of statins downstream of HMG-CoA reductase include prenylation (post-translational modification of proteins by farnesyl pyrophosphate or geranylgeranyl pyrophosphate), which regulates the subcellular location of G-proteins influencing many signalling cascades within the cell.[18] Oxysterols and farnesyl pyrophosphate derived from the cholesterol biosynthetic pathway after mevalonate, but before squalene synthase, also affect the activity of nuclear orphan receptors such as liver X receptor (LXR) and farnesoid X-activated receptor (FXR), which are important in biliary cholesterol metabolism, lipoprotein metabolism and excretion, and in macrophage foam cell formation.[19] 2. Squalene Synthase Inhibitors Squalene synthase is another enzyme in the cholesterol biosynthetic pathway (figure 1). Important differences between cholesterol-independent effects of squalene synthase inhibitors and those of HMGCoA reductase might be expected because squalene synthase, which acts downstream of mevalonate, is the first committed step of hepatic cholesterol biosynthesis at the final branch point of the cholesterol biosynthetic pathway (figure 1).[20,21]
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2.1 Safety and Efficacy of Squalene Synthase Inhibitors Compared with Statins

Preliminary studies with the squalene synthase inhibitors BMS-187745 and BMS-188494 showed that, at concentrations that markedly decreased cholesterol synthesis, no myotoxicity was found in vitro.[22] Thus, inhibition of squalene synthase did not result in myotoxicity in vitro because intermediates formed before squalene and responsible for prenylation of proteins were not depleted.[16,22] It was later shown that the squalene synthase inhibitors ER-27856[23] and TAK-475[24] and EP2302[25] decreased circulating LDL levels, as with statins, by inducing LDL receptors, assessed using HepG2 cells in culture. It was also shown in rhesus monkeys that ER-27856 lacked the hepatotoxicity found with atorvastatin,[23] and the same was shown for TAK475, in cynomolgus monkeys.[24] More recently, two new potent squalene synthase inhibitors (EP2306 and EP2302) have been described.[25] EP2302 inhibited cholesterol synthesis dose-dependently with a similar potency to that of simvastatin. In tests so far, the degree of inhibition observed in vitro has not been seen in vivo, probably because of upregulation of HMG-CoA reductase, in the case of statins, or through a compensatory increase in intestinal cholesterol uptake with both statins and squalene synthase inhibitors. Tavidrou et al.[25] also showed that oleate-induced apolipoprotein B secretion by HepG2 cells was more markedly inhibited by simvastatin than by EP2306 or EP2302.
2.2 Other Potential Toxicity of Squalene Synthase Inhibitors

HMG-CoA reductase is the site of physiological regulation of cholesterol biosynthesis, making it unlikely that accumulation of metabolites earlier in the pathway (figure 1) would be toxic, but this is not necessarily true of squalene synthase inhibition. Triparanol, another inhibitor of cholesterol biosynthesis downstream of mevalonate, was found to cause cataract formation.[26] More recently, an association between lanosterol synthase (figure 1) mutations and cholesterol deficiency resulting in cataract formation in a rat model was described.[27] However,
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in the rats with cataracts, the cholesterol deficiency was confined largely to the lens. In contrast, hepatic and serum cholesterol levels were not decreased. Since vertebrate eye lenses are not vascularised, de novo cholesterol synthesis in the lens is necessary for normal proliferation of epithelial cells in the lens. This suggests that the gene or isoform of the gene regulating lens cholesterol synthesis differs from the gene regulating hepatic cholesterol synthesis. There is evidence that statins, in much higher doses than used in the clinic, can cause cataract formation in rats;[28] this would appear to be due to a failure of upregulation of lens HMG-CoA reductase, and decreased ubiquinone (ubidecarenone) levels with statin treatment may also be a factor.[29] 3. Oxidosqualene Cyclase Inhibitors Another enzyme target in cholesterol biosynthesis is 2,3-oxidosqualene cyclase (figure 1). Selective inhibitors of oxidosqualene cyclase have been reported to decrease cholesterol biosynthesis[21,30] without influencing LDL catabolism,[31] unlike statins, which principally decrease circulating LDLcholesterol by upregulating hepatic LDL uptake. Inhibition of oxidosqualene cyclase with U18666A also, unlike HMG-CoA reductase inhibition, consistently induces cataract formation in rats. However, this may not be wholly due to inhibition of cholesterol synthesis because U18666A has been shown to have a direct toxic effect of lens epithelial cells.[31] Inhibition of oxidosqualene cyclase results in redirection of 2,3-oxidosqualene, which in turn results in increased formation of oxysterols, and downregulates HMG-CoA reductase;[21] this would not occur with inhibition of squalene synthase (figure 1). These findings suggest that squalene synthase inhibitors will prove to have less toxicity than either oxidosqualene cyclase inhibitors[21,30,31] or statins.[28,29] This is because inhibition of squalene synthase would not result in increased oxysterol formation or decreased ubiquinone levels. However, it remains for more detailed clinical assessment to be undertaken to determine whether the newer squalene synthase inhibitors, such as TAK-475 and EP2302 cause lens opacities or other toxicity.
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4. Clinical Trials with Squalene Synthase Inhibitors Squalene synthase inhibitors are now entering clinical trials and, thus, it will be fascinating to see how effectively they lower LDL-cholesterol levels and the extent to which their role might complement those of statins and other lipid-lowering drugs. Pharmacokinetic, and more especially pharmacodynamic and toxicological studies, will be required in humans to determine whether squalene synthase inhibitors do in reality offer advantages over statins. Thus far, one pharmacokinetic and pharmacodynamic study with the squalene synthase inhibitor BMS-188494 has been performed,[32] in which squalene synthase inhibition was quantified indirectly by assaying dicarboxylic acids in urine. This elegant approach to quantifying the pharmacodynamic response revealed encouragingly that farnesyl pyrophosphate, which might be expected to accumulate when squalene synthase was inhibited, was in fact metabolised through a series of oxidative steps to dicarboxylic acids, readily excreted in urine. 5. Future Directions On a final note, another source of cholesterol is from intestinal absorption. Ezetimibe is a selective inhibitor of intestinal cholesterol absorption and is increasingly finding use in the clinic as an LDLcholesterol-lowering agent, although randomised, clinical events trials are yet to be reported. Ezetimibe has a limited LDL-cholesterol-lowering effect of around 20% either alone or in the presence of a statin.[33] It acts by decreasing the intestinal cholesterol supply to the liver, lowering hepatic cholesterol levels and thus inducing LDL-receptor expression. It is effective because it not only decreases the absorption of dietary cholesterol but also interrupts the enterohepatic circulation of cholesterol entering the intestine in bile. Its limitation is the upregulation of hepatic cholesterol biosynthesis. Nonetheless, the 20% additional decrease over and above that achieved with a statin is clinically worthwhile now that therapeutic targets for LDL-cholesterol have been lowered.[34,35] The LDL-cholesterol-lowering goal can also be achieved with lower doses of the
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statin, potentially avoiding the adverse effects associated with high statin doses. Squalene synthase development will thus occur against this background. 6. Conclusions Squalene synthase inhibitors represent an interesting group of drugs for lowering LDL-cholesterol. The potential will depend on their LDL-lowering efficacy compared with and in combination with existing treatment, particularly the statin group. The inhibition of squalene synthase is likely to have fewer downstream effects on other pathways than seen with statins. This might mean that some of the adverse effects associated with statin therapy can be avoided. However, they might also lack some of the favourable pleiotropism of statins and could have other adverse effects related to accumulation of metabolites upstream of squalene synthase. The outcome of clinical trials is eagerly awaited. Acknowledgements
No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

References
1. Simons LA. Interrelations of lipids and lipoproteins with coronary artery disease mortality in 19 countries. Am J Cardiol 1986; 57: 5-10 2. Law MR, Thompson SG, Wald NJ. Assessing possible hazards of reducing serum cholesterol. BMJ 1994; 308: 373-9 3. Grundy SM. Cholesterol and heart disease: a new era. JAMA 1986; 256: 2849-58 4. Roitelman J, Masson D, Avner R, et al. Apomine, a novel hypocholesterolemic agent, accelerates degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and stimulates low density lipoprotein receptor activity. J Biol Chem 2004; 279: 6465-73 5. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stoke: systematic review and meta-analysis. BMJ 2003; 326: 1423-7 6. Baigent C, Keech A, Kearney PM, et al. Cholesterol Treatment Trialists (CTC) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366: 1267-78 7. Gaw A, Packard CJ. Comparative chemistry, pharmacology and mechanism of action of the statins. In: Gaw A, Packard CJ, Shepherd J, editors. Statins: the HMG CoA reductase inhibitors in perspective. London: Martin Dunitz, 2000: 47-61

8. Naoumova RP, Marais AD, Mountney J, et al. Plasma mevalonic acid, an index of cholesterol synthesis in vivo, and responsiveness to HMG-CoA reductase inhibitors in familial hypercholesterolaemia. Atherosclerosis 1996; 119: 203-13 9. Miettinen TA, Gylling H. Ineffective decrease of serum cholesterol by simvastatin in a subgroup of hypercholesterolemic coronary patients. Atherosclerosis 2002; 164: 147-52 10. Illingworth DR. Management of hypercholesterolemia. Med Clin North America 2000; 84: 23-42 11. Roberts WC. The rule of 5 and the rule of 7 in lipid-lowering by statin drugs. Am J Cardiol 1997; 80: 106-7 12. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in the Collaborative Atorvastatin Diabetes Study (CARDS); multicentre randomised placebo-controlled trial. Lancet 2004, 96 13. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005; 352: 1425-35 14. McKenney JM, Davidson MH, Jacobson TA, et al. Final conclusions and recommendations of the national lipid association statin safety assessment task force. Am J Cardiol 2006; 97 Suppl.: 89-94C 15. Flint OP, Masters BA, Gregg RE, et al. HMG CoA reductase inhibitor-induced myotoxicity: pravastatin and lovastatin inhibit the geranylgeranylation of low-molecular molecular weight proteins in neonatal rat muscle cell culture. Toxicol Appl Pharmacol 1997; 145: 99-110 16. Johnson TE, Zhang X, Bleicher KB, et al. Statins induce apoptosis in rat and human myotube cultures by inhibiting protein geranylgeranylation but not ubiquinone. Toxicol Appl Pharmacol 2004; 200: 237-50 17. Halcox JPJ, Deanfield JE. Beyond the laboratory: clinical implications for statin pleiotropy. Circulation 2004; 109 Suppl. II: II42-8 18. Edwards PA, Ericsson J. Sterols and isoprenoids: signalling molecules derived from the cholesterol biosynthetic pathway. Annu Rev Biochem 1999; 68: 157-85 19. Edwards PA, Kast HR, Anisfeld AM. BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis. J Lipid Res 2002; 43: 2-12 20. Gibbons GF, Mitropoulos KA, Myant NB. Biochemistry of cholesterol. Amsterdam: Elsevier Biomedical Press, 1982: 131-88 21. Mark M, M ller P, Maier R, et al. Effects of a novel 2,3-oxidosu qualene cyclase inhibitor on the regulation of cholesterol biosynthesis in HepG2 cells. J Lipid Res 1996; 37: 148-58 22. Flint OP, Masters BA, Gregg RE, et al. Inhibition of cholesterol synthesis by squalene synthase inhibitors does not induce myotoxicity in vitro. Toxicol Appl Pharmacol 1997; 145: 91-8 23. Hiyoshi H, Yangimachi M, Ito M, et al. Effect of ER-27856, a novel squalene synthase inhibitor, on plasma cholesterol in rhesus monkeys: comparison with 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors. J Lipid Res 2000; 41: 1136-44 24. Nishimoto T, Amano Y, Tozawa R, et al. Lipid-lowering properties of TAK-475, a squalene synthase inhibitor: in vivo and in vitro. Br J Pharmacol 2003; 139: 911-8 25. Tavridou A, Kaklamanis L, Megaritis G, et al. Pharmacological characterization in vitro of EP2306 and EP2302, potent inhibitors of squalene synthase and lipid biosynthesis. Eur J Pharmacol 2006; 535: 34-42 26. Laughlin RC, Carey TF. Cataracts in patients treated with triparanol. J Amer Med Assoc 1962; 181: 339-40

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Charlton-Menys & Durrington

27. Mori M, Li G, Abe I, et al. Lanosterol synthase mutations cause cholesterol deficiency-associated cataracts in the Shumiya cataract rat. J Clin Invest 2006; 116: 395-404 28. Cenedella RJ, Kuszak JR, Al-Ghoul KJ, et al. Discordant expression of the sterol pathway in lens underlies simvastatininduced cataracts in Chbb:Thom rats. J Lipid Res 2003; 44: 198-211 29. Cenedella RJ, Neely AR, Sexton P. Concentration and distribution of ubiquinone (coenzyme Q), the endogenous lipid antioxidant, in the rat lens: effect of treatment with simvastatin. Mol Vis 2005; 11: 594-602 30. Eisele B, Budzinski R, M ller P, et al. Effects of a novel u 2,3-oxidosqualene cyclase inhibitor on cholesterol biosynthesis and lipid metabolism in vivo. J Lipid Res 1997; 38: 564-75 31. Cenedella RJ, Jacob R, Borchman D, et al. Direct perturbation of the lens membrane structure may contribute to cataracts caused by U18666A, an oxidosqualene cyclase inhibitor. J Lipid Res 2004; 45: 1232-41 32. Sharma A, Slugg PH, Hammett JL, et al. Clinical pharmacokinetics and pharmacodynamics of a new squalene synthase

inhibitor, BMS-188494, in healthy volunteers. J Clin Pharmacol 1998; 38: 1116-21 33. Gupta EK, Ito MK. Ezetimibe: the first in a novel class of selective cholesterol absorption inhibitors. Heart Disease 2002; 4: 399-409 34. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Education Program Adult Treatment Panel III guidelines. Circulation 2004; 110: 227-39 35. JBS2: Joint British Societies guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005; 91: 5 (Suppl.): v1-52

Correspondence and offprints: Dr Valentine CharltonMenys, Division of Cardiovascular and Endocrine Sciences, Cardiovascular Research Group, University of Manchester, Core Technology Facility (3rd Floor), 46 Grafton Street, Manchester, M13 9NT, UK. E-mail: valentine.menys@manchester.ac.uk

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THERAPY IN PRACTICE

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Practical Issues and Challenges in the Diagnosis and Treatment of Pulmonary Sarcoidosis
Surinder K. Jindal
Department of Pulmonary Medicine, Postgraduate Institute of Medical Education & Research, Chandigarh, India

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 1. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 1.1 Suspecting the Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 1.2 Exclusion of Clinical Mimics: Differential Diagnosis from Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . 19 1.2.1 Tuberculin Anergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 1.2.2 Radiographic Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 1.3 Establishing the Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 1.3.1 Syndromic Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 1.3.2 Pulmonary Function Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 1.3.3 Biochemical Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 1.3.4 Haematological Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 1.3.5 Histocytological Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 1.3.6 Bronchoalveolar Lavage and Induced Sputum Examination . . . . . . . . . . . . . . . . . . . . . . . . 21 1.4 Disease Extent and Severity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 1.5 Disease Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 2. Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 2.1 Initial Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 2.2 Treatment of Asymptomatic Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 2.3 Standard Treatment for Patients with Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 2.3.1 Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 2.4 Treatment of Refractory and Recurrent Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 2.4.1 Methotrexate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 2.4.2 Azathioprine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 2.4.3 Other Cytotoxic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 2.4.4 Toxicity and Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 2.4.5 Other Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Abstract

Sarcoidosis is a granulomatous disease with multisystem involvement. Diagnosis is generally easy to establish from the characteristic clinical and radiographic features. In India and other developing countries, tuberculosis is the closest clinical mimic and needs to be excluded before therapy for sarcoidosis is instituted. Tuberculin anergy and histopathological demonstration of characteristic compact granulomas help in the diagnosis of sarcoidosis. Corticosteroids constitute

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the mainstay of therapy for symptomatic pulmonary and most other forms of extrapulmonary sarcoidosis. Asymptomatic disease does not require any treatment, but milder forms may be treated with topical corticosteroids and symptomatic therapy. Alternative drugs such as cytotoxic agents, hydroxychloroquine and other agents are used either alone or in combination for the treatment of relapses and recurrences and refractoriness or in the presence of complications of corticosteroids. Treatment is usually continued for about a year, but it may need to be prolonged in patients with disease that persists and the response to therapy is delayed.

Sarcoidosis is a systemic disease with primary involvement of the thoracic contents, especially the lungs, and the hilar and mediastinal lymph nodes. The skin and eyes are the other common sites of involvement. Organs of almost all other systems, such as the cardiovascular, central nervous, gastrointestinal and rarely genitourinary systems, may also be affected. Sarcoidosis, histologically characterised by the presence of noncaseating granulomas, has been confused with tuberculosis (TB) almost since its discovery. The possibility of an aetiological relationship between the two diseases has also been proposed from time to time. Both the epidemiological and the immunological evidence clearly show sarcoidosis as a distinct disease with a distinct aetiopathogenesis, type of treatment and natural history.[1] A recent analysis of surveillance data from Japan on 460 000 employees between 1941 and 1996 and a nationwide survey of the general population (195991) has revealed strong epidemiological dissimilarities between sarcoidosis and TB, which do not support a TB aetiology of sarcoidosis.[2] Despite these facts, difficulties prevail for practicing physicians in distinguishing between sarcoidosis and TB in several clinical situations, especially in countries with a high prevalence of TB.[3,4] This is generally attributable to similarities in several clinical features and the histopathological appearance of TB and sarcoidosis. TB is the most important pathological differential diagnosis of sarcoidosis in biopsy and surgical pathology of the lungs, lymph nodes, skin, liver, bone marrow and other biopsy sites.[5] Added to the difficulty of diagnosis is the fear of activating old lesions with corticosteroids and/or
2007 Adis Data Information BV. All rights reserved.

other immunosuppressant agents in patients with healed or latent TB. Therefore, it is all the more important to satisfactorily exclude TB before starting therapy for sarcoidosis. These issues are of great significance not only in countries with a higher prevalence of TB but also in other populations predisposed to TB, including patients with HIV infection and healthcare workers. 1. Diagnosis There are five important steps in the diagnosis of sarcoidosis: (i) suspecting the diagnosis; (ii) excluding the mimics, i.e. other common causes of similar clinical features (e.g. TB); (iii) establishing the diagnosis; (iv) determination of disease extent and severity; and (v) assessment of activity and treatment responsiveness.
1.1 Suspecting the Diagnosis

The algorithm for the diagnosis of sarcoidosis essentially starts from the symptoms and clinical features with which a patient presents. A patient may report with either general constitutional or respiratory symptoms to a general physician, pulmonologist or other medical practitioner. Often, patients seen in dermatology, ophthalmology, cardiology, neurology or other specialties are suspected of having sarcoidosis on the basis of abnormalities detected on a chest radiograph. Sometimes, a patient may be completely asymptomatic and present with abnormalities on chest radiograph such as hilar and mediastinal adenopathy, or with pulmonary infiltrates detected on a routine examination for medical fitness or insurance purposes.
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Isolated pulmonary sarcoidosis is rarely diagnosed from history or physical examination. Most patients with pulmonary sarcoidosis will present with general symptoms of cough; breathlessness on exertion; heaviness, tightness or pain in the chest and/or general constitutional symptoms of malaise, fatigue, joint pains, aches and fever. Other clinical manifestations are non-specific for several aetiological diagnoses. Physical examination of the chest is mostly normal, since lung involvement generally occurs in the form of isolated hilar and/or mediastinal lymph node involvement. Parenchymal lung involvement, which is characteristically present as diffuse inflammatory infiltration, is generally silent. Very rarely, there is the presence of fine crackles, which may suggest the presence of pulmonary fibrosis. Occasionally, the airways are involved, manifesting as airway obstruction and wheezing on auscultation. Lung cavities, cysts or bullae are rarely seen. Pleural effusion and thickening may also occur. Effusion, if any, is generally serous and exudative. Other rare pleural manifestations include pneumothorax, chylothorax and haemothorax.[6] There are several published reports on the frequency of involvement of organs in sarcoidosis.[3-8] The lungs are affected in >90% of patients. Involvement of extrapulmonary organs is common, along with that of thoracic structures. Some of the more characteristic features from which the diagnosis of sarcoidosis is suspected are the dermatological manifestations, such as erythema nodosum, lupus pernio and other skin lesions; uveitis, keratoconjunctivitis sicca, dacryocystitis and retinal vasculitis; and bilateral lacrimal, parotid and salivary gland enlargement.[9-11] Several other non-pulmonary organs that may also be involved either in isolation or along with the pulmonary disease include the liver, spleen, gastrointestinal tract, heart, peripheral nerves and kidneys.[12-15] Thoracic lymph node enlargement, especially bilateral hilar lymphadenopathy, is the most common feature diagnosed on chest radiograph. Enlarged retroperitoneal lymph nodes, rarely palpable, are detected on ultrasound or computerised tomograph 2007 Adis Data Information BV. All rights reserved.

ic (CT) scans. Peripheral supraclavicular, axillary, epitrochlear and inguinal lymph nodes are palpable in about one-third of patients. Almost similar groups of lymph nodes are also involved in TB. Enlargement in both conditions is painless, but tubercular lymph nodes are generally matted on palpation. On the other hand, sarcoid nodes are discrete, movable and firm in consistency. Differentiation between TB and sarcoid lymph node enlargement is not always possible on the basis of clinical examination. Fluctuations, ulceration and formation of sinuses is rare and almost rules out the diagnosis of sarcoidosis.
1.2 Exclusion of Clinical Mimics: Differential Diagnosis from Tuberculosis

Of the many clinical conditions that may simulate a similar overall clinical and/or radiological picture, TB tops the list in developing countries where the general prevalence of TB is high. But lymphomas, fungal infections, vasculitides and other granulomatous disorders are also important. Several clinical features may help in differentiating diagnosis from TB (table I). It is in only the 510% of patients who present with overlapping features that the diagnosis may not be easy to make. Demonstration of tuberculin anergy is one of the most important tests to exclude TB. Radiological and other laboratory investigations are generally essential to establish a more definitive diagnosis and to exclude other causes of similar clinical features.
1.2.1 Tuberculin Anergy

Sarcoidosis patients show less reactivity to agents that cause delayed skin reactions.[16] Tuberculin hypersensitivity is also depressed in about two-thirds of patients with sarcoidosis.[17] Anergy to tuberculin in sarcoidosis is best demonstrated with an intradermal skin test. The Mantoux test is one of the most important features to distinguish sarcoidosis from TB. A positive tuberculin test as a marker of tubercular infection has a specificity of >85%. A positive tuberculin test in a patient with hilar lymphadenopathy strongly suggests the aetiological diagnosis of TB. Even in countries with a high prevalence of TB, a positive Mantoux test
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Table I. Summary of the differences in clinical features and other parameters between tuberculosis and sarcoidosis Clinical feature Constitutional symptoms Respiratory symptoms Thoracic involvement Mediastinal and hilar nodes Lung parenchyma Pleural Heart and pericardium Skin Lymphadenopathy Most common Others Eyes Other glands Cervical Thoracic Choroiditis Rare Thoracic Peripheral Uveitis, chorioretinitis Parotid, lacrimal, salivary Less common Fibrocavitary, miliary Common Common Lupus vulgaris, sinuses Most common Nil or interstitial, miliary Rare Less common Erythema nodosum, lupus pernio, plaques Tuberculosis Fever, chills, malaise, weight loss Cough, sputum, haemoptysis Sarcoidosis Fatigue, myalgias, mild fever Dry cough, breathlessness, chest tightness/ heaviness

(irrespective of the size of reaction) in sarcoidosis is very rare, and the incidence of Mantoux negativity in sarcoidosis is not influenced by the high rates of Mantoux positivity in the general population.[18] A negative Mantoux test almost excludes the diagnosis of TB except in seriously ill patients (e.g. those with disseminated miliary disease or TB meningitis) or in heavily immunosuppressed patients such as those with HIV infection.
1.2.2 Radiographic Investigations

groups, e.g. centrilobular, perilymphatic or random in relation to the secondary lobule.[20] The distribution in sarcoidosis is typically perivascular. A galaxy sign indicating large pulmonary nodules composed of coalescent small nodules seen in sarcoidosis has been described in TB as well. Radiological findings are also useful in diagnosing the involvement of extrapulmonary organs such as the liver, spleen, kidneys, heart and CNS.[21]
1.3 Establishing the Diagnosis
1.3.1 Syndromic Presentation

Radiological findings on a plain chest radiograph may also be characteristic of sarcoidosis more than any other diagnosis. The most typical findings in sarcoidosis include bilateral hilar lymphadenopathy with or without lung interstitial involvement. Over 95% of 100 consecutive asymptomatic patients with bilateral hilar lymphadenopathy were diagnosed with sarcoidosis.[19] The hilar lymph nodes are characteristically large, symmetrical and sharply outlined and are known as potato nodes. Difficulty arises in patients with atypical features such as unilateral or asymmetrical massive lymph nodes or associated large paratracheal and mediastinal lymph node enlargement, or associated with pulmonary cavitation, pleural effusion or miliary distribution. Miliary lung involvement is also commonly seen in TB, pneumoconioses, hypersensitivity pneumonias and metastases. High-resolution CT (HRCT) images help in characterising the distribution in different
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The clinico-radiological picture is fairly characteristic of sarcoidosis in patients with syndromic presentations such as Lofgrens syndrome (fever, bilateral hilar adenopathy, erythema nodosum and arthralgia) and Heerfordt syndrome of chronic uveoparotid fever (chronic febrile illness, bilateral parotidomegaly and uveitis). Biopsy diagnosis, although useful, may not be considered essential in such patients.
1.3.2 Pulmonary Function Tests

Assessment of pulmonary function tests such as spirometry, carbon monoxide diffusion capacity, cardiopulmonary exercise test and blood gases, although useful in the overall assessment of respiratory involvement and disability, is rarely helpful in the differential diagnosis. The abnormalities depend upDrugs 2007; 67 (1)

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on the extent of involvement and whether the airways are also affected. The spirometric pattern is generally variable from restrictive to obstructive or mixed functional defect and from mild to severe in degree.
1.3.3 Biochemical Investigations

Hypercalcaemia and hypercalciuria are the only biochemical changes that are fairly characteristic of sarcoidosis. Elevated liver enzymes such as AST, ALT and serum alkaline phosphatase may occur in hepatic sarcoidosis. Hyperuricaemia may occur in about 40% of patients. Elevation of blood urea and creatinine, which indicates renal dysfunction, is more often a result of renal calculi as a result of hypercalcaemia and/or hyperuricaemia than renal sarcoidosis. Serum ACE is frequently elevated in over half the patients. Serum ACE estimation has been advocated as a measure of granuloma load and, therefore, a marker of disease activity.
1.3.4 Haematological Examination

Granulomas can also be demonstrated on biopsies of lymph nodes, skin plaques or nodules, enlarged lacrimal or salivary glands, liver, musculoskeletal tissues or other clinically involved organs. Biopsy of the accessory salivary gland was found to be quite useful in elderly patients.[26] Although skin is the most easily available site, it is futile to do a biopsy of the erythema nodosum lesions that occur as a result of a hypersensitivity reaction and do not show any granulomas. On histological examination, the sarcoid granulomas are typically compact, discrete and do not show any caseation. On the other hand, granulomas seen in TB or other infections are loose, ill formed and often show caseation. Special staining for acid-fast bacilli and fungi may be required for granulomas with atypical features.[5]
1.3.6 Bronchoalveolar Lavage and Induced Sputum Examination

A number of haematological alterations are described on peripheral blood examination, but none of these is characteristic of sarcoidosis. The commonly reported abnormalities include anaemia in up to 20% of patients and leukopenia in up to 40% of patients. Eosinophilia and thrombocytopenia are relatively rare. Most of the haematological abnormalities are mild and rarely severe. Bone marrow examination is rarely required in patients in whom haematological alterations are severe or pose difficulties in attributing a cause.
1.3.5 Histocytological Diagnosis

Total and differential cell count in the bronchoalveolar lavage (BAL) fluid and occasionally the induced sputum has been used as an index of disease activity in sarcoidosis, but is rarely helpful in the differential diagnosis. There is a lymphocytic predominance in BAL fluid in sarcoidosis. A log transformation of the ratio of lymphocytes and polymorph neutrophils is rarely found to be useful in differentiating sarcoidosis from idiopathic pulmonary fibrosis. The pattern of differential gene expression on alveolar macrophages obtained from BAL fluid has been examined to distinguish the origin of granulomas, but a large number of granuloma-associated features were found to be common.[27]
1.4 Disease Extent and Severity

Most patients with extrapulmonary sarcoidosis, most with stage IIIV pulmonary sarcoidosis and a few with stage I pulmonary sarcoidosis need histological confirmation of diagnosis. The lung is the most fruitful site for tissue biopsy. Transbronchial lung biopsy provides a diagnostic yield from 40% to >90% when four or five specimens are obtained.[22,23] Endobronchial biopsies were also positive for granulomas in about 35% of patients.[24] Combining endobronchial and transbronchial lung biopsies is shown to improve the yield even more.[25]
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The extent of the pulmonary disease is decided based on symptomatology and chest radiograph findings. On the basis of a plain posteroanterior chest radiograph, pulmonary sarcoidosis is classified into five stages: 0, no visible intrathoracic lesions; I, bilateral hilar lymphadenopathy; II, bilateral hilar lymphadenopathy along with pulmonary infiltration; III, pulmonary infiltrations without bilateral hilar lymphadenopathy; and IV, pulmonary fibrosis with honeycombing cysts and bullae formaDrugs 2007; 67 (1)

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tion.[5] Stage IV disease is generally the most severe and irreversible form of pulmonary sarcoidosis, but not all patients are always symptomatic. Some of the patients with radiological stage IV disease may have mild or even asymptomatic presentation. The disease extent and severity are also judged from the number of involved organs and the density of granuloma within the organs. These are assessed from symptomatology, number and type of organ involvement, and radiographic investigations. Symptomatic involvement of vital organs such as the eyes (especially the posterior uveal tract), lung parenchyma, liver, kidneys, and cardiovascular or neurological systems is considered to be serious and requires urgent systemic therapy. Lupus pernio, cystic bone lesions, involvement of the upper respiratory tract, e.g. nasal mucosa and larynx, hypercalcaemia and calcinosis, are also forms indicating an adverse prognosis. Isolated skin and lymph node involvement or anterior uveitis alone are considered to be milder forms. Investigations for individual organ dysfunction are helpful in assessing their involvement, but the levels of ACE or other nonspecific markers are rarely useful.
1.5 Disease Activity

rectly correlate with corticosteroid therapy. Analysis of BAL fluid as well as serological markers have been employed for this assessment.[29] There is lymphocytic predominance in BAL fluid but there is no direct correlation with disease activity. Radioisotopic scanning with Gallium-67 localises the site of active inflammation, but does not distinguish between activity due to sarcoidosis, TB, malignancies or other causes. Scanning procedures such as HRCT have been used to find soft infiltrates suggesting activity in the lungs. Contrast enhancement with gadolinium improves this sensitivity. Positron emission tomography scanning with various markers may also prove to be useful in detecting sarcoidosis activity.[30] Pulmonary function tests have sometimes been used to decide on the disease progression and to monitor the course and response to therapy.[31] Although a rough correlation was reported between forced vital capacity and overall histological score, there was no direct relationship with radiographic features.[32] 2. Management Fortunately, the therapeutic response to several anti-inflammatory drugs is good in sarcoidosis. The recommended treatments vary from none to multidrug therapy with a combination of cytotoxic drugs.[5] Corticosteroids, the use of which in sarcoidosis was first reported in 1951, remain the cornerstone of therapy.[33,34] However, more important are the issues about whom to treat and when to start (and stop) treatment. In general, there is a broad consensus on most of these issues.
2.1 Initial Evaluation

Activity implies an active ongoing disease or inflammation. It should not be confused with the disease extent, severity or unfavourable prognosis.[28] Unfortunately, there is no single test to assess disease activity. The presence of systemic constitutional symptoms (e.g. fever, aches and pains, weight loss, nausea, vomiting and headaches), active uveitis, hypercalcaemia and organ inflammation such as serositis, myocarditis, hepatitis and neurosarcoidosis, indicate the presence of active disease. Stage IIII pulmonary disease is generally considered to be active, but stage IV disease on radiography is usually seen as end-stage fibrosis from progressive pulmonary disease. Laboratory assessments, such as a raised erythrocyte sedimentation rate, leukocytosis, thrombocytopenia or raised serum ACE levels indicate ongoing inflammation. A raised serum ACE level is a good indicator of granuloma load but does not di 2007 Adis Data Information BV. All rights reserved.

As discussed in section 1, before deciding on treatment, each patient requires evaluation for the indication as well as the form of therapy. A detailed history and clinical examination, including eyes, a posteroanterior chest radiograph, electrocardiogram and tuberculin skin test, are important. Routine haematological and biochemical investigations are also carried out for their baseline values. Lung CT scans are required in patients with atypical findings,
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normal chest radiograph but strong clinical suspicion, or in the presence of complications.
2.2 Treatment of Asymptomatic Patients

the presence of adverse effects, contraindications or non-responsiveness to corticosteroids. However, each drug is likely to have its own advantages and disadvantages.
2.3.1 Corticosteroids

Most investigators agree that asymptomatic pulmonary disease rarely requires any therapy, but patients with persistent pulmonary infiltrates, even if asymptomatic, may require treatment.[5,33-36] Patients with milder forms of disease, such as skin disease (erythema nodosum) alone or anterior uveitis, may need only topical treatments, whereas patients with stage I pulmonary sarcoidosis may be observed without any treatment. Patients manifesting with only cough as a symptom may be treated with inhaled corticosteroid therapy. But all new patients with stage IV radiographic changes, even if asymptomatic, should be given a treatment trial with corticosteroids for 812 weeks before being labelled as having end-stage fibrosis. Treatment is generally started on the basis of symptoms and disease severity. Patients with vital organ involvement (such as the heart, liver or CNS), symptomatic pulmonary disease or hypercalcaemia definitely require oral treatment. Although several laboratory parameters, as discussed in section 1.5, have been used to assess the stage of disease, none has been found to be as useful as clinical features and end organ involvement for making a treatment decision. There are no clear guidelines for the treatment of patients who are strongly suspected of having sarcoidosis according to various criteria but who exhibit a positive tuberculin test. We generally practice additional anti-tubercular chemoprophylaxis with rifampicin and isoniazid in such patients during treatment for sarcoidosis.
2.3 Standard Treatment for Patients with Symptoms

Efficacy of treatment with corticosteroids was recently evaluated in a meta-analysis of 12 randomised, controlled trials that included 1051 patients.[38] The treatment was shown to improve the chest radiographic findings and a global score of chest radiograph, symptoms and spirometry, but little improvement in lung function. Long-term benefits beyond 2 years were not clearly demonstrable. Although the earlier studies reported the use of corticotropin (adrenocorticotrophic hormone; ACTH) in the initial treatment, prednisolone or prednisone remain the most commonly used drug. The initial dosage of 2040 mg/day is continued for 13 months depending upon symptomatic response. Higher dosages are required for cardiac- and neurosarcoidosis. Re-evaluation of the condition is required if no response is seen after 3 months of therapy. In patients who show an adequate response, the dosage is tapered to 510 mg/day and continued for at least a year as maintenance therapy. Alternate day therapy in equivalent dosages may also be given. Some patients show recurrent relapses and need long-term, low-dose treatment. Inhaled corticosteroids have been used in some studies with a limited benefit.[39] Adverse effects of corticosteroids are common. Some of the effects, such as fluid retention, mild elevations in blood pressure and glucose intolerance, usually disappear when treatment is tapered and discontinued, but the problems may persist, especially with prolonged corticosteroid use and in patients with pre-existing diseases such as hypertension and diabetes mellitus. Several other important complications include weight gain, cataracts, osteoporosis and bone fractures, which require additional treatment measures. Careful monitoring and control of corticosteroid-induced complications is therefore important in all patients.
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There are several options of treatment available. Corticosteroids, usually oral, constitute the first choice of treatment for stage II and III disease.[33-37] Alternative or additional drugs are required only in
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2.4 Treatment of Refractory and Recurrent Disease

Cytotoxic agents are required in patients with a recurrence of disease, which is seen in almost onethird of patients within 2 years of the discontinuation of corticosteroid therapy. Cytotoxic agents are also used in the presence of non-responsiveness to corticosteroids or with the development of complications with corticosteroids.
2.4.1 Methotrexate

Methotrexate, the most frequently employed agent, is effective in about two-thirds of patients with cutaneous, pulmonary, joint, ocular or neurological disease.[36,40] Methotrexate is generally used in a 7.515mg dose every week for a period of about 612 months. Response is usually slow and may not appear up to 6 months after the start of therapy.
2.4.2 Azathioprine

Experience with azathioprine in sarcoidosis is limited. It is generally used in patients with chronic disease at an oral dose of 23 mg/kg. Its efficacy is generally similar to that of methotrexate.[41]
2.4.3 Other Cytotoxic Agents

Chlorambucil was used in the past but is no longer favoured.[5] Cyclophosphamide is useful for refractory disease, especially neurosarcoidosis. It is used either orally in a dosage of 50150mg daily or 5002000mg intravenously every 2 weeks. In view of an increased risk of malignancy when used on a daily basis for >1 year, it is recommended to use this agent on alternate days.[42] Increased daily fluid intake is recommended with its use to minimise the occurrence of haemorrhagic cystitis. Leflunomide, an analogue of methotrexate, is less toxic but more costly.[43]
2.4.4 Toxicity and Monitoring

trointestinal symptoms, mucosal ulcers and leukopenia are common adverse effects. Folic acid supplementation at a dosage of 1mg every day is helpful to lessen these adverse effects of cyclophosphamide. Hepatic toxicity may occur with a cumulative dosage of about 1g or more; however, pulmonary toxicity is rare. Cyclophosphamide is commonly associated with haemorrhagic cystitis. Regular monitoring for hepatic, haematological and renal toxicity is required in patients receiving cytotoxic agents. Complete blood counts and urinalyses are advised every 46 weeks in patients receiving azathioprine. Patients receiving cyclophosphamide or methotrexate need similar monitoring with urinalysis, complete blood counts and liver function tests every 34 weeks. Gonadal damage and teratogenicity is an important toxicity observed with the use of cytotoxic drugs. Cyclophosphamide can cause early menopause and aspermia. Recovery from suppression of spermatogenesis as well as from ovarian failure is unpredictable. Azathioprine is relatively less teratogenic.[5] Use of cytotoxic drugs is therefore best avoided for women of childbearing age, but if the indication for the use of cytotoxic drugs is important, pregnancy is better postponed until at least 6 months after the last dose of any of these agents. There is an increased opportunity now to preserve sperm as well as ova before administration of chemotherapy with cytotoxic drugs, so as to enable pregnancy at a later stage. This has been made possible with the advancements in cryopreservation and assisted reproduction techniques such as in vitro fertilisation with intracytoplasmic sperm injections. Readers interested in cryopreservation in patients with non-malignant systemic diseases are referred to Hallak et al.,[44] Ranganathan et al.,[45] Mattle et al.[46] and Sonmezer et al.[47]
2.4.5 Other Agents

Most cytotoxic drugs can cause nausea and vomiting, which are generally dose dependent. With methotrexate, other commonly affected organs are the bone marrow, liver, kidney and the gonads. Azathioprine may cause leukopenia and gastrointestinal effects; however, its hepatic toxicity is less than that of methotrexate. With cyclophosphamide, gas 2007 Adis Data Information BV. All rights reserved.

Both chloroquine and hydroxychloroquine have been used with some success in patients with sarcoidosis, especially for cutaneous lesions, as well as for hypercalcaemia and neurosarcoidosis. Ocular toxicity, frequently seen with chloroquine, is not seen with hydroxychlorquine, even with prolonged
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use.[48] Hydroxychloroquine can also be combined with corticosteroids. Several other agents that have been used for patients with refractory sarcoidosis include ciclosporin, radiation therapy and immunomodulators such as thalidomide, pentoxifylline and infliximab. Experience with most of these agents is limited and anecdotal.[36,42,49] It is important to screen patients for occult TB and lymphoproliferative disorders before starting therapy with any of these agents. 3. Conclusion The management of sarcoidosis over the last few decades has seen many new developments. One important aspect that has emerged recently is to avoid treatment for several forms of mild or asymptomatic disease. On the other hand, valuable strategies, alternative drugs and treatment guidelines have now become available for routine decision making in the presence of recurrence, complications or associated medical conditions and co-morbid illness.[5,34-36,50,51] Acknowledgements
The author acknowledges the help of Drs Ritesh Agarwal and Dheeraj Gupta in providing some of the material for the paper, and Ms Manju Aggarwal for preparing and typing the manuscript. The author has not received any funding or other sponsorship from any source for writing this paper. The author has no conflicts of interest that are directly relevant to the content of this review.

References
1. James DG. Sarcoidosis 2001. Postgrad Med J 2001; 77: 177-80 2. Hosoda Y, Sasagawa S, Yamaguchi T. Sarcoidosis and tuberculosis: epidemiological similarities and dissimilarities: a review of a series of studies in a Japanese work population (1941-1996) and the general population (1959-1984). Sarcoidosis Vasc Diffuse Lung Dis 2004; 21: 85-93 3. Jindal SK, Gupta D, Aggarwal AN. Sarcoidosis in India: practical issues and difficulties in diagnosis and management. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19: 176-84 4. Sharma SK, Mohan A. Sarcoidosis: global scenario & Indian perspective. Indian J Med Res 2002; 116: 221-47 5. Statement on sarcoidosis. Joint statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and the ERS Executive Committee, February 1999. Am J Respir Crit Care Med 1999; 160: 736-55

6. Soskel NT, Sharma OP. Pleural involvement in sarcoidosis. Curr Opin Pulm Med 2000; 6: 455-68 7. Loddenkemper R, Kloppenborg A, Schoenfeld N, et al. Clinical findings in 715 patients with newly detected pulmonary sarcoidosis: results of a cooperative study in former West Germany and Switzerland. WATL Study Group. Sarcoidosis Vasc Diffuse Lung Dis 1998; 15: 178-82 8. James DG, Neville E, Siltzbach LE, et al. A worldwide review of sarcoidosis. Ann N Y Acad Sci 1976; 278: 321-34 9. Hutchinson J. Case of livid papillary psoriasis. In: Illustrations of clinical surgery. Vol. 1. London: J&A Churchill, 1877: 42-3 10. Sharma OP. Cutaneous sarcoidosis: clinical features and management. Chest 1972; 61: 320-5 11. Usui Y, Kaiser ED, See RF, et al. Update of ocular manifestations in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19: 167-75 12. Sharma O, Kadakia J, Sharma O. Gastrointestinal sarcoidosis. Semin Respir Med 1992; 13: 442-9 13. White ES, Lynch III JP. Sarcoidosis involving multiple systems: diagnostic and therapeutic challenges. Chest 2001; 119: 1593-7 14. Stern BJ. Neurological complications of sarcoidosis. Curr Opin Neurol 2004; 17: 311-6 15. Gullapalli D, Phillips II LH. Neurologic manifestations of sarcoidosis. Neurol Clin 2002; 20: 59-83 16. Scadding JG. Skin reaction of delayed type. Acta Med Scand 1965; 425: 191-4 17. James DG, Nevile E, Walker A. Immunology of sarcoidosis. Am J Med 1975; 59: 388-94 18. Gupta D, Chetty M, Kumar N, et al. Anergy to tuberculin in sarcoidosis is not influenced by high prevalence of tuberculin sensitivity in the population. Sarcoidosis Vasc Diffuse Lung Dis 2003; 20: 40-5 19. Winterbauer RH, Belic N, Moores KD. A clinical interpretation of bilateral hilar adenopathy. Ann Intern Med 1973; 79: 65-71 20. Andreu J, Mauleon S, Pallisa E, et al. Miliary lung disease revisited. Curr Probl Diagn Radiol 2002; 31: 189-97 21. Koyama T, Ueda H, Togashi K, et al. Radiologic manifestations of sarcoidosis in various organs. Radiographics 2004; 24: 87-104 22. Gilman MJ, Wang KP. Transbronchial lung biopsy in sarcoidosis: an approach to determine the optimal number of biopsies. Am Rev Respir Dis 1980; 122: 721-4 23. Jindal SK, Gupta D, Aggarwal AN. Sarcoidosis in developing countries. Curr Opin Pulm Med 2000; 6: 448-54 24. Gupta D, Mahendran C, Aggarwal AN, et al. Endobronchial vis a vis transbronchial involvement on fiberoptic bronchoscopy in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2001; 18: 91-2 25. Torrington KG, Shorr AF, Parker JW. Endobronchial disease and racial differences in pulmonary sarcoidosis. Chest 1997; 111: 619-22 26. Chevalet P, Clement R, Rodat O, et al. Sarcoidosis diagnosed in elderly subjects: retrospective study of 30 cases. Chest 2004; 126: 1423-30 27. Gaede KI, Mamat U, Muller-Quernheim J. Differential gene expression pattern in alveolar macrophages of patients with sarcoidosis and tuberculosis. J Mol Med 2004; 82: 206-10 28. Costabel U, Guzman J, Drent M. Diagnostic approach to sarcoidosis. Eur Res Mon 2005; 32: 259-64 29. Ziegenhagen MW, Rothe ME, Schlaak M, et al. Bronchoalveolar and serological parameters reflecting the severity of sarcoidosis. Eur Respir J 2003; 21: 407-13

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30. Lebtahi R, Crestani B, Belmatoug N, et al. Somatostatin receptor scintigraphy and gallium scintigraphy in patients with sarcoidosis. J Nucl Med 2001; 42: 21-6 31. Bradivik I, Wollmer P, Blom-Bulow B, et al. Lung mechanics and gas exchange in steroid treated pulmonary sarcoidosis: a seven year follow up. Sarcoidosis 1991; 8: 105-14 32. Gupta D, Jorapur V, Bambery P, et al. Pulmonary sarcoidosis: spirometric correlation with transbronchial biopsy. Sarcoidosis Vasc Diffuse Lung Dis 1997; 14: 77-80 33. Siltzbach LE, Posner A, Medine MM. Cortisone therapy in sarcoidosis. JAMA 1951; 147: 927-9 34. Gibson GJ. Sarcoidosis: old and new treatments (editorial). Thorax 2001; 56: 336-9 35. Fazzi P. Pharmacotherapeutic management of pulmonary sarcoidosis. Am J Respir Med 2003; 2: 311-20 36. Baughman RP, Lower EE. Therapy for sarcoidosis. Eur Respir Mon 2005; 32: 301-15 37. Gibson GJ, Prescott RJ, Muers MF, et al. British Thoracic Society sarcoidosis study: effects of long term corticosteroid treatment. Thorax 1996; 51: 238-47 38. Paramothayan S, Jones PW. Corticosteroids for pulmonary sarcoidosis. Cochrane Database Syst Rev 2005; (2): CD001114 39. Pietinalho A, Tukiainen P, Haahtela T, et al. Oral prednisolone followed by inhaled budesonide in newly diagnosed pulmonary sarcoidosis: a double-blind, placebo-controlled multicenter study. Finnish Pulmonary Sarcoidosis Study Group. Chest 1999; 116: 424-31 40. Lower EE, Baughman RP. Prolonged use of methotrexate for sarcoidosis. Arch Intern Med 1995; 155: 846-51 41. Muller-Quernheim J, Kienast K, Held M, et al. Treatment of chronic sarcoidosis with an azathiprine/prednisolone regimen. Eur Respir J 1999; 14: 1000-1 42. Doty JD, Mazur JE, Judson MA. Treatment of corticosteroidresistant neurosarcoidosis with a short-course cyclophosphamide regimen. Chest 2003; 124: 2023-6

43. Baughman RP, Lower EE. Leflunomide for chronic sarcoidosis. Sacoidosis Vasc Diffuse Lung Dis 2004; 21: 43-8 44. Hallak J, Hendin BN, Thomas AJ, et al. Investigation of fertilizing capacity of cryopreserved spermatozoa from patients with cancer. J Urol 1998; 159: 1217-9 45. Ranganathan P, Mahran AM, Hallak J, et al. Sperm cryopreservation for men with nonmalignant systemic diseases: a descriptive study. J Andrology 2002; 23: 71-5 46. Mattle V, Behringer K, Engert A, et al. Female fertility after cytotoxic therapy -protection of ovarian function during chemotherapy of malignant and nonmalignant diseases. Eur J Hematol Suppl 2005; 66: 77-82 47. Sonmezer M, Shamonki MI, Oktay K. Ovarian tissue cryopreservation: benefits and risks. Cell Tissue Res 2005; 322: 125-32 48. Jones SK. Ocular toxicity and hydroxychloroquine: guidelines for screening. Br J Dermatol 1999; 140: 3-7 49. Doty JD, Mazur JE, Judson MA. Treatment of sarcoidosis with infliximab. Chest 2005; 127: 1064-71 50. Reynolds HY. Sarcoidosis: impact of other illnesses on the presentation and management of multi-organ disease. Lung 2002; 180: 281-99 51. Sharma OP. Pulmonary sarcoidosis: management. J Postgrad Med 2002; 48: 135-41

Correspondence and offprints: Dr Surinder K. Jindal, Department of Pulmonary Medicine, Postgraduate Institute of Medical, Education & Research, Sector 12, Chandigarh, 160012, India. E-mail: skjindal@indiachest.org

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REVIEW ARTICLE

Drugs 2007; 67 (1): 27-55 0012-6667/07/0001-0027/$49.95/0 2007 Adis Data Information BV. All rights reserved.

Serotonergic Drugs
Effects on Appetite Expression and Use for the Treatment of Obesity
Jason C.G. Halford,1,2 Joanne A. Harrold,1,3 Emma J. Boyland,1 Clare L. Lawton2 and John E. Blundell2
1 2 3 Kissileff Laboratory for the Study of Human Ingestive Behaviour, School of Psychology, University of Liverpool, Liverpool, UK Institute of Psychology, University of Leeds, Leeds, UK Department of Medicine, Diabetes and Endocrinology Research Group, University of Liverpool, Liverpool, UK

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 1. Endogenous Serotonin and Serotonin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 2. The Serotonin Satiety System: Interaction with Other Neuropeptide Signalling Pathways . . . . . . . . . 30 2.1 Serotonin and Neuropeptide Y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 2.2 Serotonin and the Melanocortin System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 2.3 Serotonin and Orexin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 3. Endogenous Serotonin and Altered Nutritional Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 3.1 Reduced Energy Intake or Bodyweight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 3.2 Cachexic and Endogenous Serotonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 3.3 Increased Energy Intake or Bodyweight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 4. Effects of Serotonergic Drugs on Food Intake in Rodents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 4.1 Serotonin Receptors and Food Intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 4.2 Serotonin and Feeding Behaviour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 4.3 Serotonin Receptor Knockouts, Food Intake and Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 5. Serotonergic Drugs, Food Intake and Feeding Behaviour in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . 38 5.1 5-Hydroxytryptophan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 5.2 Fenfluramine and Dexfenfluramine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 5.3 Fluoxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 5.4 Sibutramine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 5.5 Preferential and Selective Serotonin Receptor Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 6. Serotonergic Drugs and Obesity: Rodent Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 6.1 Dexfenfluramine and Selective Serotonin Reuptake Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 6.2 Serotonin Receptor Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 7. Serotonergic Drugs and Weight Loss: Clinical Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 7.1 Fenfluramine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 7.2 Dexfenfluramine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 7.3 Sibutramine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 7.4 Selective Serotonin Reuptake Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 7.5 Serotonin Precursors and Receptor Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

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8. Current and Future Serotonergic Anti-Obesity Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 9. Novel Serotonergic Targets for Weight Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 10. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Abstract

Over 35 years of research suggests that endogenous hypothalamic serotonin (5-hydroxytryptamine) plays an important part in within-meal satiation and post-meal satiety processes. Thus, the serotonin system has provided a viable target for weight control, critical to the action of at least two effective anti-obesity treatments, both producing clinically significant weight loss over a year or more. Numerous serotonin receptor subtypes have been identified; of these, serotonin 5-HT1B and 5-HT2C receptors have been specifically recognised as mediators of serotonin-induced satiety. A number of serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs), dexfenfluramine and 5-HT2C receptor agonists, have been shown to significantly attenuate rodent bodyweight gain. This effect is strongly associated with marked hypophagia and is probably mediated by the hypothalamic melanocortin system. Additionally, sibutramine, dexfenfluramine, fluoxetine and the 5-HT2C receptor agonist chlorophenylpiperazine (mCPP) have all been shown to modify appetite in both lean and obese humans, resulting in reduced caloric intake. Clinical studies demonstrate serotonergic drugs specifically reduce appetite prior to and following the consumption of fixed caloric loads, and cause a reduction in pre-meal appetite and caloric intake at ad libitum meals. Weight loss in the obese has also been produced by treatment with both the serotonin precursor 5-hydroxytryptophan and the preferential 5-HT2C receptor agonist mCPP. A new generation of 5-HT2C receptor selective agonists have been developed and at least one, lorcaserin (APD356), is currently undergoing clinical trials. In addition, 5-HT6 receptor antagonists such as PRX-07034 and BVT74316 have been shown to potently reduce food intake and bodyweight gain in rodent models and have recently entered clinical trials. However, the role of the 5-HT6 receptor in the expression of appetite remains to be determined. The hope is that these drugs will not only be free of their predecessors adverse effect profiles, but will also be equally or more effective at regulating appetite and controlling bodyweight.

To understand the potential for serotonin (5hydroxytryptamine)-targeted treatment for obesity it is necessary to consider the nature of appetite regulation and the role of serotonin within it. Appetite is an expression of numerous regulatory processes that determine the initiation and termination of meals, the amount and types of foods consumed, and meal
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length and frequency, and govern the duration of between-meal intervals. Signals are generated from the very commencement of consumption, the shortterm consequences of which serve to terminate eating behaviour and act as powerful inhibitors of further intake. This process signals to the brain an estimation of a meal as opposed to an accurate
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analysis of content. There is an important distinction between the short-term satiety signals produced by the physiological consequences of meal intake (episodic) and the longer-term signals created by the bodys constant metabolic need for energy (tonic). Episodic signals are a crucial factor in the meal-bymeal regulation of energy intake, and are critical to both the appetite fluctuations and patterns of eating behaviour we undertake throughout the day. The monoamine neurotransmitter serotonin influences this episodic, meal-by-meal, regulation of food intake through its role in satiety.[1] Tonic inhibitory signals, by contrast, are not a result of this flux of sensory, cognitive, pre-absorption and post-absorptive factors that are crucial to the satiety development process. Tonic factors are generated instead by the storage and metabolism of energy. The adipose tissue hormone leptin is a key example of this. Leptin is secreted in response to excess fat deposition and also acts as a potent inhibitor of food intake. We have argued previously that serotonin and leptin constitute separate aspects of appetite regulation and are both generated by markedly distinct processes, but both ultimately act to inhibit food intake via the same hypothalamic circuitry.[1] Ultimately, for any anti-obesity drug that acts on reducing food intake to be successful it must influence subjective feelings of appetite experiences before, during and after food intake, enabling the individual to consume less food. With regard to serotonin, there is a greater wealth of data on the effects on human appetite and rodent eating behaviour than for any other peripheral or central target. Therefore, the purpose of this review is to explore the efficacy of serotonergic drugs at inhibiting appetite and consequently food intake. These are the effects which should ultimately induce the clinically significant weight loss required to treat obesity. This is not an in-depth review of the serotonin receptor subtype pharmacology or their role in feeding. These topics have been covered comprehensively in
2007 Adis Data Information BV. All rights reserved.

other recent reviews and are best discussed by those more qualified.[2,3] This review instead emphasises the research identifying both the role of serotonin and the functioning of the endogenous serotonin satiety system as a whole. The review then focuses on the effects of serotonergic drugs in human feeding behaviour studies as well as clinical weight loss trials. The monoamine neurotransmitter serotonin was linked to the control of food intake and of feeding behaviour for the first time 30 years ago. Early studies on this subject used serotonin precursors (such as tryptophan and 5-hydroxytryptophan [5HTP]) to increase CNS serotonin levels and demonstrated a significant reduction in the food intake of laboratory animals in response to this manipulation. This hypophagic response could also be generated via other mechanisms to increase serotonin activity, such as the direct administration of serotonin into the CNS, directly stimulating (agonising) serotonin receptors or blocking synaptic serotonin breakdown.[4-8] Additionally, it was shown that preventing serotonin synthesis (using parachlorophenlyanine [pCPA]), which depletes neuronal serotonin, or the neurotoxic lesioning of serotonin neurons (with 5,7dihyroxytryptamine [5,7-DHT]), resulted in not only a prevention of serotonin-induced hypophagia but an increase in food intake.[9] Relative to now, the pharmacological tools available to these early researchers were nonspecific; nevertheless, it became evident that CNS serotonin was implicated in the control of food intake. Blundell[10] proposed in 1977 that the serotonin system had not only an inhibitory role in feeding but was also a key satiety factor (i.e. a factor in the natural energy intake control mechanism). 1. Endogenous Serotonin and Serotonin Receptors Neuronal serotonin is synthesised from the essential amino acid tryptophan. In the cell body cytoDrugs 2007; 67 (1)

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plasm, the enzyme tryptophan hydroxylase hydroxylates dietary I-tryptophan to 5-HTP. 5-HTP is then rapidly decarboxylated at the terminal, by the enzyme I-amino acid decarboxylase, to produce serotonin. The majority of serotonin produced is taken up via a vesicle membrane transport mechanism and stored in presynaptic vesicles. After release, synaptic serotonin continues to stimulate pre- and postsynaptic receptors until it is either converted to 5hydroxyindole acetic acid (5-HIAA) by monoamine oxidase (MAO) or reabsorbed into the presynaptic neuron for reuse (a sodium-dependent process) [figure 1]. The late 1980s and early 1990s were a time for significant advances in the discovery and identification of novel serotonin receptors.[11] The serotonin receptors currently thought to be most directly implicated in the feeding control mechanisms are
O HO CH 2 C OH

the serotonin 5-HT1A, 5-HT1B and 5-HT2C receptors. The postsynaptic 5-HT1B and 5-HT2C receptors are generally thought to be involved in the serotonin satiety system.[12] However, recent attention has focused on 5-HT6 receptors with data from a number of sources demonstrating 5-HT6 receptor antagonism reduces food intake and bodyweight gain (see section 9). Whether these effects are consistent with satiety remains to be determined. 2. The Serotonin Satiety System: Interaction with Other Neuropeptide Signalling Pathways Energy balance is regulated by a number of peripherally generated signals. Many of these signals converge on the hypothalamic nuclei known to be critical to the control of feeding behaviour expression. These nuclei contain a diverse selection of neuropeptide systems which either inhibit (anorexigenic) or stimulate (orexigenic) food intake. The extent to which serotonin-induced hypophagia involves other neuropeptide signalling systems linked to the hypothalamic regulation of appetite is not yet fully understood and has been explored by a number of studies. Of particular interest is the antagonistic relationship between serotonin and the food intake stimulating neuropeptide neuropeptide Y (NPY). Similarly, links between the serotonergic neurons and another orexigenic system, orexin, may also be critical to the expression of appetite. It seems that the interaction between these orexigenic neuropeptides and serotonin may be critical in determining the expression of appetite, i.e. whether to eat or not. However, perhaps the more critical neuropeptide is the anorexigenic melanocortin system. It seems that a functioning hypothalamic melanocortin system is required for serotonergic drugs to alter feeding behaviour, and presumably for feeding-induced changes in endogenous serotonin to influence appetite. Interestingly, these systems are critical in mediating the effects of tonic peripheral signals such as
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N 5-Hydroxyindoleacetic acid (5-HIAA) Monoamine oxidase HO CH 2 N Serotonin (5-HT) Amino acid decarboxylase COOH HO CH 2 CH N 5-Hydroxytryptophan (5-HTP) Tryptophan hydroxylase COOH CH 2 CH N Tryptophan Fig. 1. The synthesis and metabolism of serotonin (reproduced from Blundell and Halford,[12] with permission). NH 2 NH 2 CH 2 NH 2

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leptin and insulin. The serotonin system itself appears to be more sensitive to peripheral episodic signals such as those produced by a number of gut peptides released in response to the ingestion of food.[12] Thus, it has been proposed that the serotonin system is a key link in the integration of episodic signals into the hypothalamic energy regulatory system.[1]
2.1 Serotonin and Neuropeptide Y

NPY plays a significant role in the control of food intake and energy balance. An interaction between NPY and serotonin was suggested by early studies in which NPY-induced hyperphagia was shown to be blocked by the serotonin receptor agonist fenfluramine. In addition to this, hypothalamic NPY levels have been reported to decrease after treatment with serotonin receptor agonists, and to increase after administration of serotonin receptor antagonists.[13,14] Reduced serotonin availability has also been found to decrease the density of NPY neurons.[15] NPY is synthesised in the arcuate nucleus (ARC) and released in a number of hypothalamic areas, predominantly the paraventricular nucleus (PVN) and ventromedial hypothalamic nucleus (VMH). Subsequent studies have narrowed their focus to specifically examine the potential interactive relationship of PVN NPY and serotonin, and the manner in which this interaction exerts influence over the control of feeding. It is worth mentioning that only administration of 5-HT2A receptor agonists and antagonists into the PVN has been shown to modulate NPY-induced hyperphagia.[16] Despite a lack of confirmation over the nature of the serotonin receptor expressed by PVN NPY neurons, the findings highlighted do provide continued support for the interaction of NPY and serotonin mechanisms.
2.2 Serotonin and the Melanocortin System

and bodyweight. It appears to be a critical site for the integration of afferent episodic and tonic signals of intake and energy status. Neuroanatomical, molecular and electrophysiological methods have been used in combination to show that serotonergic drugs are dependent on a functioning melanocortin system to exert their effects on feeding. It has been shown that anorectic serotonin drugs activate pro-opiomelanocortin (POMC) neurons in the ARC. This effect was demonstrated by specifically examining FOSlike immunoreactivity in response to dexfenfluramine administration.[17] Confirmation that dexfenfluramine directly activates these neurons comes from electrophysiological studies that investigated the expression of green fluorescent protein under control of the POMC promoter.[17] POMC is the peptide precursor of a variety of molecules, including adrenocorticotrophic hormone (ACTH), endorphins and enkephalins, all of which play important roles in metabolic processes. Many of these products can generate pronounced effects on feeding behaviour. However, -melanocyte-stimulating hormone (-MSH) appears to be the major POMC product in terms of an interaction with serotonin. Moreover, -MSH is the main breakdown product of POMC. Up to 80% of -MSH-containing neurons express mRNA for the 5-HT2C receptor[17] and it is probable that these receptors play a part in the serotonin-mediated activation of POMC neurons. Furthermore, previous reports indicate that serotonergic compounds cause the release of -MSH from superfused hypothalamic slices. As a final point, it is worth noting that a blockade of melanocortin 3 and 4 receptors, either by pharmacological or genetic means, is sufficient to attenuate the anorectic effects of serotonergic drugs.[18] These findings indicate that serotonin targets downstream melanocortin pathways and acts via the 5-HT2C receptor to reduce food intake and bodyweight. In a recent paper, Heisler et al.[19] have further demonstrated the role of downstream melanocortin
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The melanocortin system is well known to be a key system involved in the regulation of food intake
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Halford et al.

MC4R

-MSH

AgRP

GABA POMC NPY/AgRP 5-HT1BR 5-HT 5-HT2CR 5-HT

Fig. 2. Schematic diagram of proposed serotonin sites of action on melanocortin pathways. This shows the inhibition of agouti-related peptide (AgRP) neuron and the inhibition of the AgRP axonal projection by serotonin through serotonin 5-HT1B receptor (5-HT1BR) action, and the activation of the pro-opiomelanocortin (POMC) neuron through the 5-HT2C receptor (5-HT2CR) [reproduced from Heisler et al.,[19] with permission]. MC4R = melanocortin 4 receptor; MSH = melanocyte-stimulating hormone; NPY = neuropeptide Y

4 receptors (MC4R) in mediating serotonin-induced hypophagia. It seems that activation of both 5-HT2C and 5-HT1B receptors produce hypophagia by promoting the release of the endogenous agonist and inhibiting the release of the endogenous antagonist of the MC4R. This is achieved through three mechanisms (see figure 2). Firstly, Heisler et al., postulate that serotonin inhibits orexigenic agouti-related peptide (AgRP) neurons in the ARC via 5-HT1B receptor activation. This inhibits the releases of the MC4R antagonist AgRP. Secondly, activation of axonal 5HT1B receptors on AgRP neuronal projections also decreases their inhibitory effect on adjacent anorexigneic POMC neurons. This promotes the release of the MC4R agonist -MSH. Finally, as previous studies have shown, serotonin also activates these anorexignic POMC neurons via activation of 5-HT2C receptors, again promoting the re 2007 Adis Data Information BV. All rights reserved.

lease of -MSH. It would be interesting to determine whether blockade of MC4R reverses the effect of 5-HT2C and 5-HT1B receptor agonism on behaviour indicators of satiety such as the behavioural satiety sequence. Certainly, the effects of dexfenfluramine, a drug that reduces food intake through the activation of 5-HT2C and 5-HT1B receptors, is ineffective at reducing food intake at normal anorectic doses in mice with ectopic expression of endogenous AgRP.[19] Reductions in food intake are only observed at doses previously shown to produce sedation.
2.3 Serotonin and Orexin

Serotonin and orexin are both involved in feeding behaviour regulation, in addition to their roles in the sleep-wake cycle. Orexin neurons project to a vast majority of areas in the brain from their specific
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location in the lateral hypothalamus. Notably, in monoaminergic nuclei (such as the noradrenergic locus ceruleus, the serotonergic dorsal raphe nucleus and the dopaminergic ventral tegmental area) there are dense projections of orexin neurons. Of these, the serotonergic dorsal raphe nucleus is one of the densest projection sites.[20] In addition to this, within the dorsal raphe nucleus, serotonergic neurons express both orexin OX1R and OX2R receptors[21,22] and are excited by orexin-A neuropeptide.[23,24] Moreover, orexin has also been shown to alter serotonin release in the hypothalamus.[25] An involvement of a serotonergic pathway in orexin-induced behaviour is indicated by these anatomical projections and interactions.[26] However, there is to date, a lack of published studies focusing on this interaction between orexin and serotonin that influences feeding behaviour. As it is known that serotonin inhibits food intake, it is probable that orexin projection to the dorsal raphe nucleus establishes part of an inhibitory feedback loop which ultimately connects to the hypothalamus, damping down hypophagic signalling.[27] This is likely to occur via the 5-HT1A and 5-HT2C receptor mechanisms.[28,29] Support for this argument is provided by 5-HT1A receptor immunoreactivity results showing that orexin neurons in the lateral hypothalamus contain 5-HT1A receptors.[30] Additionally, serotonin has been shown to hyperpolarise orexin neurons via the 5-HT1A receptor.[31] It is worth noting that agonism of the presynaptic 5-HT1A autoreceptor could potentially stimulate rather than inhibit food intake. It is likely that this inhibitory serotonergic contribution is important for the physiological regulation of the orexin system. 3. Endogenous Serotonin and Altered Nutritional Status If a system is critical to the control of energy balance, it should fluctuate in response to nutritional status. There are a variety of models that can be used
2007 Adis Data Information BV. All rights reserved.

to cause perturbations in nutritional status. This allows an insight into the regulation (both nutritional and physiological) of neurotransmitter systems that function to control feeding and energy balance. Therefore, if endogenous serotonin is a key appetite regulation factor, its levels and functioning should reflect the organisms nutritional status, fed or fasted.
3.1 Reduced Energy Intake or Bodyweight

It would be logical to assume that a system that inhibits food intake would be inactivated in situations of energy need, allowing the organism to address this with feeding behaviour. It has been shown that malnourished animals demonstrate a significant reduction in CNS serotonin levels in several areas of the brain.[32] Furthermore, intense food-seeking behaviour and increased food intake (when food is made available) has been noted in fasting animals. Food deprivation is thought to increase turnover of serotonin within the hypothalamus.[33] Additionally, it is linked to a significant reduction in the ratio of neurons in the VMH that respond to serotonin,[34] an effect that may be due to alterations in the expression of serotonin receptor subtypes. This reduction in responsiveness to serotonin seen in these rodent models may provide a partial explanation for the increased motivation for feeding after a period of fasting. For instance, fasting-induced reductions in serotonin would allow increased NPY activity and a potent feeding response. With regard to human studies, when female volunteers were placed on a 4-week hypocaloric diet, plasma levels of tryptophan, the serotonin precursor, were reduced.[35] These reductions in tryptophan correlated with the degree of weight loss observed in the women over the 28-day study period. Several studies have noted the effect of dieting on tryptophan, which suggests that dieting in humans may result in central serotonin function being diminished. In one study, prolactin response to the 5Drugs 2007; 67 (1)

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HT2C receptor preferential agonist chlorophenylpiperazine (mCPP) was increased following dieting.[36] The data provided by these studies suggest that the sensitivity of the 5-HT2C receptor is increased in response to chronic restrictions of food intake, an effect that results from the decline in the actual transmitter. In summary, it has been shown that inadequate nutrition or hypocaloric diets seem to both reduce endogenous serotonin levels and increase serotonin receptor sensitivity.
3.2 Cachexic and Endogenous Serotonin

3.3 Increased Energy Intake or Bodyweight

Not only do enforced reductions in food availability cause changes in bodyweight; weight loss also results from malaise-induced reductions of food intake. An obvious question is whether endogenous serotonin activation contributes to the suppression of appetite produced by illness. Rat cancer models are useful for providing chronic anorexic conditions. Particularly in the VMH, the hypothalamic serotonin system plays a crucial role in the anorexia.[37] After injection of interleukin (IL)-1 into the VMH, serotonin levels within the VMH are increased in both normal and tumour-bearing rats.[38] Correspondingly, elevations of tryptophan (the serotonin precursor) in tumour-bearing rats positively correlate with the degree of anorexia.[39] In humans there is evidence that plasma tryptophan levels normalise following tumour resection in patients, resulting in improved food intake, which strengthens the relationship between serotonin, tumour and anorexia.[40] These studies again strongly support the notion that serotonin is a key anorectic agent. Interestingly, another system heavily implicated in cachexia is the melanocortins. Therefore, it is possible to hypothesise that the effects of serotonin on food intake in these models are mediated by the hypothalamic melanocortin system.
2007 Adis Data Information BV. All rights reserved.

It is also logical to assume that a system that inhibits food intake would be activated in situations of energy excess, allowing the organism to address other needs by inhibiting feeding behaviour. Thus, intake should promote increases in serotonin which normally prevent weight gain. Numerous studies have demonstrated the effects of dietary carbohydrate on serotonin precursor entry into the CNS. Moreover, central serotonergic systems appear to mediate the effects of episodic satiety signalling hormones such as cholecystokinin (CCK).[1] Furthermore, it is possible to hypothesise that animals unable to control their bodyweight show deficiencies in their endogenous serotonin system. Studies using obese Zucker rats have been instrumental in providing insights into the effects of obesity and chronic hypophagia on the regulation of serotonin. In this leptin-resistant obesity model, numerous studies have shown that abnormal hypothalamic serotonin activity contributes to both hyperphagia and weight gain. These animals demonstrate an unaltered pattern of serotonin release associated with food deprivation and re-feeding. Moreover, baseline levels of serotonin, specifically, are significantly lower in obese than lean animals.[41] It has been shown that such rats have lower hypothalamic levels of 5-HIAA, the serotonin metabolite.[42] These data indicate that obese Zucker rats have reduced rates of endogenous serotonin turnover. Furthermore, this defect in the endogenous serotonin systems functioning appears to permit weight gain. Dietary-induced obesity following exposure to highly palatable food is the rodent model that resembles human obesity the most closely. The severity of obesity varies between individual animals in this model; approximately 50% of a population develop obesity when provided with a palatable diet.[43] Such rats, demonstrably obesity-prone, exhibit abnormalities of diurnal and fasting-induced alterations in brain serotonin turnover. Specifically, the obesityDrugs 2007; 67 (1)

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prone rats, in contrast to obesity-resistant animals, fail to show diurnal variation in serotonin turnover in the PVN and ARC. Also, these rats demonstrate significant reductions in VMH nucleus serotonin turnover in comparison to their obesity-resistant equivalents.[44] It is possible that these abnormalities constitute a component of a genetic programming, predisposing prone rats to become obese when exposed to palatable food. Moreover, these abnormalities have been shown to normalise after obesity has developed. This could account for the persistence of the obesity in these rats, whereby the animals avidly defend their increased bodyweight against the food restriction. Therefore, in rodents, reduced serotonin turnover or an unresponsive endogenous serotonin system is associated with proneness to obesity. Given the rodent data, it seems logical to ask if an impaired serotonin system contributes to human obesity. In obese humans, plasma tryptophan levels are also reported to be low. This could contribute to a reduction in satiety response to food and consequent overconsumption. Moreover, low tryptophan levels are not normalised by considerable weight reductions.[45] Therefore, in humans, a reduction in CNS serotonin levels in the obese could contribute to an inability to exert sufficient control over their own daily caloric intake. Although it is difficult to prove any role for serotonin deficiency in the development of obesity, it seems appropriate to assume it may be critical in preventing the obese individual successfully losing weight. 4. Effects of Serotonergic Drugs on Food Intake in Rodents
4.1 Serotonin Receptors and Food Intake

lease of serotonin and/or preventing its reuptake). The resulting suppression of food intake was then challenged pharmacologically, using selective serotonin receptor antagonists to identify the specific serotonin receptor subtypes fundamental to druginduced hypophagia. Fenfluramine or dexfenfluramine-induced food suppression models were used in a majority of the studies to have employed antagonists to identify these receptors. This is likely to be at least partially as a result of the robustness of the models of fenfluramine or dexfenfluramine-induced reduction in food intake and bodyweight, but also partly a reflection of the known effectiveness, at that time, of their treatment for human obesity. The use of selective serotonin receptor antagonists of various 5-HT1 and 5-HT2 receptor subtypes had indicated that dexfenfluramine-induced hypophagia is mediated by 5-HT1B receptors.[46] The foundation for this was evidence gathered from numerous studies showing that the actions of dexfenfluramine were blocked with 5-HT1A/1B receptor antagonists, but that the actions of dexfenfluramine were not blocked by 5-HT2A/2C receptor antagonists.[47-49] In 2002, Simansky and Nicklous[50] infused the highly selective 5-HT1B receptor antagonist directly into the parabrachial nucleus of the rat and blocked dexfenfluramine-induced reduction in food intake. Nevertheless, the central role of 5-HT1B receptors is not confirmed by all experimental evidence. Vickers et al.[51] showed that dexfenfluramine-induced hypophagia could be blocked by pretreatment with the highly selective 5-HT2C receptor antagonist SB242084, whereas this effect was not seen following pretreatment with the highly selective 5-HT1B receptor antagonists GR-127935 and SB-224289. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) produces a consistent food intake reduction that cannot be blocked easily by serotonin antagonists.[52-54] Nevertheless, the non-selective 5HT1/2 receptor antagonist metergoline has been successful in both partially and fully blocking fluoxeDrugs 2007; 67 (1)

Following the initial identification of serotonin as a key inhibitor system, the next step was to reveal the receptors responsible for mediating the serotonin satiety response. In the beginning, studies used serotonin manipulations (i.e. drugs promoting the re 2007 Adis Data Information BV. All rights reserved.

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tine-induced hypophagia.[55,56] These data suggest that at the doses used, fluoxetine-induced hypophagia may be mediated by the 5-HT1B and 5-HT2C receptor subtypes that are critical to the mediation of the effects of dexfenfluramine on food intake. The hypophagia induced by other SSRIs such as sertraline,[57] in contrast to fluoxetine, seems to be blocked more reliably by antagonists of the 5-HT1B and 5-HT2C receptors.[58] Alongside the development of more selective serotonin receptor antagonists, further serotonin receptor agonists have also become available. More recently, scientists have been able to work with selective serotonin receptor agonists that have been developed specifically as novel obesity treatments. Direct agonism of serotonin receptors in rodents produces consistent reductions in food intake. Furthermore, agonists of the 5-HT1B and 5-HT2C receptor subtypes generate changes in feeding behaviour that are consistent with the operation of satiety (see section 4.2). These agonist agents include mCPP (preferential 5-HT1B/2C receptor agonist), TFMPP (N-[3-trifloromethyl)phenyl]piperazine) [preferential 5-HT1B/2C receptor agonist], CP-93129 (selective 5-HT1B receptor agonist), CP-94 253 (selective 5-HT1B receptor agonist), and Ro 60-0175 (selective 5-HT2C receptor agonist).[29,59-66] While these food intake studies seem to have confirmed the role of both receptor subtypes in mediating the serotonin hypophagic response, the question remains; was drug-induced hypophagia due to enhanced satiety?
4.2 Serotonin and Feeding Behaviour

intake but distinct effects on feeding behaviour.[67] More specifically, amfetamine seemed to fragment normal feeding behaviour (the duration of feeding is decreased but its frequency is increased and the decline in eating behaviour indicative of satiety disappears), whereas fenfluramine appeared to enhance satiety by reducing meal size. Subsequent studies have shown drugs that either stimulate serotonin release or inhibit serotonin reuptake produce changes in feeding behaviour, as measured by the behavioural satiety sequence (BSS) or other behavioural assays, which are consistent with the operation of satiety. Specifically, numerous serotonergic drugs have been shown to enhance the BSS.[68] The BSS is a stochastic progression of behaviour whereby as satiety develops, the initial feeding behaviour is replaced with activity, followed by grooming, and then terminated with a prolonged period of resting/inactivity. If the effects of a drug cause a reduction in food intake but also cause a disruption or delay in this temporal behavioural pattern, it is probable that drug-induced hypophagia is at least partially due to disturbance of this normal feeding behaviour by mechanisms other than satiety, for example, hyperactivity, malaise, sedation or nausea. However, if a drug is shown to induce hypophagia but does not disrupt this sequence of behaviour, it is reasonable to assume that this drug does not interfere with the natural development of satiety. Alternatively, if a drug causes a reduction in food intake and appears to enhance the BSS (i.e. feeding behaviour is terminated early and there is an earlier onset of each of the other phases of the sequence), it can be concluded that satiety is the primary mechanism of action.[68] Previous studies have shown that both fenfluramine and dexfenfluramine adjust feeding behaviour in a manner consistent with the operation of satiety.[69-71] Sertraline, fluoxetine and other SSRIs have produced similar effects to dexfenfluramine on a number of behavioural indices of appetite in roDrugs 2007; 67 (1)

It is important to clarify a key distinction between drugs that reduce food intake by exerting an effect on natural satiety mechanisms and those that cause a reduction in food intake by inducing nausea, sedation, hyperactivity or malaise. For example, when fenfluramine and amfetamine (amphetamine) were compared in early clinical studies it became clear that the two drugs produced similar effects on food
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Table I. Effect of various serotonergic drugs on rodent energy intake and expression of the behavioural satiety sequence (BSS) Drug Dexfenfluramine Fluoxetine Sertraline Paroxetine Femoxitine DOI MK-212 mCPP TFMPP RU-24969 CP-93,129 CP-94,253 Ro 60-0175 Org 12962 VER-3323 BTV-933 YM348 Lorcaserin (APD356) Sibutramine Mechanism (and receptors mediating effect if known) Serotonin releaser and reuptake inhibitor (5-HT1B and 5-HT2C) Serotonin reuptake inhibitor (5-HT1 and 5-HT2) Serotonin reuptake inhibitor (5-HT1B and 5-HT2C) Serotonin reuptake inhibitor (receptor involvement unknown) Serotonin reuptake inhibitor (receptor involvement unknown) 5-HT2 agonist 5-HT2 agonist 5-HT1B/2C agonist 5-HT1B/2C agonist 5-HT1A/1B agonist Selective 5-HT1B agonist Selective 5-HT1B agonist Selective 5-HT2C agonist Selective 5-HT2C agonist Selective 5-HT2C agonist Selective 5-HT2C agonist Selective 5-HT2C agonist Selective 5-HT2C agonist Effect on intake Unknown Unknown Unknown Unknown Unknown on BSS Disrupts (hyperactivity) Disrupts (sedation) Disrupts (hyperactivity) Unknown Unknown Unknown Unknown Unknown

Serotonin and noradrenaline reuptake inhibitor (NA1/2 and 5-HT2A/2C) DOI = 2,5-dimethoxy-4-iodoamphetamine; mCPP = m-chlorophenylpiperazine; TFMPP = N-[3-trifloromethylphenyl]piperazine; indicates increases; indicated decreases.

dents, i.e. inducing the BSS.[56,68,72-75] Additionally, the current globally licensed anti-obesity treatment sibutramine (serotonin and noradrenaline reuptake inhibitor [SNRI]) has also been shown to enhance the BSS.[68] Several selective agonists of serotonin receptors produce changes in feeding behaviour consistent with the operation of satiety, notably the 5-HT1B receptor agonist CP-94 253, the preferential 5-HT1B/2C receptor agonists mCPP and TFMPP, and the selective 5-HT2C receptor agonists.[62,66,68,73] Importantly, drugs that have also been shown to agonise other serotonin receptor subtypes, for example DOI (2,5-dimethoxy-4-iodoamphetamine) [5HT2A/2C] or RU-24 969 (5-HT1A/1B), are unsuitable for further development because they disrupt the BSS by inducing hyperactivity, a critical side effect. For a summary of the effects of serotonergic drugs on rodent food intake and the BSS see table I.

4.3 Serotonin Receptor Knockouts, Food Intake and Obesity

Knockout mice provide the final and possibly strongest argument for the vital role of 5-HT2C receptors in mediating the hypophagic effects of endogenous serotonin. A breed of mice was successfully produced by Tecott et al.[76] that did not possess a single functional 5-HT2C receptor. In these 5HT2C knockout mice, marked hyperphagia was demonstrated from 5 weeks after birth, an effect accompanied by marked hyperactivity. Hyperactivity declined later in the life of these mice, whereas hyperphagia persisted, leading to the development of obesity.[77] Interestingly, these mice were also partly resistant to dexfenfluramine-induced hypophagia.[78] However, reductions in food intake could still be produced in the mutant mice by the use of dexfenfluramine. There was also some evidence

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of enhanced satiety in the BSS paradigm in response to this drug. These responses were distinctly lesser in magnitude in the knockout mice than in the control wild-type mice. Therefore, it seems that there is a deficiency in the endogenous serotonin satiety system of obese 5-HT2C receptor knockout mice. Additionally, 5-HT1B receptor knockout mice are significantly heavier than wild types,[79] an effect associated with significantly greater food consumption. However, these animals merely appear to be larger rather than fully obese.[2] 5. Serotonergic Drugs, Food Intake and Feeding Behaviour in Humans Studies first employing racemic fenfluramine and then dexfenfluramine provided a majority of the original data on the effects of pharmacological manipulation of serotonin on food intake in humans. Subsequently, studies employing the SSRI fluoxetine and then sibutramine were also published. Over the past 13 years, numerous other studies have been published, using the serotonin precursor 5-HTP and preferential serotonin receptor subtype agonists. These studies have shown that by increasing synaptic or neuronal levels of serotonin or directly agonising specific serotonin receptor subtypes, robust hypophagia can be produced. Furthermore, is it clear from the meticulous description of the effects of the manipulation on behaviour and subjective ratings of hunger and satiety that these pharmacological interventions have produced hypophagia by modifying human appetite expression. The effects of serotonergic drugs on appetite are shown in table II.
5.1 5-Hydroxytryptophan

to follow for the first 6 weeks of the study, but during the second 6-week period the participants were given a diet regimen. Each participant recorded their food intake at regular intervals in a diary, both before treatment commenced and during both the initial (non-diet) and latter (diet) phases. From baseline, those receiving 5-HTP lost 5.0kg in bodyweight (1.7kg in the non-diet phase and 3.3kg in the diet phase) in comparison to 1.2kg, a nonsignificant reduction in bodyweight, seen in those who had received placebo for 12 weeks. Those receiving the drug reported significant decreases in daily energy intake of 41% (5636kJ) in the non-diet phase and 60% (8202kJ) in the diet phase from baseline. Conversely, reductions in self-reported food intake in the placebo group were 14% and 24%, respectively. The same research group then replicated their original findings in a shorter study.[96] In this study, 25 overweight individuals with type 2 diabetes mellitus were randomly allocated to receive either placebo or 5-HTP (750 mg/day) for 2 weeks. Diet diaries were also utilised in this study. In the group treated with 5-HTP, weight loss from baseline over the 2-week study period was 2.1kg. Significant decreases in self-reported energy expenditure accompanied this weight loss effect, with a 21% (1700kJ) reduction reported on day 7 and 22% (1760kJ) on day 14. It is likely, from an examination of these data, that participants in this trial underreported energy intake on a number of occasions. Nevertheless, it does appear that hypophagia is associated with weight loss.
5.2 Fenfluramine and Dexfenfluramine

The serotonin precursor 5-HTP has been shown to produce potent effects on self-reported food intake in obese individuals. In one study, 20 obese individuals (defined as hyperphagics) were treated with either 5-HTP (900 mg/day) or placebo over 12 weeks.[81] The participants were not prescribed a diet
2007 Adis Data Information BV. All rights reserved.

In the late 1970s, the effects of fenfluramine on human food intake were demonstrated. For example, in 1979 Rogers and Blundell[82] published a key study showing that a single dose of fenfluramine (60mg), when given to lean healthy males, could reduce food intake at a lunchtime meal by 789kJ (26%). The effect of reduced caloric intake was also
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Table II. Summary of studies that have investigated the effects of serotonergic drugs on food intake in humans Drug Study design No. of study participants (status) 16 (healthy) 20 (obese) 12 (normal bodyweight) 8 (obese) 24 (obese) 20 (obese) 13 (healthy men) 10 (lean women), 11 obese women 12 (healthy men) 11 (healthy men) Duration of treatment 1d 6wk 1d 3d 2wk 8d 1d 1d 1d 2wk Hunger and food preference NR Carbohydrate intake, early post-meal satiety NR Hunger, fullness after first meal Carbohydrate snack intake Carbohydrate intake at meal, snack intake Hunger Hunger Fat intake Hunger on days 8 and 15, but not on day 1 No macronutrient preference, hunger Hunger, food preoccupation NR Hunger, bodyweight No change in hunger, fat intake Caloric intake Reference

Tryptophan 5-HTP Fenfluramine Dexfenfluramine Dexfenfluramine Dexfenfluramine Dexfenfluramine Dexfenfluramine Dexfenfluramine Fluoxetine Fluoxetine Sertraline mCPP mCPP Sumatriptan

Laboratory study Laboratory study Laboratory study Laboratory study Laboratory study Laboratory study Laboratory study Laboratory study Laboratory study Laboratory study Laboratory study Relapse prevention trial Laboratory study Laboratory study Laboratory study

Intake Intake and bodyweight of 6wk period Test meal intake and eating rate Intake after second meal (1119%) NR Intake Intake Intake No overall effect Intake on days 1 and 8, but not on day 15 Intake (22.4%) NR Test meal intake NR Intake

80 81 82 83 84 85 86 87 88 89 90 91 92 93 94

12 (obese women) 14d 53 (obese women) 6wk 12 (healthy women) 18 (obese) 15 (healthy women) 1d 2wk 1d

Sibutramine Laboratory study 12 (obese women) 14d Hunger Daily intake 95 5-HTP = 5-hydroxytryptophan; mCPP = m-chlorophenylpiperazine; NR = not reported; indicates increase; indicates decrease.

accompanied by significant decreases in eating rate and desire to eat, both indicative of a drug-induced modulation of normal appetite. The desire to eat being significantly lower prior to the meal and the low rate of consumption at the start of the meal signify that fenfluramine had retarded normal hunger by enhancing the pre-meal satiety state. Similarly, Foltin et al.[97] found that both male and female, healthy, normal weight individuals reduced their total daily caloric intake when given fenfluramine 40 mg/day. Specifically, the participants reduced their meal size rather than the number of meals, indicating that fenfluramine had enhanced withinmeal satiation processes but had not produced any
2007 Adis Data Information BV. All rights reserved.

compensatory weakening of satiety states between meals. A number of differing laboratory-based feeding paradigms have successfully shown dexfenfluramine-induced hypophagia in humans. Not all can be detailed here but it is useful to consider some of these studies, which have indicated the efficacy of both short- and long-term dexfenfluramine on food intake, in both lean and obese individuals. Acute doses of dexfenfluramine were administered to lean healthy males in a study by Goodall and Silverstone.[86] The results of this study showed that a single 30mg dose of dexfenfluramine produced a significant reduction in cumulative intake and eating rate of approximately 23% over a 2-hour period.
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Dexfenfluramine, as with fenfluramine, in this ad libitum feeding paradigm produced a significant decrease in pre-meal hunger ratings. In another study, Blundell and Hill[83] also noted that dexfenfluramine produced significant reductions in hunger prior to a meal in both the lean and the obese. Additionally, the effect on hunger was greater in magnitude in the obese than the lean. In this study, the drug also reduced prospective consumption in the obese and the lean, and solely in the lean enhanced feelings of fullness were reported. Subsequently, Drent et al.[98] administered dexfenfluramine (30 mg/day) to overweight and obese individuals for 9 weeks, in a randomised, placebo-controlled, double-blind trial. Throughout the trial, dexfenfluramine produced a marked reduction in self-reported food intake. The placebo group actually gained 0.2kg over the study period despite self-reporting a 15% reduction in daily food intake from baseline. Conversely, the group treated with dexfenfluramine lost 3.1kg and reduced self-reported daily food intake by a significant 30% from baseline. It is possible that, as the placebo group failed to lose weight, there may have been an underreporting of energy consumed by participants in this trial. Despite this, the effects shown on bodyweight and food intake are still impressive. Analysis of the food diaries indicated that dexfenfluramine treatment reduced energy intake by reducing meal and snack size but not number. This study also demonstrated that the dexfenfluramine reductions in food intake were associated with the effect of the drug on bodyweight. Moreover, even when the drug is given long term to obese individuals, dexfenfluramineinduced reductions in food intake appear to be a robust phenomenon.
5.3 Fluoxetine

were employed in a double-blind, placebo-controlled, crossover design. Food intake and eating behaviour were assessed on three distinct probe days (days 1, 8 and 15). Over the 2-week treatment period, participants in the drug treatment group lost significantly more weight than those in the control group (1.07 vs 0.15kg). Fluoxetine treatment reduced cumulative intake at the 2-hour buffet meal on day 1 (by 15.7%) and day 8 (by 12.6%) but not day 15. Again in the fluoxetine group, a significant reduction in hunger was reported on day 8 only. From this study, it is not possible to ascertain whether day 15 was the last day of fluoxetine treatment or the first day of the washout period. Another study examined the effects of 14 days administration of fluoxetine (60 mg/day) on meal patterns.[99] The group treated with fluoxetine lost 3.6kg in comparison to a weight gain of 0.3kg seen in the placebo control group. When compared with the placebo control, fluoxetine treatment also significantly reduced reported meal and snack intake. A more detailed study of the effects of fluoxetine (60 mg/day) on the eating behaviour and food intake of obese females was carried out by Lawton et al.[90] Volunteers in this study, as with the McGuirk and Silverstone study,[89] were treated for 14 days with both drug and placebo in a randomised, doubleblind, crossover design. Patients returned to the laboratory on days 7 and 14 to receive fixed test meals. This was designed to investigate whether fluoxetine-induced hypophagia was intensified or weakened by equi-caloric test meals that differed in macronutrient composition. The results of this study were similar to those of previous studies, as over the 2-week treatment period significantly more weight was lost in the drug group than the controls (1.97 vs 0.04kg). There was also a significant associated reduction in post-test meal hunger in the drug group. Irrespective of their macronutrient composition, it was shown that fluoxetine increased the satiety impact of the fixed equi-caloric test meals. Direct
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A study by McGuirk and Silverstone[89] investigated the effect of 2 weeks fluoxetine (60 mg/day) treatment on food intake. Healthy male participants
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measurement of subsequent food intake at the ad libitum evening meal that followed the test meal on days 7 and 14 showed that fluoxetine produced a 27% (198kcal) reduction in energy consumption. During this study participants were also asked to complete daily food diaries. Analysis of these diaries showed that during the 14 days of treatment, fluoxetine produced a self-reported reduction in daily energy intake of 22.4% (421 kcal/day). It appears that a tolerance to fluoxetine-induced hypophagia develops after 2 weeks of administration, as suggested by the data from McGuirk and Silverstone.[89] However, Ward et al.,[100] carried out a 16-week outpatient study in the obese, in which participants attended the laboratory at weeks 7 and 16 of treatment. On these days, long-term fluoxetine administration was shown to reduce participants total food intake. Specifically, the mean number of total eating occasions within a study day was reduced by fluoxetine. Unlike drug-induced hypophagia, tolerance did appear to develop to drug-induced weight loss in this study. At the week 7 timepoint, fluoxetine-induced weight loss was significantly greater than with placebo, but this was not the case at the week 16 study endpoint.
5.4 Sibutramine

used to investigate the effect of a single 15mg dose of sibutramine on total daily energy consumption. The drug was taken prior to a fixed load breakfast. It was shown to reduce total caloric intake on the study by 1304 kcal, approximately 12%. This figure is achieved through significant reductions in caloric intake at both lunch and dinner (637 and 393kJ, respectively). The number of food items eaten per day was reduced by an average of 1.6 items (approximately 10%). This effect occurred mainly at lunch. In addition to the pronounced hypophagia and changes in feeding behaviour seen at lunch, the 15mg dose of sibutramine significantly reduced hunger 4 hours after administration, an effect that coincided with the start of the lunch. Rolls et al.[95] examined the effects of sibutramine on food intake and appetite in obese individuals. In this study, the double-blind, placebo-controlled, crossover design used was similar to that of previous fluoxetine studies.[89,90] It was conducted over 14 days, with participants invited into the laboratory to have their eating behaviour assessed directly on days 7 and 14. Two daily dosages of the drug were used, 10mg as is normally prescribed, and a higher 30mg dose. Participants were instructed to take the drug before breakfast. On study days, participants attended the laboratory for breakfast, lunch and dinner, all of which were ad libitum meals. The 30mg dose of sibutramine showed effects on food intake, subjective measures of appetite and bodyweight that were observed earlier in the study and were greater in magnitude than the effects of the lower dose. Specifically, the 30mg dose reduced caloric intake by 1763kJ (23%) by day 7 and by 2079kJ (26%) on day 14 (vs placebo). The 10mg dose also significantly reduced total caloric intake by 1290kJ (19%), but only on day 14. The significant reductions shown in total caloric intake (on days 7 and 14 for the 30mg dose, on day 14 only for 10mg) resulted from significant reductions in energy intake at both lunch and dinner, but not at breakDrugs 2007; 67 (1)

In addition to fluoxetine and dexfenfluramine, acute doses of sibutramine, an SNRI, have been shown to reduce food intake[101] and appetite in lean male volunteers.[101,102] Hansen et al.,[102] initially studied the effect of sibutramine (30 mg/day) on energy expenditure but also noted that the drug produced an enhancement of the inhibition of appetite resulting from the set breakfast (2.1kJ) given to all participants. Although this study did not measure the effects on subsequent ad libitum food intake, sibutramine treatment was shown to increase the satiety impact of a fixed load of food. In a subsequent study by Chapelot et al.,[101] a placebo-controlled counterbalanced design was
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fast. It is not clear whether sibutramine-induced hypophagia was greater at lunch or at dinner, but the effect does appear to have been accompanied by reductions in pre-meal hunger and prospective consumption ratings at the 30mg dose. Interestingly, both the Chapelot and Rolls studies[2,9,101] demonstrate that sibutramine-induced significant effects on appetite were observed before the ad libitum meal, but not after. Following the ad libitum meal, druginduced reductions appear to normalise the subsequent post-meal appetite ratings, whereas after a fixed load these ratings are suppressed. Importantly, in both studies the use of sibutramine treatment in the lean and the obese resulted in the same post-meal satiety being attained by significantly less food consumption. Tolerance to the hypophagic effects of sibutramine did not appear in the 14 days treatment of the Rolls et al.[95] study. Moreover, it was observed that changes in appetite and food intake were accompanied by significant drug-induced weight loss in this study. The 10mg dose of sibutramine had caused a reduction in bodyweight by 0.7kg at day 7, and by day 14 weight was reduced by 0.8kg compared with placebo. The higher 30mg dose of sibutramine had reduced bodyweight by 0.6kg on day 7 and by 1.2kg on day 14. The results of this study appear to suggest that in the obese, sibutramine treatment produces both hypophagia and associated weight loss. Hansen et al.[103] conducted an 8-week randomised, double-blind, placebo-controlled study in the obese to examine the effects of sibutramine 15 mg/ day on energy expenditure. The study design involved two laboratory visits, one at the start of treatment and one at the end, in which the participants were required to live in a respiration chamber for 32 hours. Participants ate freely at set meals during this time and their appetite was assessed. Disappointingly, the authors did not report the effects of sibutramine on food intake at these visits.
2007 Adis Data Information BV. All rights reserved.

However, it was noted that both daily hunger ratings and prospective food consumption were significantly decreased on the first (day 1) and the last (day 56) days of sibutramine treatment. The results of this study also showed that sibutramine produced a significant decrease in bodyweight of 2.4kg compared with a slight rise of 0.3kg seen in the placebo group over the course of the study. Sibutramine was shown to have little effect on energy expenditure; therefore, the weight loss observed is likely to have resulted from the effect the drug had on food intake. Barkeling et al.[104] recently provided perhaps the most persuasive argument to demonstrate the link between sibutramine-induced hypophagia and sibutramine-induced weight loss. This multiphase study was devised to examine the effects of sibutramine on appetite in the obese, particularly to see whether sibutramine still reduced food intake after 10 months of treatment and how predicted weight loss progressed on a long-term trial. Obese volunteers were recruited to a 14-day fully randomised, placebo-controlled, crossover study. Following 14 days of treatment with sibutramine 15 mg/day or placebo, the participants were invited into the laboratory to consume an ad libitum lunch. During the initial double-blind study, a 16% kcal reduction in energy intake at the test lunch was observed. Subsequently, the participants were placed on a 10-month openlabel treatment with sibutramine. At the end of this period, the participants returned to the laboratory for a final visit at which they were provided with the same ad libitum meal they had received on previous occasions. Intake at this lunch was reduced by 27% when compared with their pre-weight loss trial placebo intake. Sibutramine also significantly increased ratings of fullness and decreased prospective consumption after the fixed breakfast but not after the ad libitum lunch. Interestingly, this study demonstrated that the appetite response to sibutramine was undiminished after 10 months of treatment. It is particularly important to note that the
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initial effect of sibutramine on appetite in the 14-day trial was predictive of the effect of sibutramine on bodyweight during the subsequent 10-month openlabel weight loss trial.
5.5 Preferential and Selective Serotonin Receptor Agonists

pared with placebo (0.04kg). Participants were invited to the laboratory on the penultimate day of treatment and blood samples were taken to assess mCPP concentrations and prolactin response. During this procedure, hunger rating scales were also completed by the participants. Analysis of the scales subsequently showed that drug treatment produced a significant decrease in hunger ratings. Collectively, the three studies discussed make it evident that mCPP can effectively reduce food intake and appetite in lean individuals, and bodyweight and appetite in obese individuals. However, it is important to note that in lean participants, mCPP also produced transient but significant increases in the self-reported subjective ratings of light-headedness, anxiety and nausea.[92,105] It has also been observed that transient increases in blood pressure and heart rate can occur in response to acute doses of mCPP.[106] If more specific 5-HT2C receptor agonists could be developed (particularly if they avoid some of the aforementioned transient adverse effects produced by the less specific mCPP), this could be an important advancement in obesity treatment. However, it still remains to be demonstrated whether the hypophagic effects of mCPP and more selective 5-HT2C receptor agonists occur in obese individuals. The 5-HT2C receptor is, of course, not the only receptor that has been implicated in mediating the effects of the endogenous serotonin satiety system. Sumatriptan, a novel 5-HT1B/1D receptor agonist, has also been found to produce a significant reduction in food intake in healthy women.[94] This study used a double-blind, placebo-controlled, crossover design to examine the effects of an acute 6mg dose of sumatriptan on food intake at a buffet style lunch. A 23% reduction in food intake (approximately 850kJ) was produced by the sumatriptan injection compared with placebo. Importantly, a 34% decrease in fat intake was also observed at the lunch following drug treatment. In this study, no signifiDrugs 2007; 67 (1)

Direct agonism of serotonin receptors also potently reduces food intake. In the rat, mCPP (a 5-HT1B/2C receptor preferential agonist) has been shown to reduce food intake via activation of 5-HT2C receptors. A number of studies have also shown that mCPP reliably reduces food intake in humans. The effect of an acute dose of mCPP (0.4 mg/kg) was initially investigated in a double-blind, placebo-controlled, crossover design study, conducted with lean, healthy female volunteers.[92] Each participant was given either mCPP or placebo orally 150 minutes prior to the presentation of a buffet lunch. At this ad libitum meal, food intake in those receiving mCPP was reduced by 30% (approximately 1000kJ). This study also showed that the effect of mCPP on food intake was significantly associated with pre-meal hunger ratings being reduced. Subsequently, this study was replicated in a larger group of both male and female lean, healthy volunteers.[105] The drug was again effective at reducing food intake in women (28%, 1205kJ) and also in men (20% reduction, 1219kJ). Again, the drug produced significantly reduced hunger ratings prior to the meal in both men and women (150 minutes after administration). This effect occurred marginally after peak plasma mCPP concentrations (120 minutes after administration) and just prior to the lunch. A study in obese individuals examined the effects of mCPP on appetite and bodyweight but not food intake.[93] In this double-blind, placebo-controlled, crossover trial, participants were treated for 14 days with mCPP (20mg twice daily for women, 25mg twice daily for men). Significantly more weight (0.8kg) was lost from baseline with mCPP com 2007 Adis Data Information BV. All rights reserved.

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cant effects on ratings of nausea and light headedness were observed. However, as there were no significant effects on appetite reported, it is probable that this study was statistically underpowered. 6. Serotonergic Drugs and Obesity: Rodent Studies
6.1 Dexfenfluramine and Selective Serotonin Reuptake Inhibitors

gic drugs has also produced these effects on bodyweight gain and food intake. For example, SSRIs such as fluoxetine,[110,111] sertraline,[112] fluvoxamine[113] and paroxetine[114] have also all been shown to attenuate bodyweight gain in various rodent models, an effect normally associated with significant hypophagia.
6.2 Serotonin Receptor Agonists

It has been proven in a number of rodent models that drugs which promote serotonin release or inhibit reuptake do inhibit bodyweight gain. In one study, daily injections of dexfenfluramine (10 mg/kg) over a 12-day period were shown to be particularly effective at abolishing weight gain associated with exposure to high-fat diets in Osborne-Mendel rats (a strain particularly susceptible to dietary-induced obesity).[107] This reduction in bodyweight gain was associated with a marked reduction in caloric intake. It has also been noted in a separate study that no tolerance developed to the bodyweight gain attenuating effects of dexfenfluramine (6 mg/kg/day infused peripherally via a mini-pump) during a 14-day study in Lister hooded rats.[108] At the end of the study, the animals treated with dexfenfluramine weighed 5% less than controls. As with the previously mentioned study,[107] these effects on bodyweight were associated with drug-induced reductions in food intake. However, it was observed that in the second week of this study dexfenfluramine-induced hypophagia was less pronounced. In a longer 28-day study, dexfenfluramine was administered twice daily (2.5 mg/kg).[109] Again, the drug reduced food intake and attenuated bodyweight gain. Animals treated with dexfenfluramine for 28 days weighed approximately 50g (12%) less than controls, and no tolerance developed to the hypophagic effects of dexfenfluramine in this study. The administration of a number of other serotoner 2007 Adis Data Information BV. All rights reserved.

In rodent models it also appears that direct agonism of 5-HT2C receptors affects weight gain. In their first study, for example, Vickers et al.[108,109] have shown the inhibitory effects of the preferential 5-HT2C receptor agonist mCPP on rodent bodyweight gain. mCPP 12 mg/kg/day was delivered by implanted mini-pumps during the initial study, the results of which demonstrated that the effects of mCPP on bodyweight were associated, at least partly, with hypophagia. Furthermore, tolerance to the effects of mCPP on rodent bodyweight gain did not develop during this study and animals treated with mCPP weighed 8% less than controls by the end of the study. It is known that mCPP also agonises several other serotonin receptors (e.g. 5-HT2A and 5-HT2B receptors); therefore, it is theoretically possible that the drug-induced attenuation of bodyweight gain could be due to activation of any of these receptors. However, using selective antagonists, it has been demonstrated that mCPP-induced hypophagia is a result of activation of the 5-HT2C receptor specifically.[115] Consequently, it is probable that the hypophagic component of mCPP-induced weight loss, at least, is due to activation of the 5-HT2C receptor. In a second study,[109] mCPP (10 mg/kg/day) was given orally for 28 days. Again, mCPP induced significant attenuation of bodyweight gain and reductions in daily food intake. Animals treated with mCPP over the 28-day period subsequently weighed approximately 50g (12%) less than controls. No tolerance appears to develop to the hypophagic effects of the 5-HT2C
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receptor agonist. Pair-feeding was carried out in order to match the food intake of mCPP-treated animals, which produced the same degree of weight gain, suggesting that the drugs hypophagic effects are responsible for the attenuation of bodyweight gain. The effects of several more selective 5-HT2C receptor agonists on rodent bodyweight have recently been studied. In the study by Vickers et al.,[108] Ro 60-0175 (26 mg/kg/day) was infused into the animals via implanted mini-pumps for 14 days. The results demonstrate that Ro 60-0175 produced a significant reduction in bodyweight gain; the animals treated with Ro 60-0175 weighed 10% less than controls at the end of the study. As with mCPP, Ro 60-0175 reduced food intake over the treatment period; however, by day 11 tolerance to the hypophagic effect was evident. Similarly, YM348, another potent and highly selective 5-HT2C receptor agonist, also produced an attenuation of bodyweight gain over a 2-week treatment period (at dosages of 3 and 20 mg/kg/day).[116] Animals treated with the higher dose of YM348 weighed 21.5% less than controls at the end of the study. Tolerance to druginduced hypophagia appeared in the second week of this treatment also. Multiple doses of the novel selective 5-HT2C receptor agonist lorcaserin (APD356 [4.5, 9, 18 and 36 mg/kg]) have recently been shown to inhibit the development of dietary-induced obesity.[117] Lorcaserin significantly reduced bodyweight gain in both male and female rats. This effect was associated with an initial episode of marked hypophagia. Tolerance appeared to develop to the hypophagic effects of all dosages of lorcarserin during this study. 7. Serotonergic Drugs and Weight Loss: Clinical Data Examination of the clinical data available appears to suggest that hypophagia is the primary
2007 Adis Data Information BV. All rights reserved.

mechanism by which serotonin induces weight loss. Correspondingly, serotonergic drugs must restrain the motivation to eat and maintain lower levels of food consumption for substantial periods of time. A majority of the early clinical data on weight loss originates from studies that employed fenfluramine and dexfenfluramine, drugs that have since been withdrawn from the market. Clinical data on the effects of fenfluramine on bodyweight have been collected and published since the late 1960s, but given that this drug is now withdrawn, these studies need not be detailed. However, Haddock et al.[118] have produced an extremely useful meta-analysis of both early and more recent drug trials.
7.1 Fenfluramine

There are numerous early therapeutic trials of fenfluramine, and for those interested in this area, we recommend the extensive review published in 1975 by Pinder and colleagues.[119] Closer examination of the review demonstrates that the majority of the early fenfluramine studies were a comparison of the effects of fenfluramine with either placebo or other anorectic drugs available at the time (for example, phentermine, dexamfetamine, mazindol and amfepramone [diethylpropion]). Moreover, the studies involved treatment over periods of 12 weeks or less and were small scale (participant numbers in each condition were frequently <30). The level of fenfluramine-induced weight loss reported in these studies depended on the dose of fenfluramine given, the duration of the trial, the additional dietary advice/regimen given to the participants and the differences between the target population included in each of these trials, and inevitably varied between 1.2 and 11.9kg. Despite this variation, fenfluramine-induced weight loss was shown to be a robust clinical effect. Of the 14 trials of fenfluramine to meet inclusion criteria from Haddock and colleagues[118] metaanalysis, an average of 5.06kg weight loss (placebo subtracted = 2.41kg) was produced by the drug. The
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data were obtained from studies which varied in dosage (from 39 to 120 mg/day), duration (the longest trial was just 18 weeks, average trial length was only 9.7 weeks), dietary advice, participant numbers (the maximum number of participants in the fenfluramine groups of the included trials was 58, with an average of just 20) and other characteristics.
7.2 Dexfenfluramine

The European INDEX (INternational DEXfenfluramine) trial was a key study of the clinical efficacy of dexfenfluramine.[120] INDEX was a multicentre, randomised, double-blind, placebo-controlled trial carried out with 822 obese volunteers. Of these, 404 individuals received dexfenfluramine 15mg twice daily and the remaining participants received placebo. After 12 months, of the participants to complete the study, 52% of those receiving dexfenfluramine had lost 10% or more of their initial bodyweight compared with only 30% of those receiving placebo. Average weight loss from baseline with dexfenfluramine during this trial was 9.82kg (10.26%), a figure significantly greater than that achieved with placebo (7.15kg; 7.18%). Interestingly, withdrawal from dexfenfluramine following completion of the 12-month INDEX trial led to an immediate rise in daily energy consumption which was accompanied by rapid weight gain over a 2-month period.[121] This appears to suggest that despite weight loss stopping after 6 months, dexfenfluramine had maintained a strong influence over food intake for the entire 12-month period. The drug had reduced both self-reported hunger and bodyweight to a point of physiological resistance at which equilibrium had been reached between hunger urges and drug anorectic activity. After the drug withdrawal at 12 months, the rebound in hunger demonstrated a lack of tolerance to the hypophagic effects of dexfenfluramine. Despite the reduction in food intake being predominantly in the first 6 months, dexfenfluramine maintained an energy in 2007 Adis Data Information BV. All rights reserved.

take reduction of 610% over the year-long study period.[121] Dexfenfluramine has also been shown to inhibit human food intake and weight regain after treatment with a very low calorie diet (VLCD). A VLCD was used in a study by Finer et al.[122] to reduce weight in the obese by 14kg in 8 weeks. After adherence to a diet and such rapid weight loss, there is often a strong disposition to resume overeating and regain the weight lost. In this study, following termination of the 8-week VLCD, patients given dexfenfluramine 15mg twice daily for 26 weeks continued to lose weight. Compared with the placebo group, who regained an average of 2.9kg, the dexfenfluramine group lost an additional 5.8kg, bringing total weight loss to 21.3kg over the entire 34 weeks of the study. Therefore, in this study,[122] dexfenfluramine overcame the physiological and psychological drive to eat following rapid, substantial weight loss. Returning to Haddock and colleagues[118] metaanalysis, of the 14 trials to meet inclusion criteria, average dexfenfluramine-induced weight loss from baseline was 8.9kg. For any anti-obesity drug included within their analysis, this is the largest average effect observed. In part, this could be attributable to the longer trial length (an average of 33 weeks) in a majority of the dexfenfluramine studies analysed and also the successful lifestyle interventions. Despite these factors, the average placebosubtracted weight loss produced by dexfenfluramine was equal to or greater than that with any other drug, including current obesity treatments such as orlistat and sibutramine. These meta-analyses did not include dexfenfluramine, but Haddock et al.[118] did find exfenfluramine-induced weight loss to be in line with that from sibutramine and orlistat.
7.3 Sibutramine

The STORM (Sibutramine Trial of Obesity Reduction and Maintenance) trial demonstrated the
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clinical efficacy of the SNRI sibutramine. Obese patients were prescribed sibutramine 10 mg/day in addition to a low calorie diet over 6 months and lost 11.3kg in this randomised, double-blind trial.[123] Following this open-label run-in period, the diet phase ended and patients were entered into an 18-month randomised, double-blind, placebo-controlled study. Within this study, participants were randomly allocated to either placebo or sibutramine (10 mg/day). Of the group to be maintained on sibutramine for 18 months, there was little weight regain observed (bodyweight gain at study end was 9.3kg lower than at pre-run-in baseline 24 months previously). In contrast, those in the placebo group appeared to begin regaining weight within 2 months of entering the trial phase. Although weight loss was not observed after the first 6 months, there was little indication of any tolerance developing to sibutramine over the 24 months of treatment. A number of other 1- and 2-year studies have demonstrated the weight loss-inducing efficacy of sibutramine.[124-127] Irrespective of variation in specific protocol or patient populations (for example, diabetic or non-diabetic, hypertensive, etc.), when examining data from these studies conducted over a year or more, it is again evident that the dynamic phase of sibutramine-induced weight loss occurs within the first 6 months of treatment. Following this period, sibutramine stabilises bodyweight at a level significantly lower than at the pretreatment point (i.e. baseline). Sibutramine has produced a placebo-subtracted weight loss of 4.45 or 4.3kg, as shown by two metaanalyses of clinical data.[128,129]
7.4 Selective Serotonin Reuptake Inhibitors

analysis of 11 fluoxetine trials demonstrates that an average bodyweight reduction from baseline of 4.1kg (3.3kg placebo subtracted) was achieved by this drug. However, following the trajectory of fluoxetineinduced weight loss after a 6-month period shows that the drugs effects are not sustained.[131] Early in the trial, participants treated with fluoxetine displayed significant weight loss (at week 24, maximum weight loss of approximately 4.9kg) and even by the end of the 60-week trial weight loss was still significantly greater in the fluoxetine group than in the placebo group. However, at week 60 those receiving placebo had lost 1.5kg and those receiving fluoxetine just 2.2kg. As had been noted in previous, smaller-scale, 1-year trials and in analysis of subsets of these data, both groups were seen to begin regaining weight halfway through the study.[132,133] There is little evidence to date that any other SSRI would be any more efficacious. For example, sertraline, in contrast to dexfenfluramine, appears to be ineffective at preventing weight regain after a brief period of VLCD.[91] However, early reports on the effects of another serotonin reuptake inhibitor, zimeldine have been interesting. One study has demonstrated that 8 weeks treatment with zimelidine (100mg twice daily) can produce significant placebo-subtracted weight loss, an effect associated with a significant reduction in appetite ratings.[134] It should be noted that while most psychiatric medications produce pronounced weight gain (including lithium, tricyclic antidepressants and antipsychotic medication) and, moreover, that many of the untreated psychiatric population are also liable to gain weight, the evidence for SSRI-induced weight gain in the SSRI-treated psychiatric population is inconsistent. This appears consistent with the reported weight loss-inducing effects of SSRIs in non-psychiatric populations. It is necessary to fully re-examine the weight loss-inducing effects of currently known SSDrugs 2007; 67 (1)

In terms of anti-obesity properties, the most comprehensively studied SSRI is fluoxetine. Early clinical studies, of 68 weeks in duration, suggested that treatment with fluoxetine was able to produce weight loss of 0.5kg (on average) per week.[130] Accordingly, Haddock and colleagues[118] meta 2007 Adis Data Information BV. All rights reserved.

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RIs and their active metabolites, as this may produce suitable candidates for a new anti-obesity drug.
7.5 Serotonin Precursors and Receptor Agonists

8. Current and Future Serotonergic Anti-Obesity Drugs Dexfenfluramine was voluntarily withdrawn in 1997 because of the risk of primary pulmonary hypertension, a move which dealt a blow to the development of serotonergic anti-obesity compounds.[137] The heart valve abnormalities discovered in a few patients in the postmarketing period led to the very rapid withdrawal of this drug.[138,139] Subsequently, the SNRI sibutramine was approved for the treatment of obesity. It has been suggested that sibutramine reduces weight by inducing both satiety and thermogenesis. It has been difficult to demonstrate the latter effect in humans. Studies quoted in this review suggest that the primary action of sibutramine is on satiety in humans; therefore, it is likely that despite what the limited preclinical data suggest, this effect is mediated by serotonin activation. Without doubt, the effects of sibutramine on rodent feeding behaviour and human appetite are indistinguishable from those of dexfenfluramine, fluoxetine and the preferential and selective 5-HT2C agonists. There have been adverse effect issues associated with sibutramine itself, which are currently under investigation. As a consequence, the focus from pharmaceutical companies has been on developing 5-HT2C receptor agonists. This is partially because of the increasing evidence that this receptor subtype was critical to the dexfenfluramine mechanism of action but also because these receptors are not thought to be widely distributed outside the CNS so any issue of primary pulmonary hypertension is avoided.[2] Numerous selective 5-HT2C receptor agonists have been developed including Org 12962 from Organon, Ro 600175 from Roche and Vernalis, VER-3323 from Vernalis, BVT-933 from Biovitrum and GlaxoSmithKline and YM348 from Yamanouchi Pharmaceuticals.[2] Some of the compounds have passed into phase I and (in the case of BVT-933) phase II trials; it is regrettable that their effects on
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Currently, no large-scale clinical trial data exist on the effects of serotonin precursors or receptor agonists on weight loss in the obese. The previously mentioned studies by Cangiano et al.[81,96] have shown that 5-HTP can induce weight loss for up to 12 weeks in the obese (6% reduction in initial body mass). In addition, the preferential 5-HT2C receptor agonist mCPP has been shown to induce weight loss over a 2-week period in the obese.[93] Several selective 5-HT2C receptor agonists have reached or are about to reach phase II clinical trials, the data from which have not been made widely available, although some have been presented. For example, details have been provided on the efficacy of Org 12962, a 5-HT2C receptor agonist. The effects of Org 12962 (10mg twice daily) were studied in 40 obese participants over a 12-week study.[135] Participants treated with Org 12962 lost 13.7kg (14%) of their initial body mass. However, this study presented a strikingly large placebo effect, as those in the placebo group lost the same proportion of weight during the treatment period. There was no detailing of the effects of drug treatment on appetite. Interestingly, compliance to Org 12962 appeared to increase towards the end of the treatment phase compared with placebo. Org 12962 treatment seemed to help the participants adhere to the rigorous but effective weight loss measures that had been prescribed to all participants in this study, which could be attributable to the agonists efficacy at suppressing the hunger increases caused by dieting. As a consequence, it would have been interesting to examine if extending the trial would have shown the continued appetite modulation of Org 12962 to translate into a significantly greater weight loss than that seen in the placebo group.[136]
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human appetite, food intake and bodyweight remain largely unknown. One issue may have been drug affinity to serotonin receptors other than 5-HT2C, causing adverse effects during the clinical trial studies. However, lorcaserin (Arena Pharmaceuticals) is known to be currently undergoing clinical trials[140-142] and, according to the company, in a phase Ia study the drug significantly reduced meal size. A single 10mg dose produced a statistically significant 10.7% (122.5 kcal) mean reduction in meal size relative to placebo. The drug also completed a phase Ib safety dose-escalation study, and no effect on heart valves or pulmonary artery pressure was observed, so phase II trials were carried out in 2005. The results of these, again according to the company, are promising.[140] In phase IIa trials, a 15mg daily dose produced a statistically significant mean weight loss of 1.3kg (compared with 0.4kg in the placebo group) over a 28-day treatment period.[142] Recently, results of the phase IIb trials have also been published, showing that treatment with lorcaserin was associated with a highly significant average weight loss of 1.8, 2.6 and 3.6kg at daily doses of 10, 15 and 20mg, respectively, over the 12-week treatment period. In comparison, those in the placebo group lost just 0.3kg in that time. This drug is expected, funding permitted, to enter phase III clinical trials in the second half of 2006. The structure of lorcaserin is undisclosed, but it is likely to have come from a series of novel 3-benzazepine derivatives.[141] Halford et al.[143] described the ideal attributes of any appetite suppressant anti-obesity drug in 2003. An ultimate appetite suppressant anti-obesity drug should ideally:

reduce meal size and the number of betweenmeal eating episodes while the patient experiences greater and longer-lasting satisfaction for those still remaining selectively reduce the intake of energy-dense high-fat foods most associated with obesity and ill health (those generally being snack and socalled convenience foods). All future serotonergic drugs should be measured by these criteria, above and beyond those for antiobesity drugs in general. Furthermore, in order to make a sizeable impact on the market, any drug will need to produce placebo-subtracted weight loss over 1 year that is greater than that currently produced by anti-obesity drugs orlistat (less than 4kg) and sibutramine (over 4kg), and that reported to be produced by novel anti-obesity agent rimonabant (approximately 56kg).[144] 9. Novel Serotonergic Targets for Weight Control While most of the focus on serotonin and weight control has been on drugs agonising the 5-HT2C receptor, other targets in the serotonin system exist. The 5-HT6 receptor is one of the most recent additions to the serotonin receptor family. It is almost exclusively expressed within the CNS with high levels in cortical and limbic regions.[145] The recent development of specific 5-HT6 receptor ligands has indicated potential roles for this receptor in a number of physiological processes, including feeding.[146] Selective 5-HT6 receptor antagonists have been reported to produce significant reductions in food intake when administered to ob/ob mice, with these hypophagic effects being accompanied by significant reductions in bodyweight and insulin levels.[147] Such results identify 5-HT6 receptor antagonists as potential anti-obesity agents. Notably a number of companies have recently indicated they have preclinical 5-HT6 receptor-based anti-obesity drug development programmes and presumably a
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reliably alter feeding behaviour and food choice to produce a reduction in caloric intake sustaining the period of weight loss enable the establishment of healthier eating patterns

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number of suitable 5-HT6 receptor antagonists now exist. 5-HT6 antagonists such as PRX-08034 (Epix Pharmaceuticals) and BVT 74316 (Biovitrum AB) have recently entered clinical trials.[148,149] 10. Summary Anti-obesity treatments have targeted and will continue to target the endogenous serotonin satiety system. As levels of endogenous serotonin respond to both deprivation and energy excess, and a reduced caloric intake lowers CNS serotonin levels and turnover, serotonin appears to play a key role in appetite. Moreover, susceptibility to weight gain in both rodents and humans may be attributable to low levels of endogenous serotonin and serotonin dysfunction. The hypothalamic serotonin satiety system is known to interact with orexigenic systems such as orexin and NPY. Serotonin may inhibit feeding behaviour by, among other means, blocking these hunger signals. In addition, the hypophagic effects of serotonergic drugs appear to be mediated by the anorexigenic melanocortin system. Therefore, as an episodic satiety transmitter, serotonin (like the tonic adiposity signal leptin) influences feeding behaviour via both stimulatory and inhibitory effects on several regulatory neuropeptide systems in the hypothalamus. Drugs that either directly or indirectly stimulate hypothalamic 5-HT2C receptors in rodents produce both changes in the structure of feeding behaviour and reductions in food intake that are consistent with the satiety process. These drugs cause an enhancement of the post-meal satiety potency of fixed caloric loads and reduce pre-meal appetite and food intake at ad libitum meals in both lean and obese humans. Reductions in bodyweight gain and decreases in bodyweight from baseline are strongly associated with the hypophagic action of these drugs in both rodent dietary-induced obesity models and human clinical trials. Moreover, antagonism of 5-HT6 receptors also appears to reduce food intake
2007 Adis Data Information BV. All rights reserved.

and block weight gain in rodents. Whether druginduced hypophagia and associated effects on weight are due to selective action on appetite is unclear. A new generation of selective 5-HT2C receptor agonists have been developed and some have passed into clinical testing. The selectivity of these compounds should ensure that they avoid the adverse effects associated with their predecessors. However, it is essential that these new drugs produce marked effects on appetite and feeding behaviour, and are able to induce substantial and sustained hypophagia that is sufficient to produce clinically significant weight loss. When assessing the effects of these drugs, it is important to examine not just kilocalorie or gram reduction in intake, but also observed changes in appetite (such as hunger, prospective consumption, fullness, etc.) and feeding behaviour (eating rate, meal size, daily meal and snack number). As obesity is known to be linked to the consumption of highly palatable, energy-dense foods (high in fat and/or sugar) it is necessary to establish how a drug modifies the type of food chosen in terms of energy density, macronutrient composition and palatability. Any drug able to reduce the liking for or the wanting of highly palatable foods that are known to promote overconsumption and weight gain is likely to be of significant therapeutic value. There are also a number of non-serotonergic treatments undergoing clinical trials. Many of these are also entering phase II studies or preparing for phase III trials.[150] Ultimately, it is against these drugs, as well as existing treatments, that the efficacy of any serotonin-targeted anti-obesity treatment will be judged. Acknowledgements
The authors would like to thank Miss Lisa D.M. Richards for her help in preparing this manuscript and Dr Steve Vickers (RenaSci Consultancy Ltd) for providing much useful material for inclusion within this review. The authors would like in particular to thank Lora Heisler (University of Cam-

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bridge), Joel Elmquist (Harvard Medical School) and Michael Cowley (Oregon Health Sciences University) for providing updates on their most recent research and allowing us to reproduce their figure. The website for the Kissileff Laboratory is http://www.liv.ac.uk/Psychology/kissilefflab/ Home.html. The laboratory would like to thank corporate donors GlaxoSmithKline, NJ, USA, for providing funds for postgraduate training. Drs Harrold and Halford have received research funding from Predix Pharmaceuticals. Professor Blundell and Dr Halford have received research funding from SanofiAventis.

16. 17.

18.

19.

20. 21.

References
1. Halford JCG, Blundell JE. Separate systems for serotonin and leptin in appetite control. Ann Med 2000; 32: 222-32 2. Vickers SP, Dourish CT. Serotonin receptor ligands and the treatment of obesity. Curr Opin Invest Drugs 2004; 5: 377-88 3. Bentley JM, Adams DR, Bebbington D. Indoline derivatives as 5-HT2C receptor agonists. Bioorg Med Chem Let 2004; 14: 2367-70 4. Bray GA, York DA. Studies on food intake of genetically obese rats. Am J Physiol 1972; 233: 176-9 5. Jesperson S, Scheel-Kruger J. Evidence for a difference in mechanism of action between fenfluramine- and amphetamine-induced anorexia. J Pharm Pharmacol 1973; 22: 637-8 6. Barrett AM, McSherry L. Inhibition of drug-induced anorexia in rats by methysergide. J Pharm Pharmacol 1975; 27: 889-95 7. Pinder BM, Brogden RN, Sawyer PR, et al. Fenfluramine: a review of its pharmacological properties and therapeutic efficacy in obesity. Drugs 1975; 10: 241-323 8. Garattini S, Samanin R. Anorectic drugs and brain neurotransmitters. In: Silverstone T, editor. Food intake and appetite. Berlin: Dahlem Konferenzen, 1976: 82-208 9. MacKenzie RG, Hoebel BG, Ducret RP, et al. Hyperphagia following intraventricular p-chlorophenylalanine-, leucine- or tryptophan-methyl esters: lack of correlation with whole brain serotonin levels. Pharmacol Biochem Behav 1979; 10: 951-5 10. Blundell JE. Is there a role for serotonin (5-hydroxytryptamine) in feeding? Int J Obesity 1977; 1: 15-42 11. Hoyer D, Martin G. 5-HT receptor classification and nomenclature: towards a harmonization with the human genome. Neuropharmacology 1997; 36: 419-28 12. Blundell JE, Halford JCG. Serotonin and appetite regulation: implications for the treatment of obesity. CNS Drugs 1998; 9: 473-95 13. Rogers P, McKibbin PE, Williams G. Acute fenfluramine administration reduces neuropeptide Y concentrations in specific hypothalamic regions of the rat: possible implications for the anorectic effect of fenfluramine. Peptides 1991; 12: 251-5 14. Brown CM, Coscina DV. Ineffectiveness of hypothalamic serotonin to block neuropeptide Y-induced feeding. Pharmacol Biochem Behav 1995; 51: 641-6 15. Compan V, Dusticier N, Nieoullon A, et al. Opposite changes in striatal neuropeptide Y immunoreactivity after partial and 22.

23.

24.

25.

26.

27.

28. 29.

30.

31.

32.

33.

34.

complete serotonergic depletion in the rat. Synapse 1996; 24: 87-96 Currie PJ. Integration of hypothalamic feeding and metabolic signals: focus on neuropeptide Y. Appetite 2003; 41: 335-7 Heisler LK, Cowley MA, Tecott LH, et al. Activation of central melanocortin pathways by fenfluramine. Science 2002; 297: 609-11 Heisler LK, Cowley MA, Kishi T, et al. Central serotonin and melanocortin pathways regulating energy homeostasis. N Y Acad Sci 2003; 994: 169-74 Heisler LK, Jobst EE, Sutton GM, et al. Serotonin reciprocally regulated melanocortin neurons to modulate food intake. Neuron 2006; 51: 239-49 Nambu T, Sakurai T, Mizukami K, et al. Distribution of orexin neurons in the adult rat brain. Brain Res 1999; 827: 243-60 Hervieu GJ, Cluderay JE, Harrison DC, et al. Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord. Neuroscience 2001; 103: 777-97 Marcus JN, Aschkenasim CJ, Lee CE, et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 2001; 435: 6-25 Brown RE, Sergeeva OA, Eriksson KS, et al. Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline). J Neurosci 2002; 22: 8850-9 Cai XJ, Liu XH, Evans M, et al. Orexins and feeding: special occasions or everyday occurrence? Reg Peptides 2002; 104: 19 Orlando G, Brunetti Ll, Di Nisio C, et al. Effects of cocaine- and amphetamine-regulated transcript peptide, leptin and orexins on hypothalamic serotonin release. Eur J Pharmacol 2001; 430: 269-72 Matsuzaki I, Sakurai T, Kunii K, et al. Involvement of the serotonergic system in orexin-induced behavioral alterations in rats. Reg Peptides 2002; 104: 119-23 Brown RE, Sergeeva O, Eriksson KS, et al. Orexin A excites serotonergic neurons in the dorsal raphe nucleus of the rat. Neuropharmacology 2001; 40: 457-9 Simansky KJ. Serotoninergic control of the organisation of feeding and satiety. Behav Brain Res 1996; 73: 37-42 Hewitt KN, Lee MD, Dourish CT, et al. Serotonin 2C receptor agonists and the behavioural satiety sequence in mice. Pharmacol Biochem Behav 2002; 71: 691-700 Collin M, Backberg M, Onnestam K, et al. 5-HT1A receptor immunoreactivity in hypothalamic neurons involved in body weight control. Neuroreport 2002; 13: 945-51 Muraki Y, Yamanaka A, Tsujino N, et al. Serotonergic regulation of the orexin/hypocretin neurons through the 5-HT1A receptor. J Neurosci 2004; 24: 7159-66 Barrafan-Majia MG, Castilla-Serna L, Calderon-Guzman D, et al. Effect of nutritional status and ozone exposure on rat brain serotonin. Arch Med Res 2002; 33: 15-9 Xie QW. Experimental studies on changes of neuroendocrine functions during starvation and refeeding. Neuroendocrinology 1991; 53: 52-9 Nishimura F, Nishihara M, Torii K, et al. Changes in responsiveness to serotonin on rat ventromedial hypothalamic neurons after food deprivation. Physiol Behav 1996; 60: 7-12

2007 Adis Data Information BV. All rights reserved.

Drugs 2007; 67 (1)

52

Halford et al.

35. Wolfe BW, Metzger ED, Stollar C. The effects of dieting on plasma tryptophan concentration and food intake in healthy women. Physiol Behav 1997; 61: 537-41 36. Cowen PJ, Clifford EM, Walsh AES, et al. Moderate dieting causes 5-HT2C supersensitization. Psychol Med 1996; 26: 1156-9 37. Varma M, Torelli GF, Meguid MM, et al. Potential strategies for ameliorating early cancer anorexia. J Surg Res 1998; 81: 69-76 38. Yang ZJ, Blaha V, Meguid MM, et al. Interleukin-1 injection into ventromedial hypothalamic nucleus of normal rats depresses food intake and increases release of dopamine and serotonin. Pharmacol Biochem Behav 1999; 62: 61-5 39. Cangiano C, Laviano A, Muscaritoli M, et al. Cancer anorexia: new pathogenic and therapeutic insights. Nutrition 1996; 12: S48-51 40. Cangiano C, Testa U, Muscaritoli M, et al. Cytokines, tryptophan and anorexia in cancer patients before and after surgical tumor ablation. Anticancer Res 1994; 14: 1451-5 41. Meguid MM, Fetissov SO, Blaha V, et al. Dopamine and serotonin VMN release is related to feeding status in obese and lean Zucker rats. Neuroreport 2000; 11: 2069-72 42. Svec F, Thompson H, Porter J. Levels of hypothalamic neurotransmitters in lean and obese Zucker rats. Nutr Neurosci 2002; 5: 321-6 43. Harrold JA, Widdowson PS, Clapham JC, et al. Individual severity of dietary obesity in unselected Wistar rats: relationship with hyperphagia. Am J Physiol 2000; 279: E340-7 44. Hassanain M, Levin BE. Dysregulation of hypothalamic serotonin turnover in diet-induced obese rats. Brain Res 2002; 929: 175-80 45. Breum L, Rasmussen MH, Hilsted J. Twenty-fourhour plasma tryptophan concentrations and ratios are below normal in obese subjects and are not normalized by substantial weight reduction. Am J Clin Nutr 2003; 77: 1112-8 46. Clifton PG. The neuropharmacology of meal patterning. In: Cooper SJ, editor. Ethology and psychopharmacology. Chichester: Wiley, 1994: 313-28 47. Neill JC, Cooper SJ. Evidence that d-fenfluramine anorexia is mediated by 5-HT1 receptors. Psychopharmacology 1989; 97: 213-8 48. Samanin R, Mennini T, Bendotti C, et al. Evidence that central 5-HT2C receptors do not play an important role in anorectic activity of d-fenfluramine in the rat. Neuropharmacology 1989; 28: 465-9 49. Neill JC, Bendotti C, Samanin R. Studies on the role of 5-HT receptors in satiation and the effect of d-fenfluramine in the runway test. Eur J Pharmacol 1990; 190: 105-12 50. Simansky JJ, Nicklous DM. Parabrachial infusion of -fenfluramine reduces food intake: blockade by the 5-HT1B antagonist SB-216641. Pharmacol Biochem Behav 2002; 71: 68190 51. Vickers SP, Dourish CT, Kennett GA. Evidence that hypophagia induced by d-fenfluramine and d-norfenfluramine in the rat is mediated by 5-HT2C receptors. Neuropharmacology 2001; 41: 200-9 52. Wong DT, Reid LR, Threlkeld PG. Suppression of food intake in rats by fluoxetine: comparison of enantiomers and effects of

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

serotonin antagonists. Pharmacol Biochem Behav 1988; 31: 475-9 Grignaschi G, Samanin R. Role of serotonin and catecholamines in brain in feeding suppressant effects of fluoxetine. Neuropharmacology 1992; 31: 445-9 Lightowler S, Wood M, Brown T, et al. An investigation of the mechanism responsible for fluoxetine-induced hypophagia in rats. Eur J Pharmacol 1996; 296: 137-43 Lee MD, Clifton PG. Partial reversal of fluoxetine anorexia by the 5-HT antagonist metergoline. Psychopharmacology 1992; 107: 359-64 Halford JCG, Blundell JE. Metergoline antagonizes fluoxetine induced suppression of food intake but not changes in the behavioural satiety sequence. Pharmacol Biochem Behav 1996; 54: 745-51 Koe BK, Weissman A, Welch WM, et al. Sertraline, 1S,4S-Nmethyl-4(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphathylamine, a new uptake inhibitor with selectivity for serotonin. J Pharmacol Exp Ther 1983; 266: 686-700 Lucki I, Kreider MS, Simansky KJ. Reduction of feeding behaviour by the serotonin uptake inhibitor sertraline. Psychopharmacology 1988; 96: 289-95 Kennett GA, Curzon G. Evidence that the hypophagia induced by mCPP and TFMPP requires 5-HT1C and 5-HT1B receptors; hypophagia induced by RU-24969 only requires 5-HT1B receptors. Psychopharmacology 1988; 96: 93-100 Kennett GA, Curzon G. Evidence that mCPP may have behavioural effects mediated by central 5-HT1C receptors. Br J Pharmacol 1988; 94: 137-47 Kennett GA, Curzon G. Potencies of antagonists indicate that 5HT1C receptors mediate 1-3(chlorophenyl)piperazine-induced hypophagia. Br J Pharmacol 1991; 10: 2016-20 Halford JCG, Blundell JE. The 5-HT1B receptor agonist CP94,253 reduces food intake and preserves the behavioural satiety sequence. Physiol Behav 1996; 60: 933-9 Lee MD, Simansky KJ. CP-94,253: a selective serotonin1B (5HT1B) agonist that promotes satiety. Psychopharmacology 1997; 131: 264-70 Schreiber R, Selbach K, Asmussen M, et al. Effects of serotonin1/2 receptor agonists on dark-phase food and water intake in rats. Pharmacol Biochem Behav 2000; 67: 291-305 Clifton PG, Lee MD, Dourish CT. Similarities in the action of Ro 60-0175, a 5-HT2C receptor agonist, and d-fenfluramine on feeding patterns in the rat. Psychopharmacology 2000; 152: 256-67 Lee MD, Kennett GA, Dourish CT, et al. 5-HT1B receptors modulate components of satiety in the rat: behavioural and pharmacological analyses of the selective serotonin1B agonist CP-94,253. Psychopharmacology 2002; 164: 49-60 Blundell JE, Latham CJ. Pharmacological manipulation of feeding behaviour: possible influences of serotonin and dopamine on food intake. In: Garattini S, Samanin R, editors. Central mechanisms of anorectic drugs. New York (NY): Raven Press, 1978: 83-109 Halford JCG, Wanninayake SCD, Blundell JE. Behavioural satiety sequence (BSS) for the diagnosis of drug action on food intake. Pharmacol Biochem Behav 1998; 61: 159-68

2007 Adis Data Information BV. All rights reserved.

Drugs 2007; 67 (1)

Serotonergic Drugs in Obesity

53

69. Blundell JE, Latham CJ. Characteristic adjustments to the structure of feeding behaviour following pharmacological treatments: effects of amphetamine and fenfluramine and the antagonism by pimozide and metergoline. Pharmacol Biochem Behav 1980; 12: 717-22 70. Blundell JE, McArthur RA. Behavioural flux and feeding: continuous monitoring of food intake and food selection, and the video-recording of appetitive and satiety sequences for the analysis of drug action. In: Samanin R, Garattini S, editors. Anorectic agents: mechanisms of action and tolerance. New York (NY): Raven Press, 1981: 19-43 71. Halford JCG, Blundell JE. 5-Hydroxytryptaminergic drugs compared on the behavioural sequence associated with satiety. Br J Pharmacol 1993; 100: 95 72. Clifton PG, Barnfield AMC, Philcox L. A behavioural profile of fluoxetine induced anorexia. Psychopharmacology 1989; 97: 89-95 73. Simansky KJ, Viadya AH. Behavioural mechanisms for the anorectic actions of the serotonin (5-HT) uptake inhibitor sertraline in rats: comparison with directly acting agonists. Brain Res Bull 1990; 25: 953-60 74. McGuirk J, Muscat R, Willner P. Effects of the 5-HT uptake inhibitors femoxetine and parpexetine, and the 5-HT1A agonist cltoprazine, on the behavioural satiety sequence. Pharmacol Biochem Behav 1992; 41: 801-5 75. Kitchener SJ, Dourish CT. An examination of the behavioural specificity of hypophagia induced by 5-HT1B, 5-HT1C and 5HT2 receptor agonists using the post-prandial sequence in rats. Psychopharmacology 1994; 113: 368-77 76. Tecott LH, Sun LM, Akanna SF, et al. Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature 1995; 374: 542-6 77. Nonogaki K, Abdullah L, Goulding EH, et al. Hyperactivity and reduced energy cost of physical activity in serotonin 5-HT2C receptor mutant mice. Diabetes 2003; 52: 315-20 78. Vickers SP, Clifton PG, Dourish CT, et al. Reduced satiating effect of d-fenfluramine in serotonin 5-HT2C receptor mutant mice. Psychopharmacology 1999; 143: 309-14 79. Bouwknecht JA, van der Guten J, Hijsenm TH, et al. Male and female 5-HT1B receptor knockout mice have higher body weights than wildtypes. Physiol Behav 2001; 74: 507-16 80. Silverstone T, Goodall E. The clinical pharmacology of appetite suppressant drugs. Int J Obes 1984; 8 (1): 23-33 81. Cangiano C, Ceci F, Casinco A, et al. Eating behaviour and adherence to dietary prescription in obese adult subjects treated with 5-hydroxytryptophan. Am J Clin Nutr 1992; 56: 863-7 82. Rogers PJ, Blundell JE. Effect of anorexic drugs on food intake and the micro-structure of eating in human subjects. Psychopharmacology 1979; 66: 159-65 83. Hill AJ, Blundell JE. Sensitivity of the appetite control system in obese subjects to nutritional and serotoninergic challenges. Int J Obesity 1990; 14: 219-33 84. Wurtman JJ, Wurtman RJ, Growdon JH, et al. Carbohydrate craving in obese people: suppression by treatments affecting serotonergic transmission. Int J Eat Disord 1982; 1: 2-15 85. Wurtman JJ, Wurtman RJ, Mark S, et al. d-Fenfluramine selectively suppresses carbohydrate snacking in obese subjects. Int J Eat Disord 1985; 4: 89-99

86. Goodall E, Silverstone T. Differential effect of d-fenfluramine and metergoline on food intake in human subjects. Appetite 1988; 11: 215-88 87. Blundell JE, Hill AJ. On the mechanism of action of dexfenfluramine: effect on alliesthesia and appetite motivation in lean and obese subjects. Clin Neuropharmacol 1988; 11 Suppl. 1: 121-34S 88. Goodall EM, Cowen PJ, Franklin M, et al. Ritanserin attenuates anorectic endocrine and thermic responses to d-fenfluramine in human volunteers. Psychopharmacology 1993; 112: 461-6 89. McGuirk J, Silverstone T. The effect of 5-HT re-uptake inhibitor fluoxetine on food intake and body weight in healthy male subjects. Int J Obesity 1990; 14: 361-72 90. Lawton CL, Wales JK, Hill AJ, et al. Serotoninergic manipulation, meal-induced satiety and eating patterns: effects of fluoxetine in obese female subjects. Obes Res 1995; 3: 345-56 91. Wadden TA, Bartlet SJ, Foster GD, et al. Sertraline and relapse prevention following treatment by a very low calorie diet: a controlled clinical trial. Obes Res 1995; 3: 549-57 92. Walsh AE, Smith KA, Oldman AD. m-Chlorophenylpiperazine decreases food intake in a test meal. Psychopharmacology 1994; 116: 120-2 93. Sargent PA, Sharpley AL, Williams C, et al. 5-HT2C receptor activation decreases appetite and body weight in obese subjects. Psychopharmacology 1997; 133: 309-12 94. Boeles S, Williams C, Campling GM, et al. Sumatriptan decreases food intake and increases plasma growth hormone in healthy women. Psychopharmacology 1997; 129 (Pt 2): 17982 95. Rolls BJ, Shide DJ, Thorward ML, et al. Sibutramine reduces food intake in non-dieting women with obesity. Obes Res 1998; 6: 1-11 96. Cangiano C, Laviano A, Del Ben M, et al. Effects of oral 5hydroxy-tryptophan on energy intake and macronutrient selection in non-insulin dependent diabetic patients. Int J Obesity 1988; 22: 648-54 97. Foltin RW, Haney M, Comer S, et al. Effect of fenfluramine on food intake, mood, and performance of humans living in a residential laboratory. Physiol Behav 1996a; 59: 295-305 98. Drent ML, Zelissen PMJ, Kopperchaar HPF, et al. The effect of dexfenfluramine on eating habits in a Dutch ambulatory android overweight population with an overconsumption of snacks. Int J Obesity 1995; 19: 299-304 99. Pijl H, Koppeschaar HPF, Willekens FLA, et al. Effect of serotonin re-uptake inhibition by fluoxetine on body weight and spontaneous food choice in obesity. Int J Obesity 1991; 15: 237-42 100. Ward AS, Comer SD, Haney M, et al. Fluoxetine-maintained obese humans: effect on food intake and body weight. Physiol Behav 1999; 66: 815-21 101. Chapelot D, Mamonier C, Thomas F, et al. Modalities of the food intake-reducing effect of sibutramine in humans. Physiol Behav 2000; 68: 299-308 102. Hansen DL, Toubro S, Stock MJ, et al. Thermogenic effects of sibutramine in humans. Am J Clin Nutr 1998; 68: 1180-6 103. Hansen DL, Toubro S, Stock MJ, et al. The effect of sibutramine on energy expenditure and appetite during chronic treatment without dietary restriction. Int J Obesity 1999; 23: 1016-24

2007 Adis Data Information BV. All rights reserved.

Drugs 2007; 67 (1)

54

Halford et al.

104. Barkeling B, Elfhag K, Rooth P, et al. Short-term effects of sibutramine (Reductil) on appetite and eating behaviour and the long-term therapeutic outcome. Int J Obesity 2003; 27: 693-700 105. Cowen PJ, Sargent PA, Williams C, et al. Hypophagic, endocrine and subjective responses to m-chlorophenylpiperazine in healthy men and women. Hum Psychopharmacol 1995; 10: 385-91 106. Ghaziuddin N, Welch K, Greden J. Central serotonergic effects of m-chlorophenylpiperazine (mCPP) among normal control adolescents. Neuropsychopharmacology 2003; 28: 133-9 107. Fisler JS, Undernerger SJ, York DA, et al. d-Fenfluramine in a rat model of dietary fat-induced obesity. Pharmacol Biochem Behav 1993; 45: 487-93 108. Vickers SP, Benwell KR, Porter RH, et al. Comparative effects of continuous infusion of mCPP, Ro 60-0175 and d-fenfluramine on food intake, water intake, body weight and locomotor activity in rats. Br J Pharmacol 2000; 130: 1305-14 109. Vickers SP, Easton N, Webster LJ, et al. Oral administration of the 5-HT2C receptor agonist, mCPP, reduces body weight gain in rats over 28 days as a result of maintained hypophagia. Psychopharmacology 2003; 167: 274-80 110. Yen TT, Wong DT, Bemis KG. Reduction of food consumption and body weight of normal and obese mice by chronic treatment with fluoxetine: a serotonin reuptake inhibitor. Drug Dev Res 1987; 10: 37-45 111. Fuller RW, Wong DT. Fluoxetine: a serotonergic appetite suppressant drug. Drug Dev Res 1989; 17: 1-15 112. Nielsen JA, Chapin DS, Johson JL, et al. Sertraline, a serotoninuptake inhibitor, reduces food intake and body weight in lean rats and genetically obese mice. Am J Clin Nutr 1992; 55: 1858s 113. Wieczorek I, Schulz C, Jarry H, et al. The effects of the selective serotonin reuptake-inhibitor fluvoxamine on body weight in Zucker rats are mediated by corticotropin-releasing hormone. Int J Obesity 2001; 25: 1566-9 114. Konkle ATM, Sreter KB, Bajer SL, et al. Chronic paroxetine infusion influences macronutrient selection in male SpragueDawley rats. Pharmacol Biochem Behav 2003; 74: 883-90 115. Kennett GA, Wood MD, Bright F, et al. SB 242084, a selective and brain potent 5-HT2C receptor. Neuropharmacology 1997; 36: 609-20 116. Hayashi A, Sonoda R, Kimura Y, et al. Antiobesity effect of YM348, a novel 5-HT2C receptor agonist, in Zucker rats. Brain Res 2004; 1011: 221-7 117. Bjenning C, Williams J, Whelan K, et al. Chronic oral administration of APD356 significantly reduces body weight and fat mass in obesity-prone (DIO) male and female rats. Int J Obesity 2004; 28 (1 Suppl.): 214s 118. Haddock CK, Poston WSC, Dill PL, et al. Pharmacotherapy for obesity: a quantitative analysis of four decades of published randomized clinical trials. Int J Obesity 2002; 26: 262-73 119. Pinder RM, Brogden RN, Sawyer PR, et al. Fenfluramine: a review of the pharmacological properties and therapeutic efficacy in obesity. Drugs 1975; 10: 241-323

120. Guy-Grand B, Apfelbaum M, Creoaldi C, et al. International trial of long-term dexfenfluramine in obesity. Lancet 1989; Nov 11: 1142-5 121. Guy-Grand B. Clinical studies with d-fenfluramine. Am J Clin Nutr 1992; 55: 173-6s 122. Finer N, Finer S, Naoumova RP. Drug therapy after very-lowcalorie-diets. Am J Clin Nutr 1992; 56: 195-8s 123. James WPT, Astrup A, Finer N, et al. Effect of sibutramine on weight maintenance after weight loss: a randomised trial. Lancet 2000; 356: 2119-25 124. McMahon FG, Fujioka K, Singh BN, et al. Efficacy and safety of sibutramine in obese white and African American patients with hypertension: a 1-year, double-blind, placebo-controlled, multicenter trial. Arch Intern Med 2000; 160: 2185-91 125. Smith IG, Goulder MA. Randomized placebo-controlled trial of long-term treatment with sibutramine in mild to moderate obesity. J Fam Pract 2001; 50: 505-12 126. McNulty SJ, Ur E, Williams G. A randomized trial of sibutramine in the management of obese type 2 diabetic patients treated with metformin. Diabetes Care 2003; 26: 125-33 127. Poston WSC, Reeves RS, Haddock CK, et al. Weight loss in obese Mexican Americans treated for 1-year with orlistat and lifestyle modification. Int J Obesity 2003; 27: 1486-93 128. Arterburn DE, Crane PK, Veenstra DL. The efficacy and safety of sibutramine for weight loss: a systematic review. Arch Intern Med 2004; 164: 994-1003 129. Padwal R, Li SK, Lau DCW. Long-term pharmacotherapy for overweight and obesity: a systematic review and meta-analysis of randomized controlled trials. Int J Obesity 2003; 27: 143746 130. Wise SD. Clinical studies with fluoxetine in obesity. Am J Clin Nutr 1992; 55: 181-4s 131. Goldstein DJ, Rampey AH, Roback PJ, et al. Efficacy and safety of long-term fluoxetine treatment of obesity -maximising success. Obes Res 1995; 3 Suppl. 4: 481-90s 132. Darga LL, Carroll-Michals C, Botsford SJ, et al. Fluoxetines effect on weight loss in obese subjects. Am J Clin Nutr 1991; 54: 315-21 133. Goldstein DJ, Rampey AH, Enas GG, et al. Fluoxetine: a randomized clinical trial in the treatment of obesity. Int J Obesity 1994; 18: 129-35 134. Simpson RJ, Lawton DJ, Watt MH, et al. Effect of zimelidine, a new antidepressant, on appetite and body weight. Br J Clin Pharmacol 1981; 11: 96-8 135. Van Baak M, Lentjes M, Mujakovic S, et al. Behavior modification and societal change in the prevention of obesity. Obes Res 2003; 11 (1 Suppl.): A111 136. Halford JCG. Serotonin (5-HT) drugs: effects on appetite expression and use for the treatment of obesity. Curr Drug Targets 2004; 5: 637-46 137. Abeniam L, Moride Y, Brenot F, et al. Appetite suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996; 335: 609-16 138. Greenway FL, Caruso MK. Safety of obesity drugs. Expert Opin Drug Saf. In press 139. Bays HE, Dujovene CA. Anti-obesity drug development. Expert Opin Invest Drugs 2002; 11: 1189-204

2007 Adis Data Information BV. All rights reserved.

Drugs 2007; 67 (1)

Serotonergic Drugs in Obesity

55

140. Bays HE. Current and investigational antiobesity agents and obesity therapeutic treatment targets. Obes Res 2004; 12: 1197-211 141. Smith BM, Smith JM, Tsai JH, et al. Discovery and SAR of new benzazapines and potent and selective 5-HT2C receptor agonist for the treatment of obesity. Bioorgan Med Chem Lett 2005; 12: 1467-70 142. Smith S, Anderson J, Frank A, et al. The effects of APD356, a selective 5-HT2C agonist, on weight loss in a 4 week study in healthy obese patients [Abstract]. Obes Res 2005; 13 Suppl.: 101-R 143. Halford JCG, Cooper GD, Dovey TM, et al. Pharmacological approaches to obesity treatment; current medical chemistry. CNS Agents 2003; 3: 283-310 144. Van Gaal LF, Rissanen AM, Scheen AJ, et al. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1year experience from the RIO-Europe study. Lancet 2005; 365: 1389-97 145. Woolley ML, Marsden CA, Fone KC. 5-HT6 receptors. Current drug targets: CNS Neurol Disord 2004; 3: 59-79 146. Vickers SP, Dourish CT. Serotonin receptor ligands and the treatment of obesity. Curr Opin Invest Drugs 2004; 5: 377-88

147. Shacham S, Marantz Y, Senderowitz H, et al. Novel 5-HT6 receptor antagonists for the treatment of obesity. Obes Res 2005; 13: A192 148. EPIX Pharmaceuticals. EPIX Pharmaceuticals announces findings from obesity and cognitive impairment studies at Society for Neuroscience Meeting [online]. Available from URL: http://investor.epixpharma.com/phoenix.zhtml?c=91717&p= irol-newsArticle&ID=917339&highlight [Accessed 2006 Nov 13] 149. Biovitrums project portfolio within obesity advances [online]. Available from URL: http://www.stockholmbioregion.com/ templates/page____517.aspx [Accessed 2006 Nov 13] 150. Halford JCG. Obesity drugs in clinical development. Curr Opin Invest Drugs 2006; 7: 312-8

Correspondence and offprints: Dr Jason C.G. Halford, School of Psychology, University of Liverpool, Liverpool, L69 7ZA, UK. E-mail: j.c.g.halford@liverpool.ac.uk

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Drugs 2007; 67 (1)

REVIEW ARTICLE

Drugs 2007; 67 (1): 57-73 0012-6667/07/0001-0057/$49.95/0 2007 Adis Data Information BV. All rights reserved.

Therapeutic Applications of Sildenafil Citrate in the Management of Paediatric Pulmonary Hypertension


Leah Leibovitch,1,2 Ilan Matok1 and Gideon Paret1
1 Department of Pediatric Critical Care, Safra Childrens Hospital, The Chaim Sheba Medical Center, Tel-Hashomer and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 1. Definition of Pulmonary Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 2. Subcategories of Pulmonary Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 2.1 Idiopathic and Familial Pulmonary Arterial Hypertension (PAH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 2.2 Pulmonary Hypertension Secondary to Underlying Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 3. Diagnosis and Assessment of Pulmonary Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 4. Treatment Modalities for Pulmonary Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 4.1 Conventional Supportive Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 4.2 Specific Pharmacological Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 4.2.1 Calcium Channel Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 4.2.2 Nitric Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 4.2.3 Prostaglandins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 4.2.4 Endothelin Receptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 4.2.5 Phosphodiesterase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 5. Sildenafil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 6. Clinical Applications of Sildenafil in Pulmonary Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 6.1 Idiopathic and Familial PAH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 6.2 PAH Associated with Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 6.3 Pulmonary Hypertension Associated with Lung Diseases and/or Hypoxaemia . . . . . . . . . . . . . . . 68 6.4 Sildenafil and Inhaled Nitric Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 6.5 Persistent Pulmonary Hypertension of the Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 7. Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Abstract

Pulmonary hypertension is characterised by a progressive increase in pulmonary vascular resistance and a poor prognosis. The exact underlying mechanisms are still poorly understood; however, it is hypothesised that pulmonary medial hypertrophy and endothelial dysfunction lead to impaired production of vasodilators such as nitric oxide (NO) and prostacyclin, and increased expression of vasoconstrictors such as endothelin-1. The current treatment modalities for pulmonary hypertension include conventional supportive therapies and more specific phar-

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macological therapies that are targeted at abnormalities of endothelial function. NO and phosphodiesterase type 5 (PDE5) inhibitors induce pulmonary vasodilation by increasing intracellular cyclic guanosine monophosphate (cGMP) concentrations. Sildenafil citrate is a highly selective inhibitor of PDE5. Investigations in animal models and recent clinical case reports with some studies in the paediatric population suggest that sildenafil may be a promising agent in treating pulmonary hypertension. The effect of sildenafil on pulmonary vasculature appears to be independent of the underlying cause, thereby providing a role in idiopathic pulmonary arterial hypertension (PAH), PAH associated with congenital heart disease, pulmonary hypertension secondary to lung disease or persistent pulmonary hypertension of the newborn. It may also be beneficial in postoperative pulmonary hypertension and in neonates who are difficult to wean from inhaled NO. It is easily administered and effective, and has minimal systemic adverse effects. Although the reported results in children with pulmonary hypertension are promising, it is an experimental drug and large-scale randomised controlled studies are required to validate the safety, efficacy and dosage in the paediatric population.

Pulmonary hypertension is an important clinical presentation of various paediatric and neonatal diseases, including congenital heart disease, lung disease and liver disease, all of which cause high morbidity and mortality. The disease is characterised by a progressive increase in pulmonary vascular resistance, leading to right ventricular failure. Pulmonary hypertension has similar characteristics in adults and children; however, some differences exist[1] and they are summarised in table I. Previously, the prognosis of patients with pulmonary hyperten-

sion was poor.[2] Fortunately, significant advances in pharmacological treatments have improved quality of life and patient survival.[3] The most recent classification of pulmonary hypertension was established during the 2003 World Symposium (table II) and applies to both adults and children.[4] This classification separates the causes of pulmonary hypertension into five main categories: pulmonary arterial hypertension (PAH), pulmonary venous hypertension associated with leftsided heart disease, pulmonary hypertension associ-

Table I. Main differences between adults and children with pulmonary hypertension Characteristic Main aetiologies Adults Children Idiopathic and familial PAH, thromboembolic Most common aetiologies outside immediate and autoimmune diseases neonatal period are chronic lung disease and congenital heart disease Advanced pulmonary vascular obstructive disease with intimal fibrosis and plexiform lesions Exertional dyspnoea, chest pain Severe pulmonary arterial medial hypertrophy with marked intimal proliferation Failure to thrive, poor appetite, cyanotic events, syncope, epilepsy-like attacks About 40%

Histopathology

Presenting symptoms

The positive response rate to acute About 12% vasodilator testing with orally administered vasodilator drugs Gene mutation (BMPR2) PAH = pulmonary arterial hypertension. Up to 50% in familial PAH have mutation in the gene

About 8% of the children with familial history have mutation in the gene

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ated with lung disease and/or hypoxaemia, pulmonary hypertension due to chronic thrombotic and/or embolic disease, and miscellaneous. In the paediatric population, PAH and pulmonary hypertension associated with lung disease and hypoxia are the two most common categories. PAH can be either idiopathic, familial or associated with other underlying causes, such as connective tissue disease, congenital heart disease, portal hypertension, drugs and toxins, and persistent pulmonary hypertension of the newborn.[3] Lung diseases associated with pulmonary hypertension include respiratory distress syndrome, meconium aspiration syndrome, bronchopulmonary dysplasia, congenital diaphragmatic hernia, pulmonary hypoplasia, interstitial lung disease and others.[3] In the last three decades, there has been significant progress in understanding the pathogenic mechanisms involved in the development of PAH. As a result of this extensive research, new and effective drugs, such as prostanoids, endothelin receptor inhibitors and phosphodiesterase inhibitors, were developed. These drugs show improvement in exercise capacity, quality of life and survival of these patients.[5,6] Sildenafil is a highly selective inhibitor of phosphodiesterase (PDE)-5 which was recently discovered as a convenient and effective oral treatment for patients with pulmonary hypertension, mainly those with idiopathic PAH or PAH secondary to an underlying disease. This review highlights the recent therapeutic applications of sildenafil in pulmonary hypertension of children and neonates. We reviewed the relevant medical literature by searching MEDLINE (1995 to April 2006), using the keyword sildenafil and the combinations with the following keywords: pulmonary hypertension in children, pulmonary hypertension in neonates, pulmonary arterial hypertension in children, pulmonary arterial hypertension in neonates and pulmonary hypertension of the newborn. Our search was mainly on human studies, as well as experimental models in animals, and preference was given to manuscripts published in English.
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Table II. Revised clinical classification of pulmonary hypertensiona Classification Pulmonary arterial hypertension Idiopathic Familial Associated with collagen vascular disease, congenital systemicto-pulmonary shunts, portal hypertension, HIV infection, drugs and toxins, thyroid disorders, glycogen storage disease, Gauchers disease, hereditary haemorrhagic telangiectasia, haemoglobinopathies, myeloproliferative disorders Associated with significant venous or capillary involvement: pulmonary veno-occlusive disease, pulmonary capillary haemangiomatosis Persistent pulmonary hypertension of the newborn Pulmonary hypertension with left heart disease Left-sided atrial or ventricular heart disease Left-sided valvular heart disease Pulmonary hypertension associated with lung diseases and/ or hypoxaemia Chronic obstructive pulmonary disease Interstitial lung disease Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities Pulmonary hypertension due to chronic thrombotic and/or embolic disease Thromboembolic obstruction of proximal pulmonary arteries Thromboembolic obstruction of distal pulmonary arteries Non-thrombotic pulmonary embolism (tumour, parasites, foreign material) Miscellaneous Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumour, fibrosing mediastinitis) a This classification was adapted from the 2003 World Symposium on Pulmonary Hypertension (Venice 2003).[4]

1. Definition of Pulmonary Hypertension The definition of pulmonary hypertension in children is the same as for adult patients. It is defined as a mean pulmonary artery pressure 25mm Hg at rest or 30mm Hg during exercise, with normal pulmonary artery wedge pressure (15mm Hg) and an increased pulmonary vascular resistance index (3 Wood units/m2).[2] The inclusion of exercise-induced haemodynamic abnormalities in the definition of pulmonary hypertension is important, since the vasoactive response to triggers such as exercise and hypoventilation is greater in children than in adults.[3,7] This difference probably stems from the
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characteristic increased vascular medial hypertrophy that is more pronounced in young children and results in dynamic vasoactivity. The increase in intimal fibrosis and plexiform lesions reduces this dynamic component in adults.[7] 2. Subcategories of Pulmonary Hypertension
2.1 Idiopathic and Familial Pulmonary Arterial Hypertension (PAH)

have abnormalities in endothelial function which results in impaired release of vasodilators, such as nitric oxide (NO) and prostacyclin, or an enhanced production of vasoconstrictors, such as endothelin and thromboxane.[9]
2.2 Pulmonary Hypertension Secondary to Underlying Diseases

Idiopathic PAH is a rare disease that is diagnosed after exclusion of all known causes.[5] It is a new terminology for the subcategory that previously was known as primary pulmonary hypertension, and was officially changed in the 2003 World Pulmonary Hypertension Symposium.[4,5] The estimated incidence of idiopathic PAH ranges from 1 to 2 cases per 1 million people in the general population.[8,9] Idiopathic PAH occurs most frequently in young adult women[8,10] and is characterised by progressive, sustained elevation in pulmonary arterial pressure without a defined cause. Like other pulmonary hypertensive disorders, the average time to diagnosis is 12 years. The major difficulties in establishing the diagnosis of the idiopathic type include the subtle presentation and crossover of symptoms with other diseases. Symptoms include dyspnoea, syncope, fatigability and chest pain. In infants, children and young adults, moderate pulmonary hypertension can be tolerated well without manifesting these symptoms. The familial form of what was previously called primary pulmonary hypertension, and which accounts for only a small percentage of cases, is now categorised as familial PAH. This form is inherited as an autosomal dominant trait, with a pattern of genetic anticipation. It is found in about 6% of patients with primary pulmonary hypertension.[8,11] Recently, the gene for the familial form was mapped to chromosome 2q33 and named BMPR2 (bone morphogenic protein receptor-2).[12,13] Although the cause of idiopathic PAH is unknown, several physiological and pathological features are commonly observed. Nearly all patients
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Pulmonary hypertension in children and neonates is usually secondary to an underlying disease such as congenital heart disease, respiratory disease, persistent pulmonary hypertension of the newborn, or other less common causes. There is a wide spectrum of congenital heart diseases that result in PAH[9] (table III), and the age at which these pathologies cause irreversible pulmonary vascular disease varies significantly. It seems that a combination of high pressure and high flow causes more rapid development of severe vascular remodelling.[9] Hypoxia plays an important role in the development of pulmonary hypertension. Respiratory pathologies that result in hypoxia can be either bronchial (obstructive or restrictive) or parenchymal diseases (table III). Persistent pulmonary hypertension of the newborn is a syndrome characterised by increased pulmonary vascular resistance, extrapulmonary rightto-left shunting and severe hypoxaemia. Symptoms usually present within 12 hours of birth.[3] It is frequently associated with meconium aspiration, pneumonia, respiratory distress syndrome, sepsis, congenital diaphragmatic hernia, or pulmonary hypoplasia.[15] 3. Diagnosis and Assessment of Pulmonary Hypertension The presenting signs and symptoms of patients with pulmonary hypertension are age-specific and consist of nonspecific presentations.[9] Newborns with persistent pulmonary hypertension present with cyanosis and respiratory distress.[15,16] Infants with pulmonary hypertension often present with signs of low cardiac output, such as poor appetite, failure to thrive, lethargy, diaphoresis, tachypnoea, tachycarDrugs 2007; 67 (1)

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Table III. Causes of pulmonary hypertension in the paediatric population (adapted from Tulloh,[14] with permission) Cause Neonates persistent pulmonary hypertension of the newborn (idiopathic) respiratory distress syndrome and bronchopulmonary dysplasia structural disease: congenital diaphragmatic hernia, pulmonary hypoplasia, alveolar capillary dysplasia interstitial disease: meconium aspiration syndrome, infection Cardiac congenital heart disease: left-to-right shunt (ASD, VSD, AVSD, PDA) transposition of the great arteries obstructive anomalies (TAPVC, MS, HLHS, HOCM, DCM) Acquired interstitial lung disease cystic fibrosis scoliosis neuromuscular disease chronic obstructive pulmonary disease vasculitis hypercoagulability states (protein C and protein S deficiency, factor V Leiden) sleep-disordered breathing Idiopathic (sporadic, familial) ASD = atrial septal defect; AVSD = atrioventricular septal defect; DCM = dilated cardiomyopathy; HLHS = hypoplastic left heart syndrome; HOCM = hypertrophic obstructive cardiomyopathy; MS = mitral stenosis; PDA = persistent ductus arteriosus; TAPVC = total anomalous pulmonary venous connection; VSD = ventricular septal defect.

dia and irritability. Toddlers and children may have cyanotic events with exertion, which are caused by right-to-left shunting through a patent foramen ovale. Without adequate shunting, the patients may present with syncope. After early childhood, children present with similar symptoms to those in adults, mainly exertional dyspnoea and chest pain.[7] Patient history, physical examination and routine tests such as electrocardiography and chest radiography provide important clues to the diagnosis. However, the final diagnosis is established by right (and left) heart catheterisation, including haemodynamic testing. Echocardiography confirms the presence of pulmonary hypertension by demonstrating increased right ventricular pressure and rules out or confirms the presence of congenital heart disease, pulmonary venous disease or left ventricular dysfunction.[9] Cardiac catheterisation remains the diagnostic gold standard, as it allows accurate measurement of pulmonary artery pressure and pulmonary vascular resistance.[5,14] The degree of the pulmonary hypertension reversibility is determined by a short-acting vasodilator test (intravenous epopros 2007 Adis Data Information BV. All rights reserved.

tenol, inhaled NO, intravenous adenosine or inhaled iloprost) that is performed during the catheterisation.[5] Patients who are responsive to acute vasodilator testing (reduction of 20% in the mean pulmonary artery pressure with no change or increase in cardiac output) are likely to have a favourable response to calcium channel antagonist therapy.[7] The modified New York Heart Association (NYHA) functional classification or the WHO classification is used to clinically assess the severity of pulmonary hypertension (table IV). These classifications determine the degree of a patients daily function and are helpful in guiding treatment.[17] Another clinical test is the 6-minute walk test (6MWT), which is an independent predictor of death in adult patients with idiopathic PAH and has been used as the primary endpoint in many clinical trials. It measures the distance that the patient can walk in 6 minutes, and it is used to compare the exercise capacity during the course of the disease and the response to treatment. The WHO classification and the 6-MWT were adapted from adults and are used as clinical comparison tools.
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4. Treatment Modalities for Pulmonary Hypertension


4.1 Conventional Supportive Therapy

ity of life and survival in patients with pulmonary hypertension, mainly in patients with PAH.[6]
4.2.1 Calcium Channel Antagonists

The conventional treatments for pulmonary hypertension include diuretics (to control symptoms of volume overload from right ventricular failure), supplemental oxygen and digoxin (which has a beneficial effect in some patients).[18] Anticoagulant therapy in children is based on studies in adults. Clinical data on their long-term use in children is limited, but supportive.[3] Syncope and intractable right-sided heart failure are indications for atrial septostomy in patients who are treated with vasodilators, but whose pulmonary hypertension remains refractory to treatment. In patients who do not respond to prolonged vasodilator treatment, and in those with certain types of lesions, such as pulmonary vein stenosis, lung transplantation has been offered as the last treatment option.[7]
4.2 Specific Pharmacological Therapies

Calcium channel antagonists are used as the initial treatment option in children with pulmonary hypertension who are acute responders to the shortacting vasodilator test (about 40% of the children and the percentage of responders falls with time).[3] The frequent occurrence of significant adverse effects prevents the use of these drugs empirically or in patients who are not responders.[7,19]
4.2.2 Nitric Oxide

In the last three decades, new and effective drugs for pulmonary hypertension have emerged as a result of improved understanding of the pathogenesis of the disease. The main categories of pharmacological agents include calcium channel antagonists, inhaled NO, prostaglandins, endothelin receptor inhibitors and phosphodiesterase inhibitors. These drugs show improvement in exercise capacity, qual-

NO is an inhaled agent which acts as a selective and potent vasodilator of the pulmonary vasculature.[20] Inhaled NO is additional to or replacement of the endogenous NO. It diffuses to the pulmonary arterial smooth muscle cells and activates soluble guanylate cyclase, resulting in an increase in cyclic guanosine monophosphate (cGMP), which activates a cascade of events leading to smooth muscle relaxation[3,9,20] (figure 1). Studies show that inhaled NO is safely used and effective in treating different forms of pulmonary hypertension, including exacerbations of idiopathic PAH, persistent pulmonary hypertension of the newborn, and pulmonary hypertension following cardiac surgery.[21,22]
4.2.3 Prostaglandins

Epoprostenol (prostacyclin) has been used for two decades for the treatment of patients with PAH and has shown improvement in haemodynamics,

Table IV. World Health Organization classification of pulmonary hypertension (adapted from Hoeper,[6] with permission) Classification Class I Class II Patients with pulmonary hypertension but with no limitations of usual physical activity Ordinary physical activity does not cause increased dyspnoea or fatigue, chest pain or near syncope Patients with pulmonary hypertension resulting in mild limitation of physical activity They are comfortable at rest Ordinary physical activity causes increased dyspnoea or fatigue, chest pain or near syncope Patients with pulmonary hypertension resulting in marked limitation of physical activity They are comfortable at rest Less than ordinary activity causes increased dyspnoea or fatigue, chest pain or near syncope Patients with pulmonary hypertension with inability to perform any physical activity without symptoms These patients manifest signs of right heart failure Dyspnoea and/or fatigue may even be present at rest Discomfort is increased by any physical activity

Class III

Class IV

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Inhaled NO
+

Prostacyclin
+ + Guanylyl cyclase

L-citrulline L-arginine

eNO

cGMP
PDE5

+ +

Protein kinase G K+ channels Ca2+ channels


+

Sildenafil

GMP

Vasodilatation Fig. 1. Schematic illustration of the pathways involving endogenous nitric oxide (eNO) and cyclic guanosine monophosphate (cGMP) and the interaction with the pharmacological agents. GMP = guanosine monophosphate; NO = nitric oxide; PDE5 = phosphodiesterase type 5.

quality of life and exercise capacity in these patients.[3,5,9] The chemical instability of this medication at neutral pH and room temperature (half-life of 12 minutes) requires a continuous intravenous delivery system with cold packs to maintain stability. These requirements make the drug delivery cumbersome, inconvenient and associated with complications. Therefore, a search for alternative routes of drug delivery led to the clinical investigation of oral (beraprost, not approved in the US or Europe), inhaled (iloprost, approved in the US and UK) and subcutaneous (treprostinil, not registered in Europe, but approved recently in the US for long-term administration) epoprostenol analogues. Thus far, none has been proven to be as efficacious as intravenous epoprostenol.[3]
4.2.4 Endothelin Receptor Antagonists

Bosentan (approved in the US and Europe) is an oral dual endothelin receptor antagonist that was shown to improve exercise capacity, quality of life and cardiopulmonary haemodynamics in adult patients with PAH.[24] There are recent publications on bosentan in children with PAH, suggesting that it is safely used and efficacious, and resulting in haemodynamic improvement.[23,25] Sitaxsentan sodium is an experimental drug that acts as a highly selective antagonist of the A receptor, thereby blocking the vasoconstricting effects of the A receptor, while maintaining vasodilation through the B receptor.[2] The experience with this medication in the paediatric population is very limited.
4.2.5 Phosphodiesterase Inhibitors

Endothelin-1 is a very potent vasoconstrictor and a promoter of cell proliferation. Plasma endothelin-1 levels are increased in patients with idiopathic PAH, both in adults and paediatric patients,[23] and are correlated inversely with prognosis.[3] Thus, endothelin receptor antagonists are promising drugs for the treatment of PAH. To date, there are at least two different known receptor subtypes; A and B.[3] The A receptors are localised on smooth muscle cells and mediate vasoconstriction and proliferation,[3] while B receptors are found predominantly on endothelial cells and are associated with vasodilation through the release of vasodilators and clearance of endothelin-1.[3]
2007 Adis Data Information BV. All rights reserved.

PDEs are a large family of enzymes that catalyse hydrolytic cleavage of the 3-phosphodiester bond of the cyclic nucleotides (e.g. cyclic adenosine monophosphate [cAMP], cGMP), controlling their intracellular levels.[26] PDE inhibitors block this hydrolytic cleavage, causing an accumulation of cAMP or cGMP, which finally leads to vasodilation. Nonspecific PDE inhibitors include caffeine, theophylline, dipyridamole and pentoxifylline. Milrinone is a specific inhibitor of PDE3, whereas zaprinast and sildenafil are specific inhibitors of PDE5.[15] There is a high concentration of PDE5 in smooth muscle cells of the pulmonary vasculature.[27] Therefore, specific inhibition of this enzyme enhances the accumulation of cGMP and results in pulmonary vasodilation. 5. Sildenafil Sildenafil is a potent and highly selective inhibitor of PDE5.[28] Since pulmonary arterial medial hypertrophy and vasoconstriction is the main mechanism of PAH in the paediatric population, inhibiting PDE5 (thereby increasing the concentration of secondary messenger cGMP and enhancing NOmediated vasodilation) is a promising mode of targeting the medial muscular hypertrophy and inducing vasodilation.[29] Although sildenafil can be used intravenously, it is unique for its oral preparation.[28] Oral sildenafil,
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20mg three times daily, was recently approved by the US FDA for the treatment of adults with PAH without functional class restriction.[18] In children, it is used as rescue therapy or in experimental protocols. There is no recommended dosage for children with PAH and the current dosages used are extrapolated from the adult dose range. Nevertheless, dosages of 0.52.0 mg/kg/dose might be considered as therapeutic in children, as the plasma concentrations measured 1 hour after oral ingestion were similar to the peak plasma concentrations achieved in adults after a single dose of 25100mg, and the patients demonstrated clinical improvement.[30,31] Sildenafil is rapidly absorbed after oral administration, with absolute bioavailability of about 40%.[32] In healthy adults, maximum observed plasma concentrations are reached within 30120 minutes (median 60 minutes) of oral administration in the fasted state.[6,32] Karatza and colleagues showed that the maximum serum concentrations of the drug in children are reached an hour after administration and are dose-dependent.[31] Sildenafil is eliminated predominantly by hepatic microsomal isoenzymes of cytochrome P450 (CYP) [3A4 (major route) and CYP2C9 (minor route)]. It is converted to Ndesmethyl sildenafil, which is an active metabolite with properties similar to sildenafil. Plasma concentrations of this metabolite account for about 20% of the pharmacological effects of sildenafil. Both sildenafil and its major circulating N-desmethyl metabolite are almost completely bound to plasma proteins (96%). Protein binding is independent of total drug concentrations. Both sildenafil and its metabolite have terminal half-lives of about 4 hours.[6] The concomitant use of potent CYP3A4 inhibitors (e.g. erythromycin, ketoconazole, itraconazole), as well as the nonspecific inhibitor of CYP, cimetidine, is associated with increased plasma sildenafil concentrations. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the faeces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).
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6. Clinical Applications of Sildenafil in Pulmonary Hypertension With the increased understanding of the mechanisms involved in the pathogenesis of pulmonary hypertension, and particularly in PAH, novel treatment options become available. Sildenafil represents one of the most recently recognised drugs with a significant therapeutic potential in pulmonary hypertension.[33] This drug has been used in various pathologies associated with PAH in children, and the outcome reported in a number of comparative studies, case series and case reports.
6.1 Idiopathic and Familial PAH

Fewer than 50% of patients with idiopathic PAH are found to be responsive to the vasodilator test and these patients will benefit from calcium channel antagonist therapy. In all other patients, intravenous infusion of epoprostenol is the mainstay of therapy.[3] However, continuous intravenous infusion is not the optimal modality in the paediatric population and is associated with potential complications such as line infections, catheter dislodgement and pump malfunction.[3] For these reasons, oral sildenafil offers an attractive and effective alternative.[28,34] Several studies and case reports were published recently, investigating the effect of oral sildenafil in patients with PAH[10,35-39] (table V). Kothari and Duggal[35] conducted a prospective, uncontrolled study in nine children aged 518 years; six had primary pulmonary hypertension, and three had secondary causes. In all six children with primary pulmonary hypertension, who were graded as NYHA functional class 3 or 4, sildenafil was added to conventional therapy. The study showed a remarkable and sustained benefit of sildenafil in these patients. The improvement was subjective as well as objective, as reflected in the NYHA functional class and 6-MWT. The authors found that the mean pulmonary artery pressure decreased in three of the patients who underwent re-catheterisation after a mean period treatment with sildenafil of 7 months. In all patients, sildenafil was well tolerated and was associated with only minor adverse effects. Sastry et al.[36] evaluated the efficacy of sildenafil in six chilDrugs 2007; 67 (1)

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Sildenafil Citrate in Paediatric Pulmonary Hypertension

Table V. Summary of studies on sildenafil citrate in paediatric patients with pulmonary arterial hypertension (PAH) Study (year) Kothari & Duggal[35] (2002) Study type No. of pts 6 Age (y) Route of administration and dosage Oral, 5.5 mg/ kg/day 150 mg/day (divided in 3 doses) Main indications Treatment Outcome duration (mo) 3.58 Follow-up period (mo) Adverse reactions

Prospective, uncontrolled

518

Primary pulmonary hypertension

Improved NYHA functional 3.58 class Improved 6-MWT Improved haemodynamics

Dizziness, flushing and headache (when dose >125mg) No visual symptoms No inconvenience due to erectile effect

Sastry et al.[36] (2002)

Prospective, uncontrolled

416

Oral, 25100 mg/dose (8-hourly)

Primary pulmonary hypertension

520

Improved NYHA functional 520 class Improved 6-MWT Improved haemodynamics

Minor headache, flushing, abdominal discomfort

Oliveira & Amaral[37] (2005)

Prospective, uncontrolled

319

Oral, 28 mg/ kg/day or 100500 mg/ day (46 doses/day)

Idiopathic PAH

436

Improved NYHA functional 436 class Improved systemic saturation

No adverse effects One death after abrupt and unplanned withdrawal of medication

Humpl et al.[38] (2005)

Prospective, uncontrolled

518

Oral, 0.251 mg/kg/dose (6-hourly)

Idiopathic PAH

12

Improved 6-MWT Improved haemodynamics

12

Self-limited nosebleeds, menstrual losses with the menarche, facial flushing, headache and dizziness

Abrams et al.[10] (2000) Karatza et al.[39] (2004)

Case report

Oral, 2 mg/kg (4-hourly)

Primary pulmonary hypertension

Improved exercise capacity

None

Case report

14

Oral, 0.5 mg/ kg, increased to 2 mg/kg (4-hourly)

Primary pulmonary hypertension

Increased exercise capacity Increased oxygen saturation

None

NYHA = New York Heart Association; pts = patients; 6-MWT = 6-minute walk test.

65

2007 Adis Data Information BV. All rights reserved. Drugs 2007; 67 (1)

66

Table VI. Summary of studies on sildenafil citrate in paediatric patients with congenital heart disease and pulmonary arterial hypertension (PAH) Study (year) Study type No. of Age (y) pts 12 0.215.7 Route of administration and dosage IV, 1 mg/kg divided in 2 unequal doses, each over 10 min Main indications Treatment duration Stat doses Outcome Follow-up period Adverse reactions

Schulze-Neick et al.[40] (2003)

Prospective, uncontrolled

Preoperative catheterisation Postoperative PAH

Decreased pulmonary No follow-up No significant adverse resistance reactions Decreased pulmonary No follow-up No significant adverse resistance reactions Increased intrapulmonary shunting Sildenafil augmented No follow-up Sildenafil produced pulmonary vasodilator systemic hypotension effect of iNO and impaired oxygenation Improved 6-MWT Improved haemodynamics 12mo Self-limited nosebleeds, menstrual losses with the menarche, facial flushing, headache and dizziness Dizziness, flushing and headache (when dose >125mg) No visual symptoms No inconvenience due to erectile effect No adverse effects noted

12

0.110.65 IV, 0.025, 0.1 & 0.25 mg/kg (in 1015 min steps)

Stat doses

Stocker et al.[41] Prospective, (2003) randomised

15

0.110.7

IV, 0.35 mg/kg over 20 min + iNO

Stable infants at risk of PAH, early after cardiac surgery for VSD or ASD

20 min single dose

Humpl et al.[38] (2005)

Prospective, uncontrolled

10

618

Oral, 0.251 mg/kg/ dose (6-hourly)

PAH persisted after 12mo correction of congenital heart disease, or if considered inoperable After cardiac surgery 3.58mo

Kothari & Duggal[35] (2002)

Prospective, uncontrolled

518

Oral, 5.5 mg/kg/day 150 mg/day (divided in 3 doses)

Improved NYHA functional class Improved 6-MWT Improved haemodynamics Increased exercise capacity and increased saturation

3.58mo

Karatza et al.[31] Case (2005) reports

6.5, 10.5

Oral, 0.52 mg/kg/ dose (4-hourly)

Pulmonary hypertension associated with congenital heart disease Pulmonary hypertension associated with congenital heart disease

6mo

6mo

Carroll & Dhillon[28] (2003)

Case report

Oral, 0.52 mg/kg/ dose (6-hourly)

Unknown

Significant improvement of exercise test

Unknown

None

Leibovitch et al.

Continued next page

Sildenafil Citrate in Paediatric Pulmonary Hypertension

67

ASD = atrial septal defect; iNO = inhaled nitric oxide; IV = intravenous; NYHA = New York Heart Association; pts = patients; VSD = ventricular septal defect; 6-MWT = 6-minute walk test.

No. of Age (y) pts

dren (aged 416 years) with primary pulmonary hypertension. They found an overall improvement in the echocardiographic and haemodynamic measurements in all patients, as well as improvements in the NYHA functional class and the 6-MWT. Their study also suggested a possible survival advantage, but this could not be confirmed based on their study design and small group of patients. In a more recent prospective case series, Oliveira and Amaral[37] reported six patients aged 319 years with idiopathic PAH who had no response to previous conventional treatment. They were treated with oral sildenafil (28 mg/kg/day) during a period of 436 months. All patients achieved a good therapeutic response, with improvement by at least one functional class, and an increase in systemic arterial oxygen saturation. No major adverse effects were observed, but one patient died suddenly after unplanned withdrawal of sildenafil. Humpl et al.[38] conducted a 12-month single-drug, open-label clinical trial using oral sildenafil in 14 children; 4 of them with idiopathic PAH. Similar to the previous studies, this study also found an improvement in both exercise tolerance and pulmonary vascular haemodynamics. No adverse effects were reported. Although their study was not controlled, the authors feeling was that these patients, treated with sildenafil, had a better survival curve than patients who were treated in their institution in the past. Although all these studies are relatively small scale and uncontrolled, they suggest that sildenafil may be useful in the management of idiopathic PAH in the paediatric population. Large randomised and controlled studies will enable definite conclusions and optimal dosage recommendations.
6.2 PAH Associated with Congenital Heart Disease

Adverse reactions

None

Follow-up period

12mo

None

Decreased pulmonary 8wk pressures

Treatment duration

Outcome

Enabled to wean iNO and pulmonary artery pressure decreased

Oral, 0.75 mg/kg/dose PAH associated with (6-hourly) VSD correction

3wk

Oral, 0.25 0.5 mg/kg/ After heart dose (4-hourly) transplantation for dilated cardiomyopathy 1 Case report

Main indications

Route of administration and dosage

Case report

Case report

Study type

Oral, 0.250.5 mg/kg (6-hourly)

Pulmonary hypertension associated with congenital heart disease

11mo

8wk

Normal pulmonary 3y pressures and gaining weight

None

There are several possible applications for sildenafil in children with congenital heart disease. In the immediate postoperative phase, sildenafil can be used to decrease the pulmonary arterial pressure. Another application is in patients who develop PAH associated with congenital heart disease, later in the course of the disease[28,31,35,38,40-44] (table VI).
Drugs 2007; 67 (1)

Table VI. Contd

Saygili et al.[42] (2004)

Study (year)

2007 Adis Data Information BV. All rights reserved.

Knoderer et al.[44] (2005)

Kulkarni et al.[43] (2004)

68

Leibovitch et al.

Intravenous sildenafil has been used in pre-cardiac surgery catheterisation to evaluate the reversibility of PAH. Schulze-Neick et al.[40] compared the effects of intravenous sildenafil with inhaled NO in preoperative and postoperative patients with congenital heart disease and elevated pulmonary vascular resistance (table VI). They showed that intravenous sildenafil may be equal or superior to a standard dose of inhaled NO in reducing the elevated pulmonary vascular resistance in these patients, both during routine cardiac catheterisation and after open-heart surgery. They found no significant effect of sildenafil on intrapulmonary shunting in the preoperative group who underwent cardiac catheterisation. In the postoperative mechanically ventilated patients, the measured intrapulmonary shunting was statistically higher in the sildenafil-treated patients; however, this was not clinically significant. This is presumably related to vasodilation of pulmonary arterioles supplying non-ventilated areas of lung, a well described complication of intravenous, nonselective pulmonary vasodilation. These findings are in contrast to those with inhaled NO, where its effect is localised only to adequately ventilated areas of lung.[40] Pulmonary endothelial dysfunction is failure of the endothelium to produce adequate amounts of endogenous NO.[45] Open heart surgery with cardiopulmonary bypass is known to amplify this failure,[45] and inhaled NO is an important therapeutic modality in these patients when they return from surgery. Stocker et al.[41] conducted a prospective, randomised trial with intravenous sildenafil and inhaled NO in infants after cardiac surgery. They investigated the acute effects of intravenous sildenafil on haemodynamics and oxygenation, and its interaction with inhaled NO in stable infants at risk of pulmonary hypertension, early after cardiac surgery with cardiopulmonary bypass. Their study revealed very similar conclusions to Schulze-Neick et al.,[40] showing that intravenous sildenafil reduced pulmonary vascular resistance and enhanced the pulmonary vasodilator effects of NO. They also demonstrated that intravenous sildenafil significantly reduced the systemic blood pressure with system 2007 Adis Data Information BV. All rights reserved.

ic vasodilation. The investigators terminated the study early, because they noticed a consistent deterioration in oxygenation and increased alveolar-arterial gradient, which indicated an increase in intrapulmonary shunting in the post-bypass lung. Humpl et al.[38] performed a 12-month, openlabel clinical trial of oral sildenafil in 10 children with PAH secondary to congenital heart disease (table VI). They found that sildenafil was well tolerated and had no haematological, renal or hepatic functional impairments, as well as no vision-related abnormalities. Sildenafil was found to improve both exercise tolerance and pulmonary vascular haemodynamics. Kothari and Duggal[35] reported three patients who underwent surgery for congenital heart disease (ventricular septal defect or patent ductus arteriosus); all had severe pulmonary hypertension and received oral sildenafil in addition to conventional therapy. The authors concluded that the study showed a remarkable and sustained benefit of sildenafil, and it was well tolerated. These studies show that the use of an efficacious oral pulmonary vasodilator, such as sildenafil, may have a role in the clinical setting of PAH associated with congenital heart disease. It may allow weaning of intravenous pulmonary vasodilator support and can be administered conveniently for several days, weeks or months, and result in improvement in both exercise tolerance and pulmonary vascular haemodynamics.
6.3 Pulmonary Hypertension Associated with Lung Diseases and/or Hypoxaemia

Chronic lung disease in children can be complicated by severe chronic pulmonary hypertension.[28] Sildenafil can offer a possible therapeutic option in these patients because of its effect on the pulmonary vasculature, which is independent of the underlying cause.[28] There are several single case reports in the literature that describe the use of sildenafil in various lung pathologies such as interstitial pneumonitis, pertussis, bronchopulmonary dysplasia and diaphragmatic hernia. Carroll and Dhillon published their experience with oral sildenafil in two infants with chronic pulDrugs 2007; 67 (1)

Sildenafil Citrate in Paediatric Pulmonary Hypertension

69

monary hypertension secondary to pneumonitis.[28] One infant was treated with sildenafil as palliative treatment to allow him some time at home. In the second patient, sildenafil was commenced because intravenous prostacyclin was impractical for home use. He showed improvement with no significant adverse effects. However, both patients died from progression of their underlying pulmonary disease. McEniery et al.[46] described an infant with pertussis who developed pulmonary hypertension. Bordetella pertussis produces a number of active toxins that impair cardiovascular function and inhibit endothelial NO production; hence, pertussis is associated with pulmonary hypertension. This patient was treated with a combination of sildenafil and inhaled NO, and his haemodynamic condition was stabilised. The authors postulated that this drug combination may offer potential treatment in patients with pertussis toxaemia. Hon et al.[47] reported the use of oral sildenafil in a 5-month-old preterm infant with severe bronchopulmonary dysplasia and PAH refractory to inhaled NO. The infant was treated with oral sildenafil for 6 months until complete resolution of PAH and oxygen supplement was weaned off. There were no adverse effects during the treatment period. Chaudhari et al.[48] reported on a neonate with severe pulmonary hypertension associated with impaired alveolarisation and plexiform pulmonary arteriopathy. The neonate was treated with oral sildenafil and inhaled NO, and this resulted in significant clinical improvement with recovery from the pulmonary hypertensive crisis. Animal models may suggest another role of sildenafil in chronic lung disease. Ladha et al.[49] demonstrated that, in addition to its known vasodilatory effect, sildenafil also preserved alveolar growth and lung angiogenesis in rats. These findings suggest a role for the NO or cGMP pathway during alveolar development. If this hypothesis is validated, it might explain the beneficial effect of longterm treatment with sildenafil in patients with bronchopulmonary dysplasia, impaired alveolar structures and other parenchymal lung diseases.
2007 Adis Data Information BV. All rights reserved.

6.4 Sildenafil and Inhaled Nitric Oxide

Severe rebound hypoxaemia and pulmonary hypertension are significant problems when weaning inhaled NO in some patients, mainly after prolonged inhaled NO therapy and abrupt cessation of treatment.[15] This clinical issue is frequently seen in the paediatric population, and is also well defined in newborns with persistent pulmonary hypertension. Atz and Wessel[50] hypothesised that sildenafil may add to the pulmonary vasodilation effect of inhaled NO or blunt the rebound effect of abrupt discontinuation of inhaled NO. They reported their experience in three infants (aged 1 day, 6 weeks and 4 months) with pulmonary hypertension following surgery for congenital heart disease. Sildenafil was used after failed attempts to discontinue inhaled NO, and resulted in a rise in cGMP levels within 90 minutes of administration, with an associated drop in pulmonary arterial pressure, allowing successful weaning from NO. They found no adverse systemic effects. In another recent study,[15] oral sildenafil was used in five neonates and younger infants (age range 228 weeks) with refractory suprasystemic pulmonary hypertension after gradual withdrawal of inhaled NO, despite alkalinisation and inotropic support. Sildenafil permitted discontinuation of inhaled NO within 46 hours, without haemodynamic instability, allowing extubation in four of them within 48 hours. Mychaskiw et al.[51] reported a 17-yearold patient who had replacement of a biventricular assist device to support heart failure secondary to a viral cardiomyopathy. In this case, sildenafil ameliorated the rebound pulmonary hypertension that developed following withdrawal of inhaled NO. The fact that sildenafil seems to be as effective as inhaled NO in improving pulmonary vasodilation, and may even have an additive effect,[52-54] makes it a useful tool in weaning patients after prolonged therapy with inhaled NO.
6.5 Persistent Pulmonary Hypertension of the Newborn

Inhaled NO is currently regarded as the gold standard therapy for pulmonary hypertension of the newborn, whereas the extracorporal membrane oxyDrugs 2007; 67 (1)

70

Leibovitch et al.

genation (ECMO) is considered as a rescue therapy.[15] However, there are some difficulties which limit the use of NO: about 30% of the patients do not respond to this drug,[15] there is a risk of developing rebound pulmonary hypertension upon its withdrawal, even after relatively short periods of use, and its mode of delivery usually requires endotracheal intubation.[15] Other important considerations are the development of methaemoglobinaemia and cell membrane damage from peroxynitrites.[15] The high cost involved and the lack of infrastructure in some parts of the world makes NO and ECMO even less available. These limitations led to further studies on the possible role of sildenafil, which might overcome some of the difficulties mentioned. Juliana and Abbad[55] published a successful case of sildenafil treatment for persistent pulmonary hypertension in an infant, where inhaled NO or ECMO were not available. Just recently, a pilot randomised, blinded study on oral sildenafil in infants with persistent pulmonary hypertension of the newborn was published.[56] This study was performed in a neonatal intensive care unit in Colombia. It was well equipped but there was no inhaled NO, high frequency oscillating ventilators or ECMO available. Seven infants were treated with oral sildenafil 1 mg/ kg every 6 hours, whereas six infants received placebo. The main outcome variable was the effect of oral sildenafil on oxygenation. Oxygenation index improved in all infants within 630 hours. Sildenafil was well tolerated. In the treatment group no noticeable effect on blood pressure was observed. Six infants survived in the treatment group, whereas only one infant survived in the placebo group. The study showed that sildenafil may be effective in the treatment of persistent pulmonary hypertension of the newborn. Sildenafil has been studied in animal models of neonatal pulmonary hypertension. It was shown to be a selective pulmonary vasodilator with no effect on the systemic arterial pressure, potentiating the effects of inhaled NO when given orally,[57] as an intravenous infusion[58] or in an aerosolised form.[59] In an experimental model of pulmonary hypertension associated with meconium aspiration syn 2007 Adis Data Information BV. All rights reserved.

drome, intravenously administered sildenafil completely reversed the increased pulmonary vascular resistance without affecting systemic haemodynamics.[55] These experimental models also showed that when sildenafil was added to inhaled NO it produced unacceptable deterioration in oxygenation, as a result of an increase in intrapulmonary shunting.[60] These models point to a possibly higher risk involved in using sildenafil in parenchymal lung disease, such as meconium aspiration syndrome. In such situations, sildenafil might induce or worsen ventilation perfusion mismatch, resulting in lower arterial oxygenation. Alternative administration in an aerosolised form may lower the risk of ventilation perfusion mismatch and the systemic adverse effects.[59] It is also important to remember that infants are at risk for sepsis and septic shock and developing associated pulmonary hypertension. Inflammatory mediators that are produced during the septic state increase the concentrations of endogenous NO, which cause changes in systemic vasomotor tone.[61] In these circumstances, sildenafil may theoretically worsen the circulatory status. 7. Adverse Events Most of the studies and the reports on sildenafil in children and infants with pulmonary hypertension suggest that there is a very low incidence of adverse effects, and these are usually minor. Adverse effects that were reported in adults treated for pulmonary hypertension include headache, flushing, dizziness, postural hypotension, dyspepsia, constipation, backache, blurred vision, giddiness and short-lived erections.[34] In most of the paediatric patients reviewed here, no major adverse effects were noted. However, a few major concerns should be considered before treating patients with pulmonary hypertension with sildenafil. Intravenous sildenafil was found to significantly reduce the systemic blood pressure.[40,41,60] In some cases, the drop in systemic blood pressure was corrected with volume expanders,[55] whereas in others it was not clinically significant and did not require any specific treatment.[38] Another important consideration is the deterioration in arterial oxygenation and the increase in alveolarDrugs 2007; 67 (1)

Sildenafil Citrate in Paediatric Pulmonary Hypertension

71

arterial gradient, which is probably due to an increase in intrapulmonary shunting.[40,41,58] This can be unacceptable in infants with parenchymal lung disease and low reserves. Visual and ocular abnormalities were also reported with the use of sildenafil in pulmonary hypertension. Blurred vision, increased perception of light and blue-green colour-tinged vision are described as possible adverse effects.[45] In premature babies, retinopathy of prematurity (ROP) is a concern, but only one case report suggested that the use of sildenafil induced severe ROP in a preterm baby who had severe pulmonary hypertension.[62] However, that baby had many other risk factors for the development of ROP, as was discussed by Pierce et al.[63] 8. Conclusions Pulmonary hypertension in the paediatric population remains an incurable disease, but the recent advances in understanding the mechanisms involved in the pathogenesis of the disease are an important step in developing new and effective therapies.[6] These newly available medications improve exercise capacity, quality of life and survival.[6] Sildenafil, which is considered an experimental drug for children with pulmonary hypertension, appears as one of the most promising pulmonary vasodilator agents; it is relatively safe and simple to use,[52] and the effect it has on the pulmonary vasculature is independent of the underlying cause. There are reports of successful use of sildenafil in children with idiopathic PAH, PAH that results from congenital heart disease, or pulmonary hypertension secondary to lung disease; it may also be beneficial in postoperative pulmonary hypertension and in patients who are difficult to wean from inhaled NO.[45,50,51] Although the data from the literature are promising, they are mainly from small case series and single case reports. Treatment regimens were not uniform, the dosage of sildenafil varied between studies, and the follow-up period was not always sufficient. Therefore, large-scale randomised, controlled clinical trials are required to confirm the
2007 Adis Data Information BV. All rights reserved.

efficacy, safety and optimal dosage of sildenafil as treatment of pulmonary hypertension in the paediatric population. Acknowledgements
We thank Professor Sherin Devaskar for reviewing our manuscript and for her insightful comments. The authors have no conflicts of interest that are directly relevant to the contents of this review and received no funding for its preparation.

References
1. Haworth SG. Primary pulmonary hypertension in childhood. Arch Dis Child 1998; 79: 452-5 2. DAlonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991; 115: 343-9 3. Rosenzweig EB, Widlitz AC, Barst RJ. Pulmonary arterial hypertension in children. Pediatr Pulmonol 2004; 38: 2-22 4. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004; 43: 5-12S 5. Rosenzweig EB, Barst RJ. Idiopathic pulmonary arterial hypertension in children. Curr Opin Pediatr 2005; 17: 372-80 6. Hoeper MM. Drug treatment of pulmonary arterial hypertension. Drugs 2005; 65: 1337-54 7. Widlitz A, Barst RJ. Pulmonary arterial hypertension in children. Eur Respir J 2003; 21: 155-76 8. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997; 336: 111-7 9. Ivy D. Diagnosis and treatment of severe pediatric pulmonary hypertension. Cardiol Rev 2001; 9: 227-37 10. Abrams D, Schulze-Neick I, Magee AG. Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension. Heart 2000; 84: E4 11. Loyd JE, Butler MG, Foroud TM, et al. Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension. Am J Respir Crit Care Med 1995; 152: 93-7 12. Lane KB, Machado RD, Pauciulo MW, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet 2000; 26: 81-4 13. Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000; 67: 737-44 14. Tulloh RM. Congenital heart disease in relation to pulmonary hypertension in paediatric practice. Paediatr Respir Rev 2005; 6: 174-80 15. Travadi JN, Patole SK. Phosphodiesterase inhibitors for persistent pulmonary hypertension of the newborn: a review. Pediatr Pulmonol 2003; 36: 529-35 16. Greenough A, Khetriwal B. Pulmonary hypertension in the newborn. Paediatr Respir Rev 2005; 6: 111-6 17. Rich S, editor. Primary pulmonary hypertension: executive summary from the World SymposiumPrimary Pulmonary Hypertension 1998. Geneva: World Health Organization, 1998 18. Lee SH, Rubin LJ. Current treatment strategies for pulmonary arterial hypertension. J Intern Med 2005; 258: 199-215

Drugs 2007; 67 (1)

72

Leibovitch et al.

19. Packer M, Medina N, Yushak M, et al. Detrimental effects of verapamil in patients with primary pulmonary hypertension. Br Heart J 1984; 52: 106-11 20. Frostell C, Fratacci MD, Wain JC, et al. Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1991; 83: 2038-47 21. The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med 1997; 336: 597-604 22. Clark RH, Kueser TJ, Walker MW, et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. N Engl J Med 2000; 342: 469-74 23. Barst RJ, Ivy D, Dingemanse J, et al. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Clin Pharmacol Ther 2003; 73: 372-82 24. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896-903 25. Rosenzweig EB, Ivy DD, Widlitz A, et al. Effects of long-term bosentan in children with pulmonary arterial hypertension. J Am Coll Cardiol 2005; 46: 697-706 26. Essayan DM. Cyclic nucleotide phosphodiesterases. J Allergy Clin Immunol 2001; 108: 671-80 27. Rabe KF, Tenor H, Dent G, et al. Identification of PDE isozymes in human pulmonary artery and effect of selective PDE inhibitors. Am J Physiol 1994; 266: 536-43 28. Carroll WD, Dhillon R. Sildenafil as a treatment for pulmonary hypertension. Arch Dis Child 2003; 88: 827-8 29. Gali` N, Ghofrani HA, Torbicki A, et al., for the Sildenafil Use e in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353: 2148-57 30. Boolell M, Allen MJ, Ballard SA, et al. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 1996; 8: 47-52 31. Karatza AA, Bush A, Magee AG. Safety and efficacy of sildenafil therapy in children with pulmonary hypertension. Int J Cardiol 2005; 100: 267-73 32. Nichols DJ, Muirhead GJ, Harness JA. Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality. Br J Clin Pharmacol 2002; 53 Suppl. 1: 5-12S 33. Zaiman A, Fijalkowska I, Hassoun PM, et al. One hundred years of research in the pathogenesis of pulmonary hypertension. Am J Respir Cell Mol Biol 2005; 33: 425-31 34. Sastry BK, Narasimhan C, Reddy NK, et al. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 2004; 43: 1149-53 35. Kothari SS, Duggal B. Chronic oral sildenafil therapy in severe pulmonary artery hypertension. Indian Heart J 2002; 54: 404-9 36. Sastry BK, Narasimhan C, Reddy NK, et al. A study of clinical efficacy of sildenafil in patients with primary pulmonary hypertension. Indian Heart J 2002; 54: 410-4 37. Oliveira EC, Amaral CF. Sildenafil in the management of idiopathic pulmonary arterial hypertension in children and adolescents. J Pediatr (Rio J) 2005; 81: 390-4 38. Humpl T. Reyes JT, Holtby H, et al. Beneficial effect of oral sildenafil therapy on childhood pulmonary arterial hypertension: twelve-month clinical trial of a single-drug, open-label, pilot study. Circulation 2005; 111: 3274-80

39. Karatza AA, Narang I, Rosenthal M, et al. Treatment of primary pulmonary hypertension with oral sildenafil. Respiration 2004; 71: 192-4 40. Schulze-Neick I, Hartenstein P, Li J, et al. Intravenous sildenafil is a potent pulmonary vasodilator in children with congenital heart disease. Circulation 2003; 108 Suppl. 1: II167-73 41. Stocker C, Penny DJ, Brizard CP, et al. Intravenous sildenafil and inhaled nitric oxide: a randomised trial in infants after cardiac surgery. Intensive Care Med 2003; 29: 1996-2003 42. Saygili A, Canter B, Iriz E, et al. Use of sildenafil with inhaled nitric oxide in the management of severe pulmonary hypertension. J Cardiothorac Vasc Anesth 2004; 18: 775-6 43. Kulkarni A, Singh TP, Sarnaik A, et al. Sildenafil for pulmonary hypertension after heart transplantation. J Heart Lung Transplant 2004; 23: 1441-4 44. Knoderer CA, Ebenroth ES, Brown JW. Chronic outpatient sildenafil therapy for pulmonary hypertension in a child after cardiac surgery. Pediatr Cardiol 2005; 26: 859-61 45. Raja SG, Nayak SH. Sildenafil: emerging cardiovascular indications. Ann Thorac Surg 2004; 78: 1496-506 46. McEniery JA, Delbridge RG, Reith DM. Infant pertussis deaths and the management of cardiovascular compromise. J Paediatr Child Health 2004; 40: 230-2 47. Hon KL, Cheung KL, Siu KL, et al. Oral sildenafil for treatment of severe pulmonary hypertension in an infant. Biol Neonate 2005; 88: 109-12 48. Chaudhari M, Vogel M, Wright C, et al. Sildenafil in neonatal pulmonary hypertension due to impaired alveolarisation and plexiform pulmonary arteriopathy. Arch Dis Child Fetal Neonatal Ed 2005; 90: 527-8 49. Ladha F, Bonnet S, Eaton F, et al. Sildenafil improves alveolar growth and pulmonary hypertension in hyperoxia-induced lung injury. Am J Respir Crit Care Med 2005; 172: 750-6 50. Atz AM, Wessel DL. Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology 1999; 91: 307-10 51. Mychaskiw G, Sachdev V, Heath BJ. Sildenafil (Viagra) facilitates weaning of inhaled nitric oxide following placement of a biventricular-assist device. J Clin Anesth 2001; 13: 218-20 52. Michelakis E, Tymchak W, Lien D, et al. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 2002; 105: 2398-403 53. Watanabe H, Ohashi K, Takeuchi K, et al. Sildenafil for primary and secondary pulmonary hypertension. Clin Pharmacol Ther 2002; 1: 398-402 54. Ghofrani HA, Wiedemann R, Rose F, et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002; 136: 515-22 55. Juliana AE, Abbad FC. Severe persistent pulmonary hypertension of the newborn in a setting where limited resources exclude the use of inhaled nitric oxide: successful treatment with sildenafil. Eur J Pediatr 2005; 164: 626-9 56. Baquero H, Soliz A. Neira F, et al. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics 2006; 117: 1077-83 57. Weimann J, Ullrich R, Hromi J, et al. Sildenafil is a pulmonary vasodilator in awake lambs with acute pulmonary hypertension. Anesthesiology 2000; 92: 1702-12 58. Shekerdemian LS, Ravn HB, Penny DJ. Intravenous sildenafil lowers pulmonary vascular resistance in a model of neonatal pulmonary hypertension. Am J Respir Crit Care Med 2002; 165: 1098-102

2007 Adis Data Information BV. All rights reserved.

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73

59. Ichinose F, Erana-Garcia J, Hromi J, et al. Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension. Crit Care Med 2001; 29: 1000-5 60. Shekerdemian LS, Ravn HB, Penny DJ. Interaction between inhaled nitric oxide and intravenous sildenafil in a porcine model of meconium aspiration syndrome. Pediatr Res 2004; 55: 413-8 61. Symeonides S, Balk RA. Nitric oxide in the pathogenesis of sepsis. Infect Dis Clin North Am 1999; 13: 449-63 62. Marsh CS, Marden B, Newsom R. Severe retinopathy of prematurity (ROP) in a premature baby treated with sildenafil acetate (Viagra) for pulmonary hypertension. Br J Ophthalmol 2004; 88: 306-7

63. Pierce CM, Petros AJ, Fielder AR. No evidence for severe retinopathy of prematurity following sildenafil. Br J Ophthalmol 2005; 89: 250

Correspondence and offprints: Dr Leah Leibovitch, Division of Neonatology, Safra Childrens Hospital, The Chaim Sheba Medical Center, Tel Hashomer, 52621, Israel. E-mail: leah.leibovitch@sheba.health.gov.il

2007 Adis Data Information BV. All rights reserved.

Drugs 2007; 67 (1)

REVIEW ARTICLE

Drugs 2007; 67 (1): 75-93 0012-6667/07/0001-0075/$49.95/0 2007 Adis Data Information BV. All rights reserved.

Ocular Adverse Effects Associated with Systemic Medications


Recognition and Management
Ricardo M. Santaella and Frederick W. Fraunfelder
Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 1. Categorising Adverse Drug-Related Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 2. Medications and Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 2.1 Bisphosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 2.2 Antiepileptic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 2.2.1 Topiramate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 2.2.2 Vigabatrin and Tiagabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 2.3 Isotretinoin and Other Retinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 2.4 Ethambutol and Isoniazid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 2.5 Amiodarone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 2.6 Hydroxychloroquine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 2.7 Erectile Dysfunction Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 2.8 Tamoxifen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 2.9 Cyclo-Oxygenase-2 Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 2.10 Nicotinic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 2.11 Herbal Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 2.11.1 Canthaxanthine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 2.11.2 Chamomile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 2.11.3 Datura . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 2.11.4 Echinacea purpurea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 2.11.5 Ginkgo biloba . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 2.11.6 Liquorice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 2.11.7 Vitamin A (Retinol) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 2.11.8 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

Abstract

This article reviews several retrospective case series and reported adverse events regarding common ocular adverse effects related to systemic therapy. It is not intended as a comprehensive summary of these well described adverse drug reactions, nor is it intended to cover the complete spectrum of all ocular adverse effects of systemic therapy. Many systemic drugs may produce ocular toxicity, including bisphosphonates, topiramate, vigabatrin, isotretinoin and other retinoids, amiodarone, ethambutol, chloroquine and hydroxychloroquine, tamoxifen, quetiapine, cyclo-oxygenase (COX)-2 inhibitors, erectile dysfunction agents and some herbal medications. For this review, the certainty of the adverse effect

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profile of each medication was evaluated according to the WHO Causality Assessment Guide. A certain relationship has been established for pamidronate and alendronate as causes of scleritis, uveitis, conjunctivitis and blurred vision. Topiramate has been established as adversely causing symptoms consistent with acute angle-closure glaucoma, typically bilateral. Vigabatrin has been shown to cause bilateral irreversible visual field defects attributed to underlying medication-induced retinal pathology. Isotretinoin should be considered in the differential diagnosis of any patient with pseudotumour cerebri. Patients taking amiodarone and hydroxychloroquine should be monitored and screened regularly for development of optic neuropathy and maculopathy, respectively. Sildenafil has been reported to cause several changes in visual perception and is a possible, not yet certain, cause of anterior ischaemic optic neuropathy. Patients taking tamoxifen should also be monitored for development of dose-dependent maculopathy and decreased colour vision. COX-2 inhibitors should be included in the differential diagnosis of reversible conjunctivitis. Several herbal medications including canthaxanthine, chamomile, datura, Echinacea purpurea, Ginkgo biloba and liquorice have also been associated with several ocular adverse effects. It is the role of all healthcare professionals to detect, treat and educate the public about adverse reactions to medications as they are an important health problem.

The term side effect usually refers to an undesired or negative effect of medication that is extraneous to the intended therapy. When the effect is negative, the term adverse effect is used. Druginduced ocular adverse effects are the second most frequent reason for claims against ophthalmologists.[1,2] This may not be surprising given that prescribing medications is the most common therapeutic service provided by physicians. According to the National Center for Health Statistics, new or continued medications are ordered or provided at 41% of visits to an ophthalmologists office. Because serious injury can occur, drug-related adverse effects can be costly to defend, indemnify or settle.[2] The rich blood supply and relatively small mass of the eye make it particularly susceptible to druginduced adverse reactions. Adverse ocular reactions to drugs are diverse. Drug molecules present in the system may become selectively deposited in specific ocular tissues such as the cornea, lens and retina, causing varied symptoms of drug toxicity. Fortunately, most adverse reactions induced by systemic medications are reversible if detected early. Howev 2007 Adis Data Information BV. All rights reserved.

er, if undetected, toxic effects may progress and cause irreversible ocular damage often with an associated reduction in visual function.[3,4] For ophthalmic drugs to be effective, they must reach ocular tissue in relatively high concentrations. There are several different administration routes for ophthalmic drugs, including the topical, oral, parenteral, periocular, intracameral (intraocular administration into the anterior segment) and intravitreal routes. Topical application is the most common route of administration because it is simple, less invasive and does not involve the passage of drugs through the blood-aqueous barrier. However, some disorders require systemic drug administration to achieve adequate therapeutic levels of the drug in and around the ocular tissues. Certain factors increase the probability of an adverse ocular reaction. One such factor is use of a medication over long periods of time, for example, in cases of arthritic and cardiovascular diseases. In some patients, it may be difficult to establish whether ocular pathology is caused by the condition being treated or by a drug used to treat the condition.
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Patient age is also a significant factor in the prevalence of ocular drug reactions. Older patients are more likely to have used medications for protracted periods. Also, the metabolism and excretion of a drug can be affected by decreased efficiency of the kidney and liver secondary to the patients age, or by conditions adversely affecting these organs.[3,4] Some drug responses cannot be predicted from the drugs pharmacological mode of action. A genetic basis may underlie many of these unpredictable responses, as observed in the rapid rise in intraocular pressure reported with topical corticosteroids.[5] The prevalence of adverse reactions is closely associated with drug dosage. Most reported ocular reactions occur when the dose is beyond the therapeutic range. It is essential that clinicians try to establish whether the ocular problem coincided with the start of drug therapy or with a change in drug dosage. A useful marker is seen when the onset of the reaction coincides with commencement of the medication, but reactions can occur at any time during or after a course of medication, and can continue for years after cessation.

We performed a MEDLINE literature search using the following keywords: ocular, visual, eye, side effects, adverse effects, medication and treatment. Some of the medication adverse effects obtained through this search are summarised below; these were selected at the authors discretion, taking into account some of the more recent published medication adverse effects, and are not presented in any particular order. This brief review is not intended as a comprehensive summary of these well described adverse drug reactions, nor is it intended to cover the complete spectrum of all ocular adverse effects of systemic therapy. Interested readers are encouraged to refer to textbooks cited within the references. 1. Categorising Adverse Drug-Related Events The WHO Causality Assessment Guide of Suspected Adverse Reactions was used to classify the reported adverse drug-related events into the following categories: certain, probable/likely, possible, unlikely, conditional/unclassified and unassessable/ unclassifiable.[6] The certain category includes plausible time relationship to drug administration

Table I. WHO definitions: causality assessment of suspected adverse reactions (reproduced from Brick,[2] with permission) Certain A clinical event, including a laboratory test abnormality, occurring in a plausible time relationship to drug administration, and which cannot be explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be clinically plausible. The event must be definitive pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if necessary Probable/Likely A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition Possible A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, but which could also be explained by concurrent disease or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear Unlikely A clinical event, including laboratory test abnormality, with a temporal relationship to drug administration which makes a causal relationship improbable, and in which other drugs, chemicals or underlying disease provide plausible explanations Conditional/Unclassified A clinical event, including laboratory test abnormality, reported as an adverse reaction, about which more data is essential for a proper assessment or the additional data are under examination Unassessable/Unclassifiable A report suggesting an adverse reaction which cannot be judged because information is insufficient or contradictory, and which cannot be supplemented or verified

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Table II. Classification of adverse ocular effects associated with medication usage Medication Pamidronate Certain Blurred vision Pain Photophobia Ocular irritation Nonspecific conjunctivitis Anterior uveitis (rare posterior) Anterior scleritis (rare posterior) Episcleritis Blurred vision Pain Conjunctivitis Uveitis Scleritis No effects Probable Periocular, lid, and/or orbital oedema Possible Diplopia Visual hallucinations Yellow vision Retrobulbar neuritis Cranial nerve palsy

Alendronate

Diplopia

Glaucoma

Risedronate

Conjunctivitis Pain Scleritis Uveitis Blurred vision Conjunctivitis Blepharospasm Oculogyric crisis Retinal bleeds Uveitis Decreased colour vision Permanent loss of dark adaptation

Diplopia Papilloedema Episcleritis

Etidronate Topiramate

Blurred vision Acute glaucoma (mainly bilateral) Anterior chamber shallowing Increased ocular pressure Mydriasis Suprachoroidal effusions Abnormal meibomian gland secretion Blepharoconjunctivitis Corneal opacities Decreased dark adaptation Decreased tolerance for contact lens wear Decreased vision Increased tear osmolarity Keratitis Meibomian gland atrophy Myopia Ocular sicca Ocular discomfort Photophobia Pseudotumour cerebri Teratogenic ocular abnormalities Aggravated sicca (drug in tears) Blepharoconjunctivitis Bright lights Coloured haloes around lights Corneal microdeposits Glare Hazy vision Photosensitivity Periocular skin pigmentation Thyroid eye disease Visual sensations

Diplopia Scleritis Teratogenic effects, including ocular malformations

Isotretinoin

Corneal ulcers Diplopia Eyelid oedema Optic neuritis Idiopathic intracranial hypertension with optic disc oedema Permanent sicca-like syndrome Subconjunctival haemorrhage

Amiodarone

Anterior subcapsular lens opacities Corneal ulceration Loss of eyelashes or eyebrows Non-arteritic ischaemic optic neuropathy Pseudotumour cerebri

Autoimmune reaction (dry mouth, dry eyes, peripheral neuropathy and pneumonitis)

Continued next page

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Table II. Contd Medication Sildenafil Certain Changes in colour perception coloured tinge decreased colour vision dark colours appear darker Blurred vision central haze transitory decreased vision Changes in light perception increased perception of brightness flashing lights, especially when blinking ERG changes Conjunctival hyperaemia Ocular pain Photophobia Probable No effects Possible Mydriasis (emotional effect?) Retinal vascular accidents (secondary to exertion?) Subconjunctival haemorrhage Anterior ischaemic optic neuropathy

Tamoxifen

Corneal opacities No effects Retinal opacities, degeneration, pigmentary changes, haemorrhage Loss of visual acuity Conjunctivitis Blurred vision No effects No effects Cystoid macular oedema

No effects

COX-2 inhibitors Nicotinic acid

No effects Decreased vision, dry eyes, discoloration of the eyelids, eyelid oedema, Proptosis Loss of eyebrows and eyelashes, and superficial punctate keratitis No effects No effects No effects No effects Spontaneous hyphema Retinal haemorrhage Vasospasm, visual loss associated with migraine-like symptoms No effects

Canthaxanthine Chamomile Datura Echinacea purpurea Ginkgo biloba Liquorice

Crystalline retinopathy Allergic conjunctivitis Mydriasis No effects No effects No effects

No effects No effects No effects Conjunctivitis No effects No effects

Vitamin A

Intracranial hypertension (when taken in large doses) COX = cyclo-oxygenase; ERG = electroretinogram.

No effects

and inability to explain the adverse effect by concurrent disease or other drugs or chemicals. Dechallenge data are necessary and rechallenge should be positive. Probable is the same as certain without positive rechallenge data. Possible is an adverse event in a reasonable time sequence to administration of the drug, but could also be explained by concurrent disease or other drugs or chemicals. Positive dechallenge data are lacking or unclear in this category (table I).
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2. Medications and Adverse Effects


2.1 Bisphosphonates

Bisphosphonates inhibit bone resorption by binding to hydroxyapatite crystals and inhibiting their dissolution.[7] Different bisphosphonates vary greatly in their efficacy and their adverse-effect profiles depending on the structure of the individual drug. These medications are associated with ocular adverse effects that are mainly inflammatory, i.e. conjunctivitis, uveitis and episcleritis.[8,9] Recent studies
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have proved that pamidronate can cause scleritis.[10,11] Pamidronate disodium, an intravenous bisphosphate, has been reported to cause anterior uveitis and nonspecific conjunctivitis.[9-12] Its most striking association is that of being the first medication reported to cause scleritis.[10] Case reports have also associated pamidronate with episcleritis,[13] nerve palsy,[14] ptosis[14] and retrobulbar neuritis[15] (table II). Pamidronate bears a certain relationship to uveitis, conjunctivitis, episcleritis and scleritis when taken at standard doses between 30 and 90mg intravenously. The onset of ocular signs and symptoms was usually noted within 48 hours. Alendronate is an oral bisphosphonate widely prescribed for the treatment and prevention of osteoporosis, in particular postmenopausal osteoporosis, and for the treatment of Pagets disease of the bone.[16] This bisphosphonate has been associated with a certain relationship to blurred vision, ocular pain, conjunctivitis, uveitis and scleritis when taken in dosages ranging from 5 to 40mg daily (table II). Onset of ocular signs and symptoms was noted an average of 2 days to 2 weeks (range 1 day to 1 year) after starting therapy[11] (table II). Risedronate is taken orally and is indicated in the treatment of Pagets disease of the bone.[16] The data are not sufficiently complete to classify any ocular adverse effect as certain. However, there are positive rechallenge data on a single report of scleritis associated with this medication, which indicates there could be a cause and effect relationship.[10] Etidronate is an oral medication indicated in the treatment of symptomatic Pagets disease, or for heterotopic ossification in hip replacement and spinal cord injury patients. This medication has been associated with conjunctivitis and blurred vision[11] (table II). Clodronate is used in Europe and Canada for tumour-induced bone disease.[7] It has not been approved by the US FDA. This medication is also used by some to prolong survival in breast cancer patients. Although some studies indicate there are fewer metastases with clodronate therapy, there is no evidence of prolonged survival in patients taking
2007 Adis Data Information BV. All rights reserved.

clodronate.[17] Reports of clodronate-induced uveitis have a probable association and blurred vision is classified as having a possible association[18] (table II). Pamidronate is the first medication ever reported to cause scleritis. Bisphosphonates are high molecular weight drugs that have been described as potentially causing immune complex formation and possibly being secreted by the lacrimal gland, thus causing transient irritation to mucus membranes.[3] Pamidronate stimulates the production of a distinct subgroup of T cells to inhibit bone resorption. As analogues of pyrophosphate, they can activate receptors in T cells leading to cytokine release.[18,19] This may contribute to an immunological reaction in patients who develop uveitis and/or scleritis. Some authors have contended that the nitrogen-containing bisphosphonates (alendronate, pamidronate, risedronate) are more likely to cause uveitis.[20-23] Nitrogen-containing bisphosphonates are known to cause transient pyrexia, a flu-like syndrome and serological changes resembling a typical acute phase response.[3,18,19] The cytokines released with this acute phase response could act as adjuvants in an immune reaction with the uvea of the eye as the target organ. However, a non-nitrogen-containing bisphosphonate, clodronate, has also been reported as inducing uveitis.[18] Still, there are many more reports of uveitis associated with nitrogen-containing bisphosphonates than there are for the bisphosphonates that do not contain nitrogen (etidronate, clodronate, tiludronate). In summary, bisphosphonates are associated with ocular inflammation. Ocular pain, photophobia, blurred vision, periorbital changes and glaucoma can be due to uveitis, scleritis and other types of ocular inflammation. Ocular inflammation, especially scleritis and uveitis, is of the greatest concern in the eye care of patients taking bisphosphonates. Scleritis causes a severe deep eye pain, and can lead to structural damage of the globe and loss of vision. Patients typically present with a piercing ocular pain that is worse at night and awakens them from sleep. The sclera assumes a violaceous hue in natural sunlight and scleral vessels become inflamed and can
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have a crisscross pattern. Scleral oedema develops acutely and scleral thinning can occur, along with vision loss, if necrotising scleritis persists or inflammation is left unchecked. Ocular complications from scleritis can include keratitis, cataract, uveitis and glaucoma.[12,24] In uveitis associated with bisphosphonate therapy, the early symptoms may be mild or severe, depending on which part of the uvea is affected and on the amount of inflammation. Anterior uveitis usually has the most dramatic symptoms, typically presenting with severe pain in the eye, redness of the conjunctiva, sensitivity to bright light and a decrease in vision. The examiner may see prominent blood vessels on the conjunctiva near the edge of the iris, white blood cells floating in the aqueous humour and deposits of white blood cells on the inside surface of the cornea. Intermediate uveitis is typically painless. Vision may be decreased and the patient may see floaters (irregular floating black spots). Posterior uveitis typically produces decreased vision with or without floaters. There may also be retinal detachment and inflammation of the optic nerve (symptoms include loss of vision, which may vary from a small blind spot to total blindness). Diffuse uveitis may produce any or all of these symptoms. Uveitis can rapidly damage the eye and can produce long-term, vision-threatening complications, such as swelling of the macula, glaucoma and cataracts. Those affected may have only one episode or periodic recurrences over months to years. Suggestions for treatment of bisphosphonate-induced ocular adverse effects are as follows. If there is a persistent decrease in vision or if ocular pain occurs, examination by an ophthalmologist is necessary. Nonspecific conjunctivitis seldom requires treatment and usually decreases in intensity or may be absent on subsequent treatments. In rare instances, a nonsteroidal anti-inflammatory eye drop may be needed. More than one ocular adverse effect can occur at the same time, i.e. episcleritis with uveitis. Bilateral anterior uveitis or, rarely, posterior or bilateral uveitis may occur and can vary markedly in severity. Many patients require intensive topical ocular or systemic medication. In some instances,
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the drug may need to be discontinued for uveitis to resolve. Episcleritis may require topical ocular medication; however, the bisphosphonate may be continued. In all patients studied by Fraunfelder et al.,[11] the bisphosphonate had to be discontinued for the scleritis to resolve, even on full medical therapy.
2.2 Antiepileptic Drugs
2.2.1 Topiramate

Topiramate, a sulfamate-substituted monosaccharide, is structurally unrelated to any other antiepileptic drug (AED). This AED is also used in the management of migraine, depression and neuropathic pain. Off label, it has gained popularity as a weight reduction agent, to treat migraine headaches and to treat bipolar disorder. Topiramate has been associated with acute angleclosure glaucoma. Findings associated with topiramate-associated acute, bilateral, secondary angleclosure glaucoma syndrome include blurred vision, conjunctival hyperaemia, corneal oedema, shallow anterior chamber, cataracts, pupil changes, elevated intraocular pressure, visual field defects and blindness. Topiramate has also been associated with causing bilateral myopia, bilateral suprachoroidal effusions, blepharospasm, myokymia, nystagmus and diplopia. Scleritis has also been reported.[25] Topiramate-associated visual adverse effects and their WHO classifications are listed in table II. The entity described as topiramate-associated acute, bilateral, secondary angle-closure glaucoma[26,27] can present in the same manner as an acute angle closure glaucoma attack. All the findings of acute glaucoma, such as ocular pain, headache, nausea and vomiting, pupillary changes, hyperaemia, corneal oedema, cataracts, retinal and vascular accidents, visual field defects and blindness have been reported.[25] In most patients, this is a bilateral process. If not recognised as a drug-related event, this condition can easily be confused with acute, pupillary block, narrow angle glaucoma for which a peripheral iridectomy is indicated. However, if the drug is stopped and medical management instituted, pressure may return to normal in hours to days without the need for an iridectomy. The acute pressure elevation usually occurs
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within the first 2 weeks after starting topiramate therapy, but it has been reported within hours after doubling the dose. If pressure elevation goes untreated, serious outcomes are possible, including blindness. Acute myopia up to 8.75 diopters may occur in a matter of hours after starting topiramate use, but may take weeks to fully resolve on or off medication. Sulfa-containing medications, such as topiramate, are known to cause transient myopia. Lenticular swelling, forward rotation of the lens-iris diaphragm, ciliary body swelling causing increased curvature of the lens surfaces, and spasm of accommodation have all been proposed as the mechanism behind this occurrence.[3,25,28-31] The management of topiramate-related acute pressure elevation requires stopping the drug in consultation with the prescribing physician, since decreasing the dosage as little as 50mg may exacerbate pre-existing systemic conditions. Instituting maximal medical therapy, including oral and topical aqueous suppressants, is indicated. Laser iridotomy or peripheral iridectomy may not be beneficial if the glaucoma is only associated with topiramate therapy, but would be considered adequate in the setting of angle closure if one is not certain that it is completely medication-induced. Topical miotics are probably contraindicated, as these could precipitate a relative pupillary block that would exacerbate the condition.
2.2.2 Vigabatrin and Tiagabine

the last decade, the marked efficacy of this medication and its low toxic effects prompted widespread use in Europe. The manufacturers of vigabatrin (Hoechst Marion Roussel) had received 28 reports of visual field abnormalities worldwide by January 1997 in an estimated 140 000 patients treated.[38] This information appears to have not been released during that time. Since 1997, numerous reports have appeared of visual field abnormalities in adults and children treated with this AED. In most documented cases, the visual field defect seems to be a specific, bilateral, symmetrical and irreversible peripheral constriction.[38-40] The fact that most patients are asymptomatic with normal visual acuity may have contributed to the late recognition of these visual field defects that apparently occur in more than 30% of patients but were initially estimated to affect fewer than 0.1%.[41-44] The site of toxicity is proposed to be the retina, where GABA is an important modulatory neurotransmitter. Vigabatrin increases GABA levels by inhibiting the GABA transaminase enzyme. GABA is an inhibitory neurotransmitter in bipolar cells and some amacrine cells and may have a role in the modulation of phototransduction from the retinal photoreceptor cells to the ganglion cells.[45] Systemic vigabatrin has been shown to cross the bloodretinal barrier and can be detected immunocytochemically in the retina.[46] Vigabatrin causes white matter microvacuolation and intramyelinic oedema in the brains of rodents and dogs but not in monkeys and humans.[47] It also has been shown to cause accumulation of GABA in the retinal Muller cells.[48] How an increase in retinal GABA levels may produce visual field constriction is not clear, but the lower density of ganglion cells in the peripheral retina or a toxic effect on the retinal Muller cells has been suggested as being possibly related.[49] Thus far, the understanding of the role played by GABA in retinal transmission is not sufficient to allow for a mechanistic explanation of the adverse effects of vigabatrin. There is no consensus regarding screening visual field examinations for patients taking vigabatrin.[49] The incidence, higher than previously estimated, of
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Vigabatrin is a selective, enzyme-activated, irreversible GABA aminotransferase inhibitor.[32] It is a custom-made AED that is particularly useful in the management of drug-resistant partial seizures and infantile spasms, especially those secondary to tuberous sclerosis.[33-36] The antiepileptic effect is presumably mediated by elevation of GABA levels of the brain caused by inhibition of GABA metabolism.[36] Initially, only relatively minor adverse effects were attributed to vigabatrin use.[37] It was first introduced into clinical practice in the UK on a trial basis in the mid 1980s and granted licence in 1989. The FDA has not approved its use in the US. Over
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this complication, particularly in asymptomatic patients, suggests that screening visual field examinations may be necessary. Daneshvar et al.[49] have recommended visual field examinations covering the peripheral 60 of the visual field for all patients taking vigabatrin, before or soon after starting treatment and at regular intervals thereafter. Any reproducible visual field constriction not present at the baseline examination may be associated with vigabatrin. The decisions on continuing treatment in these patients must be individualised based on a benefit-risk assessment. Tiagabine has a mechanism of action that resembles that of vigabatrin. Thus, suspicions have been presented that tiagabine might produce similar changes in visual function to those associated with vigabatrin.[50] However, findings have not been replicated and several studies have found normal visual function in patients treated with tiagabine. Although no significant association with visual field changes or acuities has yet been found with tiagabine, cases of deteriorating colour vision have been reported.[51-53]
2.3 Isotretinoin and Other Retinoids

Retinoids are used to treat severe recalcitrant nodular acne, acne vulgaris and severe recalcitrant psoriasis, and to induce remission of leukaemia. Ocular adverse effects are dose related and probably the most frequent adverse reactions of these drugs. Isotretinoin-related ocular adverse effects are listed with their WHO classifications in table II. The retinoid family includes vitamin A and synthetic derivatives such as isotretinoin, etretinate and retinoin. Isotretinoin, the most widely prescribed retinoid, has been associated with a certain WHO classification for inducing intracranial hypertension (IH) due to positive rechallenge data, a characteristic pattern of rapid IH onset after exposure, and the fact that this agent is a degradative product of alltrans retinoic acid (tretinoin), a known contributor to IH.[54-60] Vitamin A has been well documented as a cause of IH, and other retinoids such as tretinoin can cause IH.[61-63] The incidence of IH in patients taking tretinoin has been quoted as 9%.[64] Tretinoin,
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acitretin and etretinate have been reported as having a probable causal relationship to IH.[59] The mechanism of how retinoids cause IH has been postulated as being through a common pathway.[61] It is possible that high doses of this class of drug induce a secretion of cerebrospinal fluid and alter the lipid constituents of the arachnoid villi. This may then disrupt the normal transport systems and impede the absorption of cerebrospinal fluid at the arachnoid villi.[64] Isotretinoin has been shown to be secreted in tears by the lacrimal gland and has been associated with causing meibomian gland dysfunction and thus causing eye and contact lens discomfort, dry eye complaints, blepharoconjunctivitis, transient blurring of vision and acute transient refractive changes.[3] For patients receiving retinoids, we suggest the following management guidelines. In patients on retinoid therapies who develop otherwise unexplained headaches or blurred vision, a prompt ophthalmology consultation to rule out papilloedema should be performed. Periodic ophthalmology examinations should also be completed to rule out papilloedema even in asymptomatic patients on retinoid therapy for 6 months or more because IH can develop without symptoms. Concomitant use of tetracyclines or vitamin A should be avoided, as they may potentiate the development of IH.[65,66]
2.4 Ethambutol and Isoniazid

Ethambutol is still considered a primary therapy against Mycobacterium tuberculosis and has synergistic actions when combined with other agents.[67] It can cause a multitude of dose- and time-dependent ocular adverse effects including colour vision changes, visual field defects and, of most importance, unilateral or bilateral optic neuritis which can continue to progress for 12 months after the drug is discontinued.[68] The Physicians Desk Reference (PDR) discusses the possibility of optic neuropathy and attempts to provide guidelines for clinicians to screen for optic nerve toxicity.[16] However, it remains unclear what tests should be performed and how often. The literature describes a dose-related
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incidence of ocular adverse effects with development of optic neuropathy in 50% of patients at a dose of 60100 mg/kg/day, 56% at 25 mg/kg/day and 1% with dosages 15 mg/kg/day.[3] Ethambutol optic neuropathy is usually bilateral and can be asymmetric. Ethambutol toxicity may affect only the small calibre papillomacular bundle axons, and optic atrophy will not develop until months after the fibres are lost. This means objective findings on the fundus exam are frequently absent. The literature suggests that optic neuropathy may occur, on average, 28 months after starting therapy. The earliest ophthalmological findings in toxic optic neuropathy from ethambutol may be loss of visual acuity, colour vision loss or central scotomas. Ethambutol also has an affinity for the optic chiasm with bitemporal visual field defects manifesting with toxicity.[3,69] Isoniazid is frequently prescribed concurrently with ethambutol for tuberculosis owing to multiple cases of drug resistance to single-agent therapy. Isoniazid also has been associated with optic neuropathy, and differentiating toxicity due to ethambutol versus isoniazid can be challenging.[70,71] In general, the toxicity from isoniazid is less frequent, less severe and is usually reversible.[3] When in doubt, it may be necessary to undertake dechallenge with isoniazid and/or ethambutol after consultation with the primary care physician. The pathophysiology underlying ethambutol optic neuropathy remains unclear. However, one possible explanation is that ethambutol chelates copper in the retinal ganglion cells and their fibres in the optic nerve. Ethylenediiminodibutyric acid, a metabolite of ethambutol, is a strong chelator of copper. Copper is required as a cofactor for cytochrome c oxidase, a key enzyme in the electron transport chain and cellular oxidative metabolism within mitochondria. It is possible that ethambutol decreases the levels of copper available for cytochrome c oxidase, and therefore also decreases the required energy for axonal transport around the optic nerve.[72,73] Thus, mitochondrial insufficiency in the optic nerve fibres may underlie the impairment of
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axonal transport in the optic nerve and lead to optic neuropathy. The US PDR recommends monthly ophthalmic examinations for patients taking doses of ethambutol >15 mg/kg/day.[16] No official standard of care exists regarding how often to see patients and which tests to perform for those taking >15 mg/kg/ day. Outside the US, especially in some developing countries, monthly exams are not practical and would create a large burden for eye care providers. Because of medicolegal concerns, ophthalmologists in the US should use the PDR as a guideline, as the package insert published in the PDR was agreed upon by the FDA and industry alike. The authors of this article recommend obtaining informed consent prior to assuming care for patients taking ethambutol, explaining that optic neuropathy can occur at any dose despite regular ophthalmic exams and that vision loss can be severe and irreversible. A baseline examination should be performed including visual acuity, visual field and colour vision testing, and a dilated fundus and optic nerve exam. If any visual symptoms occur, the medication should be discontinued and the patient seen by an ophthalmologist. Frequency of examinations should be monthly for dosages >15 mg/kg/day (PDR); however, monthly exams at lower doses may be necessary for patients at increased risk for toxicity, such as those with diabetes mellitus, chronic renal failure or alcoholism, and for the elderly, children and those with other ocular pathologies or ethambutol-induced peripheral neuropathy. Discontinuation of ethambutol should be considered after any signs of loss of visual acuity or colour vision or for a visual field defect. Optical coherence tomography or contrast sensitivity testing should also be considered in these patients, as these tests could pick up early ethambutol toxicity not detected with the baseline exam.
2.5 Amiodarone

Amiodarone is a well known benzofuran derivative that is used in the treatment of various cardiac arrhythmias. Its half-life ranges from 26 to 160 days.[3] Ocular adverse effects produced by this drug
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are common and are time- and dose-dependent. Because of this, ophthalmic examinations should be conducted for a baseline and every 612 months, or more frequently depending on findings. The cornea is the most commonly affected ocular structure, with superficial punctuate opacities occurring in 69100% of patients receiving amiodarone. There is often a loss of eyelashes or eyebrows along with eyelid and periocular tissue photosensitivity. Furthermore, the conjunctiva may develop yellowbrown deposits. Lenticular changes can include anterior, subcapsular, small, yellow-white punctuate opacities and cortical changes.[3] One of the most severe adverse effects of amiodarone use is optic neuropathy. Amiodarone-associated optic neuropathy has been reported to have an incidence of 1.79%.[74] The expected incidence of nonarteritic ischaemic optic neuropathy in the general population aged 50 years is 0.3%.[74] Macaluso et al.[75] characterised amiodarone-associated optic neuropathy as having an insidious onset, slow progression, bilateral visual loss and protracted disc swelling that stabilised within months of discontinuing the medication. Because patients taking amiodarone often have severe vascular disease, the incidence of nonarteritic anterior ischaemic optic neuropathy (NAION) in these patients is probably higher than that of the agematched population. At present there are no reported cases of amiodarone neuropathy causing vision of no light perception. Macaluso and colleagues proposed that the insidious onset, bilateral pathology, less severe visual loss (20/20 to 20/200 in amiodarone-induced versus 20/20 to no light perception in NAION) and slower improvement of optic disc oedema of amiodarone-induced optic neuropathy compared with that of acute NAION helps the ophthalmologist in differentiating these two causes of decreased vision associated with optic disc oedema. The WHO classification of other established visual adverse effects related to this medication are listed in table II. The cause of amiodarone-induced optic neuropathy is unknown, but this condition may be due to a
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drug-induced lipid storage disease (primary lipidosis) in optic nerve axons.[76] There is a selective accumulation of intracytoplasmic lamellar inclusions in large optic nerve axons, and this may decrease axoplasmic flow biochemically or mechanically. Many of these patients may already have a compromised optic nerve secondary to vascular disease, and the amiodarone deposition in the axons further impedes neural function, causing vision loss. The result is optic nerve head oedema, which can persist as long as transport is compromised. Resultant optic nerve head oedema may persist as long as transport is inhibited, i.e. as long as several months following discontinuation of amiodarone, which, as noted earlier in this section, has a half-life of up to 160 days. Since it may be impossible to distinguish NAION from amiodarone-induced optic neuropathy in many patients, those who experience any visual disturbance should see an ophthalmologist promptly. Patients should have a baseline ophthalmic exam and may be seen every 6 months for monitoring, although this is controversial. If optic neuropathy is suspected, discontinuation of the drug in consultation with the patients cardiologist at the first signs of optic nerve involvement must be considered unless the ophthalmologist is very confident of the diagnosis of NAION.
2.6 Hydroxychloroquine

This aminoquinoline is used in the treatment of malaria and extraintestinal amoebiasis. Hydroxychloroquine is also used for the treatment of rheumatoid arthritis and lupus erythematosus, dermatological conditions and various inflammatory disorders. Ocular adverse effects can be numerous, including an enhanced Hudson-Stahli line, whorl-like corneal depositions (cornea verticillata), transient oedema, decreased sensitivity, retina parafoveal granularity of the retinal pigment epithelium (early in the disease), bulls-eye appearance of the macula (late in the disease), attenuation of the vascular tree, peripheral fine granular pigmentary changes, prominent choroidal pattern filling defects in late phase of
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fluorescein angiography, and other angiography changes.[3] Though the side effects of hydroxychloroquine are numerous, the most adverse are mainly doserelated, seen today usually in overdose situations, obese patients or extremely thin individuals. The most serious of these effects is a form of retinal toxicity known as hydroxychloroquine bulls-eye maculopathy. This name stems from the characteristic ring-like or bulls-eye pattern of retinal pigment epithelium atrophy and hyperfluorescence on fluorescein angiography. The mechanism of this toxicity is not well understood but it seems to be related to the affinity for this medication for melanin within the retinal pigment epithelium. Patients may have abnormal sensory testing responses and distorted colour vision (late phase of disorder) with a yellow, green or blue tinge to objects and coloured haloes around lights. This maculopathy is bilateral and reproducible by Amsler grid and visual field testing. Corneal deposits are also a characteristic finding in patients taking this medication. Vortex keratopathy or cornea verticillata is not specific to hydroxychloroquine but a finding of several amphophilic drugs that can form complexes with cellular phospholipids, which cannot be metabolised by lysosomal phospholipases and, thus, are visible clinically as deposits in the superficial cornea.[3] This medication also has been found to be excreted in the tear film and can aggravate dry eye along with possibly decreasing contact lens tolerance. For patients taking antimalarial drugs, the American Academy of Ophthalmology (2002) recommends baseline dilated fundus exams and testing the central visual field by Amsler grid or a central 10degree radius visual field using automated field testing (Humphrey 10-2 or similar).[77] Ideally, these tests should be done before starting the antimalarial mediations (or at the latest within 1 year after starting the medications). Low-risk patients are considered to be those taking <6.5 mg/kg/day for less than 5 years. These patients should have a follow-up examination every 5 years. Higher-risk patients, such as those taking >6.5 mg/kg/day for more than 5 years, should be examined more frequently. Risk
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factors such as being aged >60 years and having a high body fat level, concomitant kidney or liver disease, and/or concomitant retinal disease also justify more frequent examinations.[19] A recent preliminary paper by Shroyer et al.[78] suggests that individuals with an ABCR mutation (Stargadts disease) may also be predisposed to develop retinal toxicity when exposed to chloroquine/hydroxychloroquine. The goal of these recommendations is to find early changes, i.e. relative scotomas, and is aimed at detection and not prevention, as discontinuation of the drug is the only way to prevent possible adverse effects and this is not an option for some patients. Early paracentral relative scotomas seldom advance when the drug is discontinued. Later findings include retinal changes, colour vision loss, absolute scotoma or decreased vision. Even if the drug is stopped, once these occur, changes are irreversible, and many patients may continue to lose some vision and/or peripheral fields. How to best follow patients on hydroxychloroquine was summarised in an article by Marmor et al.[77] These recommendations, although not universally adopted, follow the overall guidelines of the American Academy of Ophthalmology for examining patients. Patients aged 2029 years should have one examination; 3039, two examinations; 4064, an examination every 24 years; and those 65 an examination every 12 years. To summarise these recommendations, the baseline examination should be performed within the first year after starting this drug. Patients should have a complete, dilated ophthalmic examination, including the informed consent mentioned earlier in this section, warning of possible permanent visual problems in rare instances. This baseline examination should include visual acuity testing, Amsler grid testing (with instructions for monthly home use), and optional colour vision testing (preferably including the blue-yellow axis, such as the pseudoisochromatic plates for colour [American Optical Corporation]). If macular abnormalities are evident, it would be ideal to obtain fundus photographs. If any progressive ocular abnormality is suspected, a baseline Humphrey 10-2 visual field or other autoDrugs 2007; 67 (1)

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mated perimetry concentrated on the central visual field should be considered. Multifocal electroretinogram (ERG) is optional. Additional complete follow-up examinations may be done at 2- to 4-year intervals, in patients younger than 40 years who are not deemed high risk. High-risk patients are those who are obese, extremely thin, frail, elderly or have significant renal or hepatic disease or macular disease of any type. Patients should be seen sooner if they experience any persistent visual symptoms, if they do not meet the above criteria, or if their dosage exceeds 6.5 mg/ kg. For patients aged 4064 years, follow-up every 24 years is adequate as long as the above high-risk criteria are not met. Patients aged 64 years should be followed more closely, with follow-up every 12 years. Annual eye examinations should be considered if patients have been on hydroxychloroquine therapy for longer than 5 years. Annual examinations are also appropriate for patients considered high risk or whose dosage exceeds 6.5 mg/kg. Follow-up exams should include repeat baseline examination and fundus photography if any macular abnormalities are noted. Fluorescein angiography should be considered in the presence of suspicious pigmentary changes. Automated central visual fields are optional. Multifocal ERG is helpful in selected patients. Patients taking chloroquine should undergo the same tests mentioned above for baseline and followup exams, as described above. Patients should be seen at least annually if dosage is <3.0 mg/kg of ideal bodyweight or every 6 months if dosage is >3.0 mg/kg bodyweight. Patients who are short, obese or have renal and/or liver impairment should also be seen every 6 months.
2.7 Erectile Dysfunction Agents

leads to increasing levels of cGMP, which causes smooth muscles in the corpus cavernosum to relax, allowing blood inflow. This medication is known to cause changes in colour perception as well as blurred vision. These agents may cause changes in light perception, increased perception of brightness and/or a sensation of seeing flashing lights, especially when blinking.[79] Sildenafil has also been shown to cause ERG changes. Ocular adverse effects are uncommon, dosage dependent and thus far have all been fully reversible. The WHO classification for these medications is listed in table II. These ocular adverse effects are dose dependent with all three drugs. The incidence with sildenafil use has been quoted to be 3% in those taking 50mg, 10% with 100mg and 4050% in those taking 200mg.[80,81] The incidence is the same for all ages, and the incidence and severity of reported ocular adverse effects is directly proportional to blood drug concentrations. The adverse effects based on dosage start 1530 minutes after ingestion of the drug and usually peak 60 minutes after ingestion.[81] Sildenafil can be used safely in patients with glaucoma and macular degeneration. Postmarketing surveillance of sildenafil, vardenafil and tadalafil has produced several reports associating these medications as possible culprits for anterior ischaemic optic neuropathy in several patients. So far there are no data which confirm a certain relationship between ischaemic optic neuropathy and erectile dysfunction medications. Present evidence from postmarketing surveillance suggests visual adverse effects, due to this class of medication, are benign and transitory. From these poorly documented data, the association between sildenafil and NAION is possible according to WHO criteria requiring that a clinical event occur within a reasonable time from drug administration. There is no well researched explanation as to how sildenafil therapy could cause NAION. Over 27 million men have used sildenafil. Most are vasculopathic and fall into an age group in which they are already at risk for NAION.[79] We feel that the only patients who should not take PDE5 inhibitors are those who have previously experienced NAION in one eye. These patients may
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Sildenafil, vardenafil and longer-acting tadalafil are selective inhibitors of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5). In the treatment of erectile dysfunction, inhibition of PDE5, which is responsible for the degradation of cGMP in the corpus cavernosum,
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be more prone to developing NAION in the same or fellow eye if sildenafil or other medicines in this class are ingested.
2.8 Tamoxifen

Tamoxifen is an antiestrogen agent primarily used in the treatment of estrogen-receptor positive breast cancer, ovarian cancer, pancreatic cancer and malignant melanoma. The standard dosage is 20 mg/day and the ocular adverse event incidence levels are about 12%. Dose-dependent ocular adverse effects include corneal opacities (whorl-like subepithelial calcium map-dot changes), and retinal or macular yellow or white refractile opacities, oedema, degeneration, pigmentary changes and haemorrhages.[3] Tamoxifen retinopathy most commonly occurs after more than 1 year of therapy when a total of >100g of the drug has been taken. The retinopathy can include cystoid macular oedema, punctuate macular retinal pigment epithelial changes, parafoveal haemorrhages and peripheral retinal pigment epithelium changes. Refractile bodies located in the inner retina histologically may be the products of axonal degeneration. Visual acuity loss and the retinal lesions do not appear to regress in chronic form of tamoxifen toxicity if the drug is discontinued unless cystoid macular oedema or haemorrhages are the cause of vision loss. An acute form of toxicity has been described but is not well defined and usually occurs within a few weeks after therapy is instituted. Symptoms include vision loss, retinal oedema, retinal haemorrhage and optic disc swelling. This was thought to result from tamoxifen estrogenic activity, which may cause venous thromboembolism. However, Gorin et al.[82,83] confirmed the risk of tamoxifen in the development of posterior subcapsular cataracts, but found minimal effects of this drug on retinal small vessel occlusive disease, with no more a risk factor than hypertension or glaucoma. We offer the following recommended guidelines. Baseline ophthalmic examination within the first year of starting tamoxifen, which should include slit lamp biomicroscopy of the anterior and posterior
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segments in combination with a handheld indirect or contact lens should be performed. Baseline colour vision testing is important. In keeping with the American Academy of Ophthalmologys current recommendations, in healthy adults, a complete eye examination at least every 2 years should be completed. More frequent examinations should be carried out if ocular symptoms occur. The discovery of a limited number of intraretinal crystals in the absence of macular oedema or visual impairment does not seem to warrant discontinuation of the drug. Consultation with the oncologist is essential if significant ocular findings occur. Presence of age-related maculopathy is not a contraindication to the use of tamoxifen. However, informed consent may be advisable in our litigious society. Presence of posterior subcapsular cataracts is not an indication to stop the drug, since the condition usually progresses even if the drug is discontinued. Significant colour loss may be a valid reason to consider discontinuing the drug. Gorin et al. recommend considering discontinuing the drug for 3 months (in patients on prophylactic therapy) and retesting.[82,83] If colour vision returns to normal, then restart the drug and retest in 3 months. If, at any time, there is no rebound from stopping the drug, or continued progression, then it may be necessary to consult an oncologist and reevaluate the benefit-risk.
2.9 Cyclo-Oxygenase-2 Inhibitors

Cyclo-oxygenase (COX)-2 inhibitors are indicated in the treatment of osteoarthritis, rheumatoid arthritis, acute pain and dysmenorrhoea through selective blockade of COS-2 receptors. The anti-inflammatory activity appears to be effective with fewer gastrointestinal adverse effects than older NSAIDs. Selective COX-2 inhibitors include rofecoxib, celecoxib, valdecoxib, lumiracoxib, nimesulide and etodolac. With these medications, blurred vision and conjunctivitis appear to be identified most frequently as adverse effects associated with COX-2 inhibitors, especially for rofecoxib and celecoxib, the two most widely prescribed medications in this class[84] (table II).
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Coulter et al.[85] propose a possible mechanism behind the blurred vision some patients experience when receiving COX-2 inhibitors. Inhibition of synthesis of prostaglandins and other related compounds that control retinal blood flow could lead to visual changes. The vascular endothelium of retinal blood vessels produces compounds such as prostacyclin, thromboxane A2 and prostaglandin H2. Both COX-1 and COX-2 mediate synthesis of prostacyclin. Inhibition of either COX-1 or COX-2 may alter the COX pathway and in turn alter regulation of retinal blood flow with potential changes in vision.[86] Other NSAIDs have been reported to cause blurred vision consistent with this theory.[87,88] In the case of selective COX-2 inhibitors, another mechanism may contribute to the blurred vision some patients experience. Four of the six COX-2 inhibitors are sulfonamides: celecoxib, rofecoxib, valdecoxib and nimesulide. Sulfonamide medications are known to cause blurred vision through what is thought to be transient myopia. The mechanism is not fully understood but could include lenticular swelling, forward rotation of the lens-iris diaphragm, ciliary body swelling causing increased curvature of the lens surfaces, and spasm of accommodation.[25,87-89] The sulfonamide property of these COX-2 inhibitors could contribute to some cases of blurred vision. Curiously, the two non-sulfur-containing selective COX-2 inhibitors do not have the bulk of data to support a certain association with blurred vision including a paucity of positive rechallenge reports. Conjunctivitis also has a certain association with some COX-2 inhibitors. This may not be unusual, as many medications are secreted in the tears. It is possible these medications are secreted in the tears as well, leading to transient inflammation of the conjunctiva which resolves upon discontinuation of the drug. Many examples of this exist, such as irritative conjunctivitis from oral diazepam or oral isotretinoin.[3,55,90] Discontinuation of therapy leads to resolution without long-term sequelae. In every instance studied, the ocular adverse effect resolved within 72 hours of discontinuation of COX-2 inhibitor.
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2.10 Nicotinic Acid

Nicotinic acid (niacin) taken orally has been proven in the treatment of cardiovascular and cerebrovascular disease because of its cholesterol- and triglyceride-lowering effects.[91-93] A comprehensive review of ocular adverse effects from nicotinic acid indicates a possible association with decreased vision, cystoid macular oedema, dry eyes, discoloration of the eyelids, eyelid oedema, proptosis, loss of eyebrows and eyelashes, and superficial punctate keratitis.[91] The most serious of these is cystoid macular oedema (CME). CME occurs primarily in patients receiving 3 g/day, although it has been seen in patients taking as little as 1.5 g/day. A characteristic, but not pathognomonic, petalloid hyperfluorescence without leakage is revealed by fluorescein angiography. The mechanism behind CME is unknown but the condition usually resolves within 2 weeks after stopping treatment with nicotinic acid. A possible aetiology could be a prostaglandin-induced toxic response on the Muller cells or intracellular accumulation of fluid secondary to some as yet undocumented derangement of intracellular metabolism.[93,94]
2.11 Herbal Medications

Herbal medicines and nutritional supplements are not marketed to treat specific diseases, are exempt from the interstate commerce law and fall under the purview of the Dietary Supplement and Health Education Act of 1994 in the US. No efficacy or safety has to be proven to sell these agents, of which there are 700 botanicals and 1000 nutritional products.[16,95] These products are of clinical importance to ophthalmologists, since many of the therapies can cause adverse effects and some interfere with prescribed medications. Approximately 40% of patients who use alternative therapies do not disclose this information to their doctor.[96] Canthaxanthine, chamomile, datura, Echinacea purpurea, Ginkgo biloba, liquorice (licorice) and vitamin A are all associated with clinically significant ocular adverse effects[94,97] (table II).
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2.11.1 Canthaxanthine

This agent is used in cosmetics, as a food colouring and to produce an artificial suntan when administered orally. It is naturally occurring and is found in crustaceans and chanterelle mushrooms. When taken orally, canthaxanthine can deposit in all layers of the retina, especially the superficial layers of the macula. Clinically, the retinal findings are slowly reversible and patients are usually asymptomatic, but visual changes may be seen in static threshold perimetry, electroretinography and changes in dark adaptation.[16,98]
2.11.2 Chamomile

reaction.[101] There is evidence that echinacea may activate the bodys autoimmune response, and the PDR suggests that its use be avoided in patients with autoimmune diseases.[16]
2.11.5 Ginkgo biloba

Ginkgo biloba has been shown to act as a blood thinner and increase bleeding times.[101] Spontaneous hyphaema and retinal haemorrhages have occurred in patients taking this agent. Thus, ginkgo should be used with caution in patients who are also taking warfarin or aspirin, as the effects are additive.
2.11.6 Liquorice

Chamomile (Matricaria chamomilla) is used usually in the form of tea to treat eye disease as well as insomnia, indigestion, migraine headaches, bronchitis, fevers, colds, inflammation and burns.[95,99] There is strong evidence that this tea, when applied topically in or around the eye, can cause severe conjunctivitis. A possible mechanism for these patients conjunctivitis could be sensitivity to the allergens present in M. chamomilla pollen. Because patients are using chamomile to treat their eyes, clinicians should recognise the possibility of M. chamomilla sensitivity in patients with what appears to be allergic conjunctivitis, especially in patients who already have an atopic history.[94]
2.11.3 Datura

The dried leaves of datura are used to treat eye inflammation as well as asthma, bronchitis, influenza and coughs. The leaves contain alkaloids, in extremely varying concentrations, which are anticholinergic and parasympatholytic. Jimson weed (Datura stramonium) is the main member of this genus utilised for its potential therapeutic value. These botanicals have been shown to contain scopolamine and have been associated with pupillary dilation.[94]
2.11.4 Echinacea purpurea

Liquorice (Glycyrrhiza glabra) root derives some of its medicinal properties from the isoflavonoid glabridin. Glabridin inhibits COX activity, and has both anti-inflammatory and antiplatelet effects. It may help patients with gastric ulcers and peptic ulcers. Ocular migraine-like visual symptoms have been reported that occur without a headache.[94] The authors of this article postulate that vasospasm of the brain, retinal and/or optic nerve blood vessels plays a role in these visual symptoms, as there is strong evidence that liquorice, through its glucocorticoid and noradrenaline effects, can cause vasospasm throughout the body.[102] Clinically, it appears that individuals need to consume large amounts of liquorice for ocular adverse effects to occur. However, caution is advised if a patient has a history of migraine headaches, as the effects could be additive.
2.11.7 Vitamin A (Retinol)

Echinacea is a herbal product used to treat the common cold, cough, fevers, urinary tract infections, burns and influenza.[94,100] An allergic conjunctivitis has been associated with this product. The mechanism may be due to an anaphylactic
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Vitamin A is used primarily as an oral dietary supplement and in the treatment of vitamin A deficiency and acne. Vitamin A plays a vital role in vision and is an essential fat-soluble vitamin for many biological activities. Vitamin A deficiency can result in night blindness, xerosis of the conjunctiva and cornea, and alopecia of the eyelashes.[94] There is strong evidence that retinoids, particularly if taken in excess, can cause IH.[54,55] Physicians should be aware that large doses of vitamin A can cause IH and special caution should be exercised with patients who are taking vitamin A in addition to another type of retinoid, such as isotretinoin, as the effects could be additive in the causation of IH. This
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condition resolves in the majority of patients when vitamin A is discontinued.


2.11.8 Summary

authors have no conflicts of interest that are directly relevant to the content of this review.

Herbal medicines and nutritional supplements are being used by a large segment of the population, often without strong evidence on efficacy or safety. Fortunately, if the clinician recognises an ocular or systemic adverse effect from one of these agents, the symptoms are usually reversible. Clinicians should remain vigilant in recognising adverse ocular reactions as well as enquiring whether these alternative treatments are being used, as patients frequently do not disclose this information to their physicians. 3. Conclusion Adverse reactions to medications are an important health problem and it is the role of healthcare professionals to detect, treat and educate the public about them. Many systemic drugs may produce ocular toxicity. Any drug in any form may cause an adverse ocular reaction if it reaches the eye. Fortunately, most ocular changes induced by drugs are reversible if detected in the early stages of toxicity, although if they are not detected early, some adverse reactions may progress to cause serious and irreversible ocular damage associated with significant loss of visual performance. Diagnosing drug reactions requires a high index of suspicion and careful review of the patients history, including recent use of a drug. Withdrawal of the suspected drug should result in improvement (dechallenge), and reinstitution of the drug (rechallenge) should exacerbate the patients condition. Knowledge of drugs with potential to produce adverse ocular reactions should be updated as knowledge of these adverse outcomes arises. Acknowledgements
This study was supported in part by an unrestricted grant to Casey Eye Institute from Research to Prevent Blindness, New York, NY and by the National Registry of Drug-Induced Ocular Side Effects (www.eyedrugregistry.com). This report did not require approval by the OHSU Institutional Review Board. We would like to thank Genevieve Long for her assistance in the editing and modifications of this paper. The

References
1. Bettman JW. Seven hundred medicolegal cases in ophthalmology. Ophthalmology 1990; 97: 1379-84 2. Brick DC. Medication errors result in costly claims for ophthalmologists. Surv Ophthalmol 1995; 40: 232-6 3. Fraunfelder FT, Fraunfelder FW. Drug-induced ocular side effects. 5th rev. ed. Boston (MA): Butterworth-Heinemann, 2001 4. Chiou GCY. Ocular toxicology. 2nd ed. Philadelphia (PA): Taylor & Francis, 1999: 43-86, 225-354 5. Kersey JP, Broadway DC. Corticosteroid-induced glaucoma: a review of hte literature. Eye 2006 Apr; 20 (4): 407-16 6. Edwards R, Biriell C. Harmonisation in pharmacovigilance. Drug Saf 1994; 10: 93-102 7. Fleish H. Bisphosphonates. Pharmacology and use in the treatment of tumour-induced hypercalcaemic and metastatic bone disease. Drugs 1991; 42: 919-44 8. Fraunfelder FW, Rosenbaum JT. Drug-induced uveitis. Incidence, prevention and treatment. Drug Saf 1997; 17: 197-207 9. Macarol V, Fraunfelder FT. Pamidronate disodium and possible ocular adverse drug reactions. Am J Ophthalmol 1994; 118: 220-4 10. Fraunfelder FW, Fraunfelder FT. Scleritis and other ocular side effects associated with pamidronate disodium. Am J Ophthalmol 2003; 135: 219-22 11. Fraunfelder FW, Fraunfelder FT. Bisphosphonates and ocular side effects. N Engl J Med 2003; 348: 1187-8 12. Foster CS, Forstot SL, Wilson LA. Mortality rate and rheumatoid arthritis patients developing necrotizing scleritis or peripheral ulcerative keratitis: effects of systemic immunosuppression. Ophthalmology 1984; 91: 1253-63 13. Stewart GO, Stuckey BG, Ward LC. Iritis following intravenous pamidronate. Aust N Z J Med 1996; 26: 414-5 14. Ghose K, Waterworth R, Trolove P. Uveitis associated with pamidronate. Aust N Z J Ophthalmol 1994; 24: 320 15. Des Grottes JM, Schrooyen M, Dumon JC. Retrobulbar optic neuritis after pamidronate administration in a patient with a history of cutaneous porphyria. Clin Rheumatol 1997; 16: 93-5 16. Medical Economics Company. Physicians Desk Reference. 56th ed. Montvale (NJ): Medical Economics Company, 2002 17. Diel IJ, Solomayer EF, Costa SD, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998; 339: 357-63 18. Fietta P, Manganelli P, Lodigiani L. Clodronate induced uveitis. Ann Rheum Dis 2003; 62: 378 19. Thiebaud D, Sauty A, Burckhardt P, et al. An in vitro and in vivo study of cytokines in the acute-phase response associated with bisphosphonates. Calcif Tissue Int 1997; 61: 386-92 20. Mbekeani JN, Slamovits TL, Schwartz BH, et al. Ocular inflammation associated with alendronate therapy. Arch Ophthalmol 1999; 117: 837-8 21. Malik AR, Campbell SH, Toma NM. Bilateral acute anterior uveitis after alendronate. Br J Ophthalmol 2002; 86: 1443 22. Siris ES. Bisphosphonates and iritis. Lancet 1993; 341: 436-7 23. Vinas G, Olive A, Holgado S, et al. Episcleritis secondary to risedronate. Med Clin 2002 Apr 27; 118: 598-9 24. Watson PG. The nature and the treatment of scleral inflammation. Trans Ophthalmol Soc UK 1982; 102: 257-81

2007 Adis Data Information BV. All rights reserved.

Drugs 2007; 67 (1)

92

Santaella & Fraunfelder

25. Fraunfelder FW, Fraunfelder FT, Keates EU. Topiramate-associated acute, bilateral, secondary angle-closure glaucoma. Ophthalmology 2004 Jan; 111 (1): 109-11 26. Thambi L, Kapcala LP, Chambers W, et al. Topiramate-associated secondary angle-closure glaucoma: a case series. Arch Ophthalmol 2002 Aug; 120 (8): 1108 27. Banta JT, Hoffman K, Budenz DL, et al. Presumed topiramateinduced bilateral acute angle-closure glaucoma. Am J Ophthalmol 2001 Jul; 132: 112-4 28. Bovino JA, Marcus FF. The mechanism of transient myopia induced by sulfonamide therapy. Am J Ophthalmol 1982 Jul; 94: 99-101 29. Chirls IA, Norris JW. Transient myopia associated with vaginal sulfanilamide suppositories. Am J Ophthalmol 1984 Jul 15; 98: 120 30. Hook SR, Holladay JT, Prager TC, et al. Transient myopia induced by sulfonamides. Am J Ophthalmol 1986 Apr 15; 101: 495-6 31. Kimura R, Kasai M, Shoji K, et al. Swollen ciliary processes as an initial symptom in Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol 1983 Mar; 95: 402 32. Ben-Menachem E. Vigabatrin. Epilepsia 1995; 36 Suppl. 2: S95-104 33. Marson AG, Kadir ZA, Hutton JL, et al. The new antiepileptic drugs: a systemic review of their efficacy and tolerability. Epilepsia 1997 Aug; 38: 859-80 34. Chiron C, Dulac O, Luna D, et al. Vigabatrin in infantile spasms. Lancet 1990 Feb 10; 335: 363-4 35. Hancock E, Osborne JP. Vigabatrin in the treatment of infantile spasms in tuberous sclerosis: literature review. J Child Neurol 1999 Feb; 14: 71-4 36. Meldrum BS. GABAergic mechanisms in the pathogenesis and treatment of epilepsy. Br J Clin Pharmacol 1989; 27: 3-11S 37. Tanganelli P, Regesta G. Vigabatrin vs. carbamazepine monotherapy in newly diagnosed focal epilepsy: a randomized response conditional crossover study. Epilepsy Res 1996; 25: 257-62 38. Elke T, Talbot JF, Lawden MC. Severe persistent visual field constriction associated with vigabatrin. BMJ 1997; 314: 180-1 39. Wild JM, Martinez C, Reinshagen G, et al. Characteristics of a unique visual field defect attributed to vigabatrin. Epilepsia 1999; 40: 1784-94 40. Kalviainen R, Nousiainen I, Mantyjarvi M, et al. Vigabatrin, a GABAergic antiepileptic drug, causes concentric visual field defects. Neurology 1999; 53: 922-66 41. Miller NR, Johnson MA, Paul SR, et al. Visual dysfunction in patients receiving vigabatrin. Neurology 1999; 53: 2082-7 42. Daneshvar H, Racette L, Coupland SG, et al. Symptomatic and asymptomatic visual loss in patients taking vigabatrin. Ophthalmology 1999; 106: 1792-8 43. Harding GFA, Wild JM, Robertson KA, et al. Separating the retinal electrophysiologic effects of vigabatrin: treatment versus field loss. Neurology 2000; 55: 347-52 44. Gross-Tsur V, Banin E, Shahar E, et al. Visual impairment in children with epilepsy treated with vigabatrin. Ann Neurol 2000; 48: 60-4 45. Mustafa BA. Diversity of GABA receptors in the vertebrate outer retina. Trends Neurosci 1995; 85: 118-20 46. Pow DV, Baldridge W, Crook DK. Activity-dependent transport of GABA analogues into specific cell types demonstrated at high resolution using a novel immunocytochemical strategy. Neuroscience 1996; 73: 1129-43

47. Butler WH. The neuropathology of vigabatrin. Epilepsia 1989; 30 Suppl. 3: S15-17 48. Neal MJ, Cunningham JR, Shah MA, et al. Immunocytochemical evidence that vigabatrin in rats causes GABA accumulation in glial cells of the retina. Neurosci Lett 1989; 89: 29-32 49. Daneshvar H, Racette L, Coupland SG, et al. Symptomatic and asymptomatic visual loss in patients taking vigabatrin. Ophthalmology 1999; 106: 1792-8 50. Kaufman KR, Lepore FE, Keyser BJ. Visual fields and tiagabine: a quandary. Seizure 2001; 10: 525-9 51. Krauss G, Johnson M, Sheth S, et al. A controlled study comparing visual function in patients treated with vigabatrin and tiagabine. J Neurol Neurosurg Psychiatr 2003; 74: 339-43 52. Nousiainen I, M ntyj rvi M, K lvi inen R. Visual function in a a a a patients treated with the GABAergic anticonvulsant drug tiagabine. Clin Drug Invest 2000; 20: 393-400 53. Sorri I, Kalviainen R, Mantyjarvi M. Color vision and contrast sensitivity in epilepsy patients treated with initial tiagabine monotherapy. Epilepsy Res 2005 Dec; 67 (3): 101-7 54. Fraunfelder FW, Fraunfelder FT, Corbett JJ. Isotretinoin-associated intracranial hypertension. Ophthalmology 2004 Jun; 111 (6): 1248-50 55. Fraunfelder FT, Fraunfelder FW. Ocular side effects possibly associated with isotretinoin usage. Am J Ophthalmol 2001; 132 (3): 299-305 56. Cchroeter T, Lanvers C, Herding H, et al. Pseudotumor cerebri induced by all-trans-retinoic acid in a child treated for acute promyelocytic leukemia. Med Pediatr Oncol 2000; 34: 284-6 57. Sano F, Tsuji K, Kunika N, et al. Pseudotumor cerebri in a patient with acute promyelocytic leukemia during treatment with all-trans-retinoic acid. Intern Med 1998; 37 (6): 546-9 58. Tiamkao S, Sirijirachai C. Pseudotumor cerebri caused by alltrans-retinoic acid: a case report. J Med Assoc Thai 2000; 83 (11): 1420-3 59. Fraunfelder FW, Fraunfelder FT. Evidence for a probable causal relationship between tretinoin, acitretin, and etretinate and intracranial hypertension. J Neuroophthalmol 2004 Sep; 24 (3): 214-6 60. Guirgis MF, Lueder GT. Intracranial hypertension secondary to all-trans retinoic acid treatment for leukemia: diagnosis and management. J AAPOS 2003; 7 (6): 432-4 61. Morrice G, Havener WH, Kapetansky F. Vitamin A intoxication as a cause of pseudotumor cerebri. JAMA 1960; 173: 1802-5 62. Jacobson DM, Berg R, Wall M, et al. Serum vitamin A concentration is elevated in idiopathic intracranial hypertension. Neurology 1999; 53 (5): 1114-8 63. Visani G, Manfroi S, Tosi P, et al. All-trans-retinoic acid and pseudotumor cerebri. Leuk Lymphoma 1996; 23: 437-42 64. Roytman M, Frumkin A, Bohn TG. Pseudotumor cerebri caused by isotretinoin. Cutis 1988; 42: 399-400 65. Lee AG. Pseudotumor cerebri after treatment with tetracycline and isotretinoin for acne. Cutis 1995; 55 (3): 165-8 66. Donahue SP. Recurrence of idiopathic intracranial hypertension after weight loss: the carrot craver. Am J Ophthalmol 2000; 130 (6): 850-1 67. Hoffner SE, Kallenius G, Beezer AE, et al. Studies on the mechanisms of the synergistic effects of ethambutol and other antibacterial drugs on Mycobacterium avium complex. Acta Leprol 1989; 7 Suppl. 1: 195-9 68. Sadun AA. Metabolic optic neuropathies. Semin Ophthalmol 2002; 17 (1): 29-32

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Drugs 2007; 67 (1)

Ocular Adverse Effects Associated with Systemic Medications

93

69. Kaimbo WK, Bifuko ZA, Longo MB, et al. Color vision in 42 Congolese patients with tuberculosis receiving ethambutol treatment. Bull Soc Belge Ophtalmol 2002; 284: 57-61 70. Karmon G. Bilateral optic neuropathy due to combined ethambutol and isoniazid treatment. Ann Ophthalmol 1979; 11: 1013 71. Kass I, Mandel W. Isoniazid as a cause of optic neuritis and atrophy. JAMA 1957; 164: 1740-3 72. Kozak SF, Inderlied CB, Hsu HY, et al. The role of copper on ethambutols antimicrobial action and implications for ethambutol-induced optic neuropathy. Diagn Microbiol Infect Dis 1998; 30: 83-7 73. Sadun AA. Metabolic optic neuropathies. Semin Ophthalmol 2002 17(1):29-32 74. Feiner LA, Younge BR, Kazmier FJ, et al. Optic neuropathy and amiodarone therapy. Mayo Clin Proc 1987; 62: 702-17 75. Macaluso DC, Shults WT, Fraunfelder FT. Features of amiodarone-induced optic neuropathy. Am J Ophthalmol 1999; 127 (5): 610-2 76. Mantyjarvi M, Tuppurainen K, Ikaheimo K. Ocular side effects of amiodarone. Surv Ophthalmol 1998; 42: 360-6 77. Marmor MF, Carr RE, Easterbrook E, et al. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy: a report by the American Academy of Ophthalmology. Ophthalmology 2002; 109: 1377-82 78. Shroyer NF, Lewis RA, Lupski JR. Analysis of the ABCR (ABCA4) gene in 4 aminoquinoline retinopathy: is retinal toxicity by chloriquinine and hydroxychlorquine related to Stargardt disease? Am J Ophthalmol 2001 Jun; 131 (6): 761-6 79. Fraunfelder FW. Visual side effects associated with erectile dysfunction agents. Am J Ophthalmol 2005 Oct; 140 (4): 723-4 80. Reivich M, Holling HE, Roberts B, et al. Reversal of blood flow through the vertebral artery and its effect on cerebral circulation. N Engl J Med 1961 Nov 2; 265: 878-85 81. Laties AM, Fraunfelder FT. Ocular safety of Viagra (sildenafil citrate). Trans Am Ophthalmol Soc 1999; 97: 115-28 82. Gorin MB, Day R, Costantino JP, et al. Long-term tamoxifen citrate use and potential ocular toxicity. Am J Ophthalmol 1998; 125: 493-501 83. Gorin MB, Costantino JP, Kulacoglu DN, et al. Is tamoxifen a risk factor for retinal vaso-occlusive disease? Retina 2005; 25: 523-6 84. Fraunfelder FW, Solomon J, Mehelas TJ. Ocular side effects associated with cyclooxygenase-2 inhibitors. Arch Ophthalmol 2006; 124: 277-279 85. Coulter DM, Clark DWJ, Savage RL. Celecoxib, rofecoxib, and acute temporary visual impairment. BMJ 2003; 327: 1214-5 86. Haefliger IO, Meyer P, Flammer J, et al. The vascular endothelium as a regulator of the ocular circulation: a new concept in ophthalmology. Surv Ophthalmol 1994; 39: 123-32

87. Tullio CJ. Ibuprofen-induced visual disturbance. Am J Hosp Pharm 1981; 38: 1362 88. Nicastro NJ. Visual disturbances associated with over-thecounter ibuprofen in three patients. Ann Ophthalmol 1989; 21: 447-50 89. Bovino JA, Marcus FF. The mechanism of transient myopia induced by sulfonamide therapy. Am J Ophthalmol 1982; 94: 99-101 90. Lutz EG. Allergic conjunctivitis due to diazepam. Am J Psych 1975; 132 (5): 548 91. Fraunfelder FW, Fraunfelder FT, Illingworth DR. Adverse ocular effects associated with niacin therapy. Br J Ophthalmol 1995; 79: 54-6 92. Gass JDM. Nicotinic acid maculopathy. Am J Ophthalmol 1973; 76: 500-10 93. Jampol LM. Niacin maculopathy. Ophthalmology 1988; 95: 1704-5 94. Fraunfelder FW. Ocular side effects associated with dietary supplements and herbal medicines. Drugs Today 2005; 41 (8): 537-45 95. Physicians Desk Reference for herbal medicines. 2nd rev. ed. Montvale (NJ): Thomson Healthcare, 2004 96. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA 1998 Nov 11; 289 (18): 1569-75 97. Fraunfelder FW. Ocular side effects from herbal medicines and nutritional supplements. Am J Ophthalmol 2004 Oct; 138 (4): 639-47 98. Espaillat A. Canthaxanthine retinopathy. Arch Ophthalmol 1999; 113: 412-3 99. Subiza J. Allergic conjunctivitis to chamomile tea. Ann Allergy Asthma Immunol 1990; 65: 127-32 100. Blumenthal M, editor. The complete German Commission E monographs therapeutic guide to herbal medicines. Austin (TX): American Botanical Council, 1998 101. Grimm W, Muller H. A randomized controlled trial of the effect of fluid extract of echinacea purpurea on the incidence and severity of colds and respiratory infections. Am J Med 1999 Feb; 106: 138-43 102. Dobbins KR, Saul RF. Transient visual loss after licorice ingestion. J Neurophthalmol 2000 Mar; 20: 38-41

Correspondence and offprints: Dr Frederick W. Fraunfelder, Casey Eye Institute, 3375 SW Terwilliger Blvd, Portland, OR 97201, USA.

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ADIS DRUG PROFILE

Drugs 2007; 67 (1): 95-106 0012-6667/07/0001-0095/$49.95/0 2007 Adis Data Information BV. All rights reserved.

Fixed-Dose Combination Lercanidipine/Enalapril


Philip I. Hair, Lesley J. Scott and Caroline M. Perry
Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Conshohocken, Pennsylvania, USA

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 1. Pharmacodynamic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 2. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 3. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 4. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 5. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 6. Lercanidipine/Enalapril: Current Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

Features and properties of fixed-dose combination lercanidipine/enalapril (Zanipress, Zanitek)

Abstract
v Lercanidipine, a dihydropyridine calcium channel blocker, and enalapril, an ACE inhibitor, are established antihypertensive agents. A fixed-dose tablet formulation of lercanidipine/enalapril is approved in Germany for the treatment of hypertension in patients not responding to monotherapy. v Lercanidipine/enalapril 10mg/10mg once daily significantly reduced sitting diastolic blood pressure and sitting systolic blood pressure, relative to lercanidipine 10mg once daily, in a 12-week, randomised, double-blind trial in patients with mild to moderate hypertension who had previously not responded to 4 weeks treatment with lercanidipine. v In a similarly designed trial, lercanidipine/enalapril 10mg/20mg once daily was significantly more effective than enalapril 20mg once daily in hypertensive patients who had previously not responded to enalapril monotherapy. v Fixed-dose lercanidipine/enalapril was generally well tolerated, with a tolerability profile similar to that of either of the individual drugs alone or placebo. Cough was reported in 5.2% and peripheral oedema in 1.5% of lercanidipine/enalapril recipients.

Indication Hypertension not adequately controlled by monotherapy with lercanidipine or enalapril Mechanism of action Lercanidipine inhibits calcium entry through L-type channels into vascular smooth muscle cells; enalaprilat, the active metabolite of enalapril, inhibits angiotensin converting enzyme, thereby reducing levels of angiotensin II Dosage and administration Recommended dose Lercanidipine/enalapril 10mg/ 10mg in nonresponders to lercanidipine; lercanidipine/ enalapril 10mg/20mg in nonresponders to enalapril Route of administration Oral Frequency of administration Once daily, 15 min before a meal Steady-state pharmacokinetics of S-lercanidipine (S-LER), enalapril (EN) and enalaprilat (ENL) in patients (n = 20) with essential hypertension (lercanidipine/enalapril 10mg/20mg capsule once daily for 8 days) Peak plasma concentration 3.6; 91; 53 g/L (S-LER; EN; ENL) Time to peak plasma 1; 1; 4 hours concentration (S-LER; EN; ENL) Adverse events Most frequent Cough, headache, dizziness, peripheral oedema, flushing, vertigo

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Hypertension is a significant factor in the development of cerebrovascular disorders, heart disease and renal failure, and is estimated to contribute to 5% of the global disease burden.[1] The consequences of hypertension represent a continuum of a progressive cardiovascular syndrome, rather than just elevated blood pressure (BP) alone, leading to structural and functional changes in the heart and vascular system.[2] The aim of treatment is to reduce the long-term risk of cardiovascular morbidity and mortality, by targeting not only raised BP but also risk factors such as diabetes mellitus.[3] Reduction of systolic BP (SBP) to the desired target value (<140mm Hg, or <130mm Hg in patients with diabetes mellitus or renal disease) is not easily achieved with a single antihypertensive medication; a combination of drugs is required in a large proportion of patients to achieve this goal.[3-5] A combination regimen is more likely to achieve BP control if the component drugs have different mechanisms of action, since elevated BP is the result of a multifactorial process.[3-5] Combining a calcium channel blocker (CCB) with an ACE inhibitor is one of the combination regimens recommended in several antihypertensive guidelines;[3-5] one such potential regimen is fixeddose lercanidipine/enalapril. Lercanidipine, a dihydropyridine CCB, induces vascular relaxation, with a consequent decline in vascular resistance and arterial pressure.[5] However, this class of drugs is also likely to have some undesirable effects (e.g. peripheral oedema), as a result of activation of both the sympathetic nervous system and the renin-angiotensin-aldosterone axis.[6] The concomitant administration of an ACE inhibitor, such as enalapril, may counteract these unwanted effects.[6] A further advantage of ACE inhibitors is their potential to reduce the incidence of new-onset diabetes.[7] Furthermore, administering the agents as an individual fixed-dose tablet or gelatin capsule is likely to provide several potential advantages over separate administration, such as lower dose, improved patient compliance and greater cost effectiveness.[6]
1

Lercanidipine[8,9] and enalapril[10,11] are well established therapies for hypertension, and have been reviewed previously in Drugs. This review focuses on the use of oral fixed-dose lercanidipine/enalapril (Zanipress, Zanitek)1 in the treatment of adult patients with essential hypertension. 1. Pharmacodynamic Profile No published pharmacodynamic data are available for the combination of lercanidipine and enalapril; consequently, a brief overview of the pharmacodynamics of the individual drugs, based largely on previous reviews,[8-11] is provided in this section.
Lercanidipine
q Lercanidipine inhibits calcium entry through Ltype calcium channels, for which the S-enantiomer has 100- to 200-fold higher affinity than the Renantiomer, in smooth muscle cells of the cardiovascular system, resulting in peripheral vasodilation and reduced BP.[8,9,12] Antihypertensive effects have a gradual onset and long duration, relative to those of other CCBs such as nifedipine and nitrendipine.[8,9] q In vitro data indicate that lercanidipine is highly selective for vascular smooth muscle, relative to cardiac tissue,[8,9] possibly as a result of a greater proportion of L-type Ca2+ channels existing in a high-affinity inactivated state that is readily blocked by lercanidipine.[13] q Lercanidipine may have antiatherogenic effects that are independent of its BP-lowering effects.[8,9,14-17] In hypertensive patients with coexisting type 2 diabetes, lercanidipine 10 mg/day for 16 weeks reduced levels of low-density lipoproteincholesterol oxidation (measured as conjugated diene formation) by 35% relative to baseline (p < 0.001).[16] The drug also delayed the development of fatty streaks and hyperplastic lesions in a rabbit model,[14] and inhibited smooth muscle cell proliferation and migration[15] and the release of

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metalloproteinases and esterification of cholesterol in macrophages[17] in vitro. q Lercanidipine appears to have no clinically relevant effects on heart rate or ECG parameters in patients with hypertension.[9] In addition, there was no significant change from baseline in left ventricular mass in 23 patients with hypertension who received 6 months treatment with lercanidipine (10mg once daily for the first 4 weeks and then 10 or 20mg once daily).[18] q Lercanidipine 10[19,20] or 20[20] mg/day also appears to have renoprotective effects; creatinine clearance (CLCR) was increased by 10% (p = 0.019) in hypertensive patients with renal dysfunction (CLCR <80 mL/min [<4.8 L/h]) over 6 months,[19] and albumin excretion was reduced by 20% (p < 0.05) in hypertensive patients with microalbuminuria and type 2 diabetes over 12 months.[20] In spontaneously hypertensive rats, lercanidipine inhibited glomerular hypertrophy (18%),[21] vasodilated afferent (23% reduction in wall-to-lumen ratio) and efferent (19% reduction in wall-to-lumen ratio) glomerular arterioles[22] and reduced albuminuria (28%)[22] [all p < 0.05 vs baseline]. q Lercanidipine 1030mg once daily for 2448 weeks had neutral or favourable effects on lipids in patients with hypertension, while doses of 10 or 20 mg/day improved glucose tolerance and reduced fasting blood glucose, glycosylated haemoglobin and serum fructosamine levels in hypertensive patients with type 2 diabetes after 8 weeks.[9]
Enalapril

effect occurring 68 hours after administration; higher doses prolong the duration of the BP-lowering effect to a total of 2436 hours.[10] Enalapril 10 or 20 mg/day (n = 7) for 12 months decreased both the media-to-lumen ratio (from 0.117 to 0.093; p < 0.01) in subcutaneous small arteries and left ventricular mass index (from 94.8 to 78.7 g/m2; p < 0.05) in patients with hypertension and type 2 diabetes (n = 15).[24] Small artery remodelling is regarded as an early indicator of endorgan damage as it not only increases peripheral resistance but also impedes blood supply to organs such as heart, brain and kidney, thereby contributing to complications of hypertension.[25] q Enalapril 10 or 20 mg/day changed carotid artery intima-media thickness (IMT) by 0.080mm (95% CI 0.097, 0.063) in hypertensive patients after 2 years treatment (abstract presentation),[26] and enalapril 10 mg/day (n = 48) halved the annual increase in IMT in patients with type 2 diabetes relative to a control group (n = 50) that did not receive enalapril (0.01 vs 0.02mm; p < 0.05).[27] Increased IMT is associated with increased risk of cardiovascular and cerebrovascular disease.[27] q Enalapril improves some atherosclerotic risk factors; an index of platelet activation (the ratio of thromboglobulin to platelet factor 4) was significantly decreased (p < 0.05 vs baseline) at a dosage of 20 mg/day for 4 weeks in 12 patients with essential hypertension,[28] and plasma levels of intercellular adhesion molecule-1 were significantly reduced (p < 0.01 vs baseline) at a dosage of 10,[29] 20 or 40[30] mg/day for 24 weeks in 57 patients with essential hypertension and type 2 diabetes[29] and 21 patients with hypertension (abstract presentation).[30] q Potentiation of the effects of bradykinin may contribute to the apparent cardiovascular protection associated with enalapril treatment.[31] In patients with atypical chest pain, enalapril 10mg once daily for 7 days (n = 25) significantly (p < 0.0001) increased bradykinin-induced release of tissue plasminogen activator in the coronary circulation relative to that in a control group (n = 31) that did not receive enalapril.[31] Enalapril may inhibit degradation of
q Drugs 2007; 67 (1)

Enalapril is an orally administered prodrug that is hydrolysed to form the active ACE inhibitor enalaprilat (see section 2), reducing plasma levels of the potent vasoconstrictor angiotensin II, with a consequent decrease in aldosterone secretion and an increase in plasma renin activity.[11] The reduction in angiotensin II levels results in peripheral vasodilation and reduced vascular resistance, leading to decreased BP.[10,11,23] Enalapril has little effect on heart rate or cardiac output.[11] q Enalapril dose-dependently reduces BP in hypertensive patients at doses 10mg, with the maximum
q 2007 Adis Data Information BV. All rights reserved.

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bradykinin, as angiotensin converting enzyme also functions as kininase II.[23] q ACE inhibitors have been reported to have renoprotective effects by reducing glomerular capillary pressure.[32] In a randomised, double-blind, 6year trial in patients with type 2 diabetes and normoalbuminuria at baseline, 5 of 77 (6.5%) enalapril 510 mg/day recipients and 15 of 79 (19.0%) placebo recipients developed microalbuminuria (urinary albumin excretion >30 mg/24h) [p = 0.001]; longacting CCBs (diltiazem or verapamil) and/or hydrochlorothiazide were used for BP control when SBP/diastolic BP (DBP) was consistently 145/ 95mm Hg.[33] q However, enalapril 10mg once daily did not affect the long-term development of nephropathy in 18 patients with type 1 diabetes and albuminuria.[34] After 6 months, enalapril significantly (p < 0.05) reduced the median albumin excretion rate (from 148 to 90 g/min), but this decrease was not maintained at 3 years.[34] 2. Pharmacokinetic Profile The pharmacokinetic profile of a fixed-dose gelatin capsule of lercanidipine/enalapril 10mg/20mg (used in a phase III trial;[35] see section 3) was similar to that of the individual agents, based on absorption parameters, in a multiple-dose, randomised, double-blind, crossover study in 20 patients with essential hypertension (DBP 95mm Hg).[36] At steady state (on day 8), peak plasma concentration (Cmax) values of S-lercanidipine, enalapril and enalaprilat were 3.6, 91 and 53 g/L, respectively, at 1, 1 and 4 hours after administration of the combination.[36] In addition, the fixed-dose gelatin capsule was bioequivalent to a fixed-dose tablet formulation of lercanidipine/enalapril 10mg/ 20mg (intended for marketing) in a single-dose, randomised, open-label, crossover study in 48 healthy volunteers; the confidence intervals for the tablet : capsule ratios of the area under the plasma concentration-time curve (AUC) and Cmax for lercanidipine enantiomers, enalapril and enalaprilat were within the bioequivalence acceptance range of 0.801.25.[37] Thus, discussion in this section focus 2007 Adis Data Information BV. All rights reserved.

es on the well established pharmacokinetic profiles of the individual agents, lercanidipine[8,9] and enalapril,[10,11] including data from the prescribing information.[12,23]
Lercanidipine

Since the pharmacological activity of racemic lercanidipine is mainly attributed to the S-enantiomer (section 1), and no in vivo interconversion of the S- and R-enantiomers has been demonstrated,[12] discussion in this section focuses on the pharmacokinetic profile of S-lercanidipine. q After oral administration of racemic lercanidipine, S-lercanidipine is completely absorbed from the gastrointestinal tract and exhibits nonlinear pharmacokinetics.[9] Lercanidipine should be administered prior to meals, as the absorption of Slercanidipine is increased 4-fold when it is administered after a high-fat meal.[8,12] q Lercanidipine exhibits a high level of plasma protein binding (>98%) and is lipophilic, aggregating in lipid membranes of arterial wall cells.[8,9,12] The magnitude of the apparent volume of distribution (22.5 L/kg for intravenous infusion of lercanidipine 2mg) has been ascribed to the high lipophilicity of the drug.[9] In addition, the absolute bioavailability of lercanidipine in fed hypertensive patients is about 10%.[12] q Lercanidipine is metabolised by cytochrome P450 (CYP) 3A4, and undergoes substantial firstpass metabolism; the resulting metabolites are mainly inactive.[9] The drug is excreted as metabolites in both urine and faeces (43.8% and 50.4% after administration of lercanidipine 20mg in healthy volunteers).[38] After oral administration of lercanidipine 10mg in patients with mild to moderate hypertension, the mean plasma terminal elimination half-life (t1/2) was 8.0 hours.[9] q Coadministration of lercanidipine and strong inhibitors of CYP3A4 is not advised,[12] and caution is recommended when coadministering lercanidipine and inducers or other substrates of CYP3A4. [12] The drug should not be coadministered with ciclosporin or grapefruit juice.[12] Lercanidipine may increase Cmax of digoxin; patients receiving both drugs
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should be monitored for digoxin toxicity.[12] Lercanidipine does not interact significantly with warfarin, simvastatin, diuretics or ACE inhibitors.[12] q The use of lercanidipine in patients with severe hepatic or renal impairment is not recommended because of the risk of drug accumulation.[8,9,12] Caution is advised when increasing the dose of lercanidipine to 20mg once daily in patients with mild to moderate hepatic or renal impairment.[12]
Enalapril
q Enalapril is de-esterified in the liver to form enalaprilat, which does not undergo further metabolism.[10,11] The Cmax of enalaprilat is linearly related to the dose of enalapril across the 2.540mg dose range;[10,11] however, the AUC for enalaprilat is not linearly related to enalapril dosage because of the prolonged terminal elimination phase.[10,11] q The absolute bioavailability of oral enalapril as enalaprilat is approximately 40%,[11] and no more than 60% of circulating enalaprilat is bound to human plasma proteins.[23] Enalapril crosses the placental barrier; consequently, the drug is contraindicated in pregnant patients.[11,23] q Enalaprilat is eliminated predominantly by the renal route.[10] There is an initial elimination phase followed by a prolonged terminal phase, with respective t1/2 values of 5 hours and 3035 hours.[11] The latter phase represents tight binding to plasma angiotensin converting enzyme.[11] Following multiple doses of enalapril, the effective t1/2 of enalaprilat is 11 hours.[23] q Dose reduction of enalapril is necessary in patients with renal impairment (CLCR <80 mL/min), to reduce the risk of drug accumulation.[23] However, dosage adjustment is not necessary in patients with hepatic dysfunction.[11] q A retrospective analysis of 20 hypertensive patients demonstrated the possibility of an increase in serum lithium concentrations when it was coadministered with ACE inhibitors, including enalapril.[39] This was particularly evident in patients 50 years old (n = 12).[39] However, in a study in healthy volunteers (n = 9), enalapril did not significantly affect serum lithium concentrations.[40]

Nevertheless, concomitant use of enalapril and lithium is not recommended; if coadministration of these agents is unavoidable, then serum lithium concentrations should be closely monitored.[23] 3. Therapeutic Efficacy The efficacy of oral, once-daily, fixed-dose lercanidipine/enalapril gelatin capsules has been evaluated in adult patients with mild to moderate essential hypertension in a randomised, double-blind, multicentre, phase II, dose-finding trial (study CPL20008)[41] and two 12-week, multicentre, phase III trials (studies CPL1-0018[42] and CPL1-0019[35]), with longer-term efficacy evaluated in noncomparative 9-month extensions of the phase III trials.[35,42] Data are currently available only as data on file.[35,41,42] These data are supported by results from a randomised, double-blind trial, in which patients with mild to moderate hypertension who had not responded to 4 weeks of treatment with enalapril 20 mg/day received lercanidipine 10 mg/day (n = 56) or hydrochlorothiazide 12.5 mg/day (n = 56) as add-on therapy to enalapril for 20 weeks; lercanidipine was non-inferior to hydrochlorothiazide for reduction of sitting DBP (sDBP) at trough levels (primary endpoint; reduction of 9.3 vs 7.4mm Hg [baseline 97mm Hg]).[43] All trials of fixed-dose lercanidipine/enalapril had an initial washout period of 1117 days[41] or 5 half-lives of any previously administered antihypertensive agents,[35,42] followed by a single-blind placebo run-in phase of 2 weeks[35,42] or 2531 days.[41] Mild to moderate hypertension was defined in the phase II trial as sDBP values in the range 95109mm Hg both before and after the washout phase and also during and after the placebo run-in phase,[41] and in phase III trials as sitting SBP (sSBP) in the range 140189mm Hg and sDBP in the range 95114mm Hg both before and after the placebo run-in period.[35,42] Exclusion criteria included secondary hypertension, cardiovascular disease (with the exception of stable angina pectoris, uncomplicated hypertensive cardiovascular disease, or uncomplicated myocardial infarction at least 6
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months previously), cardiovascular surgery within the previous 6 months, a history of hypertensive encephalopathy or cerebrovascular accident, uncontrolled or complicated diabetes, hypertensive retinopathy or use of any medications (except NSAIDs) that could affect BP.[35,41,42] There were no between-group differences in the randomised trials in terms of patient characteristics at baseline (the start of the double-blind phase),[35,41,42] with the exception of one trial (CPL10018)[42] where the mean age in the fixed-dose combination group was 53.5 versus 51.0 years in the monotherapy group (p = 0.026). Analyses were based on the intent-to-treat (ITT) population, which was defined as all patients who had received at least one dose of treatment in the double-blind phase and had 1 BP measurement 1848 hours after this point, with the last observation carried forward in the event of premature withdrawal.[35,41,42] Statistical analyses were based on an analysis of covariance, with treatment and centre as main effects and baseline value as a covariate.[35,41,42]
Phase II Dose-Finding Trial

ents of this fixed-dose combination achieved a similar reduction from baseline in sDBP to that observed in recipients of lercanidipine 20mg once daily (9.9mm Hg; 95% CI 8.6, 11.2). Mean baseline sDBP was 100mm Hg in all groups.[41] q Analysis of covariance indicated that monotherapy with once-daily lercanidipine 10 or 20mg or enalapril 10mg provided better antihypertensive efficacy than placebo (all p < 0.05); there were no between-group differences for 5mg doses of lercanidipine or enalapril versus placebo.[41] Notably, all fixed-dose combinations were superior to placebo in terms of antihypertensive efficacy (all p < 0.05).[41] q Patient compliance (assessed by capsule count) was 98.5% in all treatment groups.[41]
Phase III Trials

The appropriate once-daily fixed-dose combination was determined using various combinations of lercanidipine (5, 10 or 20mg), enalapril (5 or 10mg) and placebo, in an ITT population of 653 patients (n = 5163/group).[41] The primary endpoint was the change in trough sDBP (measured 2226 hours post-dose) from baseline after 8 weeks of doubleblind treatment, assessed using a dose-response surface analysis (as recommended by the European Agency for the Evaluation of Medicinal Products[44]).[41] q Based on the additive response surface model analysis of the primary endpoint, once-daily lercanidipine/enalapril 10mg/10mg was the optimal fixed-dose combination.[41] The estimated change in trough sDBP after 8 weeks was significantly greater in recipients of lercanidipine/enalapril 10mg/10mg once daily (10.4mm Hg; 95% CI 11.4, 9.5) than in lercanidipine 10mg once daily recipients (8.2mm Hg; 95% CI 9.2, 7.3). Moreover, recipi 2007 Adis Data Information BV. All rights reserved.

The two phase III trials evaluated lercanidipine/ enalapril fixed-dose combination therapy in hypertensive patients who were not responding to lercanidipine (study CPL1-0018)[42] or enalapril (study CPL1-0019)[35] monotherapy. During the singleblind monotherapy phase, patients received either lercanidipine 10mg once daily for 4 weeks (CPL1-0018)[42] or once-daily enalapril 10mg for 2 weeks, with the dosage increased to 20mg once daily for the next 4 weeks (CPL1-0019).[35] Nonresponders were defined as patients who had a trough sDBP of 95109mm Hg after the single-blind monotherapy phase, while maintaining a trough sSBP of <180mm Hg.[35,42] Nonresponders to lercanidipine monotherapy received once-daily lercanidipine/enalapril 10mg/ 10mg (n = 165) or once-daily lercanidipine 10mg monotherapy (n = 172) for 12 weeks.[42] Mean baseline sSBP/sDBP was 152/100mm Hg in both groups.[42] Nonresponders to enalapril monotherapy received once-daily lercanidipine/enalapril 10mg/ 20mg (n = 162) or once-daily enalapril 20mg monotherapy (n = 163) for 12 weeks; mean baseline sSBP/sDBP was 154/99mm Hg in both groups.[35] In both trials, the primary efficacy endpoint was the change from baseline in mean trough sDBP after 12 weeks of double-blind treatment.[35,42] Secondary
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endpoints included the change from baseline in mean trough sSBP after 12 weeks, the proportion of patients with normalised SBP (sSBP <140mm Hg), normalised DBP (sDBP <90mm Hg) or normalised SBP/DBP (sSBP/sDBP <140/90mm Hg) after 12 weeks, and the proportion of patients classed as responders after 12 weeks (normalised SBP or sSBP decreased from baseline by 20mm Hg; normalised DBP or sDBP decreased from baseline by 10mm Hg).[35,42]
q Lercanidipine/enalapril 10mg/10mg once daily showed better antihypertensive efficacy than lercanidipine 10mg once daily after 12 weeks in lercanidipine nonresponders, according to the primary endpoint (mean change in sDBP from baseline 7.1 vs 4.3mm Hg; p < 0.001).[42] The mean change in sSBP from baseline was also significantly (p < 0.001) greater in the combination therapy group (7.7 vs 2.3mm Hg). Significantly (all p < 0.001) greater reductions in sDBP and sSBP in the fixeddose combination group than in the monotherapy group occurred after 2 weeks and were maintained throughout the 12 weeks of the study.[42]

sDBP and from 4 weeks onwards for sSBP. There was a numerically higher percentage of combination therapy, versus monotherapy, recipients with normalised DBP (48% vs 37%), normalised SBP (33% vs 28%), normalised SBP/DBP (24% vs 17%) or responder rate (sDBP 53% vs 43%, sSBP 41% vs 33%), but these differences did not attain statistical significance.[35] q A subgroup analysis of elderly nonresponders to enalapril showed that the mean change from baseline in trough sDBP at 12 weeks was significantly (both p < 0.05) greater in combination therapy, versus monotherapy, among recipients aged >60 years (n = 164; 10.9 vs 7.9mm Hg) or 65 years (n = 101; combination therapy vs monotherapy treatment difference of 2.6mm Hg).[35] In these subgroups, the treatment differences for the change from baseline in trough sSBP did not reach statistical significance (combination therapy vs monotherapy treatment difference of 3.2 and 2mm Hg in patients aged >60 and 65 years).[35]
Extension Phase

In lercanidipine nonresponders, after 12 weeks treatment, a significantly greater proportion of patients receiving the fixed-dose combination had normalised SBP (39% vs 22%; p < 0.001), normalised DBP (29% vs 19%; p = 0.023) and/or normalised SBP/DBP (22% vs 12%; p = 0.012) than lercanidipine monotherapy recipients.[42] The responder rate was also higher in combination therapy recipients than in lercanidipine monotherapy recipients (sSBP 41% vs 24%, p < 0.001; sDBP 35% vs 24%, p = 0.032).[42]
q q Similarly, in enalapril nonresponders, the fixeddose combination was more effective than enalapril monotherapy. After 12 weeks, the mean changes in trough sDBP from baseline were 9.2 and 7.5mm Hg in recipients of lercanidipine/enalapril 10mg/ 20mg once daily and enalapril 20mg once daily (p = 0.015).[35] The corresponding mean changes in sSBP from baseline were 9.8 and 6.7mm Hg (p = 0.013). Significant (all p < 0.05) between-group differences in favour of fixed-dose combination therapy were evident from 8 weeks onwards for

Patients were eligible for inclusion in the noncomparative extension phase of each of the phase III trials if they had completed the doubleblind treatment phase with an sSBP in the range of 120179mm Hg and an sDBP in the range of 80109mm Hg.[35,42] This phase was primarily designed to evaluate long-term tolerability (see section 4). In the extension phase in nonresponders to lercanidipine monotherapy, 221 patients (110 fixeddose combination and 111 lercanidipine recipients) received lercanidipine/enalapril 10mg/10mg once daily, with a switch to lercanidipine/enalapril 10mg/ 20mg once daily permitted if sSBP/sDBP was >140/ 90mm Hg; 201 patients completed 9 months treatment in the extension phase.[42] In the extension phase in nonresponders to enalapril monotherapy, 186 patients (94 fixed-dose combination and 92 enalapril recipients) received lercanidipine/enalapril 10mg/20mg once daily; 164 patients completed 9 months treatment.[35]
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q Among lercanidipine monotherapy nonresponders, 52% of extension-phase combination therapy recipients achieved a normalised SBP, 46% a normalised DBP and 37% a normalised SBP/DBP after 9 months.[42] Among patients switched from lercanidipine/enalapril 10mg/10mg to lercanidipine/ enalapril 10mg/20mg during the extension phase (n = 133; 60%), 35% achieved a normalised SBP, 33% a normalised DBP and 20% a normalised SBP/ DBP.[42] q Similarly, among nonresponders to enalapril monotherapy, 40% achieved a normalised SBP, 60% a normalised DBP and 36% a normalised SBP/ DBP in the extension phase.[35]

patients receiving lercanidipine/enalapril 10mg/ 20mg per day in the pooled analysis.[45] Common treatment-emergent adverse events are summarised in figure 1.[45]
q Discontinuation of treatment because of an adverse event occurred with a similar frequency in the combination therapy and monotherapy groups, with the incidence in lercanidipine/enalapril 10mg/10mg and 10mg/20mg groups being 4.6% and 4.4%; cough was the most common cause of treatment discontinuation (0.9% and 2.2%).[45] q Cough and dizziness were two of the most common treatment-emergent adverse events that occurred with both lercanidipine/enalapril dosages (figure 1).[45] Cough was attributed to the enalapril

4. Tolerability The fixed-dose formulation of lercanidipine/ enalapril was generally well tolerated for 52 weeks by patients with mild to moderate hypertension in the phase II and III trials[35,41,42] discussed in section 3. This section focuses on a pooled safety analysis[45] of all patients who received at least one dose of lercanidipine/enalapril 10mg/10mg or 10mg/ 20mg in these trials[35,41,42] or in a pharmacokinetic interaction trial[36] discussed in section 2. q In the 8-week dose-finding trial (section 3), treatment-emergent adverse events occurred with similar frequencies in the fixed-dose combination groups to those observed in the lercanidipine and enalapril monotherapy or placebo groups.[41] The proportion of patients experiencing any treatment-emergent adverse event was 25.042.2% in the treatment groups and 36% in the placebo group. The most frequent treatment-related adverse events were headache (1.77.4%), coughing (1.79.8% in enalapril recipients and 01.9% in those not receiving enalapril) and dizziness (frequency not reported).[41] One lercanidipine/enalapril 20mg/10mg recipient experienced a serious adverse event (circulatory collapse) that was considered to be probably treatment-related.[41] q Treatment-emergent adverse events considered to be at least possibly related to therapy occurred in 39 of 329 (11.9%) patients receiving lercanidipine/ enalapril 10mg/10mg per day and 69 of 410 (16.8%)
2007 Adis Data Information BV. All rights reserved.

a LER10/ENA10 Vertigo 1.2

Dizziness

1.5

Cough 0 b 1 2 3 4 5

5.2 6 7 8

LER10/ENA20 Flushing Peripheral oedema Dizziness Headache Cough 0 1 2 3 4 1.2 1.5 2.4 2.7 4.4 5 6 7 8

Patients (%) Fig. 1. Tolerability profile of once-daily, orally administered, fixeddose lercanidipine/enalapril in patients with mild to moderate essential hypertension receiving (a) lercanidipine/enalapril 10mg/ 10mg per day (LER10/ENA10; n = 329) or (b) lercanidipine/ enalapril 10mg/20mg per day (LER10/ENA20; n = 410) for 52 weeks. Treatment-emergent adverse events considered to be at least possibly related to therapy occurring in 1% of patients, using pooled data[45] from an 8-day, double-blind, pharmacokinetic interaction study,[36] an 8-week, double-blind, dose-finding study[41] and two 12-week, double-blind, phase III trials with 9-month, noncomparative extension phases.[35,42]

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a 7 LER10/ENA10 LER10 LER10/ENA20 ENA20

Cholesterol (mmol/L) Triglycerides (mmol/L) Glucose (mmol/L)

4 b 3

0 c 7

3 Screening Baseline Endpoint Screening Baseline Endpoint Fig. 2. Effect on plasma lipids and glucose of once-daily, orally administered, fixed-dose lercanidipine/enalapril or component drug in patients with mild to moderate essential hypertension. Mean values for (a) cholesterol, (b) triglycerides and (c) glucose in recipients of lercanidipine/enalapril 10mg/10mg per day (LER10/ENA10) [n = 167], lercanidipine 10 mg/day (LER10) [n = 175], lercanidipine/enalapril 10mg/20mg per day (LER10/ENA20) [n = 163] or enalapril 20 mg/day (ENA20) [n = 164] at screening, baseline and endpoint (the last measurement obtained during the 12-week double-blind treatment period). The normal ranges (fasting conditions) were <5.698 mmol/L (cholesterol), 0.562.15 mmol/L (triglycerides) and 3.335.55 mmol/L (glucose).[48] Data were derived from two randomised, double-blind trials: CPL1-0018,[46] in which patients received LER10/ENA10 or LER10, and CPL1-0019,[47] in which patients received LER10/ENA20 or ENA20.

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component, whereas peripheral oedema and flushing were most likely due to lercanidipine-induced peripheral vasodilation. Dizziness and vertigo were considered to be possibly linked to the BP-lowering effect of the combination.[45] q Serious adverse events occurred in 1.5% of lercanidipine/enalapril 10mg/10mg per day and 3.2% of lercanidipine/enalapril 10mg/20mg per day recipients in the pooled analysis, but all were considered to be either unrelated to treatment or unlikely to be related to treatment.[45] q In the phase III trials (section 3), the proportion of patients with clinically significant abnormalities in plasma levels of lipids or glucose was low (8%) at both baseline and endpoint (the last measurement obtained during the 12-week treatment period) with lercanidipine/enalapril 10mg/10mg per day[42] or 10mg/20mg per day.[35] The mean values for plasma lipids and glucose at screening, baseline and endpoint in the phase III trials are shown in figure 2.[46,47] 5. Dosage and Administration Fixed-dose combination lercanidipine/enalapril is indicated for the treatment of hypertension in patients aged 18 years;[49,50] the 10mg/10mg combination is used in patients in whom adequate BP control has not been achieved with lercanidipine monotherapy[49] and the 10mg/20mg combination is used in patients not achieving BP control with enalapril monotherapy.[50] The fixed-dose combination tablet is taken once daily at least 15 minutes before a meal.[49,50] Lercanidipine/enalapril 10mg/10mg or 10mg/ 20mg tablets should not be administered during pregnancy or lactation.[49,50] Local prescribing information should be consulted for detailed information, including contraindications, precautions, drug interactions and use in special patient populations. 6. Lercanidipine/Enalapril: Current Status In well controlled trials, once-daily administration of fixed-dose lercanidipine/enalapril has been
2007 Adis Data Information BV. All rights reserved.

shown to effectively lower BP in hypertensive patients inadequately controlled by either component drug, and was generally well tolerated. Only a small number of patients discontinued treatment because of an adverse event; simplification of the dosage regimen to a single once-daily capsule resulted in excellent compliance in the large phase II trial. The absence of negative effects of the combination on lipid and glucose metabolism (section 4) is also important, as glucose intolerance, diabetes and hyperlipidaemia are additional risk factors that are frequently present in the hypertensive population. The tablet formulations intended for marketing have been shown to be bioequivalent to the gelatin capsule formulations used in pivotal clinical trials, and offer the convenience of single-tablet administration of a combination therapy, with potential compliance benefits. These fixed-dose formulations are now approved in Germany for the treatment of hypertension in patients with BP not adequately controlled with lercanidipine[49] or enalapril[50] alone. Disclosure
During the peer review process, the manufacturer of the agent under review was also offered an opportunity to comment on this article; changes based on any comments received were made on the basis of scientific and editorial merit.

References
1. Whitworth JA, World Health Organization, International Society of Hypertension Writing Group. 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003; 21(11): 1983-92 2. Giles TD, Berk BC, Black HR, et al. Expanding the definition and classification of hypertension. J Clin Hypertens 2005 Sep; 7 (9): 505-12 3. European Society of Hypertension-European Society of Cardiology Guidelines Committee. 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003; 21 (6): 1011-53 4. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003 May 21; 289 (19): 2560-72 5. Williams B, Poulter NR, Brown MJ, et al. Guidelines for management of hypertension: report of the fourth working

Drugs 2007; 67 (1)

Fixed-Dose Combination Lercanidipine/Enalapril: Adis Drug Profile

105

6. 7.

8. 9.

10.

11.

12.

13.

14.

15.

16.

17.

18. 19.

20.

21.

22.

23.

party of the British Hypertension Society, 2004-BHS IV. J Hum Hypertens 2004 Mar; 18 (3): 139-85 Sica DA. Rationale for fixed-dose combinations in the treatment of hypertension: the cycle repeats. Drugs 2002; 62 (3): 443-62 Jandeleit-Dahm KAM, Tikellis C, Reid CM, et al. Why blockade of the renin-angiotensin system reduces the incidence of new-onset diabetes. J Hypertens 2005; 23 (3): 463-73 McClellan KJ, Jarvis B. Lercanidipine: a review of its use in hypertension. Drugs 2000; 60 (5): 1123-40 Bang LM, Chapman TM, Goa KL. Lercanidipine: a review of its efficacy in the management of hypertension. Drugs 2003; 63 (22): 2449-72 Todd PA, Heel RC. Enalapril: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and congestive heart failure. Drugs 1986; 31 (3): 198-248 Todd PA, Goa KL. Enalapril: a reappraisal of its pharmacology and therapeutic use in hypertension. Drugs 1992; 43 (3): 346-81 Napp Pharmaceuticals Ltd. Zanidip tablets: prescribing information. In: Medicines Compendium 2005. Epsom: Datapharm Communications Ltd, 2005: 2676-8 Brixius K, Gross T, Tossios P, et al. Increased vascular selectivity and prolonged pharmacological efficacy of the L-type Ca2+ channel antagonist lercanidipine in human cardiovascular tissue. Clin Exp Pharmacol Physiol 2005 Sep; 32 (9): 708-13 Soma MR, Natali M, Donetti E, et al. Effect of lercanidipine and its (R)-enantiomer on atherosclerotic lesions induced in hypercholesterolemic rabbits. Br J Pharmacol 1998 Dec; 125 (7): 1471-6 Corsini A, Accomazzo MR, Canavesi M, et al. The new calcium antagonist lercanidipine and its enantiomers affect major processes of atherogenesis in vitro: is calcium entry involved? Blood Press 1998; 7 Suppl. 2: 18-22 Rachmani R, Levi Z, Zadok B-S, et al. Losartan and lercanidipine attenuate low-density lipoprotein oxidation in patients with hypertension and type 2 diabetes mellitus: a randomized, prospective crossover study. Clin Pharmacol Ther 2002 Sep; 72 (3): 302-7 Canavesi M, Baldini N, Leonardi A, et al. In vitro inhibitory effect of lercanidipine on cholesterol accumulation and matrix metalloproteinases secretion by macrophages. J Cardiovasc Pharmacol 2004 Oct; 44 (4): 416-22 Cheung BMY, Man YB, Tse HF, et al. Advantages of blood pressure optimization. Adv Ther 2005; 22 (4): 285-96 Robles NR, Ocon J, Gomez CF, et al. Lercanidipine in patients with chronic renal failure: the ZAFRA study. Ren Fail 2005; 27 (1): 73-80 Dalla Vestra M, Pozza G, Mosca A, et al. Effect of lercanidipine compared with ramipril on albumin excretion rate in hypertensive type 2 diabetic patients with microalbuminuria: DIAL study (Diabete, Ipertensione, Albuminuria, Lercanidipina). Diabetes Nutr Metab Clin Exp 2004; 17 (5): 259-66 Sabbatini M, Vitaioli L, Baldoni E, et al. Nephroprotective effect of treatment with calcium channel blockers in spontaneously hypertensive rats. J Pharmacol Exp Ther 2000; 294 (3): 948-54 Sabbatini M, Leonardi A, Testa R, et al. Effect of calcium antagonists on glomerular arterioles in spontaneously hypertensive rats. Hypertension 2000 Mar; 35 (3): 775-9 The European Agency for the Evaluation of Medicinal Products. Committee for Proprietary Medicinal Products (CPMP): sum-

24.

25.

26.

27.

28.

29.

30.

31.

32. 33.

34.

35.

36. 37.

mary information on referral opinion pursuant to Article 30 of Council Directive 2001/83/EC for Renitec and associated names (see Annex I) [online]. Available from URL: http:// www.emea.eu.int [Accessed 2005 Oct 5] Rizzoni D, Porteri E, De Ciuceis C, et al. Effect of treatment with candesartan or enalapril on subcutaneous small artery structure in hypertensive patients with noninsulin-dependent diabetes mellitus. Hypertension 2005 Apr; 45 (Pt 2): 659-65 Park JB, Schiffrin EL. Small artery remodeling is the most prevalent (earliest?) form of target organ damage in mild essential hypertension. J Hypertens 2001; 19 (5): 921-30 Stumpe KO, Ludwig M, Fritschka E, et al. Differential regressive effects of amlodipine and enalapril on carotid artery intima-media thickening: outcome results of the ARES-trial [abstract no. OP 045]. J Hypertens 2004; 22 Suppl. 1: S14 Hosomi N, Mizushige K, Ohyama H, et al. Angiotensin-converting enzyme inhibition with enalapril slows progressive intima-media thickening of the common carotid artery in patients with non-insulin-dependent diabetes mellitus. Stroke 2001 Jul; 32 (7): 1539-45 Leu HB, Charng MJ, Ding PYA. A double blind randomized trial to compare the effects of eprosartan and enalapril on blood pressure, platelets, and endothelium function in patients with essential hypertension. Jpn Heart J 2004 Jul; 45 (4): 623-35 Agabiti Rosei E, Rizzoni D, Muiesan ML, et al. Effects of candesartan cilexetil and enalapril on inflammatory markers of atherosclerosis in hypertensive patients with non-insulin-dependent diabetes mellitus. CENTRO (CandEsartaN on aTherosclerotic Risk factors) study investigators. J Hypertens 2005; 23 (2): 435-44 Moiseeva O, Villevalde S, Emelyanov I, et al. Comparison of enalapril and atenolol effects on nonhemodynamic factors in cardiovascular remodeling in hypertensive patients [abstract no. P3.118]. J Hypertens 2005; 23 Suppl. 2: S310 Minai K, Matsumoto T, Horie H, et al. Bradykinin stimulates the release of tissue plasminogen activator in human coronary circulation: effects of angiotensin-converting enzyme inhibitors. J Am Coll Cardiol 2001 May; 37 (6): 1565-70 Brown NJ, Vaughan DE. Angiotensin-converting enzyme inhibitors. Circulation 1998 Apr 14; 97 (14): 1411-20 Ravid M, Brosh D, Levi Z, et al. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus: a randomized, controlled trial. Ann Intern Med 1998; 128 (12 Pt 1): 982-8 The European Study for the Prevention of Renal Disease in Type 1 Diabetes (ESPRIT) Study Group. Effect of 3 years of antihypertensive therapy on renal structure in type 1 diabetic patients with albuminuria: the European Study for the Prevention of Renal Disease in Type 1 Diabetes (ESPRIT). Diabetes 2001 Apr; 50 (4): 843-50 Recordati SpA. Efficacy and tolerability of a combination of lercanidipine and enalapril in patients with mild to moderate essential hypertension not adequately controlled by enalapril treatment (add-on to enalapril) [CPL1-0019]. Milan: Recordati SpA, 2004 Mar 25. (Data on file) Recordati SpA. Lercanidipine-enalapril interaction (PK 0031). Milan: Recordati SpA, 2004 Nov 19. (Data on file) Recordati SpA. Bioequivalence study of a fixed combination versus a combination of marketed tablets of lercanidipine HCl (10 mg) and enalapril maleate (20 mg) [PK 0159]. Milan: Recordati SpA, 2004 Nov 29. (Data on file)

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38. Barchielli M, Dolfini E, Farina P, et al. Clinical pharmacokinetics of lercanidipine. J Cardiovasc Pharmacol 1997; 29 Suppl. 2: S1-15 39. Finley PR, OBrien JG, Coleman RW. Lithium and angiotensinconverting enzyme inhibitors: evaluation of a potential interaction. J Clin Psychopharmacol 1996 Feb; 16 (1): 68-71 40. DasGupta K, Jefferson JW, Kobak KA, et al. The effect of enalapril on serum lithium levels in healthy men. J Clin Psychiatry 1992 Nov; 53 (11): 398-400 41. Recordati SpA. A multicentre, randomized, parallel group, double-blind trial to determine the optimal dose combinations of lercanidipine and enalapril in comparison to each component administered alone and to evaluate the efficacy and safety of the combinations in mild to moderate essential hypertension (CPL2-008). Milan: Recordati SpA, 2000 Dec 21. (Data on file) 42. Recordati SpA. Efficacy and tolerability of a combination of lercanidipine and enalapril in patients with mild to moderate essential hypertension not adequately controlled by lercanidipine treatment (add-on to lercanidipine) [CPL1-0018]. Milan: Recordati SpA, 2004 Mar 11. (Data on file) 43. Agrawal R, Marx A, Haller H. Efficacy and safety of lercanidipine versus hydrochlorothiazide as add-on to enalapril in diabetic populations with uncontrolled hypertension. J Hypertens 2006; 24 (1): 185-92 44. The European Agency for the Evaluation of Medicinal Products (Human Medicines Evaluation Unit). Note for guidance on

dose response information to support drug registration (CPMP/ ICH/378/95) [online]. Available from URL: http://www.em ea.eu.int/pdfs/human/ich/037895en.pdf [Accessed 2005 Oct 3] 45. Recordati SpA. Pooled safety analysis of lercanidipine/enalapril combination therapy. Milan: Recordati SpA, 2004 Nov 19. (Data on file) 46. Recordati SpA. Final clinical report: add-on to lercanidipine. Protocol no: REC 15/2375 - CPL1-0018. Milan: Recordati SpA, 2003 Dec 10. (Data on file) 47. Recordati SpA. Final clinical study report. Protocol no: REC 15/ 2375 - CPL1-0019. Milan: Recordati SpA, 2003 Dec 18. (Data on file) 48. Data on file, Recordati SpA, 2006 Oct 4 49. Recordati SpA. Gebrauchsinformation: ZANIPRESS 10mg/ 10mg filmtabletten. Milan: Recordati SpA, 2006. (Data on file) 50. Recordati SpA. Gebrauchsinformation: ZANIPRESS 10mg/ 20mg filmtabletten. Milan: Recordati SpA, 2006. (Data on file)

Correspondence: Philip I. Hair, Wolters Kluwer Health | Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 1311, New Zealand. E-mail: demail@adis.co.nz

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GUEST COMMENTARIES

Drugs 2007; 67 (1): 107-108 0012-6667/07/0001-0107/$49.95/0 2007 Adis Data Information BV. All rights reserved.

Fixed-Dose Combination Lercanidipine/Enalapril


A Viewpoint by Nicol s R. Robles a
Hypertension Unit, Service of Nephrology, Hospital Infanta Cristina, Badajoz, Spain

nation may assist treatment adherence by avoiding multiple daily pill intake. ACE inhibitor dosage is an important issue. Accumulated evidence suggests that angiotensin axisblocking drugs should be used at the highest dose tolerated by the patient to reach full (not only antihypertensive) effects. It is likely that the maximum recommended lercanidipine dosage (20 mg/day) may be combined with a high dosage of enalapril (40 mg/day), if necessary, without risk of exacerbation of the well known clinical adverse effects of CCBs. The lercanidipine/enalapril fixed-dose combination actually offers an advantage over classical ACE inhibitor/diuretic combinations in terms of effect on carbohydrate metabolism, as it does not negatively influence insulin resistance. Furthermore, the reported effects of lercanidipine on proteinuria indicate that this combination may have interesting properties in proteinuric patients with renal dysfunction. It is likely to be most useful in patients with mild to moderate chronic renal failure, where the low diuretic dose used in fixed-dose combinations is not effective. However, these advantages remain speculative and further research is needed to document these potential beneficial effects. v

A very strong recommendation, delivered by all official guidelines, is to bring blood pressure (BP) below 140/90mm Hg in every patient, and even lower in the presence of diabetes mellitus or renal disease. Reaching these targets remains a difficult task with currently available antihypertensive medications. Using monotherapies, one might indeed expect to achieve the goal BP in no more than 40% of patients. In most patients, combination therapy is required in order to achieve optimal BP control, as exemplified by the experience accumulated in large prospective interventional trials. The coadministration of two agents acting by different mechanisms considerably improves the BP control rate. Such combinations are not only efficacious, but are also well tolerated, and some fixed low-dose combinations even have a placebo-like tolerability. This is the case for the preparation containing the ACE inhibitor enalapril (10 or 20mg) and the calcium channel blocker (CCB) lercanidipine (10mg). Moreover, a single-dose combi-

GUEST COMMENTARIES

Drugs 2007; 67 (1): 107-108 0012-6667/07/0001-0107/$49.95/0 2007 Adis Data Information BV. All rights reserved.

Fixed-Dose Combination Lercanidipine/Enalapril


A Viewpoint by Roland Asmar
The CardioVascular Institute, Paris, France

CCB and an ACE inhibitor has been recently reported to be more effective than the classic combination of a -blocker and a diuretic.[1] The advantages of such CCB/ACE inhibitor combinations may remain speculative in the absence of the medical practitioners involvement. Epidemiological studies have definitely shown that inertia and passivity of doctors in the choice of drug treatment of patients with uncontrolled hypertension is a significant cause of high BP. Therefore, practitioners have to increase the use of combination therapy in order to improve the BP control rate. Further research is needed to document the efficacy : tolerability comparison between the various fixed-dose antihypertensive combinations available on the market. Moreover, clinical trials aiming to define the suitable combination to be used, according to patient characteristics, will be very helpful in further refining the guidelines for hypertension management. v

Studies have shown that the current rate of adequate blood pressure (BP) control is far from satisfactory and does not reach the level of 30% of treated hypertensive patients across almost all Western countries. Insufficient use of drug combinations has been identified as a major reason for the poor rate of BP control. Therefore, guidelines on hypertension management now support the crucial role of combination therapy in increasing the extent of BP control. A combination of two antihypertensive drugs in a single pill offers advantages that include high efficacy, a low incidence of adverse effects, good treatment compliance and relatively low cost. The combination of a calcium channel blocker (CCB) with an ACE inhibitor is one of the attractive combination regimens. In fact, studies have shown that this type of combination presents a high efficacy : tolerability ratio, reverses organ damage and improves cardiovascular prognosis in terms of morbidity and mortality. Indeed, the combination of a

Reference
1. Poulter NR, Wedel H, Dahl f B, et al. Role of blood pressure o and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). ASCOT investigators. Lancet 2005 Sep 10; 366 (9489): 907-13

ADIS DRUG PROFILE

Drugs 2007; 67 (1): 109-118 0012-6667/07/0001-0109/$49.95/0 2007 Adis Data Information BV. All rights reserved.

Limaprost
Tracy Swainston Harrison and Greg L. Plosker
Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Conshohocken, Pennsylvania, USA

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 1. Pharmacodynamic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 2. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 3. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 4. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 5. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 6. Limaprost: Current Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

Abstract
v Limaprost, an alprostadil (prostaglandin E1) analogue, is a vasodilator that increases blood flow and inhibits platelet aggregation. v The efficacy of oral limaprost was evaluated in adult Japanese patients in three randomised, double-blind, 6-week trials. One study included patients with thromboangiitis obliterans and two trials included patients with lumbar spinal canal stenosis. Limaprost was generally well tolerated and serious adverse events were uncommon. v Thromboangiitis Obliterans: In a randomised, double-blind trial in Japanese patients primarily with thromboangiitis obliterans (n = 136), there was no significant difference between patients receiving limaprost 30 g/day and those receiving oral ticlopidine 500 g/day in the improvement of ischaemic symptoms. v Lumbar Spinal Canal Stenosis: Limaprost 15 g/ day was superior to limaprost 3 g/day for overall drug usefulness and overall improvement from baseline to study end in a phase III trial in 146 patients with lumbar spinal canal stenosis. Assessment of overall improvement considered various objective symptoms (e.g. muscle strength, walking ability) and subjective symptoms (e.g. pain or numbness in extremities), while overall usefulness also considered safety issues. v The efficacy of limaprost 15 g/day was not significantly different from that of 30 g/day, but tended to be better than that of 6 g/day in a phase II trial in patients with lumbar spinal canal stenosis and normal straight leg raise test results. The optimal dosage of limaprost for this indication was therefore deemed to be 15 g/day.

Features and properties of limaprost (Opalmon)


Featured indications Thromboangiitis obliterans (TAO) [Buergers disease] Lumbar spinal canal stenosis (LSCS) [in patients with bilateral intermittent claudication and a normal straight leg raise test result] Mechanism of action Vasodilation, increased blood flow and inhibition of platelet aggregation Dosage and administration in adults Route of administration Frequency of administration Dose TAO Dose LSCS Oral Daily in three divided doses 30 g/day 15 g/day

Single-dose pharmacokinetic properties of oral limaprost in adult healthy volunteers (n = 12) Mean maximum plasma concentration Median time to maximum plasma concentration Mean area under the concentration-time curve from time 0 to infinity Mean elimination half-life Adverse events Gastrointestinal-related, rash, hot flushes/flushing, headaches and anaemia 5g: 1.18 pg/mL 10g: 2.06 pg/mL 5g: 0.75h 10g: 0.5h 5g: 1.97 pg h/mL 10g: 3.43 pg h/mL 5g: 1h 10g: 1h

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H COOH

H OH

CH3 H OH H CH3

Limaprost

Limaprost is an alprostadil (prostaglandin E1) analogue that was developed in Japan to treat numerous ischaemic symptoms of thromboangiitis obliterans (TAO) and lumbar spinal canal stenosis (LSCS)[1] because of the well known vasodilatory, antiplatelet and cytoprotective properties of prostaglandins.[2] TAO (Buergers disease) is a nonatherosclerotic, occlusive, inflammatory disease of distal, small- and medium-size arteries and veins of the arms and legs.[2,3] Signs and symptoms are pain at rest, ischaemic ulcers (in the arms, legs or both), thrombophlebitis, Raynauds phenomenon, an abnormal Allen-test result, sensory findings and intermittent claudication.[2,3] This disease is more prevalent in Japan and Korea than in Western Europe (1666% vs 0.55.6% of patients with peripheral arterial disease) and occurs mainly in young, male smokers.[3] Patients experience alternating periods of acute exacerbation and remission.[2] The only proven treatment of TAO is cessation of tobacco use; disease progression is prevented and amputations may be successfully avoided.[3] Nevertheless, alleviation of ischaemic pain, improved microcirculation and healing of ulcers may be achieved via pharmacological treatment with prostaglandins or aspirin; however, the latter agent appears less effective than prostaglandins.[2] Iloprost (an analogue of epoprostenol[4]) and alprostadil are available in numerous European countries for the treatment of TAO[2,3] and limaprost is approved only in Japan and South Korea in this indication.[1] LSCS is a constriction of the spinal canal at the third to fourth (L3/L4) or fourth to fifth (L4/L5) lumbar vertebrae, or at the fifth lumbar vertebra to
1

the sacrum (L5/S1),[5] which is usually caused by bone and ligamentous hypertrophy or intervertebral disc degeneration.[5] This constriction leads to entrapment of the cauda equina (a collection of spinal nerve roots), causing ischaemia, which is a contributing factor in the development of the intermittent neurogenic claudication.[6] Patients also experience pain in the back, buttocks, thighs and legs, a feeling of weakness and numbness in the legs, gait disturbance[5,6] and, in severe cases, bowel or bladder disturbances.[7] The middle-aged and elderly are commonly affected; disease progression is slow and the lower back and leg pain may be incapacitating.[6] Treatment of the symptoms of LSCS depends on disease severity (severity is based on level of leg pain and related disability); discussion of surgical management and conservative treatment options such as bed rest, physical therapy and lumbar bracing are beyond the scope of this review.[8] Pharmacological treatment options include epidural corticosteroids, anaesthetic nerve block or narcotic analgesics, which are used to relieve pain.[8] In Japan, limaprost is approved not only for pain relief, but also for relief of other ischaemic symptoms, such as numbness, and also of walking disturbances.[1] The pharmacological properties, efficacy and tolerability of limaprost (Opalmon)1 in patients with TAO or LSCS are the focus of this review. 1. Pharmacodynamic Profile
q Limaprost has vasodilatory properties and increases blood flow.[9] In an animal model of peripheral circulatory disorder, oral administration of limaprost inhibited the development of ischaemic lesions in limbs and peripheral extremities.[10] The effect of limaprost on ischaemic lesions in patients with TAO or LSCS is reviewed in section 3. q In animal studies with relevance for TAO, limaprost decreased coronary vessel resistance,[11] increased coronary blood flow[11] and increased femoral arterial and cutaneous blood flow in the hind limbs of dogs.[12]

The use of trade names is for product identification purposes only and does not imply endorsement.

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q The inhibitory effect of limaprost on platelet aggregation and platelet adhesiveness was 10- to 16-fold and 20-fold more potent than with epoprostenol (prostacyclin or prostaglandin I2) in an in vitro study using guinea-pig platelets.[13] This inhibitory effect on platelet function may result in inhibition of thrombus formation; in an in vivo guinea-pig model of electrically induced thrombosis, limaprost significantly (p < 0.05) inhibited thrombus formation as assessed by the change of the threshold voltage for formation of a thrombus.[14] q By contrast, limaprost inhibited platelet aggregation with similar potency to that of epoprostenol in an in vitro study with human platelets.[15] q Oral limaprost 2040g produced no significant change in platelet function (either bleeding time or platelet adhesiveness) in a single-dose study in healthy volunteers.[16] However, in patients with thromboembolic disorders (n = 6), a single 30 or 40g dose inhibited platelet aggregation by 335% and adhesiveness by 13% (30g) or 35% (40g) in a dose-dependent manner up to 2 hours after administration (values estimated from a graph).[15] Moreover, oral limaprost increased platelet cyclic AMP levels by 1020% after a single 30 or 40g dose in patients with thromboembolic disorders.[15] q Oral limaprost produced transient decreases in blood pressure in healthy volunteers in a single-dose study (n = 12).[16] These decreases were not statistically significant with a 20g dose. Significant reductions from baseline were reported in systolic blood pressure only at 2 hours post-dose with a 40g dose, and in both diastolic and mean blood pressure up to 2 hours after a 30g dose and 13 hours after a 40g dose (all p < 0.05). All blood pressure parameters returned to baseline values after 36 hours.[16] q In animal models of ischaemia with relevance for LSCS, limaprost improved blood flow to the cauda equina (p < 0.05 vs baseline),[17] sciatic nerve[18] and nerve tissue in the lumbar vertebral canal.[19] Blood flow in the tissue between two ligations around the right sciatic nerve[18] and in the nerve tissue of the fifth lumbar vertebra[19] increased significantly after multiple-dose oral administration of limaprost (p < 0.001[18] and p < 0.01[19] vs control). Limaprost

also increased the diameter of the cauda equina blood capillary (at the seventh lumbar vertebra).[20] q Additionally, animal models of LSCS have shown that limaprost may improve nerve function[18,21,22] and walking ability.[19,23] For example, intravenous limaprost inhibited an induced reduction in nerve conduction velocity in the cauda equina nerve at the seventh lumbar vertebra (p < 0.05 vs control), but had no significant effect on another measure of nerve function (the reduction of muscle action potential area).[21] q Sciatic nerve function may be affected in LSCS since the stenosis may occur at the fourth and fifth lumbar vertebrae.[5] Sciatic nerve ligation in rats caused prolongation of heat-stimulated myogenic nerve discharges in the femoral muscles ipsilateral to the nerve, but with oral administration of limaprost, this prolongation was inhibited (p < 0.05 vs control).[22] In another in vivo rat model of disturbed sciatic nerve function, chronic administration of oral limaprost reduced hyperalgesia.[18] q Oral administration of limaprost in rats significantly (p < 0.05) increased walking[23] or running[19] distance compared with a sham control in in vivo models of walking dysfunction.[19,23] By contrast, beraprost did not improve walking distance in one trial.[23] Section 3 reviews the efficacy of limaprost in improving walking ability in patients with LSCS. q There is potential for a pharmacodynamic drug interaction (an increased tendency to bleed) between limaprost and the following agents if coadministered: antiplatelets (aspirin, ticlopidine, cilostazole), thrombolytics (urokinase) and anticoagulants (heparin, warfarin).[9] 2. Pharmacokinetic Profile The pharmacokinetic properties of oral limaprost 5 and 10g have been evaluated in a single-dose, crossover study in Japanese adult healthy volunteers (n = 12).[24] Similar results to those reviewed here have been reported in a study of parallel-group design (n = 24), which is not discussed further.[25] Additional data are available from animal[26,27] and in vitro[28] studies. The pharmacokinetics of limaprost in the elderly and in paediatric patient
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populations, or in patients with renal or hepatic impairment have not been investigated.
Absorption and Distribution
q Limaprost is rapidly absorbed following oral administration; the median time to peak plasma concentration (tmax) was under 1 hour after a single dose of 5 or 10g (0.75 and 0.5 hours).[24] Oral limaprost tablets were taken with water after a meal.[24] q The mean maximum plasma concentration (Cmax) of limaprost after a single 5 and 10g dose was 1.18 and 2.06 pg/mL.[24] Respective mean area under the concentration-time curve from time zero to infinity (AUC) values were 1.97 and 3.43 pg h/ mL. q Absorption of limaprost appears to be dose-proportional; the ratios for the dose-adjusted mean Cmax and AUC values of a single 10g dose versus a single 5g dose were 0.971 and 0.935, which was within the 0.901.11 range considered by investigators to indicate linear pharmacokinetics.[24] q In an in vitro study,[28] limaprost was highly protein bound in human plasma (95.8%).

3. Therapeutic Efficacy This section reviews data from fully published, randomised, double-blind trials with more than 50 patients. All studies are in adult Japanese patients.
Thromboangiitis Obliterans

Metabolism and Elimination

According to a study in rats,[26] 70% of an orally administered radiolabelled dose of limaprost is excreted in the faeces and 30% is eliminated in the urine over a 96-hour post-dose period. Two major metabolites have been identified in rats; both metabolites are excreted primarily in the faeces and bile (518% of the administered dose).[28] The extent or site of metabolism, and route of excretion of limaprost has not yet been investigated in humans. q Limaprost is rapidly eliminated from the body after a single 5 or 10g dose. The mean elimination half-life was approximately 1 hour with either dose.[24] Thus, oral limaprost is taken daily in three divided doses (section 5). q Similarly, the apparent clearance of oral limaprost from the plasma was not dose-proportional, and was 3110 L/h for both 5 and 10g doses.[24]
q 2007 Adis Data Information BV. All rights reserved.

The efficacy of oral limaprost 30 g/day in the treatment of ischaemic symptoms (ulcer, feeling of coldness, pain) associated with TAO was evaluated versus oral ticlopidine 500 g/day in a randomised, double-blind, multicentre 6-week trial.[29] Patients with occlusive arteriosclerosis were enrolled in this trial (n = 49); however, since limaprost is not approved for use in this indication, these data are not reviewed here. A small number of patients with chronic arterial occlusion or diabetic vascular disease (n = 13) were enrolled in the trial and were grouped together with patients with TAO (n = 136) [TAO group]. Patients were required to have ulcers on their extremities and were excluded if they had any of the following: prior surgical revascularisation or excision of sympathetic ganglia; a tendency for haemorrhage; granulocytopenia or a history thereof; and severe hepatic or renal impairment. Baseline characteristics were not significantly different between treatment groups.[29] Study drugs were taken three times daily in divided doses after meals for 6 weeks following a 1-week placebo run-in period.[29] Concomitant use of antibacterial agents or analgesics was permissible, but any agents that may have affected trial results (e.g. antiplatelets, anticoagulants, vasodilators and barbiturates) were not allowed. Efficacy endpoints were the following: general usefulness, which considered both efficacy and tolerability and was assessed via a 100-point visual analogue scale (VAS) [a score of 70 of 100 was considered useful]; improvement in ulcer size (an objective symptom); improvement in rest pain (a subjective symptom); and overall improvement, which considered all clinical symptoms taken together and was assessed using a 5-point study-defined categorical scale.[29] All endpoints were investigator-rated except for an evaluation of drug effecDrugs 2007; 67 (1)

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Ulcer size improvement rate

56 57 45 38 54 53 52 53 53 56 0 10 20 30 40 50 60 70

LIM 30 g/day TIC 500 g/day

Rest pain improvement rate

Overall improvement rate

Usefulness rate (investigator)

Usefulness rate (expert)

80

90

100

Patients (%) Fig. 1. Efficacy of limaprost (LIM) vs ticlopidine (TIC) in patients (pts) with thromboangiitis obliterans (n = 136), or chronic arterial occlusion or diabetic vascular disease (n = 13).[29] In this randomised, double-blind, multicentre, 6-week trial, pts received LIM 30 g/day (n = 5360) or TIC 500 g/day (n = 6476) in three divided doses after meals; evaluable patient numbers differed for each endpoint. Efficacy endpoints were assessed via investigator-rated 5-point categorical or 100-point visual analogue scales. Improvement or usefulness rates were the ratio of the number of pts in the two highest ranking categories of improvement/usefulness to the total number of evaluable pts.

tiveness, which was based on changes in ulcer size and reported using a VAS by an expert committee (a score of 70 of 100 indicated that the drug was considered useful). Analyses were per-protocol, unless specified otherwise. The efficacy of limaprost was not significantly different from that of ticlopidine in the TAO group.[29] Thus, a similar proportion of patients in the two treatment groups had improvement ratings in the top two categories for ulcer size (healed or reduced), rest pain (markedly improved or improved), overall improvement (markedly improved or improved), investigator-rated usefulness (scores of 90100 or 7089) and usefulness rated by an expert panel (90100 or 7089) [figure 1].
q q In addition, the reduction in ulcer size from baseline to study end was significant in both the limaprost (n = 57) and ticlopidine (n = 99) treatment groups (128 mm2 and 138 mm2) [p-value not reported].[29] This analysis included patients presenting with occlusive arteriosclerosis as well as those in the TAO group.

Lumbar Spinal Canal Stenosis

Patients with LSCS and symptoms of degenerative spondylolisthesis and bilateral intermittent claudication,[30] or degenerative, combined, spondylolisthetic, or spondolytic symptoms[31] were enrolled in two randomised, double-blind, multicentre, 6-week trials.[30,31] Patients were excluded from the studies if they met any of the following criteria: had prior surgery or were suitable candidates for surgery;[30,31] had chronic occlusive arterial disease;[30] had concomitant internal organ disease;[30,31] had severe impediment to lower extremity movement;[30] or were pregnant women or nursing mothers.[30] Patients enrolled in the trials were elderly (mean patient age of 6670 years), the majority of whom had degenerative spinal canal stenosis (75%[30] and 72%[31] of patients) of mild or moderate severity (84%[30] and 90%[31]) and of less than 2 years duration (6679%).[30,31] Nerve blocking treatment was not allowed during the trial; physical therapies (e.g. physiotherapy or corsets) were permissible only where patients had been receiving these treatments prior to the trial.[30,31] Concomitant pharmacological treatment
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with vasodilatory, muscle-relaxing or bone metabolism agents and cyanocobalamin preparations was generally excluded.[30,31] In one trial, treatment of concomitant illnesses was permitted[30] and, in the other trial,[31] analgesics and anti-inflammatory agents were allowed but, in either case, only where patients had been receiving these treatments prior to the trial. Patients received oral limaprost 3[30] or 6[31] g/ day (i.e. control treatment groups; n = 77[30] and 38[31]), or 15 g/day (n = 69[30] and 47[31]) or 30 g/ day (n = 44)[31] in three divided doses after meals. Patient baseline demographic and disease characteristics were not significantly different between treatment groups in one trial,[30] although in the other study[31] there were more women in the 30 g/day than in the 6 or 15 g/day groups (n = 25 vs 13 and 16) and more patients with degenerative spondylolisthetic, combined or spondolytic spinal canal stenosis in the 6 and 15 g/day than in the 30 g/day group (n = 15 and 16 vs 5). Where stated, approximately two-thirds of patients showed onset of intermittent claudication within a walking distance of 500m.[30] Primary efficacy endpoints, which were investigator-rated measurements, were specified only in one trial and were the overall improvement in symptoms at the end of treatment (both subjective and objective symptoms were assessed) and drug usefulness.[30] The third primary endpoint was a tolerability endpoint (see section 4).[30] The straight leg raise (SLR) test score, sensation, muscle strength and, in one trial, walking ability,[30] were assessed objectively, whereas lower extremity or lumbar pain and lower extremity numbness, and walking ability in the other trial,[31] were assessed subjectively. In one trial, baseline assessment of subjective symptoms was made at the time of onset of intermittent claudication; however, further on-treatment assessments of these symptoms were conducted after patients had walked the same distance that they had walked at baseline before intermittent claudication began.[30] By contrast, at least one subjective symptom was assessed at rest in the other trial (lumbar pain).[31] Activities of daily living (everyday life
2007 Adis Data Information BV. All rights reserved.

actions),[31] patient complaints (at rest)[30] and the distance to onset of intermittent claudication[30] were additional endpoints. With the exception of the SLR test and the distance to onset of intermittent claudication, most assessments were categorical, and values at the end of study were compared with baseline values to assess the degree of improvement shown. The scales used to rate subjective and objective symptoms were different between the two trials, thus results are reported separately. Statistical analyses were generally per-protocol, unless otherwise specified. q Limaprost 15 g/day was considered by investigators to provide greater overall improvement and to be a more useful treatment than the control dosage of 3 g/day (primary endpoints) in the phase III trial in 146 patients with LSCS.[30] When comparing assessment rates, there were more patients in the higher dosage group than in the control dosage group rated as improved or markedly improved (overall improvement rate 50.7% vs 27.3%; p < 0.01) at the end of treatment or for whom limaprost was rated as useful or extremely useful (usefulness rate 50.7% vs 27.3%; p < 0.01) [figure 2].[30] Assessment of overall improvement considered vaLIM 15 g/day (n = 69) LIM 3 g/day (n = 77) 60 50 Patients (%) 40 30 20 10 0 Overall improvement rate Usefulness rate 27.3 27.3 * 50.7 * 50.7

Fig. 2. Efficacy of oral limaprost (LIM) 15 vs 3 g/day in adult patients (pts) with lumbar spinal canal stenosis in a randomised, double-blind, multicentre, 6-week trial.[30] Investigator-rated categorical global measures of efficacy were the overall improvement at end of treatment and usefulness. Overall improvement rate and usefulness rate were the ratio of the number of pts in the two highest ranking categories of improvement/usefulness to the total number of evaluable pts. * p < 0.01 vs comparator.

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70 59.4 55.2

LIM 6 g/day LIM 15 g/day LIM 30 g/day

60

59.4 51.7

50 Improvement rate (% of pts) 50 43.5 40 41.7

48.3

34.8 30 20 20 21.1

26.1

10

0 Subjective symptoms Objective symptoms Everyday life actions Overall improvement

Fig. 3. Improvement rates with oral limaprost (LIM) in patients (pts) with lumbar spinal canal stenosis and normal straight leg raise test results. In this randomised, double-blind, multicentre, 6-week trial, patients received oral LIM in three daily divided doses after meals.[31] Improvement rates are shown for subjective symptoms, objective symptoms, everyday life action and overall improvement, and represent the ratio of the number of pts in the two highest ranking categories (e.g. markedly improved or improved subjective symptoms) to the total number of evaluable pts. The total number of pts varied for each assessment: LIM 6 g/day (n = 2023), LIM 15 g/day (n = 2432) and LIM 30 g/day (n = 1929). There were no statistically significant differences between treatment groups.

rious objective symptoms (e.g. muscle strength, walking ability) and subjective symptoms (e.g. pain or numbness in extremities), while assessment of usefulness also considered safety issues.
q Between-group differences in improvement in most objective symptoms at study end were not significant except for muscular strength and distance walked to onset of intermittent claudication according to Japanese Orthopaedic Association criteria for walking ability in the same trial (secondary efficacy endpoints).[30] More patients in the 15 g/ day than the 3 g/day dosage group experienced an improvement of at least one grade in muscular strength (59% vs 15% of patients; p = 0.0025) or of at least one scale point in the distance walked to onset of intermittent claudication (40% vs 25%; p = 0.0187).[30] q The efficacy of the 15 g/day dosage was generally superior to that of the 3 g/day group according to subjective measures of efficacy.[30] At study end, the proportion of patients with improved or marked-

ly improved subjective symptoms (42% vs 26%), patient impressions of got better (39% vs 25%), or with improved or markedly improved overall general improvement (55% vs 35%) was greater in the higher than in the control dosage group (secondary efficacy endpoints) [all p < 0.05]. The optimal dosage of limaprost in LSCS was determined in a phase II trial comparing limaprost 6, 15 and 30 g/day in a total of 129 patients.[31] A post-hoc analysis was conducted in 84 patients with normal SLR test results; patients with abnormal SLR results were excluded because they are typically good surgical candidates, often having concurrent disc hernia or lateral stenosis of the lumbar canal. The efficacy of limaprost 15 g/day was not significantly different from that of 30 g/day but tended to be better than that of 6 g/day when patients with abnormal SLR were excluded (figure 3). For example, improvement rates for subjective symptoms, objective symptoms and overall improvement were approximately 1520% higher with limaprost 15 g/
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day than with limaprost 6 g/day, and results with limaprost 30 g/day were generally similar to or slightly lower than those with limaprost 15 g/day. q Efficacy data from a postmarketing surveillance study are available from 1800 patients with LSCS who received limaprost (mean dosage 15.1 g/day) for a mean duration of 116 days.[32] The overall improvement rate was 49.9%, i.e. approximately half of the patients improved or markedly improved with limaprost therapy. Lower extremity pain, both at rest and after walking, was significantly reduced by limaprost and walking ability was significantly improved. For example, 55.7% of patients could not walk 500m before administration of limaprost, but this decreased to 27.4% of patients following treatment (p < 0.0001). Mean walking time almost doubled from 12.98 minutes at baseline to 21.23 minutes with limaprost (p < 0.0001). q A total of 363 patients who were evaluated for efficacy in the postmarketing surveillance study received limaprost treatment for >6 months (including 140 who received limaprost for >1 year).[32] The overall improvement rate was 52.9% among patients treated for >6 months and 60.7% among those treated for >1 year. A comparison of improvement rates among patients treated for >1 year versus those treated for <1 year showed a significantly higher rate in the longer-term treatment group (60.7% vs 47.9%; p-value not stated). 4. Tolerability Data in this section are primarily from pooled tolerability analyses available in the manufacturers Japanese prescribing information,[9] postmarketing surveillance data[32] and the 6-week trials discussed in section 3.[29-31] The duration of drug exposure in patients included in the pooled analyses was not reported. q Oral limaprost 330 g/day was generally well tolerated in adult patients with TAO[9,29] or LSCS.[9,30-32] The overall incidence of treatmentemergent adverse events with limaprost in the latter indication appeared to be dose-related, occurring in 3% or 4% of patients receiving 3[30] or 6[31] g/day compared with 9%[30] and 6%[31] of those receiving
2007 Adis Data Information BV. All rights reserved.

15 g/day and 16%[31] of those receiving 30 g/day. However, between-group differences in the incidence of these adverse events in one trial,[30] or in the number of patients without these adverse events in the other trial,[31] were not significant. q The most frequent treatment-related adverse effects included gastrointestinal (GI)-related effects, rash, hot flushes/flushing, headaches and anaemia.[9] In patients with TAO, diarrhoea, nausea/vomiting/ retching, hot flushes/flushing, rash and abdominal or epigastric discomfort were reported in 1.1%, 0.5%, 0.5%, 0.4% and 0.4% of patients (n = 4582; pooled analysis);[9] in patients with LSCS, there were 25 reports of adverse events affecting the GI tract (e.g. stomach discomfort, diarrhoea, abdominal discomfort) among 397 patients (pooled analysis).[32] q Other treatment-related adverse events occurring in 0.20.3% of patients with TAO were abdominal or gastric pain, headache, hepatic function abnormalities (e.g. increased AST or ALT levels) and anorexia.[9] q Serious treatment-emergent adverse events described by investigators as occurring in patients for whom treatment was not safe were reported only in one trial, in three patients receiving limaprost 30 g/day.[29] These adverse events were GI-related in two patients and increased AST or ALT levels in the third patient; all three patients discontinued the study drug. q Four of 92 patients receiving limaprost and one of 106 patients receiving ticlopidine discontinued treatment because of an adverse event in a 6-week trial (see section 3 for trial design details).[29] Reasons for discontinuation were not reported for all patients; however, two patients stopped treatment because of GI-related adverse events.[29] q In this trial versus ticlopidine,[29] adverse events were not reported separately for the two indication groups (TAO and occlusive arteriosclerosis). Treatment-emergent adverse events occurred in 12% of patients receiving limaprost versus 8% of patients receiving ticlopidine. Nevertheless, the investigatorrated safety of limaprost 330 g/day was not significantly different from that of ticlopidine in the
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TAO group (safety rate of 88% [n = 69] vs 95% [n = 80] of patients).[29] q In similar investigator-rated assessments of overall safety in the trials in patients with LSCS, safety rates were 9497% of 3847 evaluable patients receiving limaprost 315 g/day,[30,31] and 84% of 44 patients receiving 30 g/day, i.e. twice the recommended dosage (section 5).[31] Between-group differences were not significant.[30,31] The safety rate was the ratio of the number of patients for whom the drug was rated by the investigator as fairly safe or safe to the number of all evaluable patients. q In addition to elevated AST and ALT levels,[9,29-31] limaprost has been associated with thrombocytopenia[30] and increased blood urea nitrogen levels[31] in a small number of patients. The drug may also be associated with hepatic impairment or jaundice.[9] q Tolerability data from a postmarketing surveillance study are available from 1930 patients with LSCS who received limaprost (mean dosage 15.1 g/day) for a mean duration of approximately 4 months.[32] Adverse events occurred in 5.2% of patients. A total of 123 events were reported, almost half of which involved GI disorders, such as stomach discomfort or diarrhoea. One serious adverse event was reported (bleeding duodenal ulcer). Among 397 patients treated for >6 months (including 141 who received limaprost for >1 year), 9.1% experienced an adverse event, in most cases a GI disorder.[32] The incidence of adverse events was significantly lower among patients who received treatment for >1 year than among those who received treatment for <1 year (2.84% vs 12.5%; p = 0.0025). 5. Dosage and Administration Oral limaprost is approved in Japan for the treatment of ischaemic symptoms (ulcer, feeling of coldness, pain) in adult patients with TAO and for the treatment of pain and numbness in the lower legs and of abnormal gait in adult patients with acquired LSCS who have bilateral intermittent claudication and a normal result on the SLR test.[2] The recommended daily dose is 30g in patients with TAO and
2007 Adis Data Information BV. All rights reserved.

15g in patients with LSCS, taken in three divided doses.[9] Currently no dosage recommendations for special patient populations exist, although the drug should be administered with caution in patients with a tendency to bleed or those receiving treatment with thrombolytic, antiplatelet or anticoagulant agents. Local prescribing information should be consulted for information on precautions, contraindications and drug interactions.[9] 6. Limaprost: Current Status In Japan, oral limaprost is approved for the treatment of various ischaemic symptoms, such as pain, ulcers and a sensation of coldness in the peripheral extremities, in patients with TAO and of subjective symptoms, such as pain and numbness in the lower legs and reduced walking ability in patients with acquired LSCS. In a randomised, double-blind trial, the efficacy of limaprost 30 g/day was not significantly different from that of ticlopidine 500 g/day in patients with TAO. In patients with LSCS who were deemed to be good candidates for medical rather than surgical intervention on the basis of SLR test results, the optimal dose of limaprost was found to be 15 g/day. Limaprost was generally well tolerated in clinical trials. Disclosure
During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article; changes based on any comments received were made on the basis of scientific and editorial merit.

References
1. Ono Pharmaceutical Co Ltd. Additional indication approved for limaprost, oral prostaglandin E1 derivative (media release) [online]. Available from URL: http://www.ono.co.jp [Accessed 2006 Apr 12] 2. Szuba A, Cooke JP. Thromboangiitis obliterans: an update on Buergers disease. West J Med 1998 Apr; 168 (4): 255-60 3. Olin JW. Thromboangiitis obliterans (Buergers disease). N Engl J Med 2000 Sep 21; 343 (12): 864-9 4. Sweetman SC. Martindale: the complete drug reference. 34th ed. London: Pharmaceutical Press, 2005 5. Arbit E, Pannullo S. Lumbar stenosis: a clinical review. Clin Orthop Relat Res 2001 Mar; (384): 137-43

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6. Alvarez JA, Hardy Jr RH. Lumbar spine stenosis: a common cause of back and leg pain. Am Fam Physician 1998 Apr 15; 57 (8): 1825-39 7. Chosa E, Sekimoto T, Kubo S, et al. Evaluation of circulatory compromise in the leg in lumbar spinal canal stenosis. Clin Orthop Relat Res 2005 Feb; (431): 129-33 8. Snyder DL, Doggett D, Turkelson C. Treatment of degenerative lumbar spinal stenosis. Am Fam Physician 2004 Aug 1; 70 (3): 517-20 9. Ono Pharmaceutical Co Ltd. Opalmon tablets 5 g prescribing information [online]. Available from URL: http://www.esearch.ne.jp/~jpr/PDF/ONO06.PDF [Accessed 2006 Apr 21] 10. Kitagawa T, Wakitani K, Ogaki Y, et al. Effects of a prostaglandin E1 analogue, OP-1206-cyclodextrin clathrate (OP-1206-CD) in a model of experimental peripheral circulation disorder in rats [in Japanese]. Gendai Iryo 1986; 18 Suppl. II: 1-11 11. Tsuboi T, Hatano K, Nakatsuji B, et al. Pharmacological evaluation of OP 1206, a prostaglandin E1 derivative, as an antianginal agent. Arch Int Pharmacodyn Ther 1980; 247 (1): 89-102 12. Kitagawa T, Sakaguchi N, Kira H, et al. Effects of a prostaglandin E1 analogue, OP-1206-cyclodextrin clathrate (OP-1206-CD) on the femoral arterial blood flow, hindlimb cutaneous blood flow and hindlimb cutaneous temperature [in Japanese]. Gendai Iryo 1986; 18 Suppl. II: 12-20 13. Tsuboi T, Fujitani B, Maeda J, et al. Effect of OP 1206, a prostaglandin E1 derivative, on guinea-pig platelet functions. Thromb Res 1980; 20 (5-6): 573-80 14. Fujitani B, Watanabe M, Kuwashima J, et al. Effect of a prostaglandin E1 derivative (OP-1206) and acetylsalicyclic acid on electrically induced thrombosis in guinea-pig mesenteric artery and its modification by an inhibitor of prostaglandin I2 synthetase, tranylcypromine. Jap J Pharmacol 1986; 40: 31-5 15. Maeda Y, Kanayama S, Okajima Y, et al. Effect of PGE1 analogue (ONO-1206) on the platelet functions [in Japanese]. Ketsueki to Myakkan 1982; 13 (1): 142-5 16. Yamamoto T, Hiromoto J. Phase I clinical trial of 17(S)-methylomega-homo-trans-delta2-prostaglandinE1-cyclodextrin (OP-1206-CD): part 1. Single dose study [in Japanese]. Yakuri To Chiryo 1981; 9 (4): 1463-76 17. Ito K, Nagashima K, Takenobu Y, et al. Effect of OP-1206 CD on cauda equina blood flow in dog cauda equina with experimental compression [in Japanese]. Kiso to Rinsho 1995; 29 (10): 2577-85 18. Sawaragi H, Takenobu Y, Nonaka S, et al. Effect of OP-1206 CD on the thermal hyperalgesia induced by constriction injury to the sciatic nerve in the rat [in Japanese]. Kiso to Rinsho 1996; 30 (2): 237-44 19. Takenobu Y, Katsube N, Nakai H. Effect of OP-1206 -CD on the walking dysfunction in the rat cauda equina nerve compressed model [in Japanese]. Kiso to Rinsho 1996; 30 (2): 221-7 20. Sekiguchi M, Kikuchi S, Konno S. Effects of liimaprost, an orally-active prostaglandin E1 analogue, in a model of experi-

mental acute cauda equine compression: a study using a video recording system (digital hi-scope) [in Japanese]. Progr ad Med 2002; 22 (2): 443-5 21. Kayama S, Konno S, Kikuchi S, et al. Effect of OP-1206 -CD (prostaglandin E1 derivative) on nerve conduction velocity in the dog cauda equina subjected to acute experimental compression [in Japanese]. Kiso to Rinsho 1996; 30 (2): 229-36 22. Fujitani B, Kii Y, Tashibu H, et al. Effect of OP-1206 -CD on electromyograms in sciatic nerve-ligated rate [in Japanese]. Kiso to Rinsho 1996; 30 (2): 245-50 23. Liu Y, Noguchi K, Takenobu Y, et al. Comparison the effect of beraprost sodium with that of limaprost alfadex in rat neuropathic intermittent claudication model [in Japanese]. Jpn Pharmacol Ther 2002; 30 (10): 875-80 24. Mikami H, Hishita N, Itoh T. Clinical pharmacokinetic study of a single oral administration of limaprost alfadex (Prorenal) [in Japanese]. Rinsho Iyaku 2005; 21 (3): 361-6 25. Komaba J, Masuda Y, Nako S, et al. Clinical pharmacokinetic study of Opalmon (limaprost alfadex) tablet in healthy Japanese male volunteers [in Japanese]. Igaku to Yakugaku 2005; 53 (2): 265-71 26. Miyamoto S, Taniguchi K, Kajiwara I, et al. Pharmacokinetics of OP-1206-cyclodextrin clathrate (OP-1206-CD): first report: absorption and excretion after oral and intracaudal administration in rats [in Japanese]. Gendai Iryo 1986; 18 Suppl. II: 56-69 27. Miyamoto S, Kida J, Okada K, et al. Pharmacokinetics of OP-1206-cyclodextrin clathrate (OP-1206-CD): second report: distribution after oral administration in rats [in Japanese]. Gendai Iryo 1986; 18 Suppl. II: 70-9 28. Miyamoto S, Ishido M, Sawada M, et al. Pharmacokinetics of OP-1206-cyclodextrin clathrate (OP-1206-CD): third report: metabolism in rats [in Japanese]. Gendai Iryo 1986; 18 Suppl. II: 80-103 29. Kusaba A, Tanabe T, Mishima Y, et al. Therapeutic effect of OP-1206-CD in patients with chronic arterial occlusive disease of the extremities: double-blind comparative trial with ticlopidine [in Japanese]. J Clin Exp Med 1986; 138: 217-26 30. Kurihara A, Kataoka O, Sugawara S, et al. Clinical benefit of OP-1206-CD on lumbar spinal canal stenosis: multi-center comparative double-blind clinical study [in Japanese]. Rinsho Iyaku 1996; 12 (3): 511-29 31. Uratsuji M, Kurihara A, Iguchi T, et al. The optimal dose for OP-1206 -CD on lumbar spinal canal stenosis: multi-center comparative double-blind clinical study [in Japanese]. Rinsho Iyaku 1996; 12 (3): 489-509 32. Ono Pharmaceutical Co Ltd. Postmarketing surveillance: April 2001-March 2004: Prospective Central Registration System Trial [data on file]. Japan: Ono Pharmaceutical Co, Ltd, 2006

Correspondence: Greg L. Plosker, Wolters Kluwer Health | Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 1311, New Zealand. E-mail: demail@adis.co.nz

2007 Adis Data Information BV. All rights reserved.

Drugs 2007; 67 (1)

GUEST COMMENTARIES

Drugs 2007; 67 (1): 119-120 0012-6667/07/0001-0119/$49.95/0 2007 Adis Data Information BV. All rights reserved.

Limaprost
A Viewpoint by Akira Dezawa
Department of Orthopedic Surgery, Teikyo University Mizonokuchi Hospital, Kawasaki, Japan

OP-1206 -CD (limaprost alfadex) is an orally active prostaglandin E1 (PGE1) analogue that was approved in 1988 for the treatment of various ischaemic symptoms, such as ulcer, pain and sensation of coldness of the hands and feet, associated with thromboangiitis obliterans (TAO). In 2001, the indication of limaprost for improvement in pain and numbness in lower limbs and walking ability was expanded to include lumbar spinal canal stenosis (LSCS). Limaprost is a potent inhibitor of platelet aggregation as well as a strong vasodilator. Limaprost 30 g/day for TAO has a beneficial effect especially on relieving pain and healing ulcers. Of course, physical training in combination with drug treatment is a useful therapeutic option. LSCS most commonly affects the middle-aged and elderly population and its main symptom is intermittent claudication. Such a narrowed spinal canal results in poor blood circulation of the cauda

equina, leading to a lack of nutrition in that area, and eventually results in neurological impairment. This causes pain and numbness in the lower limbs, which consequently lead to difficulty in walking (intermittent claudication). Surgical intervention cannot be recommended for all patients and LSCS is resistant to drug therapy, such as analgesics and anti-inflammatory drugs, as well as orthosis therapy and physiotherapy. Therefore, a multicentre, comparative, double-blind clinical study was performed for the purpose of investigating the efficacy, safety and usefulness of limaprost (15 g/day for 6 weeks) in LSCS.[1] Indeed, intravenous PGE1 infusions in intermittent claudication are effective and well tolerated, but most patients would prefer to avoid an infusion as a first-line therapy. It is therefore expected that limaprost will be useful in improving the quality of life of patients suffering from ischaemic involvement by inducing remission of various symptoms. v

Reference
1. Kurihara A, Kataoka O, Sugawara S, et al. Clinical benefit of OP-1206-CD on lumbar spinal canal stenosis: multi-center comparative double-blind clinical study [in Japanese]. Rinsho Iyaku 1996; 12 (3): 511-29

GUEST COMMENTARIES

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Limaprost
A Viewpoint by Shin-Ichi Konno
Department of Orthopaedic Surgery, Fukushima Medical University, School of Medicine, Fukushima, Japan

effect of improving vascular endothelial function and a vasodilating effect, so it is considered to be efficacious in LSCS. Because PGE1 is rapidly inactivated in the lungs, large doses are needed; this can lead to hypotension, diarrhoea and local irritation. To avoid this, lipoPGE1 was developed. Clinical studies have demonstrated that lipo-PGE1 is more effective and safer than conventional free PGE1 in the treatment of peripheral vascular disease. However, oral limaprost overcomes the safety concerns of an intravenous infusion. Most patients would prefer to avoid an infusion as first-line therapy. Oral limaprost 330 g/day was generally well tolerated in clinical trials. Larger studies that use a double-blind, randomised, controlled design are needed to evaluate the efficacy of limaprost for treatment of LSCS and peripheral vascular disease, with assessments of patient-based outcomes using instruments such as the RolandMorris disability questionnaire and the Short-Form 36. v

Prostaglandin E1 (PGE1) clathrate compounds were developed as antiplatelet drugs: alprostadil alfadex for injection (1979) and limaprost alfadex for oral use (1988). PGE1 is both a vasodilator and an inhibitor of platelet aggregation, and has been widely used in the treatment of peripheral vascular disease in Japan. Intermittent claudication due to lumbar spinal canal stenosis (LSCS) is very likely to account in part for the development of symptoms of reversible functional impairment caused by a relative ischaemic state of the cauda equina. Based on these findings, it would be reasonable to consider that reversal of compression-induced decreased blood flow in the cauda equina may be effective in improving symptoms due to LSCS. Limaprost has been proven to have an antithrombocytic effect, an

ADIS DRUG EVALUATION

Drugs 2007; 67 (1): 121-153 0012-6667/07/0001-0121/$49.95/0 2007 Adis Data Information BV. All rights reserved.

Fenofibrate
A Review of its Use in Primary Dyslipidaemia, the Metabolic Syndrome and Type 2 Diabetes Mellitus
Gillian M. Keating and Katherine F. Croom
Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Conshohocken, Pennsylvania, USA
Various sections of the manuscript reviewed by: M. Farnier, Point M dical, Rond Point de la Nation, Dijon, France; P. Gervois, Laboratoire de Biochimie, e Facult des Sciences Pharmaceutiques et Biologiques 3, Lille, France; P.H. Jones, Methodist DeBakey Heart e Center, Baylor College of Medicine, Houston, Texas, USA; D.N. Kiortsis, Medical School, University of Ioannina, Ioannina, Greece; V. Melenovsky, Department of Cardiology, IKEM, Prague, Czech Republic; K.G. Parhofer, University of Munich, Klinikum Grosshadern, Munich, Germany; G.F. Watts, School of Medicine and Pharmacology, University of Western Australia, Royal Perth Hospital, Perth, Western Australia, Australia.
Data Selection Sources: Medical literature published in any language since 1980 on fenofibrate, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug. Search strategy: MEDLINE, EMBASE and AdisBase search terms were fenofibrate or fibric acid derivatives. Searches were last updated 18 December 2006. Selection: Studies in patients with primary dyslipidaemia, the metabolic syndrome or type 2 diabetes mellitus who received fenofibrate. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included. Index terms: Fenofibrate, dyslipidaemia, metabolic syndrome, type 2 diabetes mellitus, pharmacodynamics, pharmacokinetics, therapeutic use.

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 2.1 Effects on Lipids and Apolipoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 2.2 Effects on Lipid Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 2.3 Other Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 3. Pharmacokinetics Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 3.1 Special Patient Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 3.2 Potential Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 4. Clinical Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 4.1 In Primary Dyslipidaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 4.1.1 Placebo-Controlled Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 4.1.2 Comparisons with HMG-CoA Reductase Inhibitors (Statins) . . . . . . . . . . . . . . . . . . . . . . . . . 129 4.1.3 Comparisons with Other Fibrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 4.1.4 In Combination with Statins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130

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4.1.5 In Combination with a Cholesterol Absorption Inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 4.1.6 In Combination with a Bile Acid Sequestrant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 4.2 In the Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 4.2.1 Comparisons with Placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 4.2.2 Comparison with a Statin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 4.2.3 In Combination with Statins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 4.2.4 In Combination with Metformin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 4.2.5 In Combination with Orlistat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 4.3 In Type 2 Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 4.3.1 Effects on Lipid Levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 4.3.2 Effects on Macrovascular Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 4.3.3 Effects on Microvascular Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 4.3.4 Effects on Glycaemic Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 7. Place of Fenofibrate in the Management of Primary Dyslipidaemia, the Metabolic Syndrome and Type 2 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

Abstract

Fenofibrate is a fibric acid derivative indicated for use in the treatment of primary hypercholesterolaemia, mixed dyslipidaemia and hypertriglyceridaemia in adults who have not responded to nonpharmacological measures. Its lipid-modifying effects are mediated by activation of peroxisome proliferator-activated receptor-. Fenofibrate also has nonlipid (i.e. pleiotropic) effects (e.g. it reduces fibrinogen, C-reactive protein and uric acid levels and improves flow-mediated dilatation). Fenofibrate improves lipid levels (in particular triglyceride [TG] and high-density lipoprotein-cholesterol [HDL-C] levels) in patients with primary dyslipidaemia. Its lipid-lowering profile means that fenofibrate is particularly well suited for use in atherogenic dyslipidaemia (characterised by high TG levels, low HDL-C levels and small, dense low-density lipoprotein [LDL] particles), which is commonly seen in patients with the metabolic syndrome and type 2 diabetes mellitus. Indeed, fenofibrate improves the components of atherogenic dyslipidaemia in patients with these conditions, including a shift from small, dense LDL particles to larger, more buoyant LDL particles. Greater improvements in lipid levels are seen when fenofibrate is administered in combination with an HMG-CoA reductase inhibitor (statin) or in combination with ezetimibe, compared with monotherapy with these agents. In the DAIS study, fenofibrate significantly slowed the angiographic progression of focal coronary atherosclerosis in patients with type 2 diabetes. In terms of clinical outcomes, although no significant reduction in the risk of coronary events was seen with fenofibrate in the FIELD trial in patients with type 2 diabetes, treatment was associated with a significantly reduced risk of total cardiovascular disease (CVD) events, primarily through the prevention of non-fatal myocardial infarction and coronary revascularisation. Subgroup analyses revealed significant reductions in total CVD events and coronary heart disease events in patients with no previous CVD, suggesting a potential role for primary prevention with fenofibrate in patients with early type 2 diabetes. Improvements were also seen in microvascular outcomes with fenofibrate in the FIELD trial. Fenofibrate is generally well tolerated, both as
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monotherapy and when administered in combination with a statin. Combination therapy with fenofibrate plus a statin appears to be associated with a low risk of rhabdomyolysis; no cases of rhabdomyolysis were reported in patients receiving such therapy in the FIELD trial. Thus, fenofibrate is a valuable lipid-lowering agent, particularly in patients with atherogenic dyslipidaemia.

1. Introduction There are three major classes of lipoprotein: lowdensity lipoproteins (LDL), the major cholesterolcontaining lipoproteins; high-density lipoproteins (HDL), which are integral to the transfer of cholesterol from the peripheral tissues to the liver for biliary elimination (i.e. reverse cholesterol transport); and very-low-density lipoproteins (VLDL), triglyceride (TG)-rich lipoproteins that are, along with intermediate-density lipoproteins, precursors of LDL.[1-3] There is also a fourth class of lipoprotein, the TG-rich chylomicrons, which are formed in the intestine from dietary fat.[1] Risk factors for coronary heart disease (CHD) include elevated LDL-cholesterol (LDL-C) levels, low HDL-cholesterol (HDL-C) levels and elevated TG levels (especially VLDL remnants).[1] In addition, emerging risk factors include elevated lipoprotein(a) levels, elevated apolipoprotein (Apo) B levels, low ApoAI levels, elevated homocysteine levels, elevated fibrinogen levels and elevated Creactive protein (CRP) levels.[1] A system commonly used to classify the dyslipidaemias is shown in table I. LDL-C is the primary target of lipid-lowering therapy, and the LDL-C treatment goal varies according to the risk of a CHD
Table I. Fredrickson classification of dyslipidaemias[3] Type I IIa IIb III IV Elevated particles Chylomicrons LDL LDL, VLDL IDL VLDL TC TG

Table II. Lipid goals (mmol/L) based on CHD event risk, according to the National Cholesterol Education Program Adult Treatment Panel III guidelines[1,4] Risk Primary LDL-C target <4.1 <3.4 <3.4a <2.6 Secondary nonHDL-C target (if TG 2.3) <4.9 <4.1 <4.1 <3.4

Low risk (01 risk factors) Moderate risk (2 risk factors; 10-year risk <10%) Moderate high risk (2 risk factors; 10-year risk 1020%) High risk (CHD or CHD risk equivalent [e.g. diabetes mellitus])b

Very high risk (e.g. CHD plus <1.8c other risk factors [e.g. diabetes or multiple risk factors of the metabolic syndrome]) a b c

<2.6

An LDL-C goal of <2.6 mmol/L is an option in these patients. Includes patients with 2 risk factors and a 10-year risk of >20% (considered a CHD risk equivalent). Optional target in patients at very high risk.

CHD = coronary heart disease; HDL-C = high-density lipoproteincholesterol; LDL-C = low-density lipoprotein-cholesterol; TG = triglyceride.

V Chylomicrons, VLDL IDL = intermediate-density lipoprotein; LDL = low-density lipoprotein; TC = total cholesterol; TG = triglyceride; VLDL = verylow-density lipoprotein; indicates increased; indicates greatly increased; indicates normal; indicates normal or increased.

event (table II).[1] For example, patients with preexisting CHD and the metabolic syndrome (a precursor of diabetes mellitus) or diabetes are considered to be at very high risk of a CHD event (table II).[4] There has been a substantial increase in the prevalence of obesity, the metabolic syndrome and diabetes in recent times.[5] Indeed, it was recently estimated that almost one-quarter of adults in the US have the metabolic syndrome;[6] the increase in the number of people with the metabolic syndrome in the US between 1990 and 2000 (from 50 to 64 million) suggests that its prevalence will continue to increase.[7] It has been suggested that the growing number of people affected by this disorder poses a threat to the reduction in CHD risk achieved in the US population over the past 3 decades (this reducDrugs 2007; 67 (1)

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tion has been achieved via declining LDL-C levels).[1] Indeed, the metabolic syndrome poses a substantial burden in terms of increased morbidity, mortality and healthcare costs. The metabolic syndrome is characterised by the presence of atherogenic dyslipidaemia, abdominal obesity, raised blood pressure (BP), prothrombotic and proinflammatory states and insulin resistance.[1] Atherogenic dyslipidaemia comprises the triad of high TG levels, low HDL-C levels and the presence of small, dense LDL particles (i.e. a pattern B LDL phenotype).[1] According to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III guidelines, the metabolic syndrome is diagnosed when at least three of the following criteria are present: abdominal obesity (a waist circumference of >102cm in men and >88cm in women); a TG level 1.7 mmol/L; an HDL-C level <1.0 mmol/L in men and <1.3 mmol/L in women; BP 130/85mm Hg; and a fasting glucose level 110 mg/dL.[1] Alternative diagnostic criteria have been proposed by the WHO and other organisations.[8] Patients with the metabolic syndrome have an 2-fold increase in the risk of developing cardiovascular disease (CVD) and an 5-fold increase in the risk of developing type 2 diabetes.[9] The prevalence of type 2 diabetes is also increasing; it is estimated that 366 million persons will be affected by diabetes worldwide by 2030.[10] Diabetes in itself is a strong independent risk factor for CHD,[1] with 2- to 4-fold higher rates of coronary artery disease seen in patients with diabetes than in those without.[11] Atherogenic dyslipidaemia and the metabolic syndrome are common features of type 2 diabetes.[1] Patients with diabetes are at risk of both macrovascular (e.g. CHD, peripheral vascular disease, cerebrovascular disease) and microvascular (retinopathy, nephropathy, neuropathy) complications.[12] In terms of microvascular complications, retinopathy is the most common cause of new cases of blindness in adults aged 2074 years.[13] Approximately 20% of patients with newly diagnosed type 2

diabetes have retinopathy at the time of diagnosis.[14] In addition, approximately 2040% of patients with diabetes will develop nephropathy, the most common cause of end-stage renal disease.[15] Neuropathy affects 4050% of patients with diabetes[14] and commonly leads to foot ulceration and amputation, major sources of morbidity and disability in this patient group.[15] Lipid-lowering therapy plays an important role in improving the lipid profile of patients with dyslipidaemia, thereby reducing CHD risk. Lipid-lowering agents include the HMG-CoA reductase inhibitors (statins), the fibric acid derivatives (fibrates), the bile acid sequestrants, nicotinic acid (niacin) and the cholesterol absorption inhibitors.[1,16] The fibrate fenofibrate1 has been available since 1975,[17] although the original formulation had poor solubility resulting in low bioavailability.[18] However, development of newer formulations of the drug utilising smaller fenofibrate particle sizes has improved its bioavailability. A capsule formulation of micronised fenofibrate is available in 67, 200 and 267mg doses[19-21] and a microcoated tablet formulation of micronised fenofibrate is available in 54, 160 and 215mg doses.[22,23] A new nanoparticle tablet formulation of fenofibrate utilising NanoCrystal technology has recently become available in the US, France and Canada, with launches in other countries anticipated.[18,23] This new nanoparticle formulation can be administered without regard to food (i.e. it is a non-food effect [NFE] formulation) and is available in 48 and 145mg doses (section 3).[23,24] A 200mg dose of the capsule formulation, a 160mg dose of the microcoated tablet formulation and a 145mg dose of the new NFE formulation are considered bioequivalent.[18] This article discusses the pharmacological properties of fenofibrate, and examines its efficacy and tolerability in primary dyslipidaemia, the metabolic syndrome and type 2 diabetes. Throughout this article, lipid levels are reported in mmol/L; to convert to mg/dL, total cholesterol (TC), LDL-C and

1 Trade names for the various fenofibrate formulations include Catalip, Fulcro, Lipanthyl, Lipantil, Lipidil, Lipcor, Secalip, Supralip and Tricor. The use of trade names is for product identification purposes only and does not imply endorsement.
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HDL-C values should be multiplied by 38.7 and TG values should be multiplied by 88.6. 2. Pharmacodynamic Properties
2.1 Effects on Lipids and Apolipoproteins

Fenofibrate is a prodrug that is converted into the pharmacologically active metabolite fenofibric acid (section 3).[18] The lipid-modifying effects of fenofibrate are mediated by its activation of the nuclear transcription factor peroxisome proliferator-activated receptor- (PPAR) [figure 1].[25] Activated PPAR forms a heterodimer with another nuclear receptor, retinoid X receptor, which then binds specific peroxisome proliferator response elements, thereby modulating the expression of genes regulating lipid metabolism.[25,26] It has been suggested that PPAR expression levels may determine patient response to fibrates.[27] Whereas fenofibrate appears to act as a full agonist at PPAR, gemfibrozil seems to act as a selective PPAR modulator.[27] Activation of PPAR results in increased lipolysis and plasma clearance of atherogenic TG-rich lipoproteins via the activation of lipoprotein lipase and ApoAV and reduced production of the lipoprotein lipase inhibitor ApoCIII.[2,28-32] Fenofibrate also promotes the -oxidation of fatty acids, thus reducing the availability of free fatty acids for TG syntheFibrate

PPAR Activated PPAR/RXR PPRE/target genes Inflammation Reverse cholesterol transport Fig. 1. Mechanism of action of fenofibrate.[25,28] HDL = high-density lipoprotein; LDL = low-density lipoprotein; PPAR = peroxisome proliferator-activated receptor-; PPRE = peroxisome proliferator response elements; RXR = retinoid X receptor; indicates increase; indicates decrease.

LDL particle size HDL synthesis

Triglycerides

sis.[25,32,33] De novo fatty acid synthesis is also inhibited with fenofibrate, through reductions in acetylCoA carboxylase and fatty acid synthase activity; this also reduces the availability of fatty acids for TG synthesis.[32,33] ApoB and VLDL production and secretion is also reduced with fenofibrate.[32,33] Fenofibrate increases LDL clearance and reduces small dense LDL.[34-38] Larger, less dense LDL particles have a high binding affinity for cellular LDL receptors, and are less susceptible to oxidation.[28,34-36] PPAR activation also increases ApoAI and ApoAII synthesis (the major proteins in HDL).[32,33,39,40] Fenofibrate reduces cholesteryl ester transfer protein (CETP) activity;[41,42] the reduction in CETP-mediated transfer of lipid from HDL to VLDL may also contribute to the observed increase in HDL-C levels.[34,43] In keeping with the above-mentioned mechanisms, the following significant (p < 0.05 vs baseline or placebo) changes were seen with fenofibrate in patients with primary dyslipidaemia,[37,44-62] the metabolic syndrome[63,64] or type 2 diabetes:[65-68] reduced ApoCIII levels;[37,44,46,56,60,63,64] increased ApoAI levels;[37,44-46,49,51-53,57-63,65,68] increased ApoAII levels;[37,44,60,63] reduced ApoB levels;[37,44-49,51-56,58-67] reduced lipoprotein(a) levels in some studies.[46,49,50] Clinical trials in patients with primary dyslipidaemia, the metabolic syndrome or type 2 diabetes revealed that fenofibrate monotherapy was associated with changes from baseline of 6% to 27% in TC levels, 33% to +1% in LDL-C levels, +1% to +34% in HDL-C levels and 25% to 59% in TG levels (see section 4 for detailed results). It should be noted that these studies included patients with various types of dyslipidaemia (e.g. primary hypercholesterolaemia, mixed dyslipidaemia, hypertriglyceridaemia).
2.2 Effects on Lipid Transporters

ATP-binding cassette transporter A1 (ABCA1) is involved in the control of ApoAI-mediated cholesterol efflux. Fenofibric acid increased transcription
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of ABCA1 in macrophages, as well as increasing ApoAI-mediated lipid release.[26] The effect of fenofibric acid on ABCA1 was dependent on activation of the nuclear receptor liver X receptor (LXR).[26] Significant (p < 0.05) increases from baseline in ABCA1 and LXR- mRNA levels were seen following fenofibrate therapy in patients with diabetic dyslipidaemia.[69] Scavenger receptors play a vital role in the accumulation of lipids by macrophages.[2] Scavenger receptor class B type I (SR-BI) is thought to be involved in cholesterol efflux.[2] Fenofibrate was shown to stimulate the expression of SR-BI/CD36and LIMPII-analogous 1 in vitro;[70] however, no increase in SR-BI mRNA levels was seen in patients with diabetic dyslipidaemia who received fenofibrate.[69]
2.3 Other Effects

As well as regulating lipid metabolism, PPAR modulates haemostasis and the inflammatory response.[71] Increased levels of fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and the inflammatory marker CRP have been linked with an increased risk of atherosclerosis.[71] Raised uric acid and homocysteine levels have also been linked to atherosclerosis,[72] and impaired vasoreactivity precedes the development of atherosclerosis.[51,73] By contrast, paraoxonase (PON1), an enzyme present on HDL, is thought to have an antioxidant effect,[74] and increased adiponectin levels are thought to improve insulin sensitivity.[52] The effect of fenofibrate on these various factors has been examined in studies in patients with dyslipidaemia,[37,44-49,51-54,57,58,61,72-95] the metabolic syndrome,[96-98] impaired glucose tolerance[99] or type 2 diabetes.[65,68,100] Some studies are available only as abstracts.[83,96,98,101] In patients with dyslipidaemia, fenofibrate therapy was associated with the following significant (p < 0.05 vs baseline or placebo) changes: reduced plasma fibrinogen[45-49,51-54,61,74,85,88-91] and PAI-1[51,85] levels; reduced CRP levels,[37,52,53,57,61,73,74,77,91,92,95] along with reduced levels of the pro-inflammato 2007 Adis Data Information BV. All rights reserved.

ry cytokines interleukin (IL)-6,[87,91,92,95] IL-1,[73,87] tumour necrosis factor- (TNF)[51,94,95] and monocyte chemoattractant protein-1 (MCP-1);[81,82,86,87,92] reduced intercellular adhesion molecule-1 (ICAM-1) levels were seen in some[82] but not all[92] studies; increased serum PON1 activity[58,74,83] and adiponectin levels;[52,53] improvement in flow-mediated dilatation,[51-54,73,94] but not the dilator response to nitroglycerin;[51-54,73] improved forearm blood flow in response to acetylcholine, nitroprusside and verapamil;[76] reduced uric acid levels;[44,45,48,55,57,60,72,80,84,95] increased homocysteine levels.[57,72,75,78,79,93] Given that the metabolic syndrome is characterised by a prothrombotic/proinflammatory state (section 1), the effect of fenofibrate therapy is of particular interest in patients with this condition. For example, fenofibrate 200 mg/day for 12 weeks significantly reduced fibrinogen levels from baseline by 19% (p < 0.01) in a noncomparative study in patients with the metabolic syndrome (n = 37).[97] Moreover, significantly (p < 0.05) greater reductions from baseline were seen with fenofibrate 160 mg/day than with placebo in IL-1 (3% vs 2%), MCP-1 (5% vs 1%), vascular cell adhesion molecule-1 (VCAM-1; 10% vs 3%) and ICAM-1 (15% vs 2%) levels in a well designed trial in patients with the metabolic syndrome (n = 55) [IL-1 and MCP-1 levels measured in the postprandial state and VCAM-1 and ICAM-1 levels measured in the fasting state];[98] in addition, adiponectin levels increased from baseline to a significantly greater extent with fenofibrate than with placebo (+0.34 vs +0.07 g/mL; p = 0.0003).[101] Similarly, fenofibrate 200 mg/day was associated with significant (p < 0.05) improvements in CRP (34%), IL-6 (27%) and ICAM (5%) levels, but not VCAM levels, in another placebo-controlled study in 25 patients with the metabolic syndrome.[96] Patients with impaired glucose tolerance who received fenofibrate 267 mg/day for 1 month (n = 31) had significant (p < 0.01) reductions from
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baseline in plasma levels of fibrinogen (17%), PAI-1 (26%) and CRP (25%), plasma factor VII activity (19%) and release of TNF (32%), IL-1 (35%), IL-6 (22%) and MCP-1 (17%).[99] Significant reductions in fibrinogen (21%[65] and 14%[68]) and uric acid (25%)[68] levels were seen with fenofibrate 200 mg/day in studies in patients with type 2 diabetes and dyslipidaemia (n = 40[68] and 120[65]) [p < 0.05 vs baseline or placebo].[65,68] Moreover, fenofibrate 200 mg/day was associated with a significantly greater improvement than placebo in brachial artery flow-mediated dilatation (+44% vs 9%; p = 0.01) in patients with diabetic dyslipidaemia.[68] Fenofibrate 200 mg/day was also associated with a significant increase from baseline in homocysteine levels (from 11.0 to 16.5 mol/L; p < 0.001) in patients with type 2 diabetes (n = 418), according to an analysis of the DAIS trial.[100] However, this increase did not seem to attenuate the improvement in the progression of focal coronary atherosclerosis seen with fenofibrate (section 4.3).[102] 3. Pharmacokinetics Properties Following oral administration, fenofibrate is rapidly hydrolysed by esterases to its active metabolite fenofibric acid.[18] Repeat administration of the microcoated tablet formulation of fenofibrate 160 mg/day resulted in a steady-state mean maximum plasma concentration (Cmax) of fenofibric acid of 12.2 g/mL, reached in a time (tmax) of 3.5 hours.[18] The mean trough plasma concentration of fenofibric acid was 4.1 g/mL.[18] The mean plasma concentration of fenofibric acid following administration of 200 mg/day of the capsule formulation of micronised fenofibrate was 15 g/mL.[20] The absorption of fenofibrate from these formulations is less efficient when administered in a fasting state, meaning that they must be administered with food.[20,22] For example, the extent of absorption of the microcoated tablet formulation is increased by 35% in the fed versus fasting state.[18] By contrast, the nanoparticle NFE formulation of fenofibrate may be administered without regard to food.[24] A study in healthy volunteers revealed bioe 2007 Adis Data Information BV. All rights reserved.

quivalence in terms of Cmax and area under the plasma concentration-time curve (AUC) values when 145mg of the NFE formulation was administered in the fasting state or with high- or low-fat meals.[18] In the fasting state, a single dose of fenofibrate 145mg was associated with a Cmax of 7.9 g/mL, a tmax of 2.3 hours and an AUC from time zero to infinity of 123.8 g h/mL.[18] Thus, the NFE formulation is not prone to food-related changes in bioavailability, resulting in predictable efficacy. Fenofibrate does not accumulate with repeat administration,[22] and plasma concentrations of fenofibric acid attained steady state within 5 days.[24] Fenofibric acid is >99% bound to plasma albumin.[22] No unchanged fenofibrate was detectable in plasma following oral administration of the drug and its metabolism to fenofibric acid.[24] The drug was mainly excreted in the urine as fenofibric acid and its glucuronide conjugate.[22] Following administration of radiolabelled fenofibrate, 60% of the radioactivity was detected in the urine and 25% in the faeces.[24] Fenofibric acid has an elimination halflife of 20 hours.[18]
3.1 Special Patient Populations

In elderly volunteers aged 7787 years, the oral clearance of fenofibric acid was 1.2 L/h, compared with 1.1 L/h in young adults.[24] No dosage adjustment is recommended in the elderly for the microcoated tablet formulation of fenofibrate,[22] although a reduced initial dosage is recommended for the NFE formulation of the drug, according to the US prescribing information.[24] The pharmacokinetics of fenofibrate were similar in men and women.[24] Fenofibrate has not been studied in paediatric patients or in patients with hepatic impairment. The clearance of fenofibric acid is reduced in patients with severe renal impairment, with accumulation seen with repeat administration.[24] Dose reduction is recommended in patients with renal impairment (creatinine clearance [CLCR] <50 or <60 mL/min). The initial recommended dose in patients with renal impairment (CLCR <50 mL/min) is 48mg
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of the NFE formulation, according to US prescribing information,[24] and one (CLCR <20 mL/min) or two (CLCR 2060 mL/min) 67mg capsules of micronised fenofibrate, according to UK prescribing information.[19]
3.2 Potential Drug Interactions

nine levels were significantly (p = 0.003) increased.[113] Thus, coadministration of the two agents may increase the inherent nephrotoxicity of ciclosporin. 4. Clinical Efficacy Most studies included in this section had a drugfree or placebo run-in period, in addition to dietary control, prior to starting active treatment. Dietary restrictions were generally maintained for the duration of the study. Unless stated otherwise, patients received once-daily administration of the capsule formulation of micronised fenofibrate 200mg or the microcoated tablet formulation of micronised fenofibrate 160mg. Definitions for the trial abbreviations and acronyms used in this section are found in table III.
4.1 In Primary Dyslipidaemia

Fenofibrate has a low potential for drug interactions. In vivo studies showed that neither fenofibrate nor fenofibric acid undergo significant oxidative metabolism.[24] Fenofibrate and fenofibric acid did not inhibit cytochrome P450 (CYP) isozymes CYP3A4, CYP2D6, CYP2E1 or CYP1A2, according to the results of in vitro studies in human liver microsomes.[24] They showed mild to moderate inhibition of CYP2C9 and weak inhibition of CYP2C19 and CYP2A6.[24] Concomitant administration of fenofibrate had no clinically significant effect on the pharmacokinetics of the statins simvastatin,[103] rosuvastatin,[104] fluvastatin[105] or atorvastatin,[106] and only modest effects on the exposure of pravastatin and its active metabolite 3-hydroxy-iso-pravastatin.[107] The pharmacokinetics of fenofibrate were not altered to a significant extent by the concomitant administration of simvastatin,[103] rosuvastatin,[104] atorvastatin[24] or pravastatin.[108] In terms of lipid-lowering agents other than statins, concomitant ezetimibe did not have a significant effect on the pharmacokinetics of fenofibrate in healthy volunteers[109] or patients with primary hypercholesterolaemia.[110] Although fenofibrate increased ezetimibe exposure, this effect was not considered of clinical significance.[109,110] Concomitant administration of colesevelam did not have a significant effect on the bioavailability of fenofibrate.[111] Fenofibrate did not have a significant effect on the pharmacokinetics of the meglitinide analogue repaglinide.[112] Fenofibrate has been shown to potentiate the effect of coumarin-type anticoagulants, with prolongation of the prothrombin time or international normalised ratio.[24] Whole-blood concentrations of ciclosporin were significantly (p = 0.03) reduced in heart transplant patients receiving concomitant fenofibrate, and serum creati 2007 Adis Data Information BV. All rights reserved.

The potential of monotherapy with oral fenofibrate 160[89] or 200[59,88,114-118] mg/day in the treatTable III. Trial abbreviations/acronyms and definitions Abbreviation/ acronym 4D 4S ACCORD ASCOT ASPEN Definition Deutsche Diabetes Dialyse Studie Scandinavian Simvastatin Survival Study Action to Control Cardiovascular Risk in Diabetes Anglo-Scandinavian Cardiac Outcomes Trial Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin Dependent Diabetes Mellitus Bezafibrate Infarction Prevention Collaborative Atorvastatin Diabetes Study Cholesterol and Recurrent Events Diabetes Atherosclerosis Intervention Study Diabetes and Combined Lipid Therapy Regimen Fenofibrate Intervention and Event Lowering in Diabetes Helsinki Heart Study Heart Protection Study Long-term Intervention with Pravastatin in Ischaemic Disease Study of simvastatin plus fenofibrate for combined hyperlipidemia UK Prospective Diabetes Study Veterans Affairs HDL-C Intervention Trial

BIP CARDS CARE DAIS DIACOR FIELD HHS HPS LIPID SAFARI UKPDS VA-HIT

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ment of adults with primary dyslipidaemia was shown in noncomparative trials. However, these trials are not discussed further, given the availability of numerous well designed, comparative trials. Comparative trials included patients with primary hypercholesterolaemia[48,55,119-122] and/or mixed dyslipidaemia;[48,52,55,57,60,119-121,123-127] mean patient age was 4560 years.[46,48,52,55,57,60,119-126,128,129] Where specified, primary endpoints included the change from baseline in LDL-C levels,[55,119,122,124,125,127] HDL-C levels[126] or TG levels.[119,123] Where specified, analyses were generally conducted in the intention-to-treat (ITT) population[55,119-121,123-126,129] (using last observation carried forward [LOCF] analysis)[119,123] or efficacy evaluable population.[122]
4.1.1 Placebo-Controlled Trials

4.1.2 Comparisons with HMG-CoA Reductase Inhibitors (Statins)

Studies comparing the efficacy of fenofibrate with statins in patients with primary dyslipidaemia have been reviewed previously.[130] Thus, this section provides only a brief overview, focusing on fully published studies of best design (see table IV for study design details and detailed results). In summary, fenofibrate 200 mg/day was consistently associated with significantly greater improvements than statins in TG levels,[57,119-121,126] and in HDL-C levels in most studies,[57,119,121,126] in patients with primary hypercholesterolaemia[119-121] or mixed dyslipidaemia[57,119-121,126] (table IV). By contrast, statins were generally associated with significantly greater improvements than fenofibrate in TC and LDL-C levels (table IV).[57,121,126]
4.1.3 Comparisons with Other Fibrates

The efficacy of fenofibrate in placebo-controlled trials in patients with primary dyslipidaemia (n = 20340) has been reviewed previously[130] and will only be discussed briefly in this section. Trials were of randomised, double-blind, placebo-controlled design[46,55,60,129] and, where specified, included patients with types IIa,[55] IIb,[55,60] IV[60] or V[60] dyslipidaemia. Other trials included patients with TG levels of 2.36 mmol/L and HDL-C levels of <0.9 mmol/L,[46] or TG levels 2.3 mmol/L and an LDL-C : HDL-C ratio of 5.[129] Patients received micronised fenofibrate 200 mg/day,[46] 200400 mg/day (only results pertaining to the 200 mg/day dosage will be discussed),[55] or 67201 mg/ day;[129] in one study, patients received standard fenofibrate 300 mg/day (equivalent to 200 mg/day of micronised fenofibrate).[60] In all trials, significantly (p < 0.05) greater reductions from baseline in TG levels were seen with fenofibrate than with placebo (27% to 56% vs 12% to +14%).[46,55,60,129] Significantly (p < 0.05) greater improvements in TC (6% to 25% vs +1% to +2%),[46,55,60] LDL-C (32% vs +1%)[55] and HDL-C (+11% to +34% vs 0% to +9%)[46,60] levels were also seen with fenofibrate than with placebo in some trials.
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Fenofibrate 200 mg/day was associated with significantly greater reductions from baseline in TC and LDL-C levels than sustained-release gemfibrozil 900 mg/day among 21 patients with type IIa or IIb dyslipidaemia, according to the results of a randomised, double-blind, crossover study.[48] After 6 weeks treatment, TC levels were reduced from baseline by 22% with fenofibrate and 15% with gemfibrozil (p = 0.0148) and LDL-C levels were reduced by 27% and 16% in the corresponding treatment groups (p = 0.0117). There was no significant difference between fenofibrate and gemfibrozil recipients in the change from baseline in HDL-C (+9% vs +9%) or TG (54% vs 47%) levels. Similarly, fenofibrate improved the lipid profile to a significantly greater extent than gemfibrozil in a nonblind switch study in 80 patients with dyslipidaemia (LDL-C >3.4 mmol/L or TG >2.3 mmol/ L) and CHD.[128] Almost half of the patients (n = 39) were receiving treatment with a statin at baseline and continued to do so during the study. After receiving gemfibrozil 600mg twice daily for 3 months, they switched to fenofibrate 201 mg/day (three 67mg capsules) for 12 weeks. After 12 weeks therapy, improvements from baseline in lipid levels were significantly (p < 0.001) greater with fenofibrate than gemfibrozil both among patients who
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Table IV. Efficacy of fenofibrate (FEN) [micronised FEN capsule formulation] compared with HMG-CoA reductase inhibitors (statins) in patients (pts) with primary dyslipidaemia Study (design details) Lipid entry criteria (mmol/L) Comparisons with atorvastatin (ATO) Despres et al.[126] (r, nb, pg, mc) Malik et al.[57] (r, sb, co) LDL-C >3.2, HDL-C <1.2 (women) or <1.1 (men), TG <4.5 TC >6.2, TG >1.5 FEN 200 [12wk] ATO 10 [12wk] FEN 200 [10wk] ATO 10 [10wk] 79 86 29 29 15 [6.3] 28*** [6.1] 12 [7.6] 28*** [7.6] 16 [4.2] 39*** [4.2] 8 [4.4] 34*** [4.4] +13a [0.9] 30 [2.5] 15 [2.3] +5a [0.9] +13 [1.3] 1 [1.3] 50 [5.4] 32 [5.4] Treatment (mg/day) No. of pts [treatment duration] Mean change from baseline in lipid level (%) [mean baseline level; mmol/L] TC LDL-C HDL-C TG

Comparison with pravastatin (PRA) Ducobu et al.[119] (r, db, pg, mc) IIa: TC 6.5, TG <2.3; or IIb: TC >6.5, TG 2.34.5 IIa: TC 6.2, LDL-C 4.1, TG <1.5 IIb: TC 6.2, TG >1.5 but <5.2 Steinmetz et al.[121] (r, db, pg, mc) a b c Primary endpoint. Primary endpoint in the subgroup of pts with type IIb dyslipidaemia. Pts were randomised to FEN for 3mo followed by SIM for 3mo or vice versa. Because of the absence of a washout period between the first and second treatment periods, the changes in lipid levels are only reported for the first 3mo treatment period. FEN 200 [3mo] PRA 20 [3mo] 75 76 18 [7.6] 15 [7.6] 18a [5.2] 17a [5.3] +13 [1.1] +6 [1.0] 39b [2.0] 12b [2.2]

Comparisons with simvastatin (SIM) Farnier et al.[120]c (r, db, co) FEN 200 [3mo] SIM 20 [3mo] FEN 200 [3mo] SIM 20 [3mo] 15 16 11 10 66 64 27 [8.3] 28 [8.8] 23 [7.8] 21 [7.6] 19 [7.6] 25* [7.6] 33 [6.4] 36 [6.9] 25 [5.6] 29 [5.1] 21 [5.5] 35** [5.4] +1.3 [1.5] +1.4 [1.4] +25 [1.1] +15 [1.1] +18 [1.0] +15 [0.9] 36 [1.0] 1 [1.0] 53 [2.6] +25 [3.1] 41 [2.4] 17 [2.9]

IIa: TC >6.5; or IIb: TC FEN 200 [12wk] >6.5, TG 2.95.8 SIM 20 [12wk]

IIa/b = Fredrickson classification type IIa/b; co = crossover; db = double-blind; HDL-C = high-density lipoprotein-cholesterol; LDL-C = lowdensity lipoprotein-cholesterol; mc = multicentre; nb = nonblind; pg = parallel-group; r = randomised; sb = single-blind; TC = total cholesterol; TG = triglyceride; * p < 0.05, ** p < 0.001, *** p < 0.0001 vs FEN; p < 0.05, p < 0.01, p < 0.001 vs statin.

were receiving a statin (TC: 36% vs 32%; LDLC: 44% vs 40%; HDL-C: +31% vs +26%; TG: 53% vs 48%) and those who were not (TC: 15% vs 11%; LDL-C: 18% vs 13%; HDL-C: +21% vs +14%; TG: 47% vs 42%). A significantly greater increase from baseline in ApoAI levels occurred with fenofibrate than with gemfibrozil (+9% vs +2%; p < 0.001) in patients with mixed dyslipidaemia.[27] Patients in this randomised, double-blind, multicentre study received fenofibrate 200 mg/day (n = 116) or gemfibrozil 1200 mg/day (n = 118) for 24 weeks. There was no significant difference between fenofibrate and gemfibrozil recipients in the change from baseline in TG (39% vs 41%) or HDL-C (+16% vs +12%) levels.
4.1.4 In Combination with Statins

Noncomparative[80,131,132] and nonrandomised, nonblind[49,133] trials examining the use of combination therapy are not discussed. In general, combination therapy with fenofibrate plus a statin improved lipid levels to a greater extent than fenofibrate monotherapy and/or statin monotherapy in patients with primary dyslipidaemia.[52,122,123] For example, in the SAFARI trial, fenofibrate 160 mg/day plus simvastatin 20 mg/day improved TC, LDL-C, HDL-C and TG levels to a significantly greater extent than simvastatin 20 mg/ day alone in patients with mixed dyslipidaemia (table V).[123] Similarly, fenofibrate, administered alone or in combination with atorvastatin, was associated with significantly greater improvements in HDL-C and TG levels, compared with atorvastatin alone, in patients with mixed dyslipidaemia (table V).[52] In addition, TC and LDL-C levels decreased to a significantly greater extent in patients receiving
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This section focuses on the results of well designed, randomised, double-blind trials.[52,122,123]
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atorvastatin alone or combination therapy than in those receiving fenofibrate alone.[52] Finally, improvements in TC, LDL-C, HDL-C and TG levels were significantly greater with fenofibrate plus fluvastatin, than with fenofibrate alone, in patients who mainly had primary hypercholesterolaemia (table V).[122]
4.1.5 In Combination with a Cholesterol Absorption Inhibitor

Combination therapy with fenofibrate plus the cholesterol absorption inhibitor ezetimibe was associated with significantly greater reductions from baseline in TC, LDL-C and TG levels than monotherapy with either agent alone in patients with mixed dyslipidaemia (n = 588) [figure 2], according to the results of a well designed study.[124] Fenofibrate, alone or in combination with ezetimibe, was also associated with significantly greater increases from baseline in HDL-C levels, compared with ezetimibe alone (figure 2). At baseline, 70% of patients in each treatment group had a pattern B LDL phenotype.[124] Following treatment, a shift to a larger LDL size pattern had occurred in 62% of fenofibrate monotherapy recipi-

ents, 22% of ezetimibe monotherapy recipients, 64% of fenofibrate plus ezetimibe recipients and 12% of placebo recipients. At the end of this study, 576 patients entered a 48-week, double-blind, extension study during which they received fenofibrate (n = 236) or fenofibrate plus ezetimibe (n = 340).[134] After an additional 48 weeks of treatment, improvements from baseline (i.e. the start of the initial study) in TC (23% vs 14%; p < 0.001), LDL-C (22% vs 9%; p < 0.001), HDL-C (+21% vs +18%; p = 0.02) and TG (46% vs 42%; p = 0.002) levels were significantly greater with combination therapy than with fenofibrate alone. Triple therapy with fenofibrate 160 mg/day plus a fixed combination of ezetimibe/simvastatin 10mg/ 20mg per day for 12 weeks improved the lipid profile to a significantly greater extent than fenofibrate 160 mg/day alone or ezetimibe/simvastatin 10mg/20mg per day in patients with mixed dyslipidaemia (n = 611).[127] In this randomised, doubleblind, placebo-controlled, multicentre study (available as an abstract), triple therapy reduced LDL-C levels from baseline to a significantly (p < 0.05) greater extent than fenofibrate alone or placebo

Table V. Efficacy of combination therapy with fenofibrate (FEN) [micronised FEN capsule[52,122] or microcoated tablet[123] formulation] and an HMG-CoA reductase inhibitor (statin) in patients (pts) with primary hypercholesterolaemia[122] or mixed dyslipidaemia[52,123] Study (trial design) Lipid entry criteria (mmol/L) LDL-C 4.9, TG 3.9 Treatment (mg/day) No. of pts Mean change from baseline in lipid level (%) [treatment duration] [mean baseline level; mmol/L] FEN 200 [16wk] FEN 200 + FLU 20 [16wk] FEN 200 + FLU 40 [16wk] Grundy et al.[123] (r, db, pg, mc) [SAFARI trial] Koh et al.[52] (r, db, co) LDL-C >3.4, TG 1.75.6 TC 5.2, TG 2.39.0 SIM 20 [12wk] FEN 160 + SIM 20 [12wk] FEN 200 [2mo] ATO 10 [2mo] FEN 200 + ATO 10 [2mo] a b Primary endpoint. Median value. 32 33 31 207 411 56 56 56 TC 19** [9.1] 27 [9.7] 35 [9.2] 20 [6.6] 26 [6.6] 13 [6.0] 29 [6.3] 29 [6.2] LDL-C 21**a [7.1] 32a [7.6] 41a [7.1] 26 [4.2] 31 [4.2] 6 [3.4] 40 [3.5] 30 [3.3] HDL-C +4* [1.2] +14 [1.3] +3 [1.4] +10 [1.1] +19 [1.1] +23 [1.1] 0 [1.2] +15 [1.2] TG 29* [1.8] 39 [1.8] 40 [1.6] 20a,b [2.6] 43a,b [2.6] 55 [3.8] 25 [3.4] 57 [3.6]

Farnier et al.[122] (r, db, pg, mc)

ATO = atorvastatin; co = crossover; db = double-blind; FLU = fluvastatin; HDL-C = high-density lipoprotein-cholesterol; LDL-C = lowdensity lipoprotein-cholesterol; mc = multicentre; pg = parallel-group; r = randomised; SIM = simvastatin; TC = total cholesterol; TG = triglyceride; * p < 0.05, ** p < 0.001 (analysis of variance F test for the comparison of the three treatment groups); p < 0.05 vs FEN monotherapy; p < 0.05, p < 0.001 vs statin monotherapy.

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25 20 Percentage change from baseline in lipid levels 15 10 5 0 5 10 15 20 25 30 35 40 45 50 TC LDL-C ** ** **

FEN (n = 179) EZE (n = 173) FEN + EZE (n = 175) PL (n = 61)

4.1.6 In Combination with a Bile Acid Sequestrant

* HDL-C TG

Fig. 2. Efficacy of combination therapy with fenofibrate (FEN) plus ezetimibe (EZE) in patients with mixed dyslipidaemia. Results of a randomised, double-blind, parallel-group, multicentre study in which patients received FEN 160 mg/day (micronised FEN microcoated tablet formulation), EZE 10 mg/day, FEN 160 mg/day plus EZE 10 mg/day or placebo (PL) for 12wk.[124] The primary endpoint was the change from baseline in LDL-C levels. Mean values are reported except for TG levels (median values). Baseline lipid levels (mmol/L) across treatment groups were as follows: TC = 6.76.9; LDL-C = 4.14.3; HDL-C = 1.1; TG = 2.93.2. HDL-C = high-density lipoprotein-cholesterol; LDL-C = low-density lipoprotein-cholesterol; TC = total cholesterol; TG = triglyceride; * p < 0.05, ** p < 0.001 vs FEN monotherapy; p < 0.001 vs EZE monotherapy; p < 0.001 vs PL.

Following 8 weeks treatment with fenofibrate 160 mg/day, the addition of the bile acid sequestrant colesevelam 3.75 g/day for a further 6 weeks resulted in significantly (p < 0.0001) greater reductions in TC and LDL-C levels, compared with continuation of fenofibrate alone, in patients with mixed dyslipidaemia.[125] However, the addition of colesevelam did not result in additional significant improvement in HDL-C or TG levels, compared with fenofibrate alone. Lipid levels with fenofibrate plus colesevelam versus fenofibrate alone at baseline, the end of the fenofibrate run-in period and study end were 6.6 versus 6.5 mmol/L, 6.0 versus 5.8 mmol/L and 5.6 versus 5.9 mmol/L for TC (mean values); 4.1 versus 4.1 mmol/L, 3.8 versus 3.7 mmol/L and 3.4 versus 3.8 mmol/L for LDL-C (mean values); 1.2 versus 1.2 mmol/L, 1.3 versus 1.3 mmol/L and 1.3 versus 1.3 mmol/L for HDL-C (mean values); and 2.6 versus 2.5 mmol/L, 1.8 versus 1.8 mmol/L and 1.9 versus 1.6 mmol/L for TG (median values). This randomised, double-blind, parallel-group, multicentre study included 122 patients.[125]
4.2 In the Metabolic Syndrome

(46% vs 16% and 4%); LDL-C levels were reduced in patients receiving ezetimibe/simvastatin by 47%. In addition, HDL-C levels increased by a significantly (p < 0.05) greater extent with triple therapy than with ezetimibe/simvastatin or placebo (+19% vs +9% and +1%); HDL-C levels increased in patients receiving fenofibrate alone by 18%. Both TG (50% vs 41%, 29% and 3%) and non-HDLC (51% vs 21%, 45% and 2%) levels were reduced to a significantly (p < 0.05) greater extent with triple therapy than with fenofibrate alone, ezetimibe/simvastatin or placebo.[127]
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The potential of fenofibrate in the treatment of patients with the metabolic syndrome was shown in noncomparative trials.[97,135] However, these studies are not discussed further, given the availability of well designed, comparative trials. Several comparative trials have examined the efficacy of fenofibrate in patients with the metabolic syndrome.[63,96,136-140] Where specified, randomised studies were of double-blind[63,96,136-138] or nonblind[139] design. Studies[63,136-139] generally used the NCEP definition[1] of the metabolic syndrome (section 1). Patients included in these studies did not generally have diabetes.[63,96,136-139] Where specified, mean patient age was 4663 years.[63,96,136,137,139,140] The main endpoint discussed in this section is the effect of treatment on atherogenic dyslipidaemia. The effect of treatment on other relevant endpoints (e.g. prothrombotic and proinflammatory markers) is discussed in section 2. Where specified, primary endpoints included the change from baseline in TG
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levels,[137] reversal of the metabolic syndrome diagnosis[139] and the proportion of normalised patients (i.e. patients with no biochemical abnormalities indicative of the metabolic syndrome).[136] Some of these studies are available only as abstracts.[96,138,140]
4.2.1 Comparisons with Placebo

Mean lipid level (mmol/L)

Fenofibrate improved aspects of atherogenic dyslipidaemia in patients with the metabolic syndrome, according to the results of two 12-week, placebocontrolled trials (n = 25[96] and 45[138]). Compared with placebo, fenofibrate 160[138] or 200[96] mg/day significantly reduced TG levels by 43% (from 3.2 to 1.9 mmol/L; p = 0.0003)[138] and 59% (from 5.6 to 2.3 mmol/L; p < 0.001),[96] reduced LDL-C levels by 6% (from 3.5 to 3.3 mmol/L; p = 0.006)[138] and increased LDL particle size (p < 0.0001).[138] The change from baseline in HDL-C levels in fenofibrate recipients did not significantly differ from that in placebo recipients in either trial.[96,138] Fenofibrate therapy was not associated with any significant changes in glucose metabolism.[96] In a crossover study in patients with the metabolic syndrome (n = 11), TG levels were significantly lower (1.7 vs 2.4 mmol/L; p < 0.001), and HDL-C levels were significantly higher (1.0 vs 0.9 mmol/L; p < 0.001), after 5 weeks treatment with fenofibrate 200 mg/day versus placebo.[63] Results pertaining to the atorvastatin arm of this trial are presented in section 4.2.2.
4.2.2 Comparison with a Statin

statin 10 mg/day alone in patients with the metabolic syndrome.[137] For example, after 3 months therapy in this crossover study (n = 20), TG and HDL-C levels were improved to a significantly greater extent with fenofibrate plus simvastatin than with simvastatin alone (figure 3). The ratio of large : small LDL particles was significantly (p < 0.05) larger with fenofibrate plus simvastatin than with simvastatin alone or placebo (2.4 vs 1.1 and 0.9). The addition of fenofibrate 160 mg/day to simvastatin significantly reduced mean TG levels (from 3.4 to 2.1 mmol/L; p < 0.02) and increased mean peak LDL particle size (from 251 to 259A; p < 0.0002), in 34 patients with the metabolic syndrome.[140] After 4 months treatment, 11 of 34 patients (32%) had converted from a pattern B LDL phenotype (characterised by small, dense LDL particles) to a pattern A LDL phenotype (characterised by larger, more buoyant LDL particles). The remaining patients were then randomised to receive
8 7 6 * 5 4 3 2 1 0 TC HDL-C NonHDL-C LDL-C TG * * * * * SIM FEN + SIM PL

Following 5 weeks treatment, HDL-C levels were significantly higher with fenofibrate 200 mg/ day than with atorvastatin 40 mg/day (1.0 vs 0.9 mmol/L; p = 0.001), according to the results of a crossover trial in 11 patients with the metabolic syndrome.[63] By contrast, TC (3.5 vs 5.6 mmol/L; p < 0.001) and LDL-C (1.9 vs 3.7 mmol/L; p < 0.001) levels were significantly lower with atorvastatin than with fenofibrate.
4.2.3 In Combination with Statins

Combination therapy with fenofibrate 200 mg/ day plus simvastatin 10 mg/day improved atherogenic dyslipidaemia to a greater extent than simva 2007 Adis Data Information BV. All rights reserved.

Fig. 3. Effect of fenofibrate (FEN) plus simvastatin (SIM) on atherogenic dyslipidaemia in patients with the metabolic syndrome. Results of a randomised, double-blind, crossover study in which 20 patients received SIM 10 mg/day, FEN 200 mg/day (micronised FEN capsule formulation) plus SIM 10 mg/day or placebo (PL) for 3mo each.[137] Patients had TG levels of 2.39.0 mmol/L and LDL-C levels of 4.1 mmol/L at baseline. HDL-C = high-density lipoproteincholesterol; LDL-C = low-density lipoprotein-cholesterol; TC = total cholesterol; TG = triglyceride; * p < 0.05 vs PL; p < 0.05 vs SIM alone.

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the thiazolidinedione (and PPAR agonist) rosiglitazone 8 mg/day (n = 12) or nicotinic acid 2 g/day (n = 11) for a further 6 months. Further significant (p < 0.02 vs simvastatin plus fenofibrate) improvements were seen in TG levels and peak LDL particle size with the addition of rosiglitazone, but not with nicotinic acid. A pattern A LDL phenotype was seen in 9 of 12 (75%) patients receiving simvastatin plus fenofibrate and rosiglitazone and in 7 of 11 (64%) patients receiving simvastatin plus fenofibrate and nicotinic acid.
4.2.4 In Combination with Metformin

a 20 18 16 Percentage of patients 14 12 10 8 6 4 2 0
00 00 00 17 17 10 16

Combination therapy with fenofibrate plus the oral antidiabetic agent metformin was more effective than monotherapy with either agent alone in terms of normalising biochemical abnormalities in patients with the metabolic syndrome.[136] Patients (n = 681) in this 3-month study were randomised to receive twice-daily treatment with one of the following regimens: fenofibrate 80mg plus metformin 850mg; fenofibrate 80mg plus metformin 500mg; fenofibrate 40mg plus metformin 850mg; fenofibrate 40mg plus metformin 500mg; fenofibrate 80mg; metformin 850mg; or placebo. The normalisation rate (i.e. the proportion of patients with no biochemical abnormalities at 3 months) was significantly higher in patients receiving fenofibrate 160 mg/day plus metformin 1700 mg/day than in those receiving monotherapy with fenofibrate 160 mg/day or metformin 1700 mg/day (figure 4).[136] In terms of individual parameters, normalisation rates in patients receiving fenofibrate plus metformin, fenofibrate monotherapy, metformin monotherapy and placebo were 33.339.4%, 19.6%, 30.0% and 20.0% for fasting glucose levels; 39.855.0%, 50.0%, 18.5% and 15.4% for TG levels; and 31.335.0%, 28.8%, 18.8% and 16.7% for HDL-C levels. Significant differences were seen between patients receiving fenofibrate 160 mg/day plus metformin 1700 mg/day and fenofibrate monotherapy for fasting glucose levels (p = 0.002) and metformin monotherapy for TG levels (p < 0.001). Percentage changes from baseline in fasting glucose, TG and HDL-C levels are also shown in figure 4.
2007 Adis Data Information BV. All rights reserved.

10

ET

ET

ET

ET

FE

80

16

16

FE

FE

FE

FE

80

Least squares mean percentage change from baseline

b 10 5 0 5 10 15 20 25 30 35 40 Fasting glucose ** TG **

FEN 160 + MET 1700 FEN 160 + MET 1000 FEN 80 + MET 1700 FEN 80 + MET 1000 FEN 160 MET 1700 PL *

ET

17

Fig. 4. Efficacy of fenofibrate (FEN) [the micronised FEN microcoated tablet formulation] + metformin (MET) in the metabolic syndrome. Results of a randomised, double-blind, multicentre study in patients receiving FEN 160 mg/day + MET 1700 mg/day (n = 109), FEN 160 mg/day + MET 1000 mg/day (n = 104), FEN 80 mg/ day + MET 1700 mg/day (n = 106), FEN 80 mg/day + MET 1000 mg/day (n = 104), FEN 160 mg/day (n = 103), MET 1700 mg/day (n = 100) or placebo (PL; n = 55).[136] Shown are (a) the proportion of patients with normalisation of metabolic syndrome biochemical abnormalities (primary endpoint) and (b) the change from baseline in fasting glucose, TG and HDL-C levels. p-Values were calculated against the best treatment in figure b. TG = triglyceride; HDL-C = high-density lipoprotein-cholesterol; * p = 0.001, ** p < 0.0001 vs PL; p = 0.009, p < 0.0001 vs FEN monotherapy; p < 0.01, p < 0.0001 vs MET monotherapy.

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00

HDL-C

PL

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4.2.5 In Combination with Orlistat

Fenofibrate, alone or in combination with the lipase inhibitor orlistat, improved metabolic parameters in patients with the metabolic syndrome.[139] After 3 months therapy, 48% of patients receiving monotherapy with fenofibrate 200 mg/day (n = 29), 44% of patients receiving monotherapy with orlistat 120mg three times daily (n = 29) and 50% of patients receiving fenofibrate 200 mg/day plus orlistat 120mg three times daily (n = 28) no longer fulfilled the criteria for the metabolic syndrome (all p < 0.0001 vs baseline); there were no significant between-group differences. Patients receiving fenofibrate monotherapy, orlistat monotherapy and fenofibrate plus orlistat all had significant (p < 0.05) improvements from baseline in serum levels of TC (13%, 15% and 26%), LDL-C (12%, 18% and 30%), non-HDL-C (17%, 17% and 26%) and TG (35%, 14% and 37%) after 3 months therapy.[139] Moreover, reductions from baseline in TC and LDL-C were significantly (p < 0.05) greater with combination therapy than with either monotherapy. In addition, HDL-C levels increased to a significantly (p < 0.05) greater extent with fenofibrate monotherapy than with orlistat alone or fenofibrate plus orlistat (+3% vs 9% and 10%), and TG levels decreased to a significantly (p < 0.05) greater extent with fenofibrate-containing regimens than with orlistat alone. At baseline, mean lipid levels across treatment groups were as follows: TC 7.67.9 mmol/L; LDLC 3.94.4 mmol/L; HDL-C 1.31.4 mmol/L; nonHDL-C 6.36.6 mmol/L; and TG 2.02.5 mmol/L. At 6 months, reductions in small dense LDL-C levels (63% and 77% vs 35%) and increases in mean LDL diameter (+2.3 and +2.7 vs +0.7nm) were significantly (p < 0.05) greater with fenofibrate monotherapy or fenofibrate plus orlistat, than with orlistat alone.[141] At 3 months, significant (p < 0.05) reductions from baseline in BP were also seen in all three treatment groups, with no significant between-group differences.[139] Similarly, anthropometric measurements such as body mass index, waist circumference and bodyweight were significantly (p < 0.05) improved from baseline in all three treatment groups,
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although the improvements were significantly (p < 0.05) greater with orlistat-containing regimens than with fenofibrate monotherapy. The Homeostasis Model Assessment Index was significantly (p < 0.01) improved from baseline in patients receiving fenofibrate alone (from 3.6 to 3.0), orlistat alone (from 3.9 to 2.6) and fenofibrate plus orlistat (from 3.9 to 3.0).[139] The improvement in recipients of orlistat monotherapy was significantly (p < 0.05) greater than that in recipients of fenofibrate monotherapy.
4.3 In Type 2 Diabetes Mellitus

This section examines the efficacy of fenofibrate in patients with type 2 diabetes. Small (n = 3240) trials of placebo-controlled[66-68] or noncomparative[142] design in patients with type 2 diabetes demonstrated that fenofibrate 200 mg/day had a beneficial effect on the lipid profile in this patient population; however, these trials are not discussed further. This section focuses on the results of two large, long-term, randomised, double-blind, placebo-controlled, multicentre trials in patients with type 2 diabetes: the DAIS (n = 418)[102] and FIELD (n = 9795)[143] trials. Study design details, including lipid entry criteria, are presented in table VI. Patients in the DAIS study had mild lipoprotein abnormalities.[102] Patients in the FIELD study were considered at increased risk of CHD, although they generally had no clear indication for lipid-lowering therapy; 40% of patients had dyslipidaemia at baseline (dyslipidaemia was defined as a TG level of >1.7 mmol/L and an HDL-C level of <1.03 mmol/L for men and <1.29 mmol/L for women).[143] Moreover, 2131 patients had previous CVD and 7664 did not.[143] In the FIELD study, the median duration of type 2 diabetes was 5 years and the baseline glycosylated haemoglobin (HbA1c) level was 6.9%, indicating good glycaemic control.[143] Patients (mean age 5662 years) were followed for 3 years in the DAIS trial[102] and for 5 years in the FIELD trial.[143] The drop-out rate in the FIELD study, averaged over 5 years, was 11% in fenofibrate recipDrugs 2007; 67 (1)

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Table VI. Effect of fenofibrate (FEN) [micronised FEN capsule[65,102,143-146,148] or microcoated tablet[147] formulation] on lipid levels in patients (pts) with type 2 diabetes mellitus Study Lipid entry criteria Treatment (mg/day) [treatment duration] FEN 200 [3y] PL [3y] No. of pts 207 211 Mean change from baseline in lipid level (%) [baseline level; mmol/L] TC 9.6** [5.6] +0.4 [5.6] LDL-C 5.9** [3.4] +0.4 [3.4] HDL-C +7.4** [1.0] +1.5 [1.1] TG 28.5** [2.6] +1.1 [2.4]

(trial design) (mmol/L) Compared with placebo (PL) DAIS investigators[102]a (r, db, pg, mc) TC : HDL-C ratio 4 plus either LDL-C 3.54.5 and TG 5.2, or TG 1.75.2 and LDL-C 4.5 TC 3.06.5 plus TC : HDL-C ratio 4 or TG 1.05.0

FIELD study investigators[143] (r, db, pg, mc)

FEN 200 [5y] PL [5y]

4895 4900

16* [5.0] 9 [5.0]

21* [3.1] 15 [3.1]

+3* [1.1] +2 [1.1]

25* [2.0] 3 [1.9]

Compared with, or in combination with, HMG-CoA reductase inhibitors (statins) Athyros et al.[65] (r, nb, pg) Derosa et al.[148] (r, db, pg) Durrington et al.[146]c (r, pg, mc) TC >5.7, LDL-C >3.4, TG 2.34.5, HDL-C <1.04 TC 5.2, LDL-C 2.6, TG 1.7 TC 5.2, TG 2.3 to <9.0 FEN 200 [24wk] ATO 20 [24wk] FEN 200 + ATO 20 [24wk] FLU ER 80 [12mo] FEN 200 + FLU ER 80 [12mo] PL FEN 67201 [24wk] PL ROS 1040 [24wk] ROS 5 ROS 5 + FEN 67201 [24wk] ROS 10 ROS 10 + FEN 67201 [24wk] FEN 200 [6wk] ATO 10 [6wk] FEN 160 [12wk] SIM 20 [12wk] FEN 160 + SIM 20 [12wk] FEN 200 [4wk] FLU 40 [4wk] FEN 200 + FLU 40 [12wk]f 40 40 40 23 25 49 51 60 53 11 11 100 100 100 16 16 30 16 [6.5] 31 [6.5] 37 [6.6] 20b [6.7] 26b [6.8] 8 [6.3] 37 [6.2] 31 [6.5] 36 [6.4] 16 [7.0] 24 [6.7] 13 [5.8] 26 [5.9] 27 [6.0] 22 [7.9] 22 [7.9] 31 [7.9] 15 [4.2] 40 [4.2] 46 [4.2] 25b [4.8] 35b [4.9] +1 [3.7] 47 [3.7] 34 [3.9] 42 [3.9] 11 [4.4] 29 [4.1] 10 [3.5] 34 [3.7] 29 [3.5] 26 [5.3] 28 [5.3] 41 [5.3] +16 [0.9] +9 [0.9] +22 [0.9] +14b [1.1] +34b [1.1] +9 [1.0] +6 [1.0] +11 [1.1] +12 [1.0] +11 [1.3] +10 [1.2] +14 [0.9] +7 [1.0] +13 [0.9] +16 [1.1] +9 [1.1] +25 [1.1] 41 [3.2] 30 [3.1] 50 [3.1] 17b [1.7] 32b [1.8] 34b [4.2] 30b [3.6] 41 [3.5] 47b [3.5] 39 [2.9] 4 [2.9] 38d [3.1] 25d [2.6] 49d [3.2] 42 [3.2] 23 [3.2] 45 [3.2]

Frost et al.[144] (r, nb, co) Muhlestein et al.[147] (DIACOR; r, db, pg) Sarano et al.[145]e (r, pg) a b c

LDL-C >3.5, TG >2.3 LDL-C 2.6, HDL-C <1.0, TG 2.3 LDL-C >4.1, TG 2.44.5

Percentage changes were estimated from a graph. Primary endpoint. Pts received 6 weeks of double-blind treatment with PL or ROS 5 or 10 mg/day, after which they entered an 18-week nonblind dose-titration phase. The dosage of FEN or ROS was titrated upwards as long as the LDL-C level remained >1.3 mmol/L. d Median. e Abstract. Baseline values were reported for the entire treatment group, rather than individual treatment arms. f After the initial 4-week treatment period, pts with an LDL-C level >2.6 mmol/L received combination therapy. ATO = atorvastatin; co = crossover; db = double-blind; ER = extended release; FLU = fluvastatin; HDL-C = high-density lipoprotein-cholesterol; LDL-C = low-density lipoproteincholesterol; mc = multicentre; nb = nonblind; pg = parallel-group; r = randomised; ROS = rosuvastatin; SIM = simvastatin; TC = total cholesterol; TG = triglyceride; * p < 0.05, ** p < 0.001 vs PL; p < 0.05 vs baseline; p < 0.05 vs statin monotherapy; p < 0.05 vs FEN monotherapy; p < 0.05 vs ROS 5 + FEN 67201.

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ients and 10% in placebo recipients (hazard ratio [HR] 1.01; 95% CI 0.93, 1.11).[143] The primary endpoint in the DAIS trial was the mean segment diameter, reflecting the angiographic progression of diffuse coronary atherosclerosis.[102] In the FIELD trial, the initial primary endpoint was death from CHD; however, this was subsequently amended to CHD death or non-fatal myocardial infarction (MI) [i.e. total CHD events].[143] Also discussed are the results of smaller (n = 11300) studies comparing the use of fenofibrate with a statin[65,144-147] and/or examining the effect of combination therapy with fenofibrate plus a statin[65,145-148] in patients with type 2 diabetes. Patients generally had mixed dyslipidaemia;[65,144,146-148] patients in one study also had CHD (i.e. they were secondary prevention patients).[148] Mean/median patient age was 5461 years.[65,144-148] Study design details are presented in table VI. Where specified, primary efficacy endpoints included the change from baseline in TC,[148] LDL-C,[148] HDL-C[148] and TG[146,148] levels, and the proportion of patients achieving all three NCEP goals (i.e. LDL-C level <2.6 mmol/L, HDL-C level 1.0 mmol/L and TG level <1.7 mmol/ L).[149] Where specified, efficacy analyses were conducted on the ITT population[102,143,146] using LOCF analysis.[146] Three analyses are only available as abstracts.[145,149,150]
4.3.1 Effects on Lipid Levels Comparisons with Placebo

tin monotherapy were generally not performed in these studies, although in two studies,[146,147] statin monotherapy was associated with significantly greater reductions from baseline in TC and LDL-C levels than fenofibrate monotherapy, and in one study,[147] fenofibrate monotherapy was associated with significantly greater reductions from baseline in TG levels than statin monotherapy (table VI). A significant (p < 0.05) reduction from baseline in small, dense LDL particles was also reported with fenofibrate in one study.[144]
In Combination with Statins

Results of the DAIS[102] and FIELD[143] trials in patients with type 2 diabetes revealed significantly greater improvements in the lipid profile with fenofibrate 200 mg/day than with placebo (table VI). It should be noted that patients did not have substantial dyslipidaemia at baseline in either trial.
Comparisons with Statins

As seen in patients with primary dyslipidaemia (section 4.1.2), fenofibrate and statins tended to improve different components of the lipid profile in patients with type 2 diabetes (table VI).[65,144-147] Statistical analyses comparing fenofibrate with sta 2007 Adis Data Information BV. All rights reserved.

Combination therapy with fenofibrate plus a statin was generally associated with significantly greater improvements in the lipid profile than treatment with fenofibrate alone and/or a statin alone in patients with type 2 diabetes and dyslipidaemia.[65,145-148] For example, fenofibrate plus atorvastatin generally improved the lipid profile to a significantly greater extent than monotherapy with either agent alone (table VI).[65] In addition, combination therapy with fenofibrate plus fluvastatin resulted in further improvements in the lipid profile among patients with type 2 diabetes who had an LDL-C level of >2.6 mmol/L, despite having received treatment with either agent alone (table VI).[145] Moreover, combination therapy with fenofibrate plus fluvastatin,[148] rosuvastatin[146] or simvastatin[147] improved LDL-C,[148] HDL-C[148] and/or TG[146-148] levels to a significantly greater extent than treatment with a statin alone (table VI). Preliminary results of an add-on substudy[149] of the main DIACOR trial[147] (see table VI) indicate that triple therapy with fenofibrate 160 mg/day plus simvastatin 20 mg/day and ezetimibe 10 mg/day was associated with a significantly greater proportion of patients achieving all three NCEP goals, compared with dual therapy with fenofibrate 160 mg/day plus simvastatin 20 mg/day (23.5% vs 0%; p = 0.006).[149] In the DIACOR study, patients received fenofibrate, simvastatin or fenofibrate plus simvastatin for 12 weeks, followed by 9 months dual combination therapy for all patients. Patients (n = 37) who still had an LDL-C level 2.6 mmol/L
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or a TG level 1.7 mmol/L were then randomised in a double-blind manner to receive fenofibrate plus simvastatin in combination with either ezetimibe or placebo. These results should be interpreted with caution given the small number of patients receiving triple therapy.
4.3.2 Effects on Macrovascular Endpoints

In the FIELD trial, there was no significant difference between fenofibrate and placebo recipients in the incidence of total CHD events (i.e. CHD mortality or non-fatal MI) [5.2% vs 5.9%, respectively] (HR 0.89; 95% CI 0.75, 1.05) or CHD mortality (2.2% vs 1.9%) [HR 1.19; 95% CI 0.90, 1.57]. However, fenofibrate recipients were significantly less likely than placebo recipients to experience non-fatal MI (3.2% vs 4.2% of patients; p = 0.01), corresponding to a 24% relative reduction (HR 0.76; 95% CI 0.62, 0.94).[143] In terms of prespecified secondary endpoints, the incidence of total CVD events was significantly lower with fenofibrate than with placebo (12.5% vs 13.9%; p = 0.035) [HR 0.89; 95% CI 0.80, 0.99], and fenofibrate recipients were significantly less likely than placebo recipients to undergo coronary revascularisation (5.9% vs 7.4%; p = 0.003) [HR 0.79; 95% CI 0.68, 0.93] or any revascularisation (i.e. coronary, carotid or peripheral; 7.8% vs 9.6%; p = 0.001) [HR 0.80; 95% CI 0.70, 0.92].[143] There were no significant between-group differences in the incidence of CVD mortality (2.9% vs 2.6%) [HR 1.11; 95% CI 0.87, 1.41], total mortality (7.3% vs 6.6%) [HR 1.11; 95% CI 0.95, 1.29] or total stroke (3.2% vs 3.6%) [HR 0.90; 95% CI 0.73, 1.12]. It should be noted that in the FIELD trial, significantly more placebo than fenofibrate recipients received additional lipid-lowering therapy during the study (17% vs 8%; p < 0.0001) [averaged over the 5-year study period].[143] In 93% of placebo recipients and 94% of fenofibrate recipients this additional drug was a statin. While it was expected that some patients would start other lipid-lowering therapies during the trial, it has been suggested that this higher rate of statin use among placebo recipients may partially explain the lack of a significant between 2007 Adis Data Information BV. All rights reserved.

group difference in the total incidence of CHD events in the FIELD trial.[143] A prespecified subgroup analysis of the FIELD study data revealed a greater treatment effect in patients with no previous CVD (primary prevention) than in patients with prior CVD (secondary prevention).[143] A significant (p = 0.004) 19% reduction in total CVD events occurred in patients with no previous CVD (HR 0.81; 95% CI 0.70, 0.94), but not in patients with previous CVD (HR 1.02; 95% CI 0.86, 1.20) [interaction p = 0.05]. Similarly, a post hoc subgroup analysis showed a significant (p = 0.014) 25% reduction in CHD events in patients without prior CVD (HR 0.75; 95% CI 0.59, 0.94), but not in those with prior CVD (HR 1.08; 95% CI 0.84, 1.38) [interaction p = 0.03]. Compared with placebo recipients, fenofibrate recipients also had a significant 38% reduction in the number of non-traumatic amputations (p = 0.011).[150] In the DAIS study, there was no significant difference between fenofibrate and placebo recipients in the change from baseline in mean segment diameter (0.06 vs 0.08mm); this measure reflects diffuse disease.[102] However, fenofibrate significantly slowed the angiographic progression of focal coronary atherosclerosis. The reduction in average minimum lumen diameter was 40% less with fenofibrate than with placebo (0.06 vs 0.10mm; p = 0.029), and progression in the percentage diameter stenosis was reduced by 42% (+2.11% vs +3.65%; p = 0.02).[102]
4.3.3 Effects on Microvascular Endpoints

In terms of the effect of fenofibrate on microvascular disease, patients receiving fenofibrate were significantly (p = 0.0003) less likely than those receiving placebo to need laser treatment for retinopathy in the FIELD trial (HR 0.70; 95% CI 0.58, 0.85).[143] Fenofibrate also reduced the progression of albuminuria, according to the results of the FIELD and DAIS trials.[102,143] In the FIELD trial, fenofibrate recipients were significantly (p = 0.002) more likely than placebo recipients to regress from, or not progress to, albuminuria.[143] With fenofibrate and plaDrugs 2007; 67 (1)

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cebo, 10% and 11% of patients progressed (from normo- to microalbuminuria or from micro- to macroalbuminuria) and 9% and 8% regressed. A similar significant (p = 0.031) effect on progression to albuminuria was seen in a subgroup analysis (n = 314)[151] of the DAIS trial data.[102] Progression of albuminuria occurred in 8% of fenofibrate recipients and 18% of placebo recipients, regression occurred in 13% and 11%, and no change occurred in 79% and 71%.[151] These results are of particular interest given that patients in the FIELD trial had relatively early type 2 diabetes.[143]
4.3.4 Effects on Glycaemic Control

concerning the use of fenofibrate in combination with ezetimibe, metformin or statins were also obtained from trials discussed in section 4. Fenofibrate was generally well tolerated in the treatment of dyslipidaemia.[24] The pooled analysis revealed that the most commonly occurring adverse events (regardless of causality) in fenofibrate recipients included liver function test (LFT) abnormalities, respiratory disorder, abdominal pain, back pain, increased AST levels, headache, increased ALT levels, increased creatine phosphokinase (CPK) levels, diarrhoea, nausea, rhinitis, asthenia, flu syndrome and constipation (figure 5).[24] Only LFT abnormalities and increased AST levels occurred in significantly more fenofibrate than placebo recipients (figure 5). Increases in creatinine levels have also been reported in patients receiving fibrates, including fenofibrate.[105,152] The mechanism behind this increase in creatinine levels is unclear,[105] although it has been suggested that it reflects an increase in the metabolic production of creatinine, rather than impaired renal function.[153] In patients with type 2 diabetes who participated in the FIELD trial, serious adverse effects that were deemed possibly related to treatment occurred in 0.8% of fenofibrate 200 mg/day recipients and 0.5% of placebo recipients.[143] No cases of rhabdomyolysis occurred in patients receiving combination therapy with fenofibrate plus a statin. Overall, rhabdomyolysis occurred in three fenofibrate recipients (0.06%) and one placebo recipient (0.02%); all cases fully resolved. Significantly more fenofibrate than placebo recipients developed pulmonary embolism (1.1% vs 0.7%; p = 0.022) or pancreatitis (0.8% vs 0.5%; p = 0.031), although it should be noted that the incidence of these events was low. Other clinically important adverse events occurring in <2% of patients included deep vein thrombosis (1.4% of fenofibrate recipients vs 1.0% of placebo recipients), myositis (0.04% vs 0.02%) and renal disease needing dialysis (0.3% vs 0.4%). Less than 1% of patients in either treatment arm developed ALT levels 35 times or >5 times the upper limit of normal, or CPK levels 510 times or >10 times the upper limit of normal. At study end, median creatiDrugs 2007; 67 (1)

Glycaemic control was generally not altered to a clinically significant extent in patients receiving fenofibrate. In the FIELD trial, median HbA1c was 6.9% at baseline and 7.0% at study end in fenofibrate recipients; corresponding values in placebo recipients were 6.9% and 6.9%.[143] Small increases from baseline in mean HbA1c levels occurred in recipients of both fenofibrate (from 7.50% to 7.97%) and placebo (from 7.56% to 7.80%) in the DAIS study; these increases were too small to be considered clinically relevant.[102] Moreover, HbA1c levels were unchanged in patients receiving fenofibrate, atorvastatin, or fenofibrate plus atorvastatin in another trial.[65] A significant 12% relative reduction from baseline in mean HbA1c level occurred in patients receiving combination therapy with fenofibrate plus fluvastatin in one study.[148] 5. Tolerability Information concerning the general tolerability of fenofibrate were obtained from a pooled analysis of patient data (804 patients) from randomised, double-blind, placebo-controlled trials reported in the manufacturers prescribing information.[24] Adverse event data were also obtained from the well designed FIELD trial (n = 9795) [see section 4.3 for study design details].[143] The FIELD trial included patients with type 2 diabetes who were followed for 5 years. At study end, 36% of placebo recipients and 19% of fenofibrate recipients were receiving non-study lipid-lowering drugs. Tolerability data
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8 7 6 5 4

FEN PL

Incidence (% of patients)

* 3 2 1 0
ity er in in ls ls ls e ia a a ch tis e m ro nd C on st ip ve ve pa pa ve oe se en rd al ni da rrh rm so au le le le hi al ck R th at
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ea

PK

no

Ba

As

di

in

ia

AS

AL

ab

ry

do

to

Ab

se

se

ra

LF

pi

ea

ea

es

cr

cr

In

In

Fig. 5. Tolerability of fenofibrate (FEN) in patients with dyslipidaemia. Results of a pooled analysis of data from randomised, double-blind, placebo (PL)-controlled trials.[24] Patients received FEN (n = 439) or PL (n = 365); the dosage of FEN was equivalent to 200mg of the capsule formulation. Shown are adverse events occurring with an incidence of >2%, regardless of causality. ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; LFT = liver function test; * significantly different vs PL (p-value not stated).

nine levels were significantly higher in fenofibrate than in placebo recipients (91 vs 80 mol/L; p < 0.01); creatinine levels >200 mol/L occurred in 2% of fenofibrate recipients and 1% of placebo recipients. The increase in creatinine levels seen in fenofibrate recipients was thought unlikely to be of clinical significance and reversed following discontinuation of treatment.[143] Fenofibrate was generally well tolerated when administered in combination with ezetimibe in patients with mixed dyslipidaemia.[124] Treatment-related adverse effects were reported in 11.4% of patients receiving fenofibrate 160 mg/day plus ezetimibe 10 mg/day, compared with 14.3% of patients receiving fenofibrate alone, 6.4% of patients receiving ezetimibe alone and 7.8% of placebo recipients. There were no reports of myopathy, rhabdomyolysis or pancreatitis, and no patient experienced an increase from baseline in CPK level to >10-fold the upper limit of normal.
2007 Adis Data Information BV. All rights reserved.

In

cr

ea

se

Adverse events (most commonly related to the gastrointestinal system) were reported in 44.052.8% of patients with the metabolic syndrome receiving fenofibrate 80 or 160 mg/day in combination with metformin 1000 or 1700 mg/day; no dose relationship was evident.[136] Adverse events were reported in 34.0% of patients receiving fenofibrate alone, 44.0% of patients receiving metformin alone and 38.2% of placebo recipients. Serious adverse events were reported in <4% of patients in any treatment arm. The adverse event profile in patients with primary dyslipidaemia receiving combination therapy with fenofibrate plus fluvastatin was similar to that in patients receiving fenofibrate alone.[122] The most commonly reported adverse events included gastrointestinal adverse events (26% of fenofibrate 200 mg/day recipients vs 6% of fenofibrate 200 mg/day plus fluvastatin 20 mg/day recipients and 24% of fenofibrate 200 mg/day plus fluvastatin 40 mg/day recipients), musculoskeletal adverse events (e.g.

Fl

sy

io

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myalgia) [24% vs 17% and 15%] and respiratory adverse events (15% vs 11% and 24%). There were no significant between-group differences in terms of the changes from baseline in creatinine, AST, ALT, alkaline phosphatase, CPK or myoglobin levels.[122] Similarly, changes in LFTs and muscle enzymes were generally transient and resolved following treatment discontinuation in 56 patients receiving combination therapy with fenofibrate 200 mg/day plus atorvastatin 10 mg/day.[52] In addition, no cases of rhabdomyolysis or clinical myopathy were reported among 403 patients receiving fenofibrate 160 mg/day plus simvastatin 20 mg/day in another study.[123] In patients with the metabolic syndrome[137] or type 2 diabetes,[65,146,148] combination therapy with fenofibrate plus simvastatin, fluvastatin, atorvastatin or rosuvastatin was not associated with clinically relevant changes in CPK levels. Myalgia was reported in 1.83.3% of patients receiving fenofibrate plus rosuvastatin[146] and in no patients receiving fenofibrate plus atorvastatin (n = 40).[65] Concern has been raised over the possibility of rhabdomyolysis in fibrate recipients, particularly in patients receiving a fibrate in combination with a statin. Indeed, a retrospective analysis using claims data from US managed healthcare plans revealed a 2-fold increase in the risk of rhabdomyolysis with the use of fibrate plus statin combination therapy, compared with the use of a fibrate alone,[154] and there have been rare case reports of rhabdomyolysis in patients receiving both monotherapy with fenofibrate[155] or combination therapy with fenofibrate and a statin.[156-158] Myopathy has also been reported rarely in patients receiving monotherapy with fenofibrate[159] or combination therapy with fenofibrate plus rosiglitazone.[160] However, fenofibrate is associated with a lower risk of rhabdomyolysis than gemfibrozil, according to the results of a retrospective analysis of adverse event data from two US FDA databases (January 1999 to December 2002).[161] The rate of musclerelated adverse events (excluding frank rhabdomyolysis) was 15.7 per million prescriptions with gemfibrozil compared with 8.8 per million prescrip 2007 Adis Data Information BV. All rights reserved.

tions with fenofibrate, yielding an odds ratio (OR) of 1.78 (95% CI 1.43, 2.22). The rate of rhabdomyolysis was also significantly higher with gemfibrozil than with fenofibrate (59.6 vs 5.5 per million prescriptions) [OR 10.84; 95% CI 8.44, 13.95]. There were 68 cases of rhabdomyolysis in fenofibrate recipients and 1304 cases in gemfibrozil recipients (in total, 3161 adverse events were filed that listed fenofibrate or gemfibrozil as a suspect agent). In fenofibrate recipients, 24% of patients experiencing rhabdomyolysis were receiving concomitant cerivastatin (no longer on the market), 12% were receiving another statin and 64% were receiving no statin. Corresponding percentages among gemfibrozil recipients were 89%, 10% and 1%.[161] Similarly, the use of fenofibrate plus a statin was associated with fewer reports of rhabdomyolysis than the use of gemfibrozil plus a statin, according to the results of another retrospective analysis of one of the FDA adverse event databases referred to above (January 1998 to March 2002).[162] There were 4.5 cases of rhabdomyolysis per million prescriptions reported with fenofibrate plus a statin compared with 87 cases per million prescriptions with gemfibrozil plus a statin. Notably, of the total 606 reports of rhabdomyolysis, 14 (2%) were associated with fenofibrate plus cerivastatin and 533 (88%) were associated with gemfibrozil plus cerivastatin. The mechanisms possibly underlying the higher rate of rhabdomyolysis seen with gemfibrozil plus statin combination therapy are discussed further in section 7. 6. Dosage and Administration As previously mentioned (section 1), there are several formulations of fenofibrate available, including capsule and microcoated tablet formulations of micronised fenofibrate (available in the EU), and a nanoparticle NFE formulation of fenofibrate (currently available in the US, France and Canada, with further launches anticipated). In the EU, fenofibrate is approved for use in the treatment of hypercholesterolaemia and hypertriglyceridaemia, either alone or combined (i.e. Fredrickson type IIa, IIb, III, IV or V dyslipidaemia; see
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table I), in adults who have not responded to dietary and other nonpharmacological measures.[22] Fenofibrate is also approved for use in patients with secondary hyperlipoproteinaemia that has not resolved despite treatment of the underlying disease (e.g. in patients with diabetic dyslipidaemia). The recommended dosage of the microcoated tablet formulation of micronised fenofibrate is 160mg once daily, taken with food.[22] For the capsule formulation of micronised fenofibrate, the initial recommended dosage is three 67mg capsules per day (in divided doses)[19] or one 200mg capsule per day;[20] an increased dosage of one 267mg capsule per day is appropriate in patients with severe dyslipidaemia.[21] The capsule formulation should also be administered with food. In addition, the 48 and 145mg NFE formulation is available in France and can be administered without regard to meals. In the US, fenofibrate is approved for use in adults with Fredrickson type IIa, IIb, IV or V dyslipidaemia who have not responded to nonpharmacological measures.[24] The recommended initial dosage of the NFE formulation is 145 mg/day in primary hypercholesterolaemia and mixed dyslipidaemia and 48145 mg/day in hypertriglyceridaemia; as mentioned previously, this formulation can be administered without regard to meals. Local prescribing information should be consulted for contraindications, warnings and precautions, and for information concerning drug interactions and dosage adjustments in special patient populations. 7. Place of Fenofibrate in the Management of Primary Dyslipidaemia, the Metabolic Syndrome and Type 2 Diabetes Lipid-lowering therapy is underutilised in patients with dyslipidaemia. For example, a recent US study in >6500 individuals without clinical CVD found that 30% of the population had dyslipidaemia, and that only about half of these patients were receiving lipid-lowering therapy.[163] Moreover, another recent US study (n >7000) indicated that in a managed care setting, <25% of patients
2007 Adis Data Information BV. All rights reserved.

with diabetes had an LDL-C level of <2.6 mmol/ L[164] (the NCEP target). Treatment options for dyslipidaemia include the statins, the fibrates, the bile acid sequestrants and nicotinic acid,[1] as well as newer agents such as the cholesterol absorption inhibitor ezetimibe (table VII). The benefit of statins in terms of reducing cardiovascular morbidity and mortality has been clearly demonstrated in clinical trials,[165] and these agents are generally the first-line option for lowering LDL-C levels.[1] However, statins have more modest effects on TG and HDL-C levels (table VII), meaning that even with optimal statin therapy, some patients (e.g. those with mixed dyslipidaemia) may have residual CHD risk that is amenable to further reduction.[165,166] The presence of conditions such as diabetes and the metabolic syndrome predicts a high residual risk.[12,165] For example, subgroup analysis in a recent meta-analysis of 14 trials found that statin therapy reduced the risk of major coronary events by only 22% in patients with a history of diabetes.[167] Moreover, when patients in some of the major statin trials (e.g. 4S) were classified according to whether they had lower or higher HDL-C levels, statins only reduced the risk of coronary events in patients with lower HDL-C levels to a similar extent to that seen in patients with higher HDL-C levels who were receiving placebo;[168] this finding is of particular relevance to patients with atherogenic dyslipidaemia and low HDL-C levels, such as those with type 2 diabetes. Fibrates activate PPAR. As previously mentioned, fenofibrate appears to act as a full PPAR agonist, whereas gemfibrozil appears to be a partial PPAR agonist (section 2.1).[27] Bezafibrate is an agonist at all three PPAR isoforms, including PPAR.[5] Newer formulations of fenofibrate have improved bioavailability. In particular, the new nanoparticle NFE formulation can be administered without regard to food (section 3). Fenofibrate is particularly associated with improvements in TG and HDL-C levels in patients with primary dyslipidaemia, as shown by the results of studies demonstrating the efficacy of fenofibrate monotherapy in such patients (section 4.1).
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Table VII. Mechanism of action and main lipid effects of lipid-lowering drugs[1,16,169] Drug class Fibric acid derivatives (e.g. fenofibrate, gemfibrozil, bezafibrate) Mechanism of action Agonist at the peroxisome proliferator-activated receptor-, resulting in increased lipolysis and plasma clearance of atherogenic TG-rich lipoproteins, reduced availability of fatty acids for TG synthesis, increased ApoAI and ApoAII synthesis (the major proteins in HDL), increased reverse cholesterol transport and a shift to larger, more buoyant LDL particles (see also section 2) Main lipid effects LDL-C: 520%; HDL-C: 1035%; TG: 2050%

HMG-CoA reductase inhibitors (e.g. lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin) Cholesterol absorption inhibitors (e.g. ezetimibe) Bile acid sequestrants (e.g. colesevelam, colestipol, cholestyramine) Nicotinic acid

Inhibit HMG-CoA reductase leading to reduced cholesterol synthesis, LDL-C: 1855%; HDL-C decreased hepatic cholesterol content, up-regulation of hepatic LDL 515%; TG 730% receptors and decreased serum LDL-C levels Inhibits intestinal absorption of biliary and dietary cholesterol Bind bile acids in the intestine, resulting in conversion of cholesterol to bile acids in the liver. Decreased hepatic cholesterol content increases LDL-receptor expression, resulting in decreased serum LDL-C levels LDL-C: 18%; HDL-C: 4%; TG: 5% LDL-C: 1530%; HDL-C: 35%

Inhibits lipoprotein synthesis, decreases hepatic synthesis of VLDL LDL-C: 525%; HDL-C: particles, and inhibits peripheral mobilisation of free fatty acids. Shifts 1535%; TG: 2050% LDL composition from small, dense particles to larger, more buoyant particles Apo = apolipoprotein; HDL = high-density lipoprotein; HDL-C = HDL-cholesterol; LDL = low-density lipoprotein; LDL-C = LDL-cholesterol; TG = triglyceride; VLDL = very-low-density lipoprotein.

Fibrates and statins regulate serum lipids by different mechanisms (table VII) and, as expected, fenofibrate tended to improve different components of the lipid profile as compared with statins in clinical trials (section 4.1.2). Given this, combination therapy may be a useful option, especially in patients with mixed dyslipidaemia.[123] Indeed, combination therapy with fenofibrate plus a statin generally improved lipid levels to a greater extent than monotherapy with either agent alone in patients with primary dyslipidaemia, including patients with mixed dyslipidaemia (section 4.1.4). It remains to be seen if combination therapy with fenofibrate plus a statin will have a positive impact on clinical outcomes in such patients.[123] Fixed combinations such as fenofibrate/simvastatin are currently under development for the treatment of dyslipidaemia. Such combinations have the advantage of reducing the pill burden, with the potential for improved patient adherence. Although combination therapy may be associated with increased drug acquisition costs, it has been suggested that more effective lowering of lipid levels may decrease cardiovascular events, ultimately resulting in reduced hospitalisation costs;[148] this hypothesis needs to be confirmed in
2007 Adis Data Information BV. All rights reserved.

well designed trials. Combination therapy with fenofibrate plus either ezetimibe or colesevelam also appeared beneficial in patients with primary dyslipidaemia (sections 4.1.5 and 4.1.6). Fenofibrate also demonstrated beneficial effects on various emerging risk factors (e.g. ApoB, ApoAI, fibrinogen and CRP levels) in patients with dyslipidaemia (sections 2.1 and 2.3). It appears that lowering lipids does not fully explain the beneficial effect of fibrates seen in clinical trials (e.g. in the VA-HIT study, changes in lipid levels accounted for only 23% of the beneficial effect of gemfibrozil therapy).[170] Thus, the nonlipid pleiotropic effects associated with PPAR agonism may contribute to the clinical efficacy of fibrates.[171] Homocysteine levels (another emerging risk factor) were increased with fenofibrate in patients with dyslipidaemia (section 2.3). Interestingly, results from the DAIS trial suggest that the increase in homocysteine levels seen with fenofibrate did not attenuate its beneficial effect on the progression of focal coronary atherosclerosis (section 2.3). As previously mentioned (section 1), the presence of the metabolic syndrome or diabetes increases the risk of a CHD event.[1] Although lifestyle
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modification is important in managing both conditions, pharmacological therapy also has a vital role to play. In particular, lipid-lowering therapy to address the atherogenic dyslipidaemia associated with both conditions will help reduce the CHD risk.[1] Mixed results have been seen with statin therapy in patients with diabetes in subgroup analyses of large primary and/or secondary prevention trials. Statin therapy significantly reduced the risk of CHD events in some analyses (e.g. 4S,[172,173] CARE,[174] HPS[175]), but not in others (e.g. LIPID,[176] ASCOT[177]). The differences in outcomes between trials can be explained in part by differences between the patient populations in baseline characteristics (e.g. baseline level of CHD risk). In addition, the residual risk concept has been proposed as a possible explanation for these mixed results (i.e. patients with diabetes may still have high TG and low HDLC levels despite statin therapy).[166] Atorvastatin reduced the risk of CVD events in a primary prevention trial conducted specifically in patients with type 2 diabetes (the CARDS study[178]); however, no significant reduction in CVD events occurred with atorvastatin in ASPEN (a trial conducted in patients with type 2 diabetes and LDL-C levels below guideline targets)[179] or in the 4D study (conducted in patients with type 2 diabetes who were receiving maintenance haemodialysis).[180] The potential of fibrate therapy in patients with the metabolic syndrome or diabetes was shown in subgroup analyses of the primary prevention HHS study[181] and the secondary prevention BIP[182,183] and VA-HIT[184] trials. Eighteen-year follow-up data from the HHS trial revealed that patients with risk factors for the metabolic syndrome (e.g. high body mass index, high TG levels and low HDL-C levels) received the most benefit from early gemfibrozil therapy.[181] In the BIP trial, bezafibrate reduced the incidence of MI in patients with the metabolic syndrome[183] and attenuated the progression of insulin resistance.[182] In the VA-HIT trial in patients with CHD and low HDL-C levels, gemfibrozil reduced recurrent events to a greater extent in those with diabetes or insulin resistance than in those without.[184]
2007 Adis Data Information BV. All rights reserved.

Clinical trials demonstrate that fenofibrate monotherapy has a beneficial effect on atherogenic dyslipidaemia in patients with the metabolic syndrome, reducing TG levels, tending to increase HDL-C levels and promoting a shift to larger, more buoyant LDL particles (section 4.2.1). Fenofibrate also had beneficial effects on prothrombotic and proinflammatory factors in these patients (section 2.3). Moreover, combination therapy with fenofibrate and a statin generally improved the lipid profile to a greater extent than statin therapy alone (section 4.2.3). Thus, combination therapy is an attractive option for achieving optimal improvement of atherogenic dyslipidaemia in patients with the metabolic syndrome. The oral antidiabetic agent metformin is widely used for the treatment of type 2 diabetes.[9] Indeed, intensive glucose control with metformin appeared to reduce the risk of diabetes-related endpoints in patients with type 2 diabetes in the UKPDS trial.[185] Results from a study examining the use of fenofibrate plus metformin in patients with the metabolic syndrome indicate that patients receiving combination therapy were more likely to experience normalisation of biochemical abnormalities than those receiving either agent alone (section 4.2.4). A fixed combination of fenofibrate/metformin is currently under development for the treatment of metabolic disorders; it will be available for twice daily (fenofibrate/metformin 80mg/500mg, 80mg/850mg or 80mg/1000mg) or three times daily (54mg/ 850mg) administration.[23] Such a formulation may be of particular benefit in patients with the metabolic syndrome, given that these patients often require multiple agents to treat different aspects of their condition (e.g. lipid-lowering agents, antihypertensives, antidiabetic agents),[9] as well as in patients with type 2 diabetes. According to the NCEP guidelines, type 2 diabetes constitutes a CHD risk equivalent (i.e. type 2 diabetes carries a risk for new CHD that is equal to the risk of recurrent CHD in patients with established CHD), and levels of prothrombotic and proinflammatory factors tend to be higher in patients with
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diabetes than in nondiabetics, contributing to CHD risk.[1] The placebo-controlled FIELD trial is the largest clinical outcomes trial to be completed to date in patients with type 2 diabetes (table VIII). It examined the use of fenofibrate in patients with type 2 diabetes who did not have a clear indication for lipid-lowering therapy. This study was predominantly a primary prevention study, as >75% of patients had no history of CVD. Fenofibrate did not reduce the incidence of CHD mortality or total CHD events, although a reduction was seen in the incidence of non-fatal MI and total CVD events (section 4.3.2). As discussed previously, the fact that more placebo than fenofibrate recipients received concomitant statin therapy may have masked part of the beneficial effect of fenofibrate. Further subgroup analyses revealed greater reductions in total CVD events and CHD events in patients with no previous CVD than in patients with CVD, suggesting that fenofibrate may be of particular benefit in patients with early type 2 diabetes without CVD. Interestingly, fenofibrate had beneficial effects on the progression of albuminuria and the need for retinal laser surgery in the FIELD study (section 4.3.3); this is the first major study to show a beneficial effect of lipid-lowering therapy on microvascular outcomes. The mechanism by which fenofibrate improved these microvascular endpoints is not yet
Table VIII. Fenofibrate in type 2 diabetes mellitus: summary of FIELD trial findings[143] Main findings No significant reduction in the risk of total coronary events (primary outcome) Significant reduction in the risk of total CVD events, primarily through the prevention of non-fatal MI and coronary revascularisation Significant reduction in microvascular-associated complications Generally well tolerated, both as monotherapy and in combination with a statin Potential implications Potential role in early type 2 diabetes, in patients without CVD May reduce both total CVD events and the progression of microangiopathy May provide additional benefit when used in combination with a statin CVD = cardiovascular disease; MI = myocardial infarction.

known.[143] It seems that the beneficial effect cannot be explained by changes in glycaemic control (as HbA1c was essentially unaltered during the study), or by changes in concomitant drug use or BP (only a small reduction in systolic and diastolic BP of 5mm Hg was seen with fenofibrate, compared with 3mm Hg with placebo).[143] The pleiotropic effects of fenofibrate (e.g. its beneficial effects on inflammation and endothelial dysfunction in patients with type 2 diabetes) [section 2.3] may be one possible explanation for the microvascular benefits seen in the FIELD trial. Further studies are needed to confirm these initial findings. Overall, it appears that statins remain the lipidlowering treatment of choice for reducing CHD events in patients with type 2 diabetes.[186] However, as previously mentioned, even with statin therapy, patients with type 2 diabetes are likely to have residual CHD risk. Thus, the concomitant use of fenofibrate in patients with type 2 diabetes may provide additional benefits. Indeed, it has been suggested that the main role for fibrates in patients with diabetes may be in combination with statins.[5,143] A trial comparing the effect of fenofibrate plus simvastatin with simvastatin alone on CVD event rates in patients with type 2 diabetes (the ACCORD trial) is currently underway.[187] This randomised, doubleblind, multicentre trial enrolled 10 000 patients with type 2 diabetes and will examine the effects of intensive glycaemic control, lipid-lowering therapy and intensive BP control on CVD events.[23] In terms of lipid-lowering effects, ACCORD will examine whether in the context of good glycaemic control, improving TG and HDL-C levels through the addition of fenofibrate to simvastatin will further reduce CVD event rates. Results are expected in late 2009. In other studies, fenofibrate monotherapy was associated with improvements from baseline in lipid levels in patients with diabetic dyslipidaemia (section 4.3). Moreover, combination therapy with fenofibrate plus a statin generally improved atherogenic dyslipidaemia to a greater extent than monotherapy in such patients (section 4.3). In terms of current treatment guideline recommendations, NCEP guidelines recommend the use
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of fibrates in patients with CHD who have low LDLC levels and atherogenic dyslipidaemia; for use in combination with statins in patients with elevated LDL-C levels and atherogenic dyslipidaemia; and in patients with very high TG levels (to reduce the risk of acute pancreatitis).[1] Recent guidelines from the American Heart Association/American College of Cardiology also support the use of fibrates to reduce levels of non-HDL-C after LDL-C-lowering therapy.[188] In terms of treating the atherogenic dyslipidaemia component of the metabolic syndrome, NCEP guidelines recommend that the non-HDL-C level become a secondary target of therapy in patients with high TG levels (table II); high-dose statins or moderate-dose statins plus a fibrate are options in patients with elevated non-HDL-C levels after the LDL-C target has been reached.[1] Both the NCEP[1] and American Diabetes Association[15] guidelines recommend fibrates as an option in patients with diabetic dyslipidaemia who have low LDL-C levels and atherogenic dyslipidaemia; combination therapy with a fibrate and a statin is an option in patients with diabetic dyslipidaemia in whom LDL lowering is required. European guidelines recommend target lipid levels of <2.5 mmol/L for LDL-C and <4.5 mmol/L for TC in patients with diabetes.[189] These guidelines recommend that treatment choice should be guided by HDL-C and TG levels, as well as by LDL-C levels. Fenofibrate is generally well tolerated in the treatment of dyslipidaemia (section 5). Combination therapy (e.g. with a statin plus a fibrate) is currently underutilised in patients with dyslipidaemia.[165] One reason for this may be concern over the safety of such treatment, particularly in regard to musclerelated adverse events.[105,165] However, the risk of adverse events such as rhabdomyolysis appears low in patients receiving fenofibrate plus a statin, especially compared with patients receiving gemfibrozil plus a statin (section 5). Moreover, the FIELD trial suggests that combination therapy with fenofibrate and a statin is generally well tolerated in patients with type 2 diabetes (section 5). Although incidences were low, significantly more fenofibrate than placebo recipients developed pulmonary embolism
2007 Adis Data Information BV. All rights reserved.

or pancreatitis in the FIELD trial (section 5). Pancreatitis has been noted previously in fibrate recipients,[24] although an increase in the risk of thromboembolism has not been previously reported with fenofibrate.[143] The difference in musculoskeletal tolerability between fenofibrate and gemfibrozil when given in combination with a statin may be explained by their differing propensity for pharmacokinetic interaction.[190] Fenofibrate did not generally have a clinically significant effect on the pharmacokinetics of statins (section 3.2). Even though fenofibrate is associated with mild to moderate inhibition of CYP2C9, the pharmacokinetics of statins metabolised by this isozyme (e.g. fluvastatin and rosuvastatin) were not altered to a clinically significant extent.[105] However, gemfibrozil appears to inhibit statin glucuronidation,[190,191] leading to inhibition of statin elimination and increased statin concentrations.[105] Gemfibrozil also inhibits CYP2C8[192] (cerivastatin is a CYP2C8 substrate, as are repaglinide and rosiglitazone).[105] These mechanisms may explain the myotoxicity seen with combination therapy with gemfibrozil plus a statin.[162] Thus, it has been suggested that gemfibrozil be avoided when considering combination therapy with a fibrate plus a statin.[193] Other recommendations include only using combination therapy with a fibrate plus a statin if renal function is normal; using usual, not high, statin dosages; avoiding concomitant drugs that could increase either fibrate or statin concentrations; checking baseline CPK and transaminase levels and regularly monitoring CPK, transaminase and creatinine levels; and monitoring elderly patients particularly carefully.[193] In terms of the tolerability of other lipid-lowering agents, ezetimibe appears to be generally well tolerated, with the most common adverse events in placebo-controlled trials including back pain, arthralgia, diarrhoea, sinusitis and abdominal pain (occurring in 3.04.1% of ezetimibe recipients).[194] However, the use of nicotinic acid is somewhat limited by the occurrence of adverse events such as flushing, hyperglycaemia, hyperuricaemia, gastrointestinal symptoms and hepatotoxicity.[1,16] Bile acid sequesDrugs 2007; 67 (1)

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trants are most commonly associated with gastrointestinal adverse events such as constipation, abdominal pain, bloating and nausea; these agents seem to lack systemic toxicity.[1] In conclusion, fenofibrate improves lipid levels (in particular TG and HDL-C levels) in patients with primary dyslipidaemia. Its lipid-lowering profile means that fenofibrate is particularly well suited for use in atherogenic dyslipidaemia, which is commonly seen in patients with the metabolic syndrome and type 2 diabetes. Indeed, fenofibrate improves the components of atherogenic dyslipidaemia in patients with these conditions, including a shift from small, dense LDL particles to larger, more buoyant LDL particles. Greater improvements in lipid levels are seen when fenofibrate is administered in combination with a statin or ezetimibe, compared with monotherapy with these agents. In the DAIS study, fenofibrate significantly slowed the angiographic progression of focal coronary atherosclerosis in patients with type 2 diabetes. In terms of clinical outcomes, although no significant reduction in the risk of coronary events was seen with fenofibrate in the FIELD trial in patients with type 2 diabetes, treatment was associated with a significantly reduced risk of total CVD events, primarily through the prevention of non-fatal MI and coronary revascularisation. Subgroup analyses revealed significant reductions in total CVD events and CHD events in patients with no previous CVD, suggesting a potential role for primary prevention with fenofibrate in patients with early type 2 diabetes. Improvements were also seen in microvascular outcomes with fenofibrate in the FIELD trial. Fenofibrate is generally well tolerated, both as monotherapy and when administered in combination with a statin. Combination therapy with fenofibrate plus a statin appears to be associated with a low risk of rhabdomyolysis; no cases of rhabdomyolysis were reported in patients receiving such therapy in the FIELD trial. Thus, fenofibrate is a valuable lipid-lowering agent, particularly in patients with atherogenic dyslipidaemia.
2007 Adis Data Information BV. All rights reserved.

Disclosure
During the peer review process, the manufacturer of the agent under review was also offered an opportunity to comment on this article; changes based on any comments received were made on the basis of scientific and editorial merit.

References
1. National Cholesterol Education Program Expert Panel. Third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III): final report. Circulation 2002 Dec 17; 106 (25): 3143-421 2. Fruchart J-C, Duriez P. Mode of action of fibrates in the regulation of triglycerides and HDL-cholesterol metaboism. Drugs Today 2006; 42 (1): 39-64 3. Jellinger PS. The American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of dyslipidemia and prevention of atherogenesis: 2002 amended version. Endocr Pract 2000 Mar/Apr; 6 (2): 1-52 4. Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004 Jul 13; 110: 227-39 5. Bloomfield HE. The role of fibrates in a statin world. Arch Intern Med 2006 Apr 10; 166: 715-6 6. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002 Jan 16; 287 (3): 356-9 7. Ford ES, Giles WH, Mokdad AH, et al. Increasing prevalence of the metabolic syndrome among US adults. Diabetes Care 2004 Oct; 27 (10): 2444-249 8. Grundy SM, Brewer HB, Cleeman JI, et al. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition. Circulation 2004 Jan 27; 109: 433-8 9. Grundy SM. Drug therapy of the metabolic syndrome: minimizing the emerging crisis in polypharmacy. Nat Rev Drug Discov 2006 Apr; 5 (4): 295-309 10. Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004 May; 27 (5): 1047-53 11. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 2002 May 15; 287 (19): 2570-81 12. Nesto RW. Beyond low-density lipoprotein: addressing the atherogenic lipid triad in type 2 diabetes mellitus and the metabolic syndrome. Am J Cardiovasc Drugs 2005; 5 (6): 37987 13. National Institute of Diabetes and Digestive and Kidney Diseases. National Diabetes Statistics [online]. Available from URL: http://diabetes.niddk.nih.gov/dm/pubs/statistics [Accessed 2006 May 12] 14. Donnelly R, Emslie-Smith AM, Gardner ID, et al. Vascular complications of diabetes. Br Med J 2000 Apr 15; 320: 1062-6 15. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2005 Jan; 28 Suppl. 1: S4-36

Drugs 2007; 67 (1)

148

Keating & Croom

16. Khera A, McGuire DK. Management of diabetic dyslipidemia: need for reappraisal of the goals. Am J Cardiovasc Drugs 2005; 5 (2): 83-91 17. Munoz A, Guichard JP, Reginault P. Micronised fenofibrate. Atherosclerosis 1994 Oct; 110 Suppl.: S45-8 18. Sauron R, Wilkins M, Jessent V, et al. Absence of a food effect with a 145 mg nanoparticle fenofibrate tablet formulation. Int J Clin Pharmacol Ther 2006 Feb; 44 (2): 64-70 19. Fournier Pharmaceuticals Ltd. Lipantil Micro 67: summary of product characteristics [online]. Available from URL: http:// emc.medicines.org.uk [Accessed 2006 Apr 4] 20. Fournier Pharmaceuticals Ltd. Lipantil Micro 200: summary of product characteristics [online]. Available from URL: http:// emc.medicines.org.uk [Accessed 2006 Mar 31] 21. Fournier Pharmaceuticals Ltd. Lipantil Micro 267: summary of product characerteristics [online]. Available from URL: http://emc.medicines.org.uk [Accessed 2006 Apr 6] 22. Fournier Pharmaceuticals Ltd. Supralip 160mg: summary of product characteristics [online]. Available from URL: http:// emc.medicines.org.uk [Accessed 2006 Apr 6] 23. Data on file, Fournier Pharmaceuticals Ltd, 2006 24. Abbott Laboratories. Tricor 48mg and 145mg (fenofibrate tablets): prescribing information [online]. Available from URL: http://tricortablets.com/ [Accessed 2006 Apr 3] 25. Schoonjans K, Martin G, Staels B, et al. Peroxisome proliferator-activated receptors, orphans with ligands and functions. Curr Opin Lipidol 1997 Jun; 8 (3): 159-66 26. Arakawa R, Tamehiro N, Nishimaki-Mogami T, et al. Fenofibric acid, an active form of fenofibrate, increases apolipoprotein A-I-mediated high-density lipoprotein biogenesis by enhancing transcription of ATP-binding cassette transporter A1 gene in a liver X receptor-dependent manner. Arterioscler Thromb Vasc Biol 2005 Jun; 25 (6): 1193-7 27. Duez H, Lefebvre B, Poulain P, et al. Regulation of human apoA-I by gemfibrozil and fenofibrate through selective peroxisome proliferator-activated receptor modulation. Arterioscler Thromb Vasc Biol 2005 Mar; 25 (3): 585-91 28. Chapman MJ. Fibrates: therapeutic review. Br J Diabetes Vasc Dis 2006 Jan-Feb; 6 (1): 11-18, 20 29. Schoonjans K, Peinado-Onsurba J, Lefebvre A-M, et al. PPAR and PPAR activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J 1996; 15 (19): 5336-48 30. Haubenwallner S, Essenburg AD, Barnett BC, et al. Hypolipidemic activity of select fibrates correlates to changes in hepatic apolipoprotein C-III expression: a potential physiologic basis for their mode of action. J Lipid Res 1995 Dec; 36 (12): 2541-51 31. Staels B, Vu-Dac N, Kosykh VA, et al. Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase: a potential mechanism for the hypolipidemic action of fibrates. J Clin Invest 1995 Aug; 95: 705-12 32. Schoonjans K, Staels B, Auwerx J. The peroxisome proliferator activated receptors (PPARs) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta 1996; 1302: 93-109 33. Schoonjans K, Staels B, Auwerx J. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J Lipid Res 1996; 37: 907-25 34. Gu rin M, Bruckert E, Dolphin PJ, et al. Fenofibrate reduces e plasma cholesteryl ester transfer from HDL to VLDL and

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

normalizes the atherogenic, dense LDL profile in combined hyperlipidemia. Arterioscler Thromb Vasc Biol 1996 Jun; 16 (6): 763-72 Shepherd J, Caslake MJ, Lorimer AR, et al. Fenofibrate reduces low density lipoprotein catabolism in hypertriglyceridemic subjects. Arteriosclerosis 1985 Mar/Apr; 5 (2): 162-8 Caslake MJ, Packard CJ, Gaw A, et al. Fenofibrate and LDL metabolic heterogeneity in hypercholesterolemia. Arterioscler Thromb 1993 May; 13 (5): 702-11 Ikewaki K, Tohyama J, Nakata Y, et al. Fenofibrate effectively reduces remnants, and small dense LDL, and increases HDL particle number in hypertriglyceridemic men: a nuclear magnetic resonance study. J Atheroscler Thromb 2004; 11 (5): 278-85 Winkler K, Weltzien P, Friedrich I, et al. Qualitative effect of fenofibrate and quantitative effect of atorvastatin on LDL profile in combined hyperlipidaemia with dense LDL. Exp Clin Endocrinol Diabetes 2004; 112: 241-7 Berthou L, Duverger N, Emmanuel F, et al. Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice. J Clin Invest 1996; 97 (11): 2408-16 Vu-Dac N, Schoonjans K, Kosykh V, et al. Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor. J Clin Invest 1995; 96: 741-50 Ji J, Barrett PHR, Johnson AG, et al. Lipid transfer proteins and apolipoprotein B-100 metabolism in the metabolic syndrome treated with fenofibrate [abstract no. We-P11:111]. Atherosclerosis 2006 Jun; 7 (3 Suppl.): 370 Kiyanagi T, Miyazaki T, Kume A, et al. Decrease in CETP activity by fenofibrate may increase LDL particle size measured by HPLC method in patients with coronary artery disease [abstract no. Th-P16:301]. Atherosclerosis 2006 Jun; 7 (3 Suppl.): 559 McPherson R, Agnani G, Lau P, et al. Role of Lp A-I and Lp AI/A-II in cholesteryl ester transfer protein-mediated neutral lipid transfer: studies in normal subjects and in hypertriglyceridemic patients before and after fenofibrate therapy. Arterioscler Thromb Vasc Biol 1996 Nov; 16 (11): 1340-6 Bertolini S, Elicio N, Daga A, et al. Effect of a single daily dose treatment of fenofibrate on plasma lipoproteins in hyperlipoproteinaemia IIb. Eur J Clin Pharmacol 1988; 34: 25-8 Elisaf M, Tsimichodimos V, Bairaktari E, et al. Effect of micronized fenofibrate and losartan combination on uric acid metabolism in hypertensive patients with hyperuricemia. J Cardiovasc Pharmacol 1999 Jul; 34 (1): 60-3 Genest Jr J, Nguyen N-H, Theroux P, et al. Effect of micronized fenofibrate on plasma lipoprotein levels and hemostatic parameters of hypertriglyceridemic patients with low levels of high-density lipoprotein cholesterol in the fed and fasted state. J Cardiovasc Pharmacol 2000 Jan; 35 (1): 164-72 Haak T, Haak E, Kusterer K, et al. Fenofibrate improves microcirculation in patients with hyperlipidemia. Eur J Med Res 1998 Feb 21; 3 (1-2): 50-4 Insua A, Massari F, Rodrguez Moncalvo JJ, et al. Fenofibrate i or gemfibrozil for treatment of types IIa and IIb primary hyperlipoproteinemia: a randomized, double-blind, crossover study. Endocr Pract 2002 Mar/Apr; 8 (2): 96-101 Kiortsis DN, Millionis H, Bairaktari E, et al. Efficacy of combination of atorvastatin and micronised fenofibrate in the treatment of severe mixed hyperlipidemia. Eur J Clin Pharmacol 2000 Dec; 56 (9-10): 631-5

2007 Adis Data Information BV. All rights reserved.

Drugs 2007; 67 (1)

Fenofibrate: A Review

149

50. Ko HS, Kim CJ, Ryu WS. Effect of fenofibrate on lipoprotein(a) in hypertriglyceridemic patients: impact of change in triglyceride level and liver function. J Cardiovasc Pharmacol 2005 Oct; 46 (4): 405-11 51. Koh KK, Ahn JY, Han SH, et al. Effects of fenofibrate on lipoproteins, vasomotor function, and serological markers of inflammation, plaque stabilization, and hemostasis. Atherosclerosis 2004 Jun; 174 (2): 379-83 52. Koh KK, Quon MJ, Han SH, et al. Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of combined hyperlipidemia. J Am Coll Cardiol 2005 May 17; 45 (10): 1649-53 53. Koh KK, Han SH, Quon MJ, et al. Beneficial effects of fenofibrate to improve endothelial dysfunction and raise adiponectin levels in patients with primary hypertriglyceridemia. Diabetes Care 2005 Jun; 28 (6): 1419-24 54. Koh KK, Quon MJ, Han SH, et al. Additive beneficial effects of fenofibrate combined with candesartan in the treatment of hypertriglyceridemic hypertensive patients. Diabetes Care 2006 Feb; 29 (2): 195-201 55. Krempf M, Rohmer V, Farnier M, et al. Efficacy and safety of micronised fenofibrate in a randomised double-blind study comparing four doses from 200 mg to 400 mg daily with placebo in patients with hypercholesterolemia. Diabetes Metab 2000 May; 26 (3): 184-91 56. Lemieux I, Salomon H, Despr s J-P. Contribution of apo CIII e reduction to the greater effect of 12-week micronized fenofibrate than atorvastatin therapy on triglyceride levels and LDL size in dyslipidemic patients. Ann Med 2003; 35 (6): 4428 57. Malik J, Melenovsky V, Wichterle D, et al. Both fenofibrate and atorvastatin improve vascular reactivity in combined hyperlipidaemia (fenofibrate versus atorvastatin trial - FAT). Cardiovasc Res 2001 Nov; 52 (2): 290-8 58. Paragh G, Seres I, Harangi M, et al. The effect of micronised fenofibrate on paraoxonase activity in patients with coronary heart disease. Diabetes Metab 2003 Dec; 29 (6): 613-8 59. Ralov K, Dubovsk D, Mongiellov V, et al. Relationship s a a a between plasma fenofibric acid levels and the effect of micronized fenofibrate on cholesterol, low-density-lipoprotein cholesterol and apolipoprotein B in patients with primary hypercholesterolemia. Eur J Clin Pharmacol 1997 Apr; 52: 101-6 60. Sasaki J, Yamamoto K, Ageta M. Effects of fenofibrate on highdensity lipoprotein particle size in patients with hyperlipidemia: a randomized, double-blind, placebo-controlled, multicenter, crossover study. Clin Ther 2002 Oct; 24 (10): 1614-26 61. Tsimihodimos V, Kostoula A, Kakafika A, et al. Effect of fenofibrate on serum inflammatory markers in patients with high triglyceride values. J Cardiovasc Pharmacol Ther 2004 Mar; 9 (1): 27-33 62. Tsimihodimos V, Tambaki A, Tzovaras V, et al. Comparison of the effects of atorvastatin and fenofibrate on apolipoprotein Bcontaining lipoprotein subfractions in patients with combined dyslipidemia. Hellenic J Cardiol 2004; 45 (4): 225-30 63. Watts GF, Barrett PHR, Ji J, et al. Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome. Diabetes 2003 Mar; 52: 803-11 64. Watts GF, Ji J, Chan DC, et al. Relationships between changes in plasma lipid transfer proteins and apolipoprotein B-100 kinetics during fenofibrate treatment in the metabolic syndrome. Clin Sci (Lond) 2006 May 16; 111 (3): 193-9

65. Athyros VG, Papageorgiou AA, Athyrou VV, et al. Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined hyperlipidemia. Diabetes Care 2002 Jul; 25 (7): 1198-202 66. Cavallero E, Dachet C, Assadolahi F, et al. Micronized fenofibrate normalizes the enhanced lipidemic response to a fat load in patients with type 2 diabetes and optimal glucose control. Atherosclerosis 2003 Jan; 166 (1): 151-61 67. Feher MD, Caslake M, Foxton J, et al. Atherogenic lipoprotein phenotype in type 2 diabetes: reversal with micronised fenofibrate. Diabetes Metab Res Rev 1999 Nov-Dec 31; 15 (6): 395-9 68. Playford DA, Watts GF, Best JD, et al. Effect of fenofibrate on brachial artery flow-mediated dilatation in type 2 diabetes mellitus. Am J Cardiol 2002 Dec 1; 90: 1254-7 69. Forcheron F, Cachefo A, Thevenon S, et al. Mechanisms of the triglyceride- and cholesterol-lowering effect of fenofibrate in hyperlipidemic type 2 diabetic patients. Diabetes 2002 Dec; 51: 3486-91 70. Chinetti G, Gbaguidi FG, Griglio S, et al. CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and regulated by activators of peroxisome proliferator-activated receptors. Circulation 2000 May 23; 101 (20): 2411-7 71. Zambon A, Gervois P, Pauletto P, et al. Modulation of hepatic inflammatory risk markers of cardiovascular diseases by PPAR- activators: clinical and experimental evidence. Arterioscler Throm Vasc Biol 2006 May; 26 (5): 977-86 72. Milionis HJ, Papakostas J, Kakafika A, et al. Comparative effects of atorvastatin, simvastatin, and fenofibrate on serum homocysteine levels in patients with primary hyperlipidaemia. J Clin Pharmacol 2003 Aug; 43 (8): 825-30 73. Wang T-D, Chen W-J, Lin J-W, et al. Efficacy of fenofibrate and simvastatin on endothelial function and inflammatory markers in patients with combined hyperlipidemia: relations with baseline lipid profiles. Atherosclerosis 2003 Oct; 170 (2): 315-23 74. Yesilbursa D, Serdar A, Saltan Y, et al. The effect of fenofibrate on serum paraoxonase activity and inflammatory markers in patients with combined hyperlipidemia. Kardiol Pol 2005 Jun; 62 (6): 526-30 75. Bissonnette R, Treacy E, Rozen R, et al. Fenofibrate raises plasma homocysteine levels in the fasted and fed states. Atherosclerosis 2001 Apr; 155 (2): 455-62 76. Capell WH, DeSouza CA, Poirier P, et al. Short-term triglyceride lowering with fenofibrate improves vasodilator function in subjects with hypertriglyceridemia. Arterioscler Thromb Vasc Biol 2003 Feb; 23: 307-13 77. Coban E, Ozdogan M, Yazicioglu G, et al. The effect of fenofibrate on the levels of high sensitivity C-reactive protein in dyslipidaemic hypertensive patients. Int J Clin Pract 2005 Apr; 59 (4): 415-8 78. Dierkes J, Westphal S, Luley C. Serum homocysteine increases after therapy with fenofibrate or bezafibrate [letter]. Lancet 1999 Jul 17; 354 (9174): 219-20 79. de Lorgeril M, Salen P, Paillard F, et al. Lipid-lowering drugs and homocysteine [letter]. Lancet 1999 Jan 16; 353 (9148): 209-10 80. Ellen RLB, McPherson R. Long-term efficacy and safety of fenofibrate and a statin in the treatment of combined hyperlipidemia. Am J Cardiol 1998 Feb 26; 81 (4A): 60-5B 81. Kowalski J, Okopie B, Madej A, et al. Effects of atorvastatin, n simvastatin, and fenofibrate therapy on monocyte chemoattractant protein-1 secretion in patients with hyperlipidemia. Eur J Clin Pharmacol 2003 Jul; 59 (3): 189-93

2007 Adis Data Information BV. All rights reserved.

Drugs 2007; 67 (1)

150

Keating & Croom

82. Kowalski J, Okopien B, Madej A, et al. Effects of fenofibrate and simvastatin on plasma sICAM-1 and MCP-1 concentrations in patients with hyperlipoproteinemia. Int J Clin Pharmacol Ther 2003 Jun; 41 (6): 241-7 83. Mackness MI, Phuntuwate W, Suthisisang C, et al. Effect of fenofibrate treatment on paraoxonase 1 [abstract no. A68]. Diabet Med 2006 Mar 1; 23 Suppl. 2: 18-9 84. Noguchi Y, Tatsuno I, Suyama K, et al. Effect of fenofibrate on uric acid metabolism in Japanese hyperlipidemic patients. J Atheroscler Thromb 2004; 11 (6): 335-40 85. Okopien B, Cwalina L, Lebek M, et al. Effects of fibrates on plasma prothrombotic activity in patients with type IIb dyslipidemia. Int J Clin Pharmacol Ther 2001 Dec; 39 (12): 551-7 86. Okopien B, Krysiak R, Haberka M, et al. Effect of monthly atorvastatin and fenofibrate treatment on monocyte chemoattractant protein-1 release in patients with primary mixed dyslipidemia. J Cardiovasc Pharmacol 2005 Apr; 45 (4): 314-20 87. Okopie B, Kowalski J, Krysiak R, et al. Monocyte suppressing n action of fenofibrate. Pharmacol Rep 2005; 57 (3): 367-72 88. Pf tzner A, Ambrosch A, Forst T, et al. The influence of u micronized fenofibrate on cardiovascular risk factors [in German]. Z Allg Med 1994; 70: 510-5 89. Ramjattan BR, Callaghan DJG, Theiss U. Efficacy and tolerability of a suprabioavailable formulation of fenofibrate in patients with dyslipidemia: a pooled analysis of two open-label trials. Clin Ther 2002 Jul; 24 (7): 1105-16 90. Saklamaz A, Comlekci A, Temiz A, et al. The beneficial effects of lipid-lowering drugs beyond lipid-lowering effects: a comparative study with pravastatin, atorvastatin, and fenofibrate in patients with type IIa and type IIb hyperlipidemia. Metabolism 2005 May; 54 (5): 677-81 91. Staels B, Koenig W, Habib A, et al. Activation of human aortic smooth-muscle cells is inhibited by PPAR but not by PPAR activators. Nature 1998 Jun 25; 393 (6687): 790-3 92. Undas A, Celinska-L wenhoff M, Domagala TB, et al. Early o antithrombotic and anti-inflammatory effects of simvastatin versus fenofibrate in patients with hypercholesterolemia. Thromb Haemost 2005 Jul 1; 94 (1): 193-9 93. Westphal S, Dierkes J, Luley C. Effects of fenofibrate and gemfibrozil on plasma homocysteine [letter]. Lancet 2001 Jul 7; 358 (9275): 39-40 94. Yang T-L, Chen M-F, Xia X, et al. Effect of fenofibrate on the level of asymmetric dimethylarginine in individuals with hypertriglyceridemia. Eur J Clin Pharmacol 2006; 62: 179-84 95. Ye P, Li J-J, Su G, et al. Effects of fenofibrate on inflammatory cytokines and blood pressure in patients with hypertriglyceridemia [letter]. Clin Chim Acta 2005 Jun; 356 (1): 229-32 96. Belfort RS, Berria R, DeFronzo R, et al. Fenofibrate improves the atherogenic lipid profile and markers of vascular inflammation independent of changes in insulin sensitivity in hypertriglyceridemic subjects with the metabolic syndrome [abstract no. 620]. Diabetologia 2004 Aug; 47 Suppl. 1: A225-6 97. Idzior-Walus B, Sieradzki J, Rostworowski W, et al. Effects of comicronised fenofibrate on lipid and insulin sensitivity in patients with polymetabolic syndrome X. Eur J Clin Invest 2000 Oct; 30 (10): 871-8 98. Rosenson RS, Huskin AL, Wolff DA. Fenofibrate reduces postprandial cytokine production in metabolic syndrome patients [abstract no. 3789]. Circulation 2005 Oct 25; 112 (17 Suppl.): 818. Plus poster presented at the 78th Scientific Sessions of the American Heart Association; 2005 Nov 13-16; Dallas (TX) 99. Okopie B, Krysiak R, Herman ZS. Effects of short-term fen nofibrate treatment on circulating markers of inflammation

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

114. 115.

and hemostasis in patients with impaired glucose tolerance. J Clin Endocrinol Metab 2006 May; 91 (5): 1770-8 Genest J, Frohlich J, Steiner G. Effect of fenofibrate-mediated increase in plasma homocysteine on the progression of coronary artery disease in type 2 diabetes mellitus. Am J Cardiol 2004 Apr 1; 93 (7): 848-53 Rosenson RS, Huskin AL, Wolff DA. Adiponectin and the antiinflammatory effects of fenofibrate in patients with hypertriglyceridemia and the metabolic syndrome [abstract no. TuW27:5]. Atherosclerosis 2006 Jun; 7 (3 Suppl.): 175 Diabetes Atherosclerosis Intervention Study Investigators. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet 2001 Mar 24; 357 (9260): 905-10 Bergman AJ, Murphy G, Burke J, et al. Simvastatin does not have a clinically significant pharmacokinetic interaction with fenofibrate in humans. J Clin Pharmacol 2004 Sep; 44 (9): 1054-62 Martin PD, Dane AL, Schneck DW, et al. An open-label, randomized, three-way crossover trial of the effects of coadministration of rosuvastatin and fenofibrate on the pharmacokinetic properties of rosuvastatin and fenofibric acid in healthy male volunteers. Clin Ther 2003 Feb; 25 (2): 459-71 Davidson MH. Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions. Expert Opin Drug Saf 2006; 5 (1): 145-56 Whitfield LR, Abel R, Hartman D, et al. Effects of co-administration of gemfibrozil and fenofibrate on the pharmacokinetic profile of atorvastatin and major metabolites [abstract no. 547P]. Diabetes 2005 Jun; 54 Suppl. 1: A135 Gustavson LE, Schweitzer SM, Koehne-Voss S, et al. The effects of multiple doses of fenofibrate on the pharmacokinetics of pravastatin and its 3-hydroxy isomeric metabolite. J Clin Pharmacol 2005 Aug; 45 (8): 947-53 Pan W-J, Gustavson LE, Achari R, et al. Lack of a clinically significant pharmacokinetic interaction between fenofibrate and pravastatin in healthy volunteers. J Clin Pharmacol 2000; 40: 316-23 Gustavson LE, Schweitzer SM, Burt DA, et al. Evaluation of the potential for pharmacokinetic interaction between fenofibrate and ezetimibe: a phase I, open-label, multiple-dose, three period crossover study in healthy subjects. Clin Ther 2006 Mar; 28 (3): 373-87 Kosoglou T, Statkevich P, Fruchart J-C, et al. Pharmacodynamic and pharmacokinetic interaction between fenofibrate and ezetimibe. Curr Med Res Opin 2004 Aug; 20 (8): 1197-207 Jones MR, Baker BA, Mathew P. Effect of colesevelam HCl on single-dose fenofibrate pharmacokinetics. Clin Pharmacokinet 2004; 43 (13): 943-50 Kajosaari LI, Backman JT, Neuvonen M, et al. Lack of effect of bezafibrate and fenofibrate on the pharmacokinetics and pharmacodynamics of repaglinide. Br J Clin Pharmacol 2004 Oct; 58 (4): 390-6 Boissonnat P, Salen P, Guidollet J, et al. The long-term effects of the lipid-lowering agent fenofibrate in hyperlipidemic heart transplant recipients. Transplantation 1994 Jul; 58 (2): 245-7 Julius U, Schwartz T. Micronized fenofibrate in lipometabolism disorders [in German]. Therapiewoche 1994; 44 (25): 1442-5 Kornitzer M, Dramaix M, Vandenbroek MD. Efficacy and tolerance of 200 mg micronised fenofibrate administered over a 6-month period in hyperlipidaemic patients: an open Belgian

2007 Adis Data Information BV. All rights reserved.

Drugs 2007; 67 (1)

Fenofibrate: A Review

151

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

multicenter study. Atherosclerosis 1994 Oct; 110 Suppl.: S4954 M rz W, Schmitz H, Bach G, et al. Micronised fenofibrate: a efficacy and tolerability in the treatment of isolated and combined dyslipidemia [in German]. Munch Med Wochenschr 1994 Nov 11; 136 (45): 690-4 Kirchg ssler KU, Schmitz H, Bach G. Effectiveness and toleraa bility of 12-week treatment with micronised fenofibrate 200mg in a drug-monitoring programme involving 9884 patients with dyslipidaemia. Clin Drug Invest 1998 Mar; 15 (3): 197-204 Zhu J, Ye P. A survey on the efficacy and tolerability of micronized fenofibrate in patients with dyslipidemia. Chin Med J 2003 Jun; 116 (6): 840-3 Ducobu J, VanHaelst L, Salomon H. Comparison of micronized fenofibrate and pravastatin in patients with primary hyperlipidemia. J Cardiovasc Pharmacol 2003 Jan; 41 (1): 60-7 Farnier M, Bonnefous F, Debbas N, et al. Comparative efficacy and safety of micronized fenofibrate and simvastatin in patients with primary type IIa or IIb hyperlipidemia. Arch Intern Med 1994 Feb 28; 154: 441-9 Steinmetz A, Schwartz T, Hehnke U, et al. Multicenter comparison of micronized fenofibrate and simvastatin in patients with primary type IIA or IIB hyperlipoproteinemia. J Cardiovasc Pharmacol 1996; 27 (4): 563-70 Farnier M, Dejager S, and the French Fluvastatin Study Group. Effect of combined fluvastatin-fenofibrate therapy compared with fenofibrate monotherapy in severe primary hypercholesterolemia. Am J Cardiol 2000 Jan 1; 85 (1): 53-7 Grundy SM, Vega GL, Yuan Z, et al. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI Trial). Am J Cardiol 2005 Feb 15; 95 (4): 462-8 Farnier M, Freeman MW, Macdonell G, et al. Efficacy and safety of the coadministration of ezetimibe with fenofibrate in patients with mixed hyperlipidaemia. Eur Heart J 2005 May; 26 (9): 897-905 McKenney J, Jones M, Abby S. Safety and efficacy of colesevelam hydrochloride in combination with fenofibrate for the treatment of mixed hyperlipidemia. Curr Med Res Opin 2005 Sep; 21 (9): 1403-12 Despr s J-P, Lemieux I, Salomon H, et al. Effects of micronized e fenofibrate versus atorvastatin in the treatment of dyslipidaemic patients with low plasma HDL-cholesterol levels: a 12-week randomized trial. J Intern Med 2002 Jun; 251 (6): 490-9 Roth E, Farnier M, Gil-Extremera B, et al. Coadministration of ezetimibe/simvastatin and fenofibrate is an efficacious and well-tolerated treatment for patients with mixed hyperlipidemia [abstract no. 2246-PO]. Diabetes 2006 Jun; 55 Suppl. 1: 519 Packard KA, Backes JM, Lenz TL, et al. Comparison of gemfibrozil and fenofibrate in patients with dyslipidemic coronary heart disease. Pharmacotherapy 2002 Dec; 22 (12): 152732 Levin A, Duncan L, Djurdjev O, et al. A randomized placebocontrolled double-blind trial of lipid-lowering strategies in patients with renal insufficiency: diet modification with or without fenofibrate. Clin Nephrol 2000 Feb; 53 (2): 140-6 Keating GM, Ormrod D. Micronised fenofibrate: an updated review of its clinical efficacy in the management of dyslipidaemia. Drugs 2002; 62 (13): 1909-44 Farnier M, Salko T, Isaacsohn JL, et al. Effects of baseline level of triglycerides on changes in lipid levels from combined

132.

133.

134.

135.

136.

137.

138.

139.

140.

141.

142.

143.

144.

145.

146.

fluvastatin + fibrate (bezafibrate, fenofibrate, or gemfibrozil). Am J Cardiol 2003 Oct 1; 92 (7): 794-7 Stefanutti C, Bucci A, Di Giacomo S, et al. Efficacy, safety and tolerability of combined low-dose simvastatin-fenofibrate treatment in primary mixed hyperlipidaemia. Clin Drug Invest 2004; 24 (8): 465-77 Liamis G, Kakafika A, Bairaktari E, et al. Combined treatment with fibrates and small doses of atorvastatin in patients with mixed hyperlipidemia. Curr Med Res Opin 2002; 18 (3): 125-8 McKenney JM, Farnier M, Lo K-W, et al. Safety and efficacy of long-term co-administration of fenofibrate and ezetimibe in patients with mixed hyperlipidemia. J Am Coll Cardiol 2006 Apr 18; 47 (8): 1584-7 Wysocki J, Belowski D, Kalina M, et al. Effects of micronized fenofibrate on insulin resistance in patients with metabolic syndrome. Int J Clin Pharmacol Ther 2004 Apr; 42 (4): 212-7 Nieuwdorp M, Stroes ESG, Kastelein JJP, on behalf of the Fenofibrate/Metformin Study Group. Normalisation of metabolic syndrome using fenofibrate, metformin or their combination. Diabetes Obes Metab. In press Vega GL, Ma PTS, Cater NB, et al. Effects of adding fenofibrate (200 mg/day) to simvastatin (10 mg/day) in patients with combined hyperlipidemia and metabolic syndrome. Am J Cardiol 2003 Apr 15; 91: 956-60 Rosenson RS, Huskin AL, Wolfe DA. Fenofibrate markedly reduces postprandial dyslipidemia in metabolic syndrome patients [abstract no. 979-P]. Diabetes 2005 Jun; 54 Suppl. 1: A239 Filippatos TD, Kiortsis DN, Liberopoulos EN, et al. Effect of orlistat, micronised fenofibrate and their combination on metabolic parameters in overweight and obese patients with the metabolic syndrome: the FenOrli study. Curr Med Res Opin 2005 Dec; 21 (12): 1997-2006 McIvor ME. In combination with statins, fenofibrate, niacin and rosiglitazone effectively treat the atherogenic dyslipidemia of the metabolic syndrome [abstract no. 1084]. Circulation 2005 Oct 25; 112 (17 Suppl.): 209. Plus poster presented at the 78th Scientific Sessions of the American Heart Association; 2005 Nov 13-16; Dallas (TX) Filippatos TD, Gazi IF, Liberopoulos EN, et al. The effect of orlistat and fenofibrate, alone or in combination, on small dense LDL and lipoprotein-associated phospholipase A2 in obese patients with metabolic syndrome. Atherosclerosis. Epub 2006 Aug 12 Tan CE, Chew LS, Tai ES, et al. Benefits of micronised fenofibrate in type 2 diabetes mellitus subjects with good glycemic control. Atherosclerosis 2001 Feb 1; 154 (2): 469-74 The FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005 Nov 26; 366 (9500): 1849-61 Frost RJA, Otto C, Geiss HC, et al. Effects of atorvastatin versus fenofibrate on lipoprotein profiles, low-density lipoprotein subfraction distribution, and hemorheologic parameters in type 2 diabetes mellitus with mixed hyperlipoproteinemia. Am J Cardiol 2001 Jan 1; 87 (1): 44-8 Sarano N, Kozlov S, Tvorogova M, et al. Combined therapy with fluvastatin and fenofibrate in patients with hyperlipidaemia and non-insulin-dependent diabetes mellitus [abstract no. 111]. Heart 2000 Jun; 83 Suppl. II: 28 Durrington PN, Tuomilehto J, Hamann A, et al. Rosuvastatin and fenofibrate alone and in combination in type 2 diabetes patients with combined hyperlipidaemia. Diabetes Res Clin Pract 2004 May; 64 (2): 137-51

2007 Adis Data Information BV. All rights reserved.

Drugs 2007; 67 (1)

152

Keating & Croom

147. Muhlestein JB, May HT, Jensen JR, et al. The reduction of inflammatory biomarkers by statin, fibrate, and combination therapy among diabetic patients with mixed dyslipidemia: the DIACOR (Diabetes and Combined Lipid Therapy Regimen) study. J Am Coll Cardiol 2006 Jul 18; 48 (2): 396-401 148. Derosa G, Cicero AFG, Bertone G, et al. Comparison of fluvastatin + fenofibrate combination therapy and fluvastatin monotherapy in the treatment of combined hyperlipidemia, type 2 diabetes mellitus, and coronary heart disease: a 12month, randomized, double-blind, controlled trial. Clin Ther 2004 Oct; 26 (10): 1599-607 149. Pearson RR, Thomas H, Jensen JR, et al. Triple-therapy with a statin, fibrate and ezetimibe safely allows more diabetic patients with mixed dyslipidemias to reach national cholesterol education program guidelines: an analysis of the DIACOR study [abstract no. 808-6 plus oral presentation]. 55th Annual Scientific Session of the American College of Cardiology; 2006 Mar 11-14; Atlanta (GA) 150. Keech A, on behalf of the FIELD Study Investigators. Effects of long-term fenofibrate therapy on cardiovascular events among 9795 people with type 2 diabetes mellitus: the FIELD study, a randomised controlled trial [abstract no. We-S15:2]. Atherosclerosis 2006 Jun; 7 (3 Suppl.): 342 151. Ansquer J-C, Foucher C, Rattier S, et al. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebocontrolled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DAIS). Am J Kidney Dis 2005 Mar; 45 (3): 485-93 152. Hottelart C, El Esper N, Achard J-M, et al. Fenofibrate increases blood creatinine, but does not change the glomerular filtration rate in patients with mild renal insufficiency [in French]. Nephrologie 1999; 20 (1): 41-4 153. Hottelart C, El Esper N, Rose F, et al. Fenofibrate increases creatininemia by increasing metabolic production of creatinine. Nephron 2002; 92 (3): 536-41 154. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. J Am Med Asso 2004 Dec 1; 292 (21): 2585-90 155. Barker BJ, Goodenough RR, Falko JM. Fenofibrate monotherapy induced rhabdomyolysis. Diabetes Care 2003 Aug; 26 (8): 2482-3 156. Jacob SS, Jacob S, Williams C, et al. Simvastatin, fenofibrate, and rhabdomyolysis. Diabetes Care 2005 May; 28 (5): 1258 157. Kursat S, Alici T, Colak HB. A case of rhabdomyolysis induced acute renal failure secondary to statin-fibrate-derivative combination and occult hypothyroidism. Clin Nephrol 2005 Nov; 64 (5): 391-3 158. Ireland JHE, Eggert CH, Arendt CJ, et al. Rhabdomyolysis with cardiac involvement and acute renal failure in a patient taking rosuvastatin and fenofibrate. Ann Intern Med 2005 Jun 7; 142 (11): 949-50 159. Ghosh B, Sengupta S, Bhattacharjee B, et al. Fenofibrateinduced myopathy. Neurol India 2004 Jun; 52 (2): 268-9 160. Ledl M, Hohenecker J, Francesconi C, et al. Acute myopathy in a type 2 diabetic patient on combination therapy with metformin, fenofibrate and rosiglitazone. Diabetologia 2005 Oct; 48 (10): 1996-8 161. Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with fibrates. Am J Cardiol 2004 Oct 1; 94 (7): 935-8 162. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin. Am J Cardiol 2005 Jan 1; 95 (1): 120-2 163. Goff Jr DC, Bertoni AG, Kramer H, et al. Dyslipidemia prevalence, treatment, and control in the Multi-Ethnic Study of

164.

165.

166.

167.

168.

169.

170.

171.

172.

173.

174.

175.

176.

177.

178.

Atherosclerosis (MESA): gender, ethnicity, and coronary artery calcium. Circulation 2006 Feb 7; 113: 647-56 Beaton SJ, Nag SS, Gunter MJ, et al. Adequacy of glycemic, lipid, and blood pressure management for patients with diabetes in a managed care setting. Diabetes Care 2004 Mar; 27 (3): 694-8 Davidson MH. Reducing residual risk for patients on statin therapy: potential role of combination therapy. Am J Cardiol 2005 Nov 7; 96 (9A): 3-13K Steiner G. A new perspective in the treatment of dyslipidemia: can fenofibrate offer unique benefits in the treatment of type 2 diabetes mellitus? Treat Endocrinol 2005; 4 (5): 311-7 Cholesterol Treatment Trialists (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005 Oct 8; 366 (9493): 1267-78 Ballantyne CM, Herd A, Ferlic LL, et al. Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy. Circulation 1999 Feb 16; 99: 736-43 Woodman RJ, Chew GT, Watts GF. Mechanisms, significance and treatment of vascular dysfunction in type 2 diabetes mellitus: focus on lipid-regulating therapy. Drugs 2005; 65 (1): 31-74 Robins SJ, Collins D, Wittes JT, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: VAHIT: a randomized controlled trial. JAMA 2001 Mar 28; 285 (12): 1585-91 Robins SJ. Cardiovascular disease with diabetes or the metabolic syndrome: should statins or fibrates be first line lipid therapy? Curr Opin Lipidol 2003 Dec; 14 (6): 575-83 Py r l K, Olsson AG, Pedersen TR, et al. Cholesterol lowering oaa with simvastatin improves prognosis of diabetic patients with coronary heart disease: a subgroup analysis of the Scandinavian Simvastatin Survival Study. Diabetes Care 1997 Apr; 20 (4): 614-20 Haffner SM, Alexander CM, Cook TJ, et al. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med 1999 Dec 13/27; 159: 2661-7 Goldberg RB, Mellies MJ, Sacks FM, et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the Cholesterol and Recurrent Events (CARE) trial. Circulation 1998 Dec 8; 98: 2513-9 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003 Jun 14; 361 (9374): 2005-16 Keech A, Colquhoun D, Best J, et al. Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial. Diabetes Care 2003 Oct; 26 (10): 2713-21 Sever PS, Dahl f B, Poulter NR, et al. Prevention of coronary o and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003 Apr 5; 361 (9364): 1149-58 Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study

2007 Adis Data Information BV. All rights reserved.

Drugs 2007; 67 (1)

Fenofibrate: A Review

153

179.

180.

181.

182.

183.

184.

185.

186.

187.

(CARDS): multicentre randomised placebo-controlled trial. Lancet 2004 Aug 21; 364 (9435): 685-96 Knopp RH, DEmden M, Smilde JG, et al. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-insulindependent diabetes mellitus (ASPEN). Diabetes Care 2006 Jul; 29 (7): 1478-85 Wanner C, Krane V, M rz W, et al. Atorvastatin in patients with a type 2 diabetes mellitus undergoing haemodialysis. N Engl J Med 2005 Jul 21; 353 (3): 238-48 Tenkanen L, M ntt ri M, Kovanen PT, et al. Gemfibrozil in the a a treatment of dyslipidemia: an 18-year mortality follow-up of the Helsinki Heart Study. Arch Intern Med 2006 Apr 10; 166: 743-8 Tenenbaum A, Fisman EZ, Boyko V, et al. Attenuation of progression of insulin resistance in patients with coronary artery disease by bezafibrate. Arch Int Med 2006 Apr 10; 166: 737-41 Tenenbaum A, Motro M, Fisman EZ, et al. Bezafibrate for the secondary prevention of myocardial infarction in patients with metabolic syndrome. Arch Intern Med 2005 May 23; 165: 1154-60 Rubins HB, Robins SJ, Collins D, et al. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT). Arch Intern Med 2002 Dec 9/23; 162: 2597-604 UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998 Sep 12; 352: 854-65 Colhoun H. After FIELD: should fibrates be used to prevent cardiovascular disease in diabetes? Lancet 2005 Nov 26; 366 (9500): 1829-31 ClinicalTrials.gov. Strategies to reduce cardiovascular disease risk in individuals with diabetes [online]. Available from URL:

http://www.clinicaltrials.gov/ct/gui/show/NCT00000620?ord er=2 [Accessed 2006 Feb 4] 188. Smith Jr SC, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update. Circulation 2006 May 16; 113: 2363-72 189. De Backer G, Ambrosioni E, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice: third joint task force of European and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of eight societies and by invited experts). Atherosclerosis 2004 Apr; 173 (2): 381-91 190. Prueksaritanont T, Tang C, Qiu Y, et al. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos 2002; 30 (11): 1280-7 191. Prueksaritanont T, Zhao JJ, Ma B, et al. Mechanistic studies on metabolic interactions between gemfibrozil and statins. J Pharmacol Exp Ther 2002; 301 (3): 1042-51 192. Wang J-S, Neuvonen M, Wen X, et al. Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes. Drug Metab Dispos 2002; 30 (12): 1352-6 193. Farnier M. Combination therapy with an HMG-CoA reductase inhibitor and a fibric acid derivative: a critical review of potential benefits and drawbacks. Am J Cardiovasc Drugs 2003 Jan; 3 (3): 169-78 194. Merck/Schering-Plough Pharmaceuticals. Zetia (ezetimibe) tablets: prescribing information [online]. Available from URL: http://www.fda.gov [Accessed 2006 May 10]

Correspondence: Gillian M. Keating, Wolters Kluwer Health | Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 1311, New Zealand. E-mail: demail@adis.co.nz

2007 Adis Data Information BV. All rights reserved.

Drugs 2007; 67 (1)

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