8

SUPPLEMENT TO JAPI february 2012 VOL. 60

Newer Therapies for Chronic Obstructive Pulmonary Disease

Rahul Kodgule*, Abhijit Vaidya**, Sundeep Salvi***
he thick cloud cover over the understanding of pathophysiology of Chronic Obstructive Pulmonary Disease (COPD) is unveiling rapidly and this has contributed significantly to recent drug development and is likely to do so even in the future. Persistent exposure to an inhaled irritant like cigarette smoke, biomass smoke or industrial smoke leads to activation of several inflammatory pathways which contribute to the pathology of COPD in multiple ways.1-3 These irritants activate macrophages in the respiratory tract which then release multiple chemotactic factors to attract neutrophils, monocytes and T lymphocytes. These cells release a battery of proteins called as chemokines and cytokines which get involved in the various complex inflammatory and destructive pathways leading to chronic bronchitis and emphysema. Moreover, the steroids which arrest asthmatic inflammation quite effectively are found to be disappointingly less potent in COPD. As a ray of hope, the inflammatory process in COPD, has the potential to be inhibited at different stages of its pathway. Hence, recent drug discovery has focused on intervention of these pathways by inhibiting one of the steps. However, real challenge lies in developing such drugs that are not only effective, but also safe.2-4 Another important mechanism implicated in the pathogenesis of COPD is oxidative stress. Physiologically, the load of oxidants
Blood

Introduction

is balanced by the levels of anti-oxidants in the lung. When the oxidant load exceeds the anti-oxidant response, it is known as oxidative stress. This oxidative stress fuels the inflammation in COPD and also contributes to airway remodeling and emphysema. Oxidative stress is also accused of contributing to steroid resistance in COPD. This knowledge has stimulated wide interest in the development of potent anti-oxidants.5-7

Emerging Therapy
In this review article, we discuss the recent advances taken place in the development of newer drugs for managing Chronic Obstructive Pulmonary Disease.

Smoking Cessation
Smoking cessation is the only intervention that has been shown to attenuate the progression of disease (FEV1 decline) in COPD. However, attempts by smokers to quit smoking end up more commonly in failures than success. To assist smokers in smoking cessation, several drugs have recently been developed successfully. Drugs like Bupropion and Varenicline have been used as Nicotine replacement therapy (NRT) which has been shown to double the chances of smoking cessation in those who attempt it. Currently, research is focusing on development of antibodies against the free nicotine circulating in the blood, in order to form antigen-antibody complexes. These antigen-antibody complexes being unable to cross the blood-brain barrier would not be able to stimulate the nicotine receptors and will thus make smoking non-enjoyable (Figure 1). Preliminary results of early clinical trials support a beneficial effect of this approach (Figure 2). Nicotine-Qbeta, CYT002-NicQb and NicVAX are currently three such vaccines under development. The combination of active and passive immunization may also be a good strategy.8,9

Nicotine
Blood-Brain Barrier

Nicotine bound to Nicotine - Receptors

Brain

Newer Bronchodilators
Fig. 1a : Mechanism of nicotine action
Antigenantibody Complex Blood-Brain Barrier

Blood

Bronchodilators are the main stay of COPD management as they improve symptoms and quality of life significantly mainly by emptying the trapped air through dilatation of the distal airways. Thus bronchodilators provide symptomatic relief only and do not necessarily modify the disease process. Short
60%

56.6%

P=0.174
40.3%

P=0.004 P=0.920
32.1%

Ab: Antibody

Smoking abstainers (%)

50% 40% 30% 20% 10% 0% -10%

P=0.920
32.1%

31.3%

Unbound receptors Brain

Fig. 1b : Immunization mechanism against nicotine

* Senior Research Fellow, Chest Research Foundation, Pune; **Project Manager, Cipla Ltd., Mumbai; ***Director, Chest Research Foundation, Marigold Complex, Kalyani Nagar, Pune 411014, Maharashtra

Vaccinated Subjects

High Ab responders

Medium Ab responders

Low Ab responders

Placebo

Fig. 2 : Continuous abstinence rate in smokers after immunization

 SUPPLEMENT TO JAPI february 2012 VOL. 60

60 40 20 0 -20 -40 -60

Novel Combinations
Placebo

Roumilast 250 mcg Roumilast 500 mcg

Prebronchodilator FEV1 in ml

Fig. 3 : Change in lung function parameters after treatment with roflumilast

acting-bronchodilators have met with serious problems of noncompliance to the treatment because of the discomfort caused by multiple dosing. This has led to the development of long acting- and ultra long acting-bronchodilators which produce sustained bronchodilation lasting for 12-24 hours. This allows for once-daily or twice-daily dosing which improves patient compliance.

Some COPD patients respond well to LAMAs and some to LABAs depending on various factors including variable predominance of beta-adrenergic or muscarinic receptors in these patients. Using a combination of the two may solve the problem of such variation in response to bronchodilators. Furthermore, LAMAs and LABAs have been shown to have synergistic effects.13,18 Since, these combinations are more likely to be used in severe or very severe COPD cases, addition of a steroid or anti-inflammatory drug would make sense, as steroids are likely to reduce the exacerbations in these patients.19 Various such triple drug combinations are presently available or would be available soon in the market. India leads competition in this respect by launching the first triple inhaler containing tiotropium, formoterol and ciclesonide is already available in India while such combinations are presently not there in most of the other countries including Europe and US.20 Some of the combinations in development are: aclidinium+formoterolfluticasone/budesonide, tiotropium + formoterol Fluticasone /Budesonide, glycopyronium+form oterolmometasone, indacaterol+glycopyrronium (QVA-169), olodaterol + tiotropium, milveterol/vilanterol + darotropium, carmoterol + tiotropium and formoterol + dexpirronium.9-16 One of the limitations of such approach is delivery of LAMA and LABA at different locations in the lung which reduces their synergistic potential. A novel approach of combining these drugs in a single dimer molecule holds promise to deliver both the drugs at same locations in order to have maximum synergistic effect. Such molecules are known as dual-acting muscarinic antagonist- 2-agonist (MABA) bronchodilators. GSK-961081, Bicyclohept-7-ylamine derivatives, THRX-200495, THRX-198321, LAS190792 and TD-5959 are some of the potential MABAs currently under development.9,13

Ultra Long Acting Muscarinic Antagonists (ultra-LAMA)

Ultra-LAMAs are presently the best treatment available for COPD. The action of ultra-LAMAs like Tiotropium is mediated by good selectivity (for blocking) for and slow dissociation from M3 receptors in the lungs. They not only have better and sustained bronchodilatory effect but recently they also have been shown to have anti-inflammatory properties. It appears that LAMAs reduce the rate of exacerbation in COPD patients and hence, have the potential to partially halt progress of the disease and improve mortality.10,17 Aclidinium, glycopyrronium, darotropium, TD-4208, CHF5407, QAT-370, GSK-573719, Dexpirronium and RBx 343E48F0 are some of the ultra-LAMAs under development. Aclidinium is faster acting. Recent clinical trials have casted doubt on once-daily dosing of aclidinium and trials to investigate efficacy and safety of twice-daily dosing are underway. The other bronchodilators are being evaluated in clinical trials.9-16

Anti-Inflammatory Drugs
Drugs that can reduce the lung inflammation in COPD, safely and effectively, will undoubtedly be the drugs of choice for managing COPD. Years of research to discover such wonder drug has given birth to some anti-inflammatory agents or ideas, which may not be as effective as desired but can be of pragmatic use in clinical practice. Toiling research to understand the molecular reasons behind the unresponsiveness of COPD inflammation to corticosteroids, has led to the understanding that oxidative stress-mediated reduction in an enzyme known as Histone Deacetylase (HDAC) might be the culprit. Interestingly, theophylline has been shown to increase the cellular levels of HDAC. Hence, it is thought that oral theophylline given in low doses may augment the anti-inflammatory effect of inhaled steroids. A study on theophylline with budesonide (ADC4022) has already been successfully completed.21-23

Ultra long acting 2 agonists (ultraLABA)

Ultra-LABAs have duration of action that lasts for at least 24 hours. Carmoterol, indacaterol, milveterol, vilanterol, olodaterol, LAS100977, PF610355, JNJ39758979, Saligenin- or indolecontaining 2-agonists, UK-503590 and Compound X are some of the ultra-LABAs currently under development. Carmoterol, indacaterol, vilanterol, LAS100977 are faster acting compared to salmeterol. Indacaterol, a promising ultra-LABA has been approved in Europe and USA for bronchodilator treatment. Large clinical trials have shown that indacaterol may be better than salmeterol, formoterol and tiotropium in increasing trough FEV1 in COPD patients at doses of 150 and 300 mg and there was no evidence of tachyphylaxis. In asthma milveterol has been found to be safe and well-tolerated, with efficacy comparable to salmeterol. Its role in COPD is yet unexplored. Vilanterol is another ultra-LABA in clinical trials, and has been found to be safe and effective in both asthma and COPD patients.9-16 The deposition of inhaled drug into the lungs is usually less than 30%. However, using a formulation process like Modulite technology, the drug deposition of carmoterol has been shown to be improved up to 41%.9

PDE4 Inhibitors
Phosphodiesterase-4 (PDE4), an isoenzyme of phosphodiesterase, is specifically expressed in many proinflammatory cells such as neutrophils, macrophages, eosinophils, mast cells and lymphocytes. As a consequence, selective PDE4 inhibition may have inhibitory effects upon various inflammatory and immunomodulatory cells. Considering the problem of compliance with inhaled drugs and lack of availability of an effective anti-inflammatory drug, oral PDE4 inhibitors hold great promise. Roflumilast, a selective PDE4 inhibitor, has been developed and approved as an anti-

10

SUPPLEMENT TO JAPI february 2012 VOL. 60

Table 1 : Common adverse events recorded in roflumilast trial

Placebo n=280 Patients experiencing 1 adverse event COPD exacerbation Nasopharyngits Diarrhea Upper respiratory tract infection Nausea 174 (62%) 65 (23%) 19 (7%) 6 (2%) 14 (5%) 2 (1%)

Roflumilast 250 mcg n=576 500 mcg n=555 382 (66%) 370 (67%) 135 (23%) 42 (7%) 28 (5%) 27 (4%) 16 (3%) 113 (20%) 46 (8%) 50 (9%) 23 (4%) 27 (5%)

Chemokine antagonists
-Cigarette smoke -Air pollutants -Neutrophils -Macrophages -mucin -glutathione -uric acid -proteins -alpha tocopherol -ascorbic acid

The chemotactic effects of chemokines CXCL8, CXCL1 and CXCL5 on neutrophils and monocytes are mediated by a common receptor, CXC receptor (CXCR)-2. ADZ8309, an oral CXCR1/2 antagonist has shown to inhibit neutrophil inflammation in humans. Antagonists have also been developed for other important chemokine receptors like CXCR3 and CXCR5. SCH-527123 and GSK656933 have already completed phase I studies.9-16

TGF- Inhibitors
Fig. 4 : Oxidant-Antioxidant Imbalance

inflammatory agent for COPD. In a multi-centric clinical trial Roflumilast also improved FEV1 marginally, but significantly in COPD patients over and above tiotropium (Figure 3).24-27 Recently it has been suggested that PDE4 inhibitors are the best add-on therapy over LAMAs and LABAs for COPD. A combination of the inhaled PDE4 inhibitor GSK256066 (phase II) with a LAMA (potentially darotropium) in addition to, a LABA (either milveterol or Vilanterol) is also being explored. However, intolerable gastrointestinal side effects of present PDE4 inhibitors have prompted development of specific PDE4B and PDE7 inhibitors (Table 1).13

Transforming growth factor (TGF)- plays a key role in fibrosis of small airways, which is a major cause of progressive FEV1 decline and reduced exercise capacity in COPD patients. SD-280, a TGF- inhibitor has been developed. However, there are long-term concerns about inhibition of TGF-.9-16

Nuclear factor-kB inhibitors

Nuclear factor-kB is a transcription factor that plays a key role in COPD inflammation by regulating the expression of CXCL8 and other chemokines, TNF- and other inflammatory cytokines, as well as MMP9. Therefore, inhibition of NF-kB by inhibition of the inhibitor of NF-kBkinase (IKK)-2 seems to be a promising therapeutic option. Several (IKK)-2 inhibitors are currently under development.9-16

Antiproteases
Proteases like matrix metalloproteinases (MMP), which are released from macrophages, neutrophils and epithelial cells, digest elastin to cause emphysema. Selective MMP inhibitors like AZ11557272, have been shown to prevent emphysema and airway thickening in guinea pigs. MMP-9 and MMP-12 inhibitors are being currently investigated in Phase II and Phase III clinical trials and the results are awaited with interest. Midesteine and BAY-71-9678 are few other elastase inhibitors that have completed phase I studies.9-16

p38 MAP Kinase inhibitors:

p38 mitogen-activated protein kinase (p38 MAP kinase) is activated by cellular stress and regulates the expression of IL-8, TNF- and MMPs, proteins involved in driving COPD airway inflammation. Inhaled formulations of p38 MAP kinase inhibitors, currently in the development phase, are GSK681323 and GSK856553.9-16

PI3K Inhibitors
Phosphoinositol 3-kinases (PI3Ks) are involved in the inflammatory process, specifically in neutrophil recruitment and activation. PI3K- and PI3K- have been targeted for inhibition and several such inhibitors are currently in early drug development phase.9-16

Cytokine Inhibitors
TNF- (Tumour Necrosis Factor-) is a key mediator of inflammation including systemic inflammation in COPD. Infliximab, an inhibitor of TNF-, has been clinically tested and was however, not been found to be of any clinical benefit in COPD. Other cytokines that are being targeted presently for inhibition include interleukin (IL)-1, IL-6 and IL-7. Tocilizumab, a potent inhibitor of IL-6, is yet to be tested in COPD patients. These drugs are still in the development phase.9-16

PPAR Agonists
Peroxisome Proliferator-activated Receptors (PPARs) are a family of ligand-activated nuclear hormone receptors belonging to the steroid receptor super-family. Recently, PPAR- and PPAR- have demonstrated immunomodulatory properties. PPAR- agonists also inhibit TGF- and hence may be helpful in preventing fibrosis. The PPAR agonists currently being studied for therapeutic use in COPD are rosiglitazone and SB 219994.9-16

 SUPPLEMENT TO JAPI february 2012 VOL. 60

11

Mean change in eCO from baseline

Mean change in FEV1 from baseline

N-Acetyl
120 100 80 60 40 20 0 -20 -40
Fluticasome

Mitochondria
Superoxide dismutase Superoxide anion
N-Acetyl Fluticasome

0
Mean change in eCO (in ppm)

-0.4 -0.6 -0.8 -1 -1.2

Mean change in FEV1 (in Mililiters)

Hydrogen peroxide

-0.2

O2
Endoplasmic Reticulum NADH/NADPH Oxidase Xanthine oxidase Lipooxygenase Cyclooxygenase P450 monooxygenase Mitochondrial oxidation phosphorylation

O2

.Oxidative Stress - DNA damage -Oxidize proteins (enzymes, histones) -Oxidize lipids -Apoptosis -Neutrophil sequestration -Inactivation of antiproteases - Steroid unresponsiveness -Transcription of proinflammatory cytokines

H2O2
Fenton Reaction/ Haber Weiss Reaction

-0.4347

113

-31

-1.087

p=0.017

Fig. 6: Outcomes of clinical trial using higher dose NAC

OH

Statins
Statins or 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) are used widely as lipid lowering agents. However, recently statins have been found to have anti-inflammatory, antioxidant, anti-thrombogenic and vascular function-restoring actions. Retrospective studies indicate that statins might improve all-cause mortality, deaths from COPD, respiratory-related urgent care, COPD exacerbations, intubations for exacerbations of COPD, exercise capacity and lung function decline in COPD patients. Lipophilic statins such as atorvastatin and simvastatin are thought to be more effective than the hydrophilic pravastatin. However, statins have been inadequately studied and need further evaluation in objective clinical trials before they can be used in the management of COPD.32-34

Generation of oxidant radicals and eects of oxidative stress

Fig. 5 : Reactive oxygen species generation and its effects

Antioxidants
Oxidative stress arising out of oxidant-antioxidant imbalance, contributes quite significantly to the pathophysiology of COPD in multiple ways (Figures 4 and 5). N-Acetyl-Cysteine (NAC) is one of the most widely used and tested anti-oxidants. NAC has been shown to reduce both local as well as systemic oxidative stress. Some studies have demonstrated that NAC reduces bronchial hypersecretion, prevents the decline in FEV1 and helps reduce the numbers of COPD exacerbations.5,28 In our own study (unpublished data) comparing high dose NAC (1200 mg OD) with inhaled fluticasone in a randomized, double blind study in 23 subjects with moderate-to-severe COPD, we found a significant reduction of exhaled carbon monoxide (which is a biomarker for oxidative stress) by 1.09 ppm in NAC group against 0.43 ppm decrease in the fluticasone group after a 4 weeks treatment. Intriguingly, this was accompanied by an increase in FEV1 by 112ml in NAC group against a 30ml reduction in the fluticasone group (Figure 6). This suggests that in higher doses NAC reduces oxidative stress and may lead to mild bronchodilation, an added advantage over corticosteroids. However, the results are needed to be confirmed by large scale multi-centric clinical trial.29 Several anti-oxidants like N-acestelyn (NAL), N-isobutyrylcysteine (NIC), erdosteine, procysteine and carbocysteine are currently under development. As against NAC, effective inhaled preparation of these anti-oxidants can be developed making it possible to deliver them in higher doses locally. NAL has been tested in clinical trials and was well tolerated. Erdosteine has additional property of reducing bacterial adhesiveness suggesting potential use to prevent bacterial exacerbations. NIC is less effective and procysteine more toxic.5,28

Regenerative Therapies
Presently COPD is managed only symptomatically and is a progressive disease. Any drug/therapy that restores the destroyed alveolar tissue may actually reverse the disease.

Stem Cells
Infusion with allogenic mesenchymal stem cells offer hope, as they have the potential to regenerate alveolar tissue by themselves or by secreting growth hormones, specifically, vasculo-endothelial growth factor (VEGF). However, lodging of the pulmonary blood vessels with the infused stem cells (arborization) leading to fatal outcome is an undeniable possibility. Trials investigating the efficacy and safety of stem cells in COPD patients are underway.

Retinoic Acid
Retinoic acid is known to increase alveolar septation during lung development. All-trans-retinoic acid has been shown to induce regeneration of the terminal respiratory tract and reverse elastase induced emphysema. However, this was not substantiated by a clinical trial evaluating health status on CT density.9-16

Anti-ageing Therapy
Accumulating DNA damage caused by oxidative stress is a hallmark of accelerated ageing. Accelerated aging has been implicated in the pathogenesis of COPD and is mediated by inactivation of Silent Information Regulator Two (SIR2) protein-1 or sirtuin1 (SIRT1). Resveratrol, found in grape skin, seeds and nuts, activates SIRT1, and is being studied as a possible therapeutic agent for COPD. New SIRT1 activators under development are SRT1720, SRT501 and SRT2104. These molecules are many times more potent than resveratrol.5,28,35 Apart from new drug discoveries, a lot of research is taking place to discover new devices, formulation strategies and drug

NRF-2 Activators
Nuclear factor erythroid-2 related factor 2 (NRF2), a transcription factor, induces antioxidant expression, thus inhibiting oxidative stress. Plant products 6-methylsulfinylhexyl isothiocyanate (6-HITC) found in Japanese horseradish, sulforaphane isolated from broccoli and wasabi are the NRF-2 activators currently being studied.30,31

12

SUPPLEMENT TO JAPI february 2012 VOL. 60

Table 2: Summary of newer therapies for COPD

a. Smoking Cessation 1. 1. Vaccines: a. Nicotine-Qbeta b. CYT002-NicQb c. NicVAX Ultra long acting -2 agonists: a. Carmoterol b. Indacaterol c. Milveterol d. GSK-642444 e. BI-1744-CL f. Saligenin or indole containing -2 agonists g. UK-503590 h. Compound X 2. Ultra long acting anti-muscarinic agents: a. Aclidinium bromide b. Glycopyrronium bromide c. TD-4208 d. QAT-370 e. CHF 5407 f. Darotropium bromide g. dexpirronium 1. MABA (Muscarinic-antagonist- -2agonist): a. GSK-91081 b. Bicyclohept-7-ylamine derivatives 2. LABA and ICS: a. Carmoterol and budesonide b. Formoterol and mometasone (MFF258) c. Formoterol and ciclesonide d. Indacaterol and mometasone (QMF-149) e. Indacaterol and QAE-397 (a novel corticosteroid) f. Fluticasone furoate and GSK-642444 3. LABA, LAMA and anti-inflammatory compounds: a. Tiotropium, salmeterol and fluticasone/ciclesonide b. Indacaterol, glycopyrronium and mometasone c. Milveterol, darotropium and fluticasone furoate d. GSK-642444, dartropium and fluticasone furoate 1. Roflumilast 2. Cilomilast 1. Cytokine Inhibitors : a. Infliximab (Anti-TNF) b. Tocilizumab 2. Chemokine antagonists: a. ADZ8309: CXCR1/2 antagonist b. Anti-CXCR3 c. Anti-CXCR5 3. TGF- Inhibitors: a. SD-280 4. Antiproteases: a. Marimastat: Non-selective MMP Inhibitor b. AZ11557272: Dual MMP-9/MMP-12 Inhibitor 5. Drugs for improving steroid resistance: a. Low dose theophylline b. Anti-oxidants 6. Nuclear factor-kB inhibitors 7. p38 MAP Kinase inhibitors 8. PI3K Inhibitors 9. PPAR Agonists: a. Rosiglitazone b. SB 219994 f. Anti-oxidants 1. N-acetyl cysteine (NAC) derivatives: a. N-acestelyn (NAL) b. N-isobutyrylcysteine (NIC) c. Erdosteine d. Procysteine e. Carbocysteine 2. NRF-2 Activators: a. 6-methylsulfinylhexyl isothiocyanate (6-HITC) b. Sulforaphane g. Statins Statins being studied for effects on COPD: a. Simvastatin b. Atorvastatin c. Pravastatin h. Regenerative therapies 1. Retinoic acid: a. All-trans-retinoic acid b. 9-cis-retinoic acid 2. Stem cells i. Anti-ageing therapy 1. SIRT1 Activators: a. Resveratrol b. SRT1720 c. SRT501 d. SRT2104 j. Inhalation devices New carrier systems: 1. Matrix particle carrier formulations (using chitosan) 2. Liposomes: Poly-lactide-co-glycolide (PLGA) 3. Polymeric Nano-particles 4. Absorption enhancers: surfactant, fatty acid, taurochlorate, saturated polyglycolysed glyceride, trihydroxy bile salt and hyaluronic acid 5. Cyclodextrins: Cyclosporine A

b. Bronchodilators

c. Novel combinations:

d. PDE4 Inhibitors e. Anti-Inflammatory drugs:

delivery agents as present devices and drug delivery systems are able to deliver only a marginal amount of the drug to the desired portion of the lung.12 Although the exciting novel therapies may take some time to reach practicing physicians, it is encouraging to realize that our COPD patients will be receiving more effective and safe treatment in near future (Table 2). We may soon make the inflammation in COPD respond to therapy. By then, smoking cessation remains the most important intervention and long acting-bronchodilators the most effective symptom-relievers.

References
1. 2. Sundeep S Salvi, Peter J Barnes. Chronic obstructive pulmonary disease in non-smokers. Lancet 2009;374:73343. William MacNee, and Rubin M. Tuder. New Paradigms in the Pathogenesis of Chronic Obstructive Pulmonary Disease I. Proc Am Thorac Soc 2009;6:527531. Leonardo M. Fabbri, Fabrizio Luppi, Bianca Beghe, and Klaus F. Rabe. Update in Chronic Obstructive Pulmonary Disease 2005. Am J Respir Crit Care Med 2006;173:10561065. Barnes PJ. Mediators of Chronic Obstructive Pulmonary Disease. Pharmacol Rev 2004;56:515-548.

3.

4.

 SUPPLEMENT TO JAPI february 2012 VOL. 60

13

5. 6. 7.

Irfan Rahman. Review: Antioxidant therapeutic advances in COPD. Ther Adv Respir Dis 2008;2:351-74. William MacNee. Oxidants/Antioxidants and COPD. Chest 2000;117;303S-317S. Z. Kluchov, D. Petrov1, P. Joppa, Z. Dorkov, R. Tkov. The Association between Oxidative Stress and Obstructive Lung Impairment in Patients with COPD. Physiol Res 2007;56:51-56. Jacques Cornuz. A Vaccine against Nicotine for Smoking Cessation: A Randomized Controlled Trial. PLoS ONE 3(6): e2547. doi:10.1371/ journal.pone.0002547 Carola Seifart and Claus Vogelmeier. Emerging drugs in chronic obstructive pulmonary diseases. Expert Opinion. Emerging Drugs 2009;14:181-194

21. P J Barnes. Theophylline for COPD. Thorax 2006;61:742744. 22. Peter J. Barnes. Theophylline. New Perspectives for an Old Drug. Am J Respir Crit Care Med 2003;167:813818. 23. Barnes PJ. Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol 2009;71:451-64. 24. Peter M. A. Calverley et al. Effect of 1-Year Treatment with Roflumilast in Severe Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2007;176:154161 25. Klaus F Rabe, Eric D Bateman, Denis ODonnell, Stephan Witte, Dirk Bredenbrker, Thomas D Bethke. Roflumilastan oral antiinflammatory treatment for chronic obstructive pulmonary disease: a randomized controlled trial. Lancet 2005;366:56371 26. Victoria Boswell-Smith, Domenico Spina and Clive P. Page. Phosphodiesterase inhibitors. British Journal of Pharmacology 2006;147:S252-S257. 27. Giembycz MA, Field SK. Roflumilast: first phosphodiesterase-4 inhibitor approved for treatment of COPD. Drug Design, Development and Therapy 2010;4:147-58. 28. Irfan Rahman. Antioxidant therapies in COPD. International Journal of COPD 2006;1:1529. 29. Brashier B, Ravindaran L, Kapoor S, Deshpande PK, Ghongane B, Madas S, Mandrekar S, Limaye S, Salvi S. Four weeks of treatment with n-acetyl cysteine (NAC) (1200mg/day) reduces lung oxidative stress and improves lung function in moderate-to-severe COPD subjects. European Respiratory Society Congress 2009;Abstract 2016. 30. Aruna Kode,1 Saravanan Rajendrasozhan,1 Samuel Caito,1 Se-Ran Yang,1 Ian L. Megson, and Irfan Rahman1. Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 2008;294:L478L488. 31. Yasujiro Morimitsu et al. A Sulforaphane Analogue That Potently Activates the Nrf2-dependent Detoxification Pathway. The Journal of Biological Chemistry 2002;277:34563463. 32. Claudia C Dobler, Keith K Wong and Guy B Marks. Associations between statins and COPD: a systematic review BMC Pulmonary Medicine 2009;9:32 33. Eric M Mortensen Impact of statins and ACE inhibitors on mortality after COPD exacerbations. Respiratory Research 2009;10:45 34. B. John Mancini et al. Reduction of Morbidity and Mortality by Statins, Angiotensin-Converting Enzyme Inhibitors, and Angiotensin Receptor Blockers in Patients With Chronic Obstructive Pulmonary Disease. Journal of the American College of Cardiology 2006;47:12, 35. Francine Z. Marques, M. Andrea Markus, Brian J. Morris Resveratrol: Cellular actions of a potent natural chemical that confers a diversity of health benefits. The International Journal of Biochemistry & Cell Biology 2009;41:21252128.

8.

9.

10. Peter J. Barnes. Emerging Pharmacotherapies for COPD. Chest 2008;134;1278-1286 11. Peter J. Barnes. Future Treatments for Chronic Obstructive Pulmonary Disease and Its Comorbidities. The Proceedings of the American Thoracic Society 2008;5:857-864 12. Satomi Onoue, Shinger Misaka, Yohei Kawabata and Shizuo Yamada. New treatments for chronic obstructive pulmonary disease and viable formulation/device options for inhalation therapy. Expert Opin. Drug Deliv 2009;6:793-811. 13. Matera MG, Page CP, Cazzola M. Novel bronchodilators for the treatment of chronic obstructive pulmonary disease. Trends in Pharmacological Sciences 2011;1-12. Article in Press. 14. M. Cazzola and M.G. Matera. Emerging inhaled bronchodilators: an update. Eur Respir J 2009;34:757769. 15. M Cazzola and MG Matera. Novel long-acting bronchodilators for COPD and Asthma. British Journal of Pharmacology 2008;155:291 299 16. Jean Bourbeau and Malcolm Johnson. New and Controversial Therapies for Chronic Obstructive Pulmonary Disease. Proc Am Thorac Soc 2009;6:553554, 17. D.J. Powrie et al. Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD. Eur Respir J 2007;30:472478. 18. Becky J. Proskocil and Allison D. Fryer. 2-Agonist and Anticholinergic Drugs in the Treatment of Lung Disease. Proc Am Thorac Soc 2005;2:305310 19. Douglas W Mapela, Judith S Hurleyb, Anand A Dalalc, Christopher M Blanchetted. The role of combination inhaled corticosteroid/ long-acting -agonist therapy in COPD management. Primary Care Respiratory Journal 2010;ahead of print. 20. Barnes PJ. Triple inhalers for obstructive airways disease: will they be useful? Expert Rev Respir Med 2011;5:297-300.