Key Articles Related to Complementary and Alternative

Medicine in Cardiovascular Disease: Part 2

Sheryl L. Chow, Pharm.D., Harleen Singh, Pharm.D., Robert J. DiDomenico, Pharm.D.,
Steven P. Dunn, Pharm.D., Samuel G. Johnson, Pharm.D., Joel C. Marrs, Pharm.D.,
Orly Vardeny, Pharm.D., M.S., and Barry E. Bleske, Pharm.D., FCCP

The utilization of complementary and alternative medicine (CAM) has

increased over the past several years, largely based on unsubstantiated benefits
and aggressive marketing. However, the safety of nontraditional products is
often overlooked and undocumented. Clinicians should become familiar with
the potential risks of CAM and inform patients about associated adverse
effects and/or serious drug interactions. This bibliography paper compiled
key articles specific to CAM therapy and cardiovascular disease, which
include primary literature and review articles. Based on the numerous
published reports available on this topic, this bibliography, as part 2 of 2,
focuses on the safety of CAM therapy in cardiovascular disease.
Key Words: cardiovascular disease, complementary medicine, alternative
medicine, nutraceutical, key articles, consensus statements.
(Pharmacotherapy 2011;31(10):208e–277e)

An estimated 15 million people in the U.S.
purchase Complementary and Alternative
Medicines (CAM) for a variety of medical
conditions. Misconceptions regarding their
purported efficacy have largely driven the
From the Department of Pharmacy Practice and
Administration, Western University of Health Sciences,
Pomona, CA (Dr. Chow), the LA BioMed at Harbor-UCLA,
Torrance, CA (Dr. Chow), the University of Illinois at
Chicago College of Pharmacy, Chicago, IL (Dr.
DiDomenico), the University of Virginia Health System,
Charlottesville, VA (Dr. Dunn), the Departments of
Cardiology, Kaiser Permanente Colorado, Denver, CO (Dr.
Johnson), the University of Colorado School of Pharmacy,
Aurora, CO (Dr. Marrs), the College of Pharmacy, Oregon
State University, Portland, OR (Dr. Singh), the Institute for
Clinical and Translational Research, University of
Wisconsin, Madison, WI (Dr. Vardeny), and the College of
Pharmacy, University of Michigan, Ann Arbor, MI (Dr.
Bleske).
For reprints, please visit http://www.
pharmacotherapyjournal.org. For correspondence, please
contact Sheryl L. Chow, Pharm.D., BCPS, Assistant
Professor of Pharmacy Practice, Western University of
Health Sciences, 309 E. Second Street, Pomona, CA 91766;
e-mail: schow@westernu.edu.
popularity of these products whereas the adverse
effects have been underemphasized and
underreported. Furthermore, patients who
purchase over-the-counter CAM products are
often treated with concomitant prescription
medications, which could lead to serious drug
interactions without proper counseling.
Therefore, it is important for clinicians to be
informed of the potential safety concerns related
to these products.
This compilation is part of a series of annotated
bibliographies specific to CAM therapy and
cardiovascular diseases compiled by members of
the Cardiology Practice and Research Network of
the American College of Clinical Pharmacy. The
list of publications was compiled by 7 authors
and reviewers who identified key articles and
subtopics related to the safety of CAM therapy
and cardiovascular diseases. The paper includes
annotated bibliographies of published clinical
and animal studies, and reviews. The level of
evidence will also be assigned under each of the
following sections: (1) adverse effects and (2)
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al 209e

drug interactions. This bibliography was Lycium

published as part 2, out of a 2-part series. The Magnesium
first of the series focuses on the efficacy of CAM Mango
therapy in cardiovascular disease, whereas the Night-blooming cereus
second part of the series (presented in this Motherwort
bibliography paper) will emphasize CAM adverse Oat bran
effects and interactions relative to cardiovascular Oleander
disease. Omega-3 Fatty Acids (Fish Oil)
OUTLINE Omega-6 Polyunsaturated Fatty Acids
Strength of Evidence Key Papaya
Guidelines and Reviews Pectin
CAM Products Policosanol
alpha-linolenic acid Pomegranate
Aconitum species Psyllium
Alcohol Red Yeast Rice
Alfalfa Resveratrol
Aloe Vera Roseroot
Angelica (Dong quai) Saw Palmetto
Bilberry Soy Protein and Isoflavones (Soy Milk)
Bitter Orange St. John’s wort
Blue Cohosh Stanols and Sterol Esters
Buther’s broom Storphanthus
Caffeine Tamarind
Capsicum Tea (Black and Green)
Coffee Thiamine
Curbicin Tussilago farfara
Dark Chocolate Vitamin C
Danshen Vitamin D
Devil’s claw Vitamin E
Echinacea Wintergreen
Ephedra Yohimbine
Feverfew Zinc
Folic Acid and B Vitamins
Funugreek Strength of Evidence Key:
Fumitory
Garlic A = Randomized controlled trials/meta-analysis
Ginger B = Non-randomized clinical studies
Ginko Biloba (cohort/case-control)
Ginsing C = Case Reports/case series
Gossypol D = Animal and/or laboratory studies
Grape Juice E = Theoretical interaction
Grapefruit Juice
Guarna and Guar Gum GUIDELINES AND REVIEWS
Guggulipid
Hawthorn
Ernst E. Cardiovascular adverse effects of herbal
Horney Goat Weed medicines: A systematic review of the recent
Horse Chestnut literature. Can J Cardiol. 2003;19(7):818–27.
Irish Moss Herbal and alternative medications are likely to
Jin-bu-huan cause adverse effects, but reporting of these
Kelp events is largely performed through a voluntary,
Khella post-market system that likely does not reveal the
L-Arginine full scope of potential adverse events. This paper
L-Carnitine was a systematic review focusing on the
Licorice cardiovascular adverse effects of a wide variety of
Lilly of the Valley herbal and alternative medicines. An electronic
210e PHARMACOTHERAPY Volume 31, 2011
search of Medline (via PubMed), Embase,
Cochrane Library, Amed, and CISCOM was
utilized for the review, in addition to evaluation
of the author’s own files. Bibliographies for each
paper that was identified were also evaluated for
additional resources. Search terms used include
adverse effects, cardiotoxic, cardiovascular,
complications, heart, herbal medicine,
interactions, phytomedicine, risk, safety, side
effects, supplements, toxicity, and toxic effects.
Reports on the adverse event were included in
the review if the event was recent and severe,
resulting in hospitalization, a life-threatening
condition, or death. The review is grouped
according to adverse events found to be reported
with various herbal agents, including
arrhythmias (tachycardia and bradycardia),
arteritis, chest pain, congestive heart failure,
hypertension, hypotension, myocardial
infarction, and pericarditis. Cases of drug-drug
interactions with warfarin and herbal
medications, causing over- or insufficient
anticoagulation are briefly reviewed as well. In
addition, the author includes a number of tables
which summarize known pharmacologic effects,
reported cardiovascular adverse effects,
theoretical adverse effects, and theoretical or
reported drug-drug interactions for each herbal
agent. Nearly all of the evidence reviewed for
each adverse effect is based on either case reports
or case series. The author concludes that while
adverse effects with herbal or alternative
medicine are reported, the true incidence of such
events is unknown and reliant upon reporting
mechanisms to the FDA.
Izzo AA, Carlo GD, Borrelli F, Ernst E.
Cardiovascular pharmacotherapy and herbal
medicines: the risk of drug interaction. Int J
Cardiol. 2005;98:1–14.
This review focused on the interaction between
herbal or alternative medications with traditional
cardiovascular pharmacotherapy. Systematic
evaluations of PubMed were undertaken (January
1966–2003) utilizing the search terms herbal
medicine, botanical medicine, phytotherapy, drug
interaction, adverse effects, side effects, adverse
drug reaction, safety, and toxicity. Overall, 43
case reports and eight clinical studies were
identified for inclusion into the review. The
overall most common traditional
pharmacotherapeutic agent involved was
warfarin (37 cases and 1 clinical trial). Other
reported interactions include alterations in serum
concentrations of digoxin, enhanced levels or
effects of aspirin, and alterations in
concentrations of statin therapies, which are
primarily metabolized by the cytochrome P450
isoenzyme 3A4. The authors conclude that
interactions between herbal medications and
traditional cardiovascular medications are an
important safety issue and that increased
awareness of this issue should be a focus of
healthcare practitioners and researchers.
Violi F, Pignatelli P, Basili S. Nutrition,
supplements, and vitamins in platelet function
and bleeding. Circulation. 2010;121:1033–44.
Platelet function and related thrombosis play
an important role in the pathophysiology of
cardiovascular disease. This review examines the
evidence on whether dietary changes or
nutritional components of such diets, including
supplements and vitamins, can result in
efficacious changes in platelet function. Various
dietary modifications, including the
Mediterranean diet and the Indian Heart Study,
have demonstrated that dietary modifications can
be associated with fewer cardiovascular events
and mortality. Several components of these diets
have been associated with lower levels of platelet
function, including monounsaturated fatty acids
(olive oil), plant derived n-3 fatty acids (α-
linolenic), and n-3 polyunsaturated fatty acids in
fish oil [eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA)]. Data appears to
demonstrate that antithrombotic effects of fish oil
supplementation appear to be greater than that
seen with plant-derived fatty acids. Polyphenol
use, including those found in wine, grapes, and
cocoa have also been associated with improved
rates of cardiovascular events and decreased
platelet function, although this association is
more inconsistent than that shown with
increased fatty acid intake or supplementation.
While decreased levels of platelet aggregation are
generally seen as desirable in the prevention of
cardiovascular disease, large clinical trials with
vitamin E have shown higher rates of bleeding
related adverse effects, including hemorrhagic
stroke. The authors conclude that some
supplemental medication and vitamins are
strongly associated with reduced levels of platelet
aggregation, including fish oils and some
polyphenol-rich nutrients such as grape juice and
cocoa. These effects may explain some of the
epidemiologic benefit with diets rich in these
ingredients in observational trials. However,
many of the studies evaluating platelet function
have fundamental methodologic concerns and
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
none of the agents reviewed should be utilized in
practice for its antiplatelet effects as
monotherapy or in place of traditional agents
until more definitive studies are performed.
Tachjian A, Maria V, Jahangir A. Use of herbal
products and potential interactions with patients
with cardiovascular diseases. J Am Coll Cardiol.
2010;55:515–25.
This review comprehensively examined the
potential for drug-drug interactions with herbal
or alternative medications and traditional
cardiovascular medicines. The authors also
review potential adverse effects of herbal
medications which could result in deleterious
effects in patients with various cardiovascular
diseases. Potential articles for inclusion in the
review were identified via a search of PubMed for
the years 1966–2008, utilizing the search terms
cardiovascular agents, complementary therapies,
herb-drug interaction, and cardiovascular
disease. The most likely herbal or alternative
medications identified that could produce
adverse effects in cardiovascular disease include
St. John’s wort, motherwort, ginseng, gingko
biloba, garlic, grapefruit juice, hawthorn, saw
palmetto, danshen, echinecea, tetrandine,
aconite, yohimbine, gynura, licorice, and black
cohosh. In addition, the authors assembled a
table of herbal or alternative medications that
should be avoided in patients with cardiovascular
diseases (reproduced below). A significant
portion of the review is also dedicated to
identifying systematic problems with the use of
complementary and alternative medications,
including lack of scientific evidence of safety and
efficacy, lack of regulatory oversight, lack of
quality control procedures, public misin-
formation, lack of knowledge about herbal and
alternative medications by patients and health
care providers, and under-reporting of adverse
effects of herbal and alternative medications.
The authors conclude that many herbal
medications have significant potential to result in
harm to patients with cardiovascular disease and
that both more regulatory oversight, in addition
to improved educational efforts to both health
care practitioners and the general public about
these therapies, are warranted.
CAM PRODUCTS
Alpha-Linoleic Acid
Alpha-linolenic acid (ALA) is a precursor for
the n-3 polyunsaturated fatty acids
211e
eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA) found in various
plant-derived food sources (e.g., flaxseed oil).
When given as a supplement or incorporated into
fortified foods such as vegetable spreads, ALA has
been shown to have favorable effects on serum
lipoproteins and blood pressure. Consequently,
dietary supplementation of ALA is frequently
used to reduce risk of coronary heart disease.
Some studies suggest ALA or ALA-fortified foods
may reduce high-density lipoprotein (HDL)
cholesterol levels and raise triglycerides,
theoretically increasing the risk of cardiovascular
disease. However, the magnitude of these effects
were small and of questionable clinical
significance. One study suggested that flax seed-
containing bread may have an inhibitory effect
on platelet aggregation.
Cardiovascular adverse effects: increased risk of
bleeding (E).
Drug interactions: increased risk of bleeding
with antithrombotic drugs due to antiplatelet
activity (E).
Aconitum species
The Aconitum species [e.g., A. kusnezoffii , A.
carmichaeli] are used for a variety of ailments
including relief of pain, inflammation, bruising,
and fever. The roots of these plants contain
diterpenoid ester alkaloids, such as aconitine,
mesaconitine, and hypacontine, which activate
sodium channels and increase muscarinic activity
resulting in membrane excitation in various
tissues and increased cholinergic activity. The
increase in cellular sodium uptake prolongs
depolarization, delays repolarization, and induces
afterdepolarizations. Increased intracellular
sodium concentrations may lead to increased
sodium-calcium exchange resulting in increased
intracellular calcium and increased automaticity.
Each of these effects on the conduction system
may lead to the development of arrhythmias.
Additionally, hypaconitine may possess both
positive and negative inotropic effects.
Cardiovascular adverse effects: Atrial
fibrillation/flutter (D), bradycardia (C),
ventricular tachyarrhythmias (C), and
cardiovascular collapse (C).
Drug interactions: None reported.
Hibino S. Clinical and experimental studies on
auricular fibrillation. Jpn Circ J. 1967
Nov;31(11):1523–31.
Although controlled clinical trials
212e PHARMACOTHERAPY Volume 31, 2011
demonstrating the proarrhythmic effects of
aconite are lacking, these effects of aconite were
utilized in experimental studies to stimulate
auricular fibrillation (e.g., atrial fibrillation)
dating back to 1967. Hibino reviewed and
summarized the clinical features of 1,381 patients
with atrial fibrillation over a 10-year period.
Described in this analysis were the incidence,
concomitant disease states, demographics,
symptoms, electrocardiographic findings,
functional status, and death. Next, an
experimental model of atrial fibrillation and atrial
flutter was reported using an isolated rabbit
atrium. The atrial tissue was first irrigated with
Tyrode’s solution and a surface electrocardiogram
and membrane action potential was obtained.
Atrial fibrillation was then induced by applying
0.5 x 10-6 g/ml of aconitine solution. The atrial
rate following aconitine application was observed
between 350–400 beats/minute. From
quantitative estimations of intracellular
potassium and sodium and changes in the
transmembrane potential, it was believed that
aconitine activated latent pacemakers in the atrial
tissue and stimulated the ectopic foci promoting
the development of atrial fibrillation. The
remainder of this report described the author’s
experience with “intensive quinidine therapy” as
a means to convert and maintain normal sinus
rhythm in patients with atrial fibrillation. This
report demonstrates the potential proarrhythmic
effect of Acontinum species on atrial tissue.
Given that the experimental model reported here
utilized isolated atrial tissue, it is possible that
aconitine has similar effects on ventricular tissue
and may explain the many reports of ventricular
tachyarrhythmias and cardiovascular collapse
observed in the literature.
Alcohol (Ethanol)
Orally, ethanol is used for reducing the risk of
cardiovascular disease, ischemic stroke, and
diabetes mellitus. Ethanol has also been used for
slowing cognitive decline later in life. Research in
patients free from cardiovascular disease has
shown mortality reduction associated with light-
to-moderate ethanol intake—largely related to a
reduction in coronary heart disease. Studies in
patients with known cardiac disease have been
inconclusive.
Cardiovascular adverse effects: Exacerbation of
angina (E), heart failure (E), idiopathic
cardiomyopathy (B), and atrial fibrillation (A).
Drug Interactions: Increased risk for
gastrointestinal bleeding with concomitant use of
aspirin (C), increased risk for hemorrhage due to
decreased metabolism of warfarin (C), and
possible reduced therapeutic effectivess of
anticoagulation due to induced metabolism of
warfarin (E).
Kodama S, Saito K, Tanaka S, et al. Alcohol
consumption and risk of atrial fibrillation: a
meta-analysis. J Am Coll Cardiol. 2011 Jan
25;57(4):427–36.
This meta-analysis sought to estimate risk of
atrial fibrillation (AF) related to alcohol
consumption. Previous observational studies
examining the relationship between alcohol
consumption and AF show inconsistent results.
A search of Medline (January 1966 to December
2009) and Embase (January 1974 to December
2009) databases was conducted to find studies
using key words related to alcohol and AF.
Studies were included if data on effect measures
for AF associated with habitual alcohol intake
were reported or could be computed. The effect
measures for AF for the highest versus lowest
alcohol intake in individual studies were pooled
with a variance-based method. Linear and spline
regression analyses were conducted to quantify
the relationship between alcohol intake and AF
risk. Fourteen eligible studies were included in
this meta-analysis. The pooled estimate of AF for
the highest versus the lowest alcohol intake was
1.51 (95% CI 1.31–1.74). A linear regression
model showed that the pooled estimate for an
increment of 10 g per day alcohol intake was
1.08 (95% CI 1.05–1.10; R(2) = 0.43, p<0.001).
A spline regression model also indicated that risk
of AF increased with increasing levels of alcohol
consumption. These results suggest that
avoiding alcohol consumption may reduce the
risk of incident atrial fibrillation.
Padilla H, Gaziano MJ, and Djousse L. Alcohol
consumption and risk of heart failure: a meta-
analysis. Phys Sportsmed 2010;38(3):84–9.
This meta-analysis sought to examine the
relation between various levels of alcohol intake
and incident heart failure. Six prospective cohort
studies obtained through a PubMed literature
search were included in the analysis. 46,252
patients were included in the study—including
5,510 cases of heart failure (HF). Alcohol
drinkers were classified as never, former, and
current drinkers of < 1, 1 to 7, 8 to 14, and > 14
drinks per week. Compared with never drinkers,
the pooled relative risks were 1.16 (95%
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
confidence interval [CI], 0.90–1.51) for former
drinkers, 0.90 (95% CI, 0.83–0.98), 0.80 (95%
CI, 0.73–0.88), 0.78 (95% CI, 0.65–0.95), and
0.77 (95% CI, 0.63–0.95) for current drinkers of
< 1, 1–7, 8–14, and > 14 drinks per week,
respectively, in a random effects model.
Compared with never drinkers, former drinkers
had a 16% higher risk of HF; however, current
drinking of < 1, 1–7, 8–14, and > 14 drinks per
week was associated with a 10%, 20%, 22%, and
23% lower risk for HF. These findings suggest
that infrequent and light-to-moderate drinking is
associated with a lower risk of HF, and may be
appropriate for people at risk for HF in the
absence of contraindications. These findings do
not support heavy or binge drinking due to
effects on increased mortality.
De Schepper PJ, Tjandramaga TB, Verhaest L, et
al. Diflunisal versus aspirin: a comparative study
of their effect of fecal blood loss, in the presence
and absence of alcohol. Curr Med Res Opin
1978;5(7):520–4.
This study sought to determine if alcohol
influenced fecal blood loss in healthy male
volunteers on either diflunisal or aspirin. Fecal
blood loss was measured using 51Cr-labelled red
cells. In a double-blind parallel study in 10
subjects, the effect of 250 mg diflunisal twice
daily was compared with 750 mg aspirin 4-times
daily. Drugs were taken during two 7-day
periods separated by a 1-week control period.
Mean daily fecal blood loss during the two
treatment periods was 0.32 ml and 0.53 ml in the
diflunisal group versus 6.87 ml and 3.20 ml in
the aspirin group. Diflunisal did not significantly
increase blood loss, while aspirin had a
significant effect. In a double-blind crossover
study in 12 subjects, the effect of 250 mg
diflunisal twice daily was compared with 600 mg
aspirin 4-times daily. Alcohol (120 ml, 40%) was
added during the last 2 days of each 6-day
treatment period. Fecal blood loss was not
significantly affected by diflunisal and there was
also no significant effect on blood loss with
concomitant alchohol use. Aspirin significantly
increased fecal blood loss and this was
significantly enhanced by concomitant alcohol
use. These data support an association between
alcohol and aspirin coadministration with
increased risk for gastrointestinal bleeding as
evidenced by fecal blood loss. Additionally,
insufficient statistical analyses prevent firm
conclusions—additional data are needed to
characterize increased absolute risk for bleeding
213e
in patients who take low-dose aspirin (81–162
mg daily) for cardioprotection.
Melander O, Liden A, Melander A.
Pharmacokinetic interactions of alcohol and
acetylsalicylic acid. Eur J Clin Pharmacol
1995;48(2):151–3.
This prospective observational study sought to
determine the influence of acetylsalicylic acid
(ASA, 1,000 mg), ibuprofen (800 mg) and
paracetamol (1,000 mg) on the single-dose
kinetics of ethanol in 12 healthy volunteers
ingesting the drug and a standardized breakfast
one hour before intake of ethanol. It also
assessed the influence of ethanol on the single-
dose kinetics of 1,000 mg of ASA in ten fasting
healthy volunteers. Plasma concentrations of
ethanol were measured by gas chromatography,
and those of the drugs by liquid chromatography.
There was no effect of ASA, ibuprofen or
paracetamol on the single-dose kinetics of
ethanol, but concurrent intake of ethanol
reduced the peak concentration of ASA by 25%.
These data suggest that ethanol interferes with
pharmacokinetics of ASA and potentially reduces
systemic exposure. The clinical significance of
this interaction is questionable, as this does not
explain the pharmacodynamic observation of
increased risk for gastrointestinal bleeding
associated with ASA and ethanol co-
administration. More studies are needed to
determine the clinical significance of this
interaction.
Aguilar D, Skali H, Moye LA, et al. Alcohol
consumption and prognosis in patients with left
ventricular systolic dysfunction after a
myocardial infarction. J Am Coll Cardiol 2004
Jun 2;43(11):2015–21.
The SAVE trial was a randomized, multicenter,
double-blind, placebo-controlled study designed
to assess survival in patients with left ventricular
dysfunction following myocardial infarction.
This secondary analysis sought to evaluate the
influence of alcohol intake on the development
of symptomatic heart failure (HF) in patients
with left ventricular systolic dysfunction (LVSD,
ejection fraction [EF] <40%) after a myocardial
infarction (MI) previously studied in SAVE. Two
thousand two hundred thirty-one patients
following MI were randomized to an angiotensin-
converting enzyme inhibitor (ACE-I) or placebo.
Patients were classified as nondrinkers, light-to-
moderate drinkers (1 to 10 drinks/week), or
heavy drinkers (>10 drinks/week) based on
214e PHARMACOTHERAPY Volume 31, 2011
reported baseline alcohol consumption. The
primary outcome was hospitalization for HF or
need for an open-label ACE-I. Univariate
analyses showed that baseline light-to-moderate
alcohol intake was associated with a lower
incidence of HF compared with nondrinkers
(hazard ratio [HR] 0.71; 95% confidence interval
[CI] 0.57 to 0.87), whereas heavy drinking was
not (HR 0.91; 95% CI 0.67 to 1.23); however,
after adjustment for baseline differences, light-to-
moderate baseline alcohol consumption no
longer significantly influenced the development
of HF (light-to-moderate drinkers HR 0.93; 95%
CI 0.75 to 1.17; heavy drinkers HR 1.25; 95% CI
0.91 to 1.72). Alcohol consumption reported
three months after MI also did not modify the
risk of adverse outcome. These findings suggest
that for patients with LVSD following an MI,
light-to-moderate alcohol intake either at
baseline or following MI did not alter the risk for
development of HF. While heavy drinking
trended toward increased HR (1.25, as above),
this was not statistically significant.
Mukamal KJ, Tolstrup JS, Friberg J, et al.
Alcohol consumption and risk of atrial
fibrillation in men and women. The Copenhagen
City Heart Study. Circulation 2005;112:
1736–1742.
While available scientific literature indicates
that moderate alcohol intake reduces the risk of
cardiovascular disease, as well as the
development of heart failure as compared to
abstinence, there is some evidence that would
suggest heavy alcohol intake may lead to the
development of atrial fibrillation (AF). However,
the available data at the time of publication was
mixed in terms of the relation of alcohol
ingestion and the development of AF. The
present analysis is a prospective cohort study in
1,645 men and women enrolled in the
Copenhagen City Heart Study. Alcohol
consumption for individuals determined though
questionnaires, and the development of AF was
ascertained through routine ECG recordings as
well as review of hospital admission records.
Moderate drinking in this analysis was defined
differently from the general consensus of 1–2
drinks daily. Throughout what was defined as a
moderate range of drinking in this analysis (<
than 35 drinks per week), there was no
association with an increased risk of AF.
However, in heavy drinkers (> 35 drinks per
week), there was a statistically significant
increased risk in the development of AF (HR
1.45, 95% CI 1.02–2.04). Adjustment for
confounders such as heart failure, CAD or
hypertension did not alter the risk estimate. The
prospective cohort study confirmed the notion
that heavy drinking does indeed increase the risk
of AF.
Mukamal KJ, Smith CC, Karlamangla AS,
Moore AA. Moderate alcohol consumption and
safety of lovastatin and warfarin among men: the
post-coronary artery bypass graft trial. Am J Med
2006 May;119(5):434–40.
Although moderate drinking has been
associated with lower mortality among patients
with coronary heart disease, its safety among
patients taking common cardiac medications is
unknown. This study included 1,244 men
enrolled in the Post-Coronary Artery Bypass
Graft (CABG) Trial who had undergone previous
coronary bypass surgery. Participants were
randomly assigned to lovastatin in low (mean 40
mg) or high (mean 76 mg) doses and to low-dose
warfarin (mean international normalized ratio
[INR] 1.4, goal INR <2.0) or placebo in a
factorial design. Alanine aminotransferase (ALT)
and INR levels were measured every 6 to 12
weeks for 4 to 5 years. Alcohol intake was
characterized as abstention (<1 drink per week),
light (1–6 drinks per week), moderate (7–13
drinks per week), and heavier (≥ 14 drinks per
week). During follow-up, 66% of men taking
warfarin had an INR of 2.0 or higher, and 7% of
men had an ALT of 80 IU/L or higher. Maximum
INR (P=0.72) and ALT (P=0.51) levels did not
differ across categories of alcohol intake. The
risks of an INR of 2.0 or higher were 67%, 66%,
68%, and 61% among non-, light, moderate, and
heavier drinkers (P=0.86), respectively. The
corresponding risks of an ALT of 80 IU/L or more
were 8%, 10%, 9%, and 6% (P=0.70),
respectively. Findings from this trial show that
moderate drinking did not adversely influence
the safety of low-dose warfarin or even high-dose
lovastatin among men enrolled in the study, as
evidenced by INR and ALT levels. While these
findings do not necessarily have broad external
validity in the absence of more conclusive data
regarding higher or therapeutic doses of warfarin,
it is intriguing that objective results do not
indicate an association of harm. It is reasonable
to counsel patients to avoid heavier alcohol
intake; however, mild-to-moderate intake of
alcohol does not appear to adversely interact
with low-intensity warfarin or with lovastatin
therapy.
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
Djousse L, Gaziano JM. Alcohol consumption
and heart failure in hypertensive US male
physicians. Am J Cardiol 2008 Sept 1;102(5):
593–7.
This post-hoc analysis of the Physician’s Health
Study aimed to identify the association between
light to moderate drinking and incident HF in
5,153 hypertensive male physicians free of
stroke, myocardial infarction, or major cancers at
baseline. Alcohol consumption was self-reported
and classified as <1, 1–4, 5–7, and ≥ 8
drinks/week. HF was ascertained using follow-up
questionnaires and validated using Framingham
criteria. Average age was 58 years, and about
70% of subjects consumed 1–7 drinks/week.
Compared with subjects consuming <1
drink/week, hazard ratios for HF were 0.89 (95%
confidence interval [CI] 0.70–1.12), 0.72 (95%
CI 0.57–0.91), and 0.38 (95% CI 0.20–0.72) for
alcohol consumption of 1–4, 5–7, and ≥ 8
drinks/week after adjustment for age, body mass
index, smoking, exercise, and history of atrial
fibrillation, respectively (p<0.001). These data
suggest that light-to-moderate alcohol
consumption was associated with a lower risk of
HF in hypertensive male physicians. Although
alcohol drinking increases blood pressure and
heavy drinking has been associated with
alcoholic cardiomyopathy, little is known about
the association between light to moderate
drinking and risk of heart failure (HF); however,
the authors postulate that since alcohol is a
diuretic it may prevent volume overload and
delay onset of signs and symptoms for HF. The
key element to these data, in conjunction with
findings from other prospective studies, is degree
of alcohol intake. These findings suggest that
light to moderate alcohol consumption was
associated with a lower risk of HF in
hypertensive male physicians.
Conen D Tedrow UD, Cook NR et al. Alcohol
consumption and risk of incident atrial
fibrillation in women. JAMA. 2008 Dec 3;
300(21):2489–96.
Previous studies suggest that consuming
moderate to high amounts of alcohol on a regular
basis might increase the risk of developing atrial
fibrillation in men but not in women. However,
these studies were not powered to investigate the
association of alcohol consumption and atrial
fibrillation among women.
The purpose of this observational cohort study
of patients enrolled in the Womens’ Health Study
was to prospectively assess the association
215e
between regular alcohol consumption and
incident atrial fibrillation among women. This
investigation included 34,715 initially healthy
women who agreed to document alcohol
consumption on questionnaires at baseline and at
48 months of follow-up and were grouped into 4
categories (0, > 0 and < 1, ≥ 1 and < 2, and ≥2
drinks per day). After more than 12 years of
follow-up, 653 cases of incident atrial fibrillation
were confirmed. Age-adjusted incidence among
women consuming 0 (n = 15,370), more than 0
and less than 1 (n = 15,758), 1 or more and less
than 2 (n = 2228), and 2 or more (n = 1359)
drinks per day were 1.59, 1.55, 1.27, and 2.25
events/1000 person-years of follow-up.
Compared with nondrinking women, women
consuming 2 or more drinks per day had an
absolute risk increase of 0.66 events/1000
person-years. This prospective cohort study
confirmed that healthy middle-aged women,
consuming up to 2 alcoholic beverages per day
were not at increased risk of incident atrial
fibrillation; however, heavier drinking (> than 2
drinks per day) was associated with increased
risk.
Alfalfa
Alfalfa is legume that has been used in
complementary and alternative medicine
practices to treat several ailments including
genitorurinary disorders, arthritis, asthma,
dyslipidemia, thrombocytopenic purpura, and
diabetes. It is also a good dietary source of many
vitamins and minerals, including vitamin K.
Therefore, alfalfa may reduce the efficacy of
vitamin K antagonists such as warfarin,
increasing the risk of thromboembolic events.
Cardiovascular adverse effects: None reported.
Drug interactions: Reduced effectiveness of
warfarin (E) due to vitamin K content of alfalfa
(D).
Haroon Y, Hauschka PV. Application of high-
performance liquid chromatography to assay
phylloquinone (vitamin K1) in rat liver. J Lipid
Res. 1983 Apr;24(4):481–4.
An animal study investigating vitamin K
content in rat livers suggests that the vitamin K
content in alfalfa is significant and may warrant
caution in patients taking warfarin. In their
study, Haroon and Hauschka sought to use high-
performance liquid chromatography (HPLC) to
quantify the amount of vitamin K 1 , phyllo-
quinone, in rat livers given the limitations of
216e PHARMACOTHERAPY Volume 31, 2011
previous analytical methods to do so. Two
groups of Sprague-Dawley CD strain rats were
fed identical diets except that one group was
supplemented with alfalfa while the other was
not. Once the animals reached 7–8 weeks old,
they were sacrificed and their livers were
removed and stored at –20° C until HPLC
analysis could be performed. Following a
stepwise approach to extracting samples,
preparing the HPLC assay, and assessing the
precision and accuracy of the assay, the vitamin
K1 content of the rat livers was compared. The
mean vitamin K1 content in the liver of the rats
fed a diet not supplemented with alfalfa was
7.3±2.7 ng/g in the female rats (n=6) and 8.0±2.7
ng/g in the male rats (n=6) but was nearly 6-fold
higher in the four rats fed a diet supplemented
with alfalfa (44±1.5 ng/g, statistical comparisons
not performed). The authors concluded that the
vitamin K1 content in the rat liver was derived
primarilyfrom nutritional sources, in this case
from alfalfa. Since this study demonstrated that
alfalfa was a primary nutrition source for vitamin
K 1 in rats, it is probably prudent to counsel
patients taking warfarin and alfalfa in
combination to maintain a consistent intake of
alfalfa as is recommended for ingestion of foods
high in vitamin K content to minimize
fluctuations in antithrombotic effects.
Aloe Vera
Aloe Vera is a cactus-like plant that contains
dozens of active compounds. It exists in
predominantly two forms: a gel and latex,
although a homogenized leaf extract contains
constituents of both forms. Aloe Vera gel
contains mono- and polysaccharides, amino
acids, sterols, tannins, enzymes, vitamins, and
minerals while the latex form contains
anthraquinolones, including several glycosides;
resins; and aloesin. Both have potential
medicinal uses. The gel may inhibit
thromboxane A2 synthesis via inhibition of
cyclooxygenase resulting in antiplatelet and anti-
inflammatory effects similar to aspirin. It is often
used to treat diabetes and promote wound
healing, including burn wounds.
Anthraquinones found in Aloe Vera latex are
cleaved in the colon to form anthrones, which
promote secretion of mucous, fluid and
electrolytes into the colon as well as peristalsis.
Additionally, Aloe Vera promotes potassium loss
from cells, which may result in paralysis of
intestinal muscles and decreased efficacy as a
cathartic leading to higher doses and potential
electrolyte deficiencies. The latex form may be
used to treat psoriasis, constipation,
inflammatory bowel disease. Aloe products may
be ingested orally or applied topically depending
on the intended use.
Cardiovascular adverse effects: Hypokalemia
(C)
Drug interactions: Increased risk of bleeding
with sevoflurane (C), in combination with
antithrombotic drugs due to antiplatelet effects
(E), and warfarin due to diarrhea-induced
alteration of gastrointestinal flora affecting
vitamin K production (E); digoxin toxicity
secondary to hypokalemia (E); increased risk for
hypokalemia with diuretics (E).
Vázquez B, Avila G, Segura D, Escalante B.
Antiinflammatory activity of extracts from Aloe
vera gel. J Ethnopharmacol. 1996
Dec;55(1):69–75.
To investigate the anti-inflammatory effects of
Aloe vera gel, Vázquez et al compared
carrageenan-induced edema, neutrophil
migration into the peritoneal cavity, and an in
vitro analysis of prostaglandin production in
male Wistar rats. The Aloe extracts prevented
carrageenan-induced edema in the hind paw to a
similar extent as indomethacin and
dexamethasone. Similarly, Aloe vera gel appeared
to exert a dose-dependent decrease in neutrophil
migration, comparable to dexamethasone and
indomethacin at the highest doses. The in vitro
analysis of prostaglandin production involved the
incubation of ram seminal vesicles (RSV). The
incubation was carried out using the RSV
cyclooxygenase preparation with either the
aqueous extract of the Aloe vera or indomethacin
in the control subjects. Arachidonic acid
metabolites were then extracted and the
concentration of prostaglandin E 2 (PGE 2 )
eventually estimated from densitometry. The
aqueous extract of Aloe vera reduced the
production of PGE2 by 48% compared to 63%
reduction observed with indomethacin (p<0.05
compared to control for both). The authors
concluded that this reduction was secondary to
inhibition of cyclooxygenase. Although not
measured in this analysis, thromboxane is
another metabolite of arachidonic acid via the
cyclooxygenase enzyme and a potent platelet
activator. Given that Aloe vera was shown to
reduce the production of PGE 2 , it may also
reduce the production of thromboxane and,
therefore, possess antiplatelet activity as well.
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
The latter was the rationale given by Lee and
colleagues in their report of bleeding
complications associated with the use of
sevoflurane and Aloe vera in a surgical patient
and may be possible when combined with
antithrombotic drugs as well.
Angelica (Dong Quai)
Dong quai is a traditional Chinese medicine
that is used for several conditions including
dysmenorrheal, anemia, “blood purification”,
infertility, dyspepsia, constipation, and others. It
is obtained from the root of the Angelica sinensis
plant. In animal models, dong quai has
estrogenic effects and therefore is often
considered a phytoestrogen. However, the
estrogenic effects have not been well studied in
humans. Dong quai has been associated with the
development of hypertension in a pregnant
woman and in her neonate following birth. Dong
quai may increase the risk of bleeding in patients
taking concomitant antithrombotic drugs as it
contains several natural coumarin derivatives and
ferulic acid that are believed to inhibit platelet
aggregation.
Cardiovascular adverse effects: Hypertension
(C), increased risk of bleeding (E)
Drug interactions: Increased risk of bleeding
(E) in combination with antithrombotic drugs
due to antiplatelet effects (A), potentiates the
antithrombotic effects of warfarin (C, D).
Lo AC, Chan K, Yeung JH, Woo KS. Danggui
(Angelica sinensis) affects the
pharmacodynamics but not the pharmacokinetics
of warfarin in rabbits. Eur J Drug Metab
Pharmacokinet. 1995 Jan–Mar;20(1):55–60.
Lo and colleagues conducted two studies to
investigate the effects of dong quai on the
pharmacokinetics and pharmacodynamics of
warfarin in male New Zealand white rabbits. The
first of these studies was a single-dose study in
which six rabbits were given a single dose of
warfarin (2 mg/kg) subcutaneously and serial
measurements were made to establish baseline
prothrombin times (PT) and warfarin
concentrations through 72 hours. After a 7-day
washout period, dong quai extract was then
administered to the rabbits orally (2 g/kg twice
daily for three days) followed by a single dose of
warfarin and repeated blood samples to assess PT
and warfarin concentrations. The pharmaco-
kinetic parameters of warfarin were not
significantly different following dong quai
217e
administration. Likewise, although PT values
increased in both groups there were no
differences noted between rabbits treated with
and without dong quai. The second analysis was
a steady-state study. In this analysis, six different
rabbits were treated with daily doses of warfarin
(0.6 mg/kg) subcutaneously for seven days.
Beginning on day 4, the animals were also treated
with dong quai for three days at the same dose
used in the single-dose study. Dong quai had no
effect on the mean steady-state concentrations of
warfarin. However, unlike the single-dose study,
dong quai significantly increased the PT within 2
days (day 6) and the PT was nearly 3-fold higher
after three days of the combination of warfarin
and dong quai (day 7). Notably, two of the
rabbits died following dong quai administration.
Therefore, the authors concluded that dong quai
does not appear to have a pharmacokinetic
interaction with warfarin. Thus, the mechanism
of the interaction with warfarin appears to be
unknown and may be pharmacodynamic in
nature.
Dong WG, Liu SP, Zhu HH, Luo HS, Yu JP.
Abnormal function of platelets and role of
angelica sinensis in patients with ulcerative
colitis. World J Gastroenterol. 2004 Feb
15;10(4):60–9.
While there are several reports that one of the
primary components of Angelica sinensis, sodium
ferulate, possesses antiplatelet activity, most of
this data is derived from animal and/or in vitro
studies. In patients with ulcerative colitis,
thrombophilia and platelet activation are
common characteristics of this disease state.
With this as a background, Dong and colleagues
sought to investigate the antiplatelet effects of
injectable Angelica sinensis in patients with
ulcerative colitis. A total of 64 patients (39 with
active disease, 25 in remission) were recruited
along with 30 healthy volunteers. Patients with
ulcerative colitis were randomly assigned to
standard therapy (n=33) and Angelica sinensis
injection (n=31). Standard therapy consisted of a
semifluid diet and mesalamine 2 g/day. Patients
in the Angelica sinensis arm received 40 ml
intravenously once daily for three weeks. The
healthy volunteers consisted of nonsmokers who
were not taking any platelet active therapy.
Various indicators of platelet activity were
assessed at baseline and after three weeks of
therapy including alpha-granule membrane
protein (GMP-140), thromboxane B2 (metabolite
of thromboxane A2, a potent platelet activator),
218e PHARMACOTHERAPY Volume 31, 2011
6-keto-prostaglandin F 1a (6-keto-PGF 1a,
metabolite of the vasodilatory prostaglandin I2),
von Willebrand factor related antigen (vWF:Ag),
platelet count, and 1 minute platelet aggregation
rate (1 min PAR). Compared to control subjects,
1 min PAR, GMP-140, thromboxane B 2 , and
vWF:Ag were all significantly increased, patients
with active disease experiencing greater increases
than those in remission. 6-keto-PGF 1a was
decreased in patients with active ulcerative colitis
but unchanged in patients whose ulcerative
colitis was in remission. Following three weeks
of Angelica sinensis therapy, each of the platelet
activity parameters that were increased at
baseline significantly declined by approximately
20–30% while 6-keto-PGF 1a remained
unchanged. None of the platelet activity
parameters were significantly changed in patients
receiving standard therapy alone. The authors
concluded that Angelica sinensis inhibited platelet
activation, attenuated vascular injury, and
improved microcirculation. This also indicates
that the antiplatelet effects of Angelica sinensis,
similar to those observed by Dong and colleagues
may contribute to bleeding risk in patients on
chronic oral anticoagulants like warfarin.
BILBERRY
Bilberry (Vaccinium myrtillus) is also known as
the European blueberry, huckleberry,
whortleberry, or blueberry. A perennial plant, its
fruit is often used as a food source. The fruit,
fruit extracts, and leaves have been used for
medicinal purposes to treat arthritis,
inflammation, gastrointestinal disturbances,
night vision, diabetes, chest pain, cancer and
other conditions. The anthocyanoside flavonoids
(anthocyanins) are thought to be the most
important and pharmacologically active
component of bilberry. The anthocyanins have
been shown to have many pharmacologic effects
including antioxidant activity, anti-inflammatory
effects, antiplatelet effects, and hypoglycemic
effects.
Cardiovascular adverse effects: Increased risk of
bleeding (E).
Drug interactions: Increased risk of bleeding
(E) in combination with antithrombotic drugs
due to antiplatelet effects (A).
BITTER ORANGE
Bitter orange (Citrus aurantium) is known by
several other names including Zhi shi, a
traditional Chinese herbal. The plant’s fruit and
peel are most often used to extract bitter orange
for medicinal purposes which include fungal skin
infections (topical application) and a variety of
gastrointestinal disorders (oral). More recently,
bitter orange has been added to many “ephedra
free” over-the-counter weight loss products
because it contains sympathomimetic alkaloids
such as synephrine and acts as a stimulant.
Synephrine and similar alkaloids contained in
bitter orange stimulate adrenergic receptors,
particularly ␣ 1 -adrenoreceptors, leading to
increased blood pressure. Because the bitter
orange-containing weight loss products often
contain other stimulants like caffeine as well,
there is potential for cardiovascular adverse
events, particularly ischemic events.
Cardiovascular adverse effects: Acute coronary
syndrome/myocardial ischemia (C), increased
blood pressure (A), increased heart rate (A).
Drug interactions: Antagonize the effects of
antihypertensive and heart rate-slowing drugs
(E) due to increases in blood pressure (A) and
heart rate (A).
Haller CA, Benowitz NL, Jacob III P.
Hemodynamic effects of ephedra-free weight-loss
supplements in humans. Am J Med. 2005
Sep;118(9):998–1003.
Because several ephedra-free supplements now
contain Citrus aurantium, the active component
of bitter orange, and this plant contains
adrenergic amines such as synephrine which
stimulates ␣ 1 -adrenoreceptors, Haller and
associates sought to evaluate the hemodynamic
effects of two C. aurantium-containing
supplements (Advantra Z and Xenadrine EFX).
Each capsule of Xenadrine EFX contains
synephrine 2.75 mg, octopamine 2.96 mg, and
caffeine 119.6 mg while Advantra Z contains five
times as much synephrine (15.6 mg) with only
trace amounts of octopamine and no caffeine.
Ten healthy subjects (mean age, 27 years) were
included in this randomized, double-blind, 3-arm
crossover study. Subjects were instructed to
avoid caffeine, over-the-counter products, and
herbal remedies for 24 hours prior to
participation. Subjects were hospitalized the
evening before initiating therapy, fasted after
midnight, and were administered a single dose of
the supplement (2 tablets of Xenadrine EFX or 3
tablets of Advantra Z) or matching placebo.
Blood pressure, heart rate, physical and
emotional symptoms, and concentrations of
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
synephrine, octopamine, and caffeine were
measured at predetermined intervals for 12 hours
after dosing. Synephrine pharmacokinetics did
not differ between the two supplement groups,
suggesting the additional ingredients of
Xenadrine do not affect synephrine
pharmacokinetics. Xenadrine increased blood
pressure 9.6±6.2 / 9.1±7.8 mmHg (p=0.047 for
systolic blood pressure, p=0.002 for diastolic
blood pressure) and heart rate increased by
16.7±12.4 beats/minute (p=0.011) compared to
placebo. In contrast, Advantra Z had no effect on
blood pressure while increasing heart rate
11.4±10.8 beats/minute (p=0.031 vs placebo).
The authors concluded that ingestion of C.
aurantium as a single ingredient in modest
amounts had little effect on blood pressure while
producing a transient increase in heart rate,
suggesting some ␤1-adrenergic stimulation. In
contrast, when taken as part of the multi-
ingredient supplement (Xenadrine EFX), both
blood pressure and heart rate were increased
suggesting an additive effect of the combination
of active ingredients. Based on these findings
following a single dose in healthy volunteers, the
authors warn against the use of ephedra-free
supplements in patients with hypertension, heart
disease, or other conditions that may be
exacerbated by sympathetic stimulation.
Bui LT, Nguyen DT, Ambrose PJ. Blood pressure
and heart rate effects following a single dose of
bitter orange. Ann Pharmacother. 2006
Jan;40(1):53–7.
Bui and colleagues conducted a similar analysis
of a single dose of bitter orange on
hemodynamics in healthy volunteers. Subjects
were randomized to receive either 2 capsules of
Nature’s Way Bitter Orange or matching placebo
and then crossed over to receive the other
therapy one week later. Subjects fasted for at
least 10 hours prior to each study day and were
advised to refrain from ingesting any citrus-
containing products for three days prior to each
study day and any over-the-counter
sympathomimetics, caffeine, and dietary
supplements for the duration of the study
including the washout period. On each study
day, blood pressure and heart rate were measured
at baseline and hourly following study drug
ingestion for six hours. Fifteen subjects (10
men) were enrolled, 13 of whom completed both
study days. Systolic blood pressure increased
significantly at each time period following bitter
219e
orange administration compared to placebo, with
a maximal increase of 7.3±4.6 mmHg observed 3
hours after the dose. Diastolic blood pressure
decreased in both groups at all time periods but
was higher following bitter orange. Similarly,
heart rate was increased significantly at all time
periods with the peak change occurring at hour 4
(4.2±4.5 beats/minute). Like the previous
hemodynamic study, the authors suggest caution
when considering the use of bitter orange in the
elderly, obese, patients with comorbid disease
states, and those taking concurrent drug therapy.
BLACK COHOSH
Black cohosh (Cimicifuga racemosa) is an herb
that is frequently used to treat a variety of
women’s health issues such as postmenopausal
symptoms, premenstrual syndrome, osteoporosis,
and induction of labor. From a cardiovascular
perspective, black cohosh has been shown to
increase low-density lipoprotein (LDL)
cholesterol in animal models. Since LDL
cholesterol is an independent risk factor for
coronary heart disease, the potential exists for
black cohosh to increase cardiovascular risk.
Furthermore, there is conflicting evidence that
black cohosh and its metabolites inhibit the
cytochrome P450 (CYP) 2D6 isoenzyme, which
may have important implications for a variety of
cardiovascular medications (e.g., anti-arrhythmic
drugs, ␤-blockers) as well as other medications
where cardiovascular adverse events (e.g.,
torsades de pointe) when these CYP enzymes are
inhibited. It is important to note that the active
components of black cohosh differ from blue
cohosh and white cohosh and should not be used
interchangeably.
Cardiovascular adverse effects: Increased LDL
cholesterol (D).
Drug interactions: Elevated liver enzymes with
atorvastatin (C), inhibits CYP2D6 (A), may
increase risk of toxicity of CYP2D6 substrates
such as ␤-blockers and certain anti-arrhythmic
drugs (E).
Gurley BJ, Gardner SF, Hubbard MA, et al. In
vivo effects of goldenseal, kava kava, black
cohosh, and valerian on human cytochrome P450
1A2, 2D6, 2E1, and 3A4/5 phenotypes. Clin
Pharmacol Ther. 2005 May;77(5):415–26.
Noting some inconsistencies between in vitro
findings and human in vivo studies evaluating
the effects of herbal remedies on CYP enzyme
activity and the risk of drug interactions, Gurley
220e PHARMACOTHERAPY Volume 31, 2011
and colleagues sought to investigate the effects of
prolonged exposure to goldenseal, kava kava,
black cohosh, and valerian on various CYP
phenotypes in humans. Twelve healthy subjects
(mean age 24±3 years, 6 women) participated in
the study. Each of the subjects was confirmed as
a CYP2D6 extensive metabolizer via debrisoquin
urinary recovery screenings. The effects of the
four herbal remedies were evaluated in four
separate analyses in open-label fashion,
randomized only to sequence of
supplementation. For each analysis, subjects
took the assigned supplement for 28 days
followed by a washout period of 30 days.
Phenotypes for the CYP isoenzymes 1A2, 2D6,
2E1, and 3A4/5 were assessed at baseline (days -1
and 0) and at the end of the supplement period
(days 27 and 28). Forty-eight hours prior to the
study period, subjects received caffeine 100 mg
and midazolam 8 mg orally and blood obtained
for CYP3A4/5 and 1A2 phenotyping at hours 1
and 6. Phenotyping for CYP2E1 and 2D6 were
performed 24 hours later. On day 0, each subject
received chlorzoxazone 250 mg and debrisoquin
5 mg orally with blood and urine samples
collected for analysis. Phenotyping was repeated
in similar fashion on days 27 and 28 during each
supplement period. Assessment of phenotype
was based on the metabolite/parent serum ratios
for each of the probes. Because the focus of this
section is black cohosh, only the effects observed
in the black cohosh analysis will be reported
here. Black cohosh significantly decreased the
CYP2D6 phenotype (p=0.02) but only by a
magnitude of about 7% as assessed by
debrisoquin urinary recovery ratios. No effect
was observed by black cohosh on the other CYP
phenotypes. The authors concluded that the
inhibitory effect of black cohosh on CYP2D6 was
mild, but the clinical relevance was questionable
given the magnitude of change observed.
Gurley BJ, Swain A, Hubbard MA, et al. Clinical
assessment of CYP2D6-mediated herb-drug
interactions in humans: effects of milk thistle,
black cohosh, goldenseal, kava kava, St. John’s
wort, and Echinacea. Mol Nutr Food Res. 2008
Jul;52(7):755–63.
A similarly designed study evaluated the effects
of six different herbal supplements on CYP2D6
activity. The study consisted of three separate
experiments conducted on groups of 16 healthy
subjects in an open-label fashion where
randomization was performed to determine the
sequence of supplementation. As above, all
subjects were confirmed as CYP2D6 extensive
metabolizers. For each experiment, subjects
received the assigned supplement for 14 days
followed by a 30-day washout period and then
the alternative supplement was taken for 14 days.
Phenotyping for CYP2D6 was performed at
baseline (day 0) and again at day 14. The day
before phenotyping, patients emptied their
bladder and ingested debrisoquin 5 mg orally and
collected their urine for the proceeding eight
hours at which time the total urine volume was
recorded and an aliquot was obtained for
analysis. The supplements of interest included
black cohosh and milk thistle (study 1),
goldenseal and kava (study 2), St. John’s wort
and Echinacea purpurea (study 3). Because the
focus of this section is black cohosh, only the
effects observed in the black cohosh analysis will
be reported here. Subjects assigned to the black
cohosh group received 40 mg of black cohosh
extract twice daily. Unlike the previous study
where black cohosh mildly inhibited CYP2D6,
black cohosh had no effect on CYP2D6 activity.
Taken together with the previous findings, the
authors concluded that black cohosh is not a
potent modulator of CYP2D6 activity and is
unlikely to result in clinically relevant herb-drug
interactions with CYP2D6 substrates.
BLUE COHOSH
Blue cohosh (Caulophyllum thalictroides) is a
perennial herb whose root is used for medicinal
purposes, often to regulate menstrual cycles or to
induce labor. Various glycosides are found in
blue cohosh including quinolizidine, lupine, and
aporphine alkaloids as well as triterpene
saponins. These glycosides have been shown in
animals to not only cause uterine contraction but
also coronary artery vasoconstriction and
nicotinic stimulation.
Cardiovascular adverse effects: Myocardial
infarction (C), stroke (C), tachycardia (C),
negative inotropic effects (D), coronary artery
vasoconstriction (D).
Drug interactions: Reduced efficacy of anti-
anginal medication (E).
Ferguson HC, Edwards LD. A pharmacological
study of a crystalline glycoside of Caulophyllum
thalictroides. J Am Pharm Assoc 1954;43(1):16-
21.
Perhaps the earliest report of the
pharmacological effects of blue cohosh
(Caulophyllum thalictroides) was described by
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
Ferguson and Edwards in 1954. They report the
effects of blue cohosh on various tissues
including the uterus, intestine, blood pressure,
heart, hemotologic system, and subcutaneous
tissue derived from several separate animal
models. Because the focus of this paper is
cardiovascular adverse events and drug
interactions, only the studies evaluating
cardiovascular function will be reported here. To
assess the effects of blue cohosh on blood
pressure, 12 intact rats, 12 pithed rats, and one
dog experienced a transient drop in blood
pressure followed by a slight elevation from
baseline. The authors concluded that this effect
was clinically irrelevant and did not warrant
further study. Myocardial perfusion was
evaluated in 12 turtle hearts and 12 frog hearts
after administration of blue cohosh. The animals
received doses of 0.3–0.6 mg (turtle) and
0.05–0.14 mg (frog) resulting in positive
inotropy and slight bradycardia. Large doses and
repeated administration of small doses resulted in
partial heart block and systolic arrest, suggesting
toxic effects on the myocardium and the
potential for accumulation with repeated
administration. The cardiovascular effects were
also assessed on rat hearts in separate
experiments. Administration of 10 µg of blue
cohosh initially produced an inotropic effect
followed by a longer acting negative inotropic
effect. Additionally, coronary flow was reduced
by a 25.6%±1.36, which was thought to
contribute to the negative inotropic effects that
were observed. Another experiment on albino
rats demonstrated that a dose of 2 mg/kg caused
positive inotropic effects and mild tachycardia
that persisted for 50 minutes. However, at doses
above 4 mg/kg, a substantial increase in
contractility was noted ending in diastolic
stoppage. Finally, in cattle and hog models, blue
cohosh produced a dose-dependent contraction
of the carotid arteries. In summary, the authors
concluded that blue cohosh causes
vasoconstriction of the coronary arteries, leading
to hypoperfusion and myocardial toxicity.
Similarly, carotid artery vasoconstriction occurs
in response to blue cohosh but the effects on end
organ function are not known.
BUTCHER’S BROOM
Butcher’s broom (Ruscus aculeatus) is a shrub
belonging to the lily family. The plant’s root
contains several active components including
steroid saponins and flavonoids which are
221e
vasoactive and also have anti-inflammatory
properties. Butcher’s broom has been used for
centuries as a treatment for venous insufficiency
and for pain/inflammation. Butcher’s broom has
been shown to stimulate ␣1- and ␣2-adrenergic
receptors as well as stimulate the release of
norepinephrine in isolated canine veins.
Cardiovascular adverse effects: Hypertension
(E).
Drug interactions: Decreased effectiveness of
␣1-receptor blockers (E).
CAFFEINE (also see Coffee, Tea, and Guarana)
Caffeine is a methylxanthine derivative found
in coffee, guarana, tea, and other agents, and is
used primarily as a stimulant and diet
supplement. Although beneficial cardiovascular
effects have been reported based on inhibition of
thromboxane and platelet inhibition, caffeine
also adversely affects the central nervous and
cardiovascular systems. Proposed mechanisms of
actions include adenosine receptor blockade
(diuresis), phosphodiesterase inhibition
(inotropic effects), and catecholamine
stimulation (pressor effects).
Cardiovascular adverse effects: Hypertension
with habitual use of cola (sugared or diet) (B),
tachycardia(C), angina (C), premature
ventricular contractions (C), arrhythmia (C).
Drug Interactions: Antagonizes adenosine (A)
and dipyridamole (A), additive stimulatory
effects with ephedrine (C), mexilitine (B) and
verapamil (E), diltiazem (E).
Joeres R, Klinker H, Heusler H, Epping J,
Richter E. Influence of mexiletine on caffeine
elimination. Pharmacol Ther 1987;33:49–52.
A caffeine elimination study of five healthy
individuals and seven individuals with cardiac
arrhythmias was performed to evaluate whether
mexiletine has any effects on caffeine excretion.
The healthy individuals were given 400 mg
caffeine monohydrate after an overnight fast
together with 200 mg mexiletine. The patients
on mexiletine chronically (600 mg daily) were
given the same dose of caffeine in the same
conditions as the healthy individuals. Blood
samples were drawn pre-caffeine administration
and from one to twenty-four hours post caffeine
administration. In the healthy volunteers
caffeine clearance was decreased from 126 ± 15
ml/min to 54 ± 4 ml/min after co-administration
with mexiletine, the elimination half-life
increased from 246 ± 25 min to 419 ± 28 min. In
222e PHARMACOTHERAPY Volume 31, 2011
the individuals receiving chronic mexiletine
therapy caffeine clearance was increased from 37
± 16 ml/min to 71 ± 12 ml/min after mexiletine
therapy was discontinued, the elimination half-
life decreased from 878 ± 137 min to 330 ± 46
min. Mexiletine inhibited caffeine elimination by
50% in both the healthy volunteers and the
individuals with cardiac arrhythmias on
mexiletine chronically.
Smits P, Boekema P, De Abreu R, Thien T, van’t
Laar A. Evidence for an antagonism between
caffeine and adenosine in the human
cardiovascular system. J Cardiovasc Pharmacol.
1987 Aug;10(2):136–43.
Much of the vasopressor action attributed to
caffeine may be due, in whole or in part, to an
observation that caffeine inhibits adenosine
induced vasodilation. This trial was a
randomized, double-blind, placebo controlled
crossover study in 10 healthy male volunteers.
The volunteers were given a “caffeine test” at
study baseline to ensure adequate hemodynamic
response and were instructed to abstain from
caffeine and nicotine products prior to the study
date. Afterwards, each subject was randomized
to two “adenosine tests” where they were given
caffeine (250 mg intravenous over 10 minutes) or
placebo followed by adenosine at continuous
intravenous infusions of 0.04, 0.08, 0.12, and
0.16 mg/kg/min, titrated every 15 minutes. Each
test was separated by at least 1 week.
Hemodynamic and laboratory measurements
were performed 10 minutes after the caffeine or
placebo infusion and 5 minutes after each
adenosine dose titration. One subject was
withdrawn from analysis after basal caffeine
concentrations were revealed to abnormally high;
therefore only 9 subjects were included in data
analysis. Administration of caffeine alone
resulted in an increase in the mean arterial
pressure (MAP) of 9 mmHg over baseline
(p<0.001) and a decrease in the mean heart rate
(HR) of 3 bpm compared to baseline (p<0.05).
Adenosine infusion after caffeine compared to
placebo resulted in significantly lower adenosine-
induced rises in hemodynamic measurements of
systolic blood pressure (SBP) (p<0.05) and HR
(p<0.025), and significantly decreased metabolic
effects of adenosine on mean plasma
concentrations of epinephrine (–0.03 nM),
norepinephrine (0.3 nM), plasma renin activity
(–0.18 ng/ml/hr), and aldosterone (0.5 ng/100
mL) (all p-values < 0.01 vs. placebo). MAP and
diastolic blood pressure changes with adenosine
were unaffected by caffeine administration.
Overall, the authors conclude that these results
support the presence of an antagonistic
interaction between caffeine and adenosine,
although the clinical implications of this
interaction are not clear from this study.
Smits P, Straatman C, Pijpers E, Thien T. Dose-
dependent inhibition of the hemodynamic
response to dipyridamole by caffeine. Clin
Pharmacol Ther. 1991 Nov;50(5 Pt 1):529–37.
In a follow-up to the previous study, eight
healthy volunteers were enrolled in a
randomized, double-blind, placebo-controlled
crossover study where each volunteer
participated in 5 tests: placebo after placebo,
dipyridamole (0.4 mg/kg intravenous over 4
minutes) after placebo, and dipyridamole after 1,
2, and 4 mg/kg of intravenous caffeine. Infusion
of caffeine alone resulted in a mean increase in
mean arterial pressure (MAP) compared to
baseline of 6.1±0.5 mmHg vs. only 1.5±0.9
mmHg compared to baseline with placebo
(p<0.05). Hemodynamic measurements were
obtained at the beginning of each study visit, 15
minutes after the infusion of caffeine, and 30
minutes after the infusion of dipyridamole.
Infusion of dipyridamole alone resulted in a
mean increase in systolic blood pressure
(+8.4±2.4 mmHg), pulse pressure (+7.0±2.4
mmHg), heart rate (+25.7±3.8 bpm), and
calculated rate-pressure product (+3419 mmHg x
bpm) (all p-values < 0.05 vs. placebo). Caffeine
administration exhibited significant dose
dependent negative correlation with
hemodynamic response induced by dipyrid-
amole, including decreased systolic blood
pressure (r = –0.53), pulse pressure (r = –0.50),
heart rate (r = –0.95), and rate-pressure product
(r = –0.93). This study provides further evidence
for the ability of caffeine to attenuate the
hemodynamic response of direct or indirect
adenosine compounds. These findings may have
implications for the use of these drugs,
particularly in the setting of myocardial imaging.
Carrillo JA, Benitez J. Clinically significant
pharmacokinetic interactions between dietary
caffeine and medications. Clin Pharmacokinet
2000;39:127–53.
This review article evaluates the potential of
caffeine to interact with a number of drugs
including a specific section on cardiovascular
drugs. Caffeine intoxication has been linked to
cardiac arrhythmias, circulatory failure,
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
palpitations, and tachycardia. Mexiletine,
diltiazem, and verapamil have been shown to
decrease the clearance of caffeine or caffeine
derivatives. This review highlights many other
drugs and classes of drugs that have documented
and potential drug interactions with caffeine or
methyxanthine derivatives. Based on this review
there may be a potential for caffeine intoxication
when dietary caffeine is co-administered with
diltiazem, mexiletine, or verapamil.
Underwood DA. Which medications should be
held before a pharmacologic or exercise stress
test? Cleve Clin J Med 2002;69:449–50.
Caffeine can interact with one of the potential
agents used in a pharmacologic stress test. The
stress agents that can be used include adenosine,
dipyridamole, or dobutamine which are given
prior to nuclear perfusion imaging. In patients
given dypyridamole, there can be an interaction
with caffeine that results in a blocking of the
adenosine reuptake. Therefore, the general
recommendation related to caffeine and any
caffeine containing products is to avoid any
consumption for 24 hours prior to the stress test
when dipyridamole is being used as the stressing
agent. It is important to remind patients not only
to not consume caffeine in beverages, but any
other product that contains caffeine, especially
herbal products such as guarana.
Cabalag MS, Taylor DM, Knott JC, Buntine P,
Smit D, Meyer A. Recent caffeine ingestion
reduces adenosine efficacy in the treatment of
paroxysmal supraventricular tachycardia. Acad
Emerg Med. 2010 Jan;17(1):44–9.
While the ability of caffeine to attenuate the
hemodyamic effects of adenosine has been
identified, few data describe the effect of caffeine
intake on the therapeutic use of adenosine to
terminate supraventricular tachycardias (SVT).
This study was a multicenter, case-control study
of 68 adult patients with SVT treated with
adenosine. Caffeine intake was assessed via a
self-administered questionnaire. Patients were
excluded if they refused participation, had an
antiarrhythmic drug administered prior to the
adenosine (for termination of the SVT episode),
were taking other adenosine receptor–blocking
agents (theophylline, carbamazepine, dipyrid-
amole), had communication difficulties, or had
significant illness as determined by the attending
physician (e.g., myocardial infarction). The
primary endpoint of the study was the
conversion rate of the SVT to sinus rhythm after
223e
an initial 6 mg dose of intravenous adenosine.
Of the 68 patients enrolled, 52 (76.5%) converted
successfully to sinus rhythm after receiving the 6
mg adenosine dose. No difference was identified
between patients who did or did not convert by
age, sex, or daily amount of caffeine intake.
However, significant interaction between timing
of caffeine intake (2, 4, 6, or 8 hours prior to
adenosine) and successful conversion was
identified. The conversion rate among patients
consuming caffeine 2 hours prior to the
adenosine dose was 42.9% vs. 80.3% who did not
(OR 0.18, 95% CI 0.04–0.93). Subsequently,
patients consuming caffeine 8 hours prior to the
adenosine dose had a conversion rate of 67.6%
vs. 87.1% who did not (OR 0.31, 95% CI
0.09–1.08). Overall, this study demonstrates that
caffeine intake may also affect the antiarrhythmic
properties of adenosine in SVT and that higher
initial doses may be warranted in these patients.
CAPSICUM
Capsicum is a genus of flowering plants whose
fruit generates edible peppers (e.g., chili pepper)
that are common components of diets globally.
Capsaicin is the active component of Capsicum
and is often used topically as an analgesic (FDA
approved indication). When ingested orally,
Capsicum has been shown to increase energy
expenditure thought to be mediated by beta 1-
receptor stimulation. Additionally, it appears to
possess antiplatelet activity, potentially increasing
the risk of bleeding in patients taking
antithrombotic therapy.
Cardiovascular adverse effects: Hypertension
(C), increased risk of bleeding (E), myocardial
infarction (C).
Drug interactions: Decreased effectiveness of
beta blockers (E), may increase bleeding in
combination with antithrombotic medications
(E).
COFFEE (also see Caffeine)
Coffee is a major source of caffeine and one of
the most highly consumed beverages in the
world due to its mild central nervous system
(CNS) stimulatory effects which increase
alertness and decrease fatigue. Caffeine, available
as a purified formulation (caffeine citrate), is
used commercially for the treatment of
somnolence, migraine, and premature apnea and
also has a number of effects on vascular smooth
muscle via competitive inhibition of
phosphodiesterase. In addition to caffeine, coffee
224e PHARMACOTHERAPY Volume 31, 2011
contains a variety of chlorogenic acids which may
possess strong antioxidant activity. The
cardiovascular risk of coffee has been examined
in multiple prospective and retrospective studies
with very dichotomous findings, with some
studies demonstrating risk and some
demonstrating benefit.
Cardiovascular adverse effects: Hypertension
(A), increase rates of myocardial infarction (B),
increase sudden cardiac death (B), increase
arrhythmias (B).
Drug Interactions: Methylxanthine stimulants
(A), antihypertensives (A), adenosine (A),
increased bleeding with anticoagulants or
antiplatelets (E), increase in caffeine
concentrations with verapamil (E).
LaCroix AZ, Mead LA, Liang KY, Thomas CB,
Pearson TA. Coffee consumption and the
incidence of coronary heart disease. N Engl J
Med. 1986 Oct 16;315(16):977–82.
This prospective, observational study was
conducted in 1130 male medical students with a
follow up period of 19 to 35 years. The change
in coffee consumption relative to baseline intake,
average intake, and most recent intake were
examined relative to the incidence of coronary
heart disease (myocardial infarction, angina, or
sudden cardiac death). The incidence of
coronary artery disease for men drinking 5 or
more cups of coffee was 2.80 (95% CI 1.27–6.51)
times that of nondrinkers and 2.49 (95% CI
1.08–5.77) after adjustment for age, smoking
status, hypertension, and baseline cholesterol.
While these data do not specifically indict
caffeine as a potential factor in the increased risk,
caffeine is a major component of coffee. In
addition, while these data are suggestive of
increased risk with high caffeine intake, potential
confounders in lifestyle or other characteristics
may not be accounted for and introduce selection
bias.
Grobbee DE, Rimm EB, Giovannucci E, Colditz
G, Stampfer M, Willett W. Coffee, caffeine, and
cardiovascular disease in men. N Engl J Med.
1990 Oct 11;323(15):1026–32.
This was a prospective database analysis of
45,589 men (aged 40–75) examining the effect of
coffee consumption on the risk of myocardial
infarction, coronary revascularization with
bypass grafting or angioplasty, or stroke. None of
the participants had a prior history of
cardiovascular disease. After two years of follow-
up, coffee consumption > 4 cups per day was not
associated with an increased risk of cardio-
vascular disease or stroke relative to nondrinkers
after adjusting for age (RR 1.04, 95% CI
0.74–1.46). Further adjustment for common
cardiovascular and dietary risk factors did not
significantly alter the risk ratio (RR 0.90, 95% CI
0.67–1.22). Higher consumption of coffee (> 6
cups per day) was also not predictive of adverse
outcomes compared to nondrinkers (RR 0.65,
95% CI 0.31–1.35). The results of this study
suggest that coffee intake (and by extension,
caffeine) is not associated with cardiovascular
disease and stroke. However, the period of follow
up is of shorter duration than the previous study.
Noordzij M, Uiterwaal CS, Arends LR, Kok FJ,
Grobbee DE, Geleijnse JM. Blood pressure
response to chronic intake of coffee and caffeine:
a meta-analysis of randomized controlled trials. J
Hypertens. 2005 May;23(5):921–8.
Caffeine intake may increase the risk of
hypertension, which may in turn increase the
risk of cardiovascular disease. This study was a
meta analysis of 16 randomized, controlled trials
(totaling 1010 patients) examining the effect of
caffeine or coffee intake on blood pressure after a
minimum of 7 days. Nine coffee trials included
were not blinded to treatment. Overall, coffee or
caffeine intake was found to slightly increase
both systolic (2.04 mmHg, 95% CI 1.10–2.99)
and diastolic (0.73 mmHg, 95% CI 0.14–1.31)
blood pressure. However, when coffee (n=18)
and caffeine (n=7) trials were separated, BP
elevations were more significant with caffeine
(systolic: 4.16 mmHg, 95% CI 2.13–6.20;
diastolic: 2.41 mmHg, 95% CI 0.98–3.84) than
with coffee (systolic: 1.22 mmHg, 95% CI
0.52–1.92); diastolic 0.49, 95% CI –0.06–1.04).
Additionally, in trials with high caffeine intake (>
410 mg/day) the increase in systolic BP was
higher than those with lower caffeine intake
(p=0.029). An analysis of publication bias
demonstrated the potential lack of studies
showing large changes in blood pressure with
caffeine intake. These results suggest that
caffeine intake may worsen blood pressure
control and that these effects may be worse with
non-coffee caffeine containing beverages, such as
soft drinks or energy drinks. This may be
attributed to higher caffeine concentrations these
beverages in addition to other stimulant
compounds that may be included.
Lopez-Garcia E, Rodriguez-Artalejo F, Rexrode
KM, Logroscino G, Hu FB, van Dam RM. Coffee
consumption and risk of stroke in women.
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
Circulation. 2009 Mar 3;119(8):1116–23.
This study was an analysis of 83,955 women
enrolled in the Nurse’s Health Study, a cohort
study established in 1976. Subjects (n=879)
were excluded from this analysis with either a
history of stroke, coronary heart disease,
diabetes, or cancer at study baseline, leaving
83,076 included in the final analysis. Assessment
of coffee intake was determined through food
questionnaires distributed to cohort participants
every 2 years beginning in 1980 and ending in
2002. Participants were asked how often on
average they consumed coffee or tea during the
previous year. Caffeinated soft drinks and
decaffeinated coffee were added to the survey in
1984. Coffee consumption was then categorized
into 5 groups: < 1 cup per month, 1 cup per
month to 4 cups per week, 5–7 cups per week,
2–3 cups per day, and ≥ 4 cups per day. The
primary endpoint of the study was the incidence
of nonfatal or fatal stroke, defined as the first
event occurring after the baseline questionnaire
in 1980 and before June 1, 2004. Strokes were
further classified into ischemic stroke,
hemorrhagic stroke, or stroke of undetermined
type, with cerebrovascular pathology caused by
infection, trauma, or malignancy excluded from
the analysis. Multivariate Cox regression models
were then fit to adjust for differences in age,
smoking status, body mass index, physical
activity, alcohol intake, menopausal status,
hormone replacement therapy, aspirin use, and
dietary factors. Overall, stroke risk appeared to
be related to coffee consumption, with lower risk
among subjects consuming 5–7 cups per week
(RR 0.88, 95% CI 0.77–1.02), 2–3 cups per day
(RR 0.81, 95% CI 0.70–0.95), and ≥ 4 cups per
day (RR 0.80, 95% CI 0.64–0.98) compared to
subjects consuming < 1 cup per month of coffee
(p-value for trend = 0.003). This association
persisted despite further adjustment for
hypertension, hypercholesterol-emia, and type 2
diabetes. Interestingly, although caffeinated soft
drinks and tea were not associated with reduction
in stroke, decaffeinated coffee consumption of ≥
2 cups per day was associated towards a trend in
reduction in stroke compared to < 1 cup per
month (RR 0.89, 95% CI 0.73–1.08, p=0.05).
This study supports the opposite of previous
cohort studies; namely that besides the fact that
coffee consumption was not associated with
adverse or neutral effects on cardiovascular
disease and stroke, but rather that higher
consumption was associated with lower risk of
stroke. Interestingly, this difference was also
225e
evident in patients consuming decaffeinated
coffee, suggesting that it may be other
components of coffee (such as chlorogenic acids)
that may provide benefit, if benefit truly exists.
Hasan AS, Morton C, Armstrong MA, et al.
Coffee, caffeine, and risk of hospitalization for
arrhythmias. 50th Cardiovascular Disease
Epidemiology and Prevention/Nutrition, Physical
Activity and Metabolism (EPI|NPAM) Annual
Conference 2010; March 2–5, 2010, San
Francisco, CA. Abstract P461.
Because coffee intake is frequently associated
the development of palpitations, it is common
practice to recommend abstinence from coffee
and other caffeinated beverages in an effort to
reduce the likelihood of arrhythmia
development. However, there is limited data
establishing a link between coffee intake and
arrhythmia risk. Therefore, Hasan and colleagues
performed a retrospective analysis of 130,054
members of prepaid Kaiser Permanente
comprehensive health plans to examine the
association between coffee intake and
hospitalizations for dysrhythmias. Between 1978
and 1985 members had provided baseline
information about health habits, including coffee
intake. Hospitalizations for the discharge
diagnosis of cardiac dysrhythmia (ICD-9 code
427) were identified from billing records and
compared among those who consumed coffee on
a daily basis and those who did not. Overall,
27% of the members reported daily coffee intake.
There were a total 3,137 discharges for cardiac
dysrhythmia. Using Cox proportional hazard
models, controlling for 8 covariates, including
body mass index, blood pressure, total
cholesterol, and “yes” response to any one of 27
cardiorespiratory queries, hospitalization for
dysrhythmia was compared between coffee
drinkers and nondrinkers. For patients who
drank < 3 cups of coffee daily, no differences were
noted in hospitalizations for arrhythmia
compared to nondrinkers. However, in patients
consuming > 4 cups of coffee daily, the risk of
arrhythmia hospitalization was 18% lower than
nondrinkers (adjusted RR 0.82, 95% confidence
interval 0.73–0.93, p=0.001). When coffee was
analyzed as a continuous variable (adjusted
RR/cup/day), an inverse relationship was
observed with respect to hospitalizations for
dysrhythmias (p=0.001). Controlling for the
number of cups of coffee per day, total caffeine
intake was also inversely associated with lower
hospitalization risk (adjusted RR highest intake
226e PHARMACOTHERAPY Volume 31, 2011
quartile vs lowest intake 0.6, p=0.03). In a
subset analysis of patients who reported coffee
intake as either caffeinated or decaffeinated,
hospitalization risk was not reduced in those
who drank decaffeinated coffee. No differences
were noted based on gender, race, smoking
status, or arrhythmia type. Other clinical
parameters analyzed, including blood pressure,
total cholesterol, and blood glucose had minimal
influence on risk. This analysis suggests that, in
contrast to conventional thinking that significant
caffeine ingestion in the form of coffee may
increase the risk of arrhythmias, hospitalizations
for dysrhythmias were, in fact, lower in patients
who consumed large quantities of coffee. These
findings are limited by the retrospective nature of
this study and should be confirmed in a
prospective clinical trial.
de Koning Gans JM, Uiterwaal CS, van der
Schouw YT, Boer JM, Grobbee DE, Verschuren
WM, Beulens JW. Tea and coffee consumption
and cardiovascular morbidity and mortality.
Arterioscler Thromb Vasc Biol. 2010
Aug;30(8):1665–71. Epub 2010 Jun 18.
This study was an analysis of 37,514 subjects
enrolled in the EPIC-NL cohort, which includes
Dutch patients identified either through breast
cancer screenings or random population
sampling. Subjects were excluded included those
with either prior prevalent cardiovascular
disease, missing coffee or tea consumption
information, lack of follow-up or permission to
follow-up, and extreme energy intakes (< 600 or
> 5000 kcal/day), leaving a total of 37,514
patients eligible for analysis. Coffee and tea
consumption was assessed only at study baseline,
where patients indicated the number of cups
consumed per day, week, month, or year. Coffee
or tea consumption was further subdivided into
regular, instant, decaffeinated, or other type and
categorized into less than 1, 1–2, 2.1–3, 3.1–4,
4.1–6, and more than 6 cups per day. Most tea
consumed in the study was black tea. The
primary endpoints of the study were the
incidence of coronary heart disease (CHD),
morbidity and mortality for stroke and CHD, and
all-cause mortality. After multivariate
adjustment, patients consuming 2.1–3 cups of
coffee per day had the lowest risk of CHD (HR
0.79, 95% CI 0.65–0.96, p=0.01) compared to
patients consuming less than 1 cup per day. Tea
consumption was also found to be associated
with lower CHD risk, with patients consuming >
6 cups per day having the lowest risk (HR 0.64,
95% CI 0.46–0.90, p=0.02). In comparison to
the previous study, no association between coffee
and tea consumption and stroke risk was
identified (p-values for trend = 0.63 and 0.32,
respectively), nor was there a reduction in all-
cause mortality (p-values for trend = 0.33 and
0.43, respectively). Overall, this study provides
evidence that coffee and tea consumption are
associated with lower risk of cardiovascular
disease (not including stroke), although beverage
consumption was only measured at study
baseline and not throughout follow-up.
Regardless, coffee consumption is associated with
wildly different effects on cardiovascular disease,
stroke, and mortality in cohort studies, including
detrimental, neutral, and beneficial effects.
Further analysis is required, including
prospective, randomized examination.
CURBICIN (also see saw palmetto and vitamin
E)
Curbicin is a preparation that contains saw
palmetto (Serenoa repens), pumpkin seeds
(Cucurbita pepo), and vitamin E that is often used
for the treatment of benign prostatic hypertrophy.
Little is known regarding the cardiovascular
adverse effects of curbicin. However, because it
contains saw palmetto, which may possess
antiplatelet effects (discussed later), and vitamin
E, which is known to antagonize the effects of
vitamin K, Curbicin may increase the risk of
bleeding in patients taking antithrombotic drugs,
particularly warfarin.
Cardiovascular adverse effects: Coagulopathy
(C), increased risk of bleeding (E).
Drug interactions: Increased risk of bleeding in
combination with warfarin and other
antithrombotic medications (C).
DARK CHOCOLATE (COCOA)
Cocoa (Theobroma cacao), obtained from cocoa
beans, is one of the main ingredients of chocolate
and other foods. It provides a dietary source of
polyphenols (cocoa flavanols) which have been
associated with a variety of beneficial health
effects including antioxidant properties,
improvements in lipid metabolism, blood
pressure lowering, and antiplatelet effects.
Consequently, chocolate and cocoa have been
reported to have a potential role in the treatment
of cardiovascular disease (e.g., cardioprotective)
and cancer. As these effects are thought to be
related to the cocoa content, it is important to
understand that the different types of chocolate
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
differ in cocoa content. White chocolate has the
lowest cocoa content (< 35%) whereas dark
chocolate has the highest (> 70%) and is,
therefore, the primary nutraceutical touted for its
health benefits among the chocolates. While
dark chocolate may have beneficial effects on
health, consumption must be balanced against its
high fat and caloric content. Therefore, with
excessive consumption, the potential
cardioprotective effects may be offset by the
increased intake of saturated fat and calories.
Cardiovascular adverse effects: Increased risk of
bleeding (E), increased risk of heart failure with
more frequent intake (B).
Drug interactions: Increased bleeding risk with
antithrombotic agents (E) due to antiplatelet
effects.
Mostofsky E, Levitan EB, Wolk A, Mittleman
MA. Chocolate intake and the incidence of heart
failure: a population-based, prospective study of
middle-aged and elderly women. Circ Heart Fail
2010;3:612–6. Epub 2010 Aug 16.
Given the association between hypertension
and heart failure risk and potential
antihypertensive effects of chocolate, Mostofsky
and colleagues prospectively evaluated the
association between chocolate intake and heart
failure incidence in middle-aged and elderly
women in Sweden. Women included in this
analysis were part of the Swedish Mammography
Cohort, a population-based prospective cohort.
Subjects included in this cohort received a free
mammogram; completed a questionnaire on diet,
intake of alcoholic beverages, height, weight, and
education at baseline; and completed a similar
follow-up questionnaire 7–10 years later that also
requested information regarding lifestyle factors
and presence of certain medical conditions. The
dietary component of the questionnaire
investigated the frequency of consumption of 96
foods and beverages, including chocolate. For
this study, subjects were excluded if histories
were found to be inaccurate, incomplete, or
judged as implausible. Additionally, patients
with history of myocardial infarction and
diabetes were excluded because of the likelihood
of receiving dietary counseling and its impact on
dietary changes and reporting. The primary
endpoint was hospitalization or death from heart
failure as documented on the national inpatient
register. The analysis included 31,823 women
and 419 were either hospitalized for or died from
heart failure over 9 years of follow-up (15.1 cases
per 10,000 person-years). Compared to women
227e
who did not regularly consume chocolate, the
adjusted rate ratio of heart failure ranged from
32% lower in women who consumed 1–2
servings of chocolate weekly (adjusted rate ratio
0.68, 95% CI 0.50–0.93) to 23% higher in
women who consumed ≥ 1 serving daily
(adjusted rate ratio 1.23, 95% CI 0.73–2.08),
although the latter was not statistically
significant. Thus, a J-shaped relationship was
observed between chocolate intake and heart
failure (p value for quadratic trend = 0.0005).
The observed association between chocolate and
heart failure was not influenced by consumption
of other foods strongly related to chocolate
intake such as dairy, pastries, candy, and ice
cream. The authors concluded that moderate
habitual chocolate intake (3 servings or less per
week) was associated with lower rates of heart
failure but the “protective effect” was lost with
higher intake. Though not statistically
significant, daily intake of chocolate was
associated with a higher rate of heart failure.
Therefore, although heart failure may be less
common in those who consume chocolate,
moderation may be the key as the rate of heart
failure appears to increase with increasing intake
of chocolate.
DANSHEN
Danshen (salvia miltiorrhiza) is a perennial
herb related to sage. The active contents of
danshen consist of hydrophilic (salvianolic acid
derivatives) and lipophilic (diterpenoid
tanshinones) fractions. Several of these
components have been shown to possess a
variety of beneficial health effects, predominantly
in animal or in vitro models. The proposed
benefits include antiplatelet activity, vasodilation
(thought to be related to calcium channel
blockade and/or angiotensin converting enzyme
inhibition), anti-inflammatory effects,
antioxidant effects, anti-tumor and anti-
mutagenic effects, etc. In traditional Chinese
medicine it is often used in the treatment of the
following disease states coronary artery disease,
cerebrovascular disease, hepatitis, thyroid
disorders, diabetes, and menstrual disorders.
Cardiovascular adverse effects: Blood pressure
lowering effects (D), increased risk of bleeding
(E).
Drug interactions: Increased risk of bleeding
with antithrombotic agents (E) due to
antiplatelet effects; may potentiate effects of
antihypertensives (E); inhibits CYP1A2 (D), may
228e PHARMACOTHERAPY Volume 31, 2011
increase toxicity of CYP1A2 substrates such as
mexelitine (E); induces CYP2C11 (D) as an
animal equivalent to CYP2C9 in humans, may
decrease effectiveness of CYP2C9 substrates such
as warfarin (E); induces CYP3A4 isoenzyme (D),
may decrease effectiveness of CYP3A4 substrates
such as quinidine (E) digoxin assay interference
(D).
Chan K, Lo ACT, Yeung JHK, Woo KS. The
effects of danshen (Salvia miltiorrhiza) on
warfarin pharmacodynamics and pharmaco-
kinetics of warfarin enantiomers in rats. J Pharm
Pharmacol 1995;47:402–6.
Chan and colleagues sought to follow-up on
previous work in which danshen was shown to
affect the pharmacokinetics and
pharmacodynamics of warfarin in rats by
conducting a similar analysis of the R- and S-
enantiomers of warfarin using the same rat
model. Two separate studies were conducted on
male Sprague-Dawley rats: a single dose study
and a steady-state study. In the single dose study,
10 rats were given danshen 5 g/kg
intraperitoneally twice daily while control
subjects (n=10) were injected with saline. After
3 days of danshen therapy, a single dose of
warfarin 2 mg/kg was administered and blood
samples were obtained at predetermined intervals
for 72 hours to assess warfarin pharmacokinetics
and pharmacodynamics (PT). In the steady-state
study, 10 rats were administered warfarin 0.2
mg/kg/day for five days after which danshen
extract 2 g/kg was given intraperitoneally twice
daily for 3 days. Blood samples were collected
daily to assess the effect of danshen on warfarin
pharmacokinetics and pharmacodynamics. From
the steady-state study, danshen therapy
significantly increased the PT within 24 hours
(day 6) of coadministration with warfarin
compared to control subjects. By day 8, the PT
in the danshen-warfarin group was more than 2-
fold higher than that observed at steady-state in
the absence of danshen. This was likely due to
accumulation of both the R- and S-enantiomers
of warfarin as the steady-state concentrations of
each increased approximately 40% by day 8. In
the single dose study, danshen appeared to have a
similar effect on both warfarin enantiomers. The
AUC of the R-warfarin increased nearly 3-fold
while the AUC of S-warfarin more than doubled.
Similar effects were observed for C max and
elimination half-life (t 1/2 ) while volume of
distribution (Vd) and clearance each decreased by
a similar magnitude for both enantiomers. The
authors concluded that the interaction between
danshen and warfarin is clinically relevant.
However, the mechanism by which this
interaction manifests is not known. Because the
risk of bleeding may be increased when danshen
is taken concomitantly with warfarin, more
frequent monitoring of the INR may be
warranted and avoidance of danshen in warfarin-
treated patients may be prudent.
Liu J, Wang X, Cai Z, Lee FSC. Effect of
tanshinone IIA on the noncovalent interaction
between warfarin and human serum albumin
studied by electrospray ionization mass
spectrometry. J Am Soc Mass Spectrom
2008;19:1568–75.
In this study, the authors sought to elucidate
the mechanisms by which danshen affects the
pharmacokinetics of warfarin using electrospray
ionization mass spectrometry. Male Sprague-
Dawley rats were sorted into groups of three and
administered warfarin 4 mg or a mixture of
warfarin 4 mg and tanshinone IIA (a major
physiologically active component of danshen) 4
mg orally. Urine was collected for 12 hours after
administration following which concentrations of
warfarin and its metabolites were measured.
Initial analyses suggested that warfarin
underwent two phases of metabolism mediated
by the CYP isoenzymes. The first phase resulted
in the production of several monohydroxylated
metabolites along with some minor metabolites
while the phase II resulted in glucuronidation
and sulfation of the intermediate metabolites
before elimination occurred. Following the
addition of danshen, no new metabolites were
identified, suggesting that danshen does not alter
the metabolic pathways of warfarin metabolism.
Warfarin itself was not detected in the urine of
rats given warfarin alone during 12 hours of
follow-up but was detected in the urine of
subjects also given danshen. Similarly, warfarin
metabolites were detected in the blood of animals
given danshen whereas trace amounts of
metabolites were detected in rats given warfarin
alone. The authors postulate that danshen
displaced warfarin, a highly protein-bound drug,
from albumin resulting in higher free
concentrations of warfarin in the blood and
greater production of warfarin metabolites. This
was the first study to suggest that the alteration
in warfarin pharmacokinetics by danshen is not
only mediated by alterations in its metabolic fate
(alteration in CYP isoenzyme activity) but also
via displacement of warfarin from protein
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
binding sites.
Ueng YF, Kuo YH, Peng HC, et al. Diterprene
quinine tanshinone IIA selectively inhibits mouse
and human cytochrome P4501A2. Xenobiotica
2003;33:603–13.
This study evaluated the in vitro effects of
danshen derivatives (tanshinones) on the murine
and human liver enzymes and, more specifically,
on the activity of CYP1A1 and 1A2 isoenzymes.
The main active components (diterpene
quinones: anshinone I, tanshinone IIA, and
cryptotanshinone) of Salvia miltiorrhiza were
isolated from for the analyses. Male C57BL/6J
mice were given a single injection of 3-
methylcholanthrene (3-MC) 80 mg/kg
intraperitoneally. After 48 hours, liver
microsomal preparations were prepared.
Additionally, both Caucasian and Chinese liver
samples were obtained from different sources
(Tennessee Donor Services, National Taiwan
University Hospital) and microsomal
preparations prepared from these. Finally,
bicistronic human CYP1A1 and 1A2 constructs
were prepared. Enzyme assays were assessed
including aryl hydrocarbon hydroxylation
(AHH), dealkylation of 7-ethoxyresorufin
(EROD) and 7-methoxyresorfin (MROD),
tolbutamide hydroxylation (TOH), chlorz-
oxazone hydroxylation, N-nitrosodimethylamine
demethylation (NDM), and nifedipine oxidation
(NFO). The activities of EROD and MROD were
both inhibited by tanshinone I, tanshinone IIA,
and cryptotanshinone. Tanshinone I and
cryptotanshinone also decreased the activity of
TOH by approximately 20% each. Following
treatment with the CYP1A1 and 1A2 enzyme
inducer 3-MC, the activities of EROD, MROD,
and AHH increased 8–16-fold. Addition of the
Salvia miltiorrhiza isolates to 3-MC-treated mice
inhibited MROD activity but had no affect on
EROD and AHH activity. Tanshinone IIA was
found to be a competitive inhibitor of MROD
activity in the mouse liver with a Ki = 7.2±0.7
nM. In human liver preparations, tanshinone IIA
inhibited both EROD and MROD activity by 52%
and 47%, respectively. However, tanshinone IIA
had no effect on the other markers for
microsomal activity. The activity of tanshinone
IIA (inhibition of catalytic activity, IC 50 ) on
CYP1A1 EROD activity was 48 times greater than
that observed for CYP1A2 activity. Tanshinone I
and cryptotanshinone also exhibited greater
1A1:1A2 inhibitory activity but the magnitude of
this ratio was much less (IC50 ratio 1A1:1A2 = 4).
229e
The authors concluded that the isolated
components of danshen are selective inhibitors of
CYP1A2 in both mice and humans but have no
effect on CYP2C, 2E1, or 3A.
Wang X, Lee WYW, Or PMY, Yeung JHK.
Pharmacokinetic interaction studies of
tanshinones with tolbutamide, a model CYP2C11
probe substrate, using liver microsomes, primary
hepatocytes and in vivo in the rat. Phytomedicine
2010;17:203–11.
Wang et al have conducted several studies
investigating the effects of danshen on the
cytochrome P450 liver enzymes. In the study
reported here, the effect of danshen on rat
CYP2C11 activity, the rat equivalent to human
CYP2C9, was investigated in both in vitro and in
vivo analyses. The in vitro studies were done
using danshen extract, tanshinone I, tanshinone
IIA, cryptotanshinone, and dihydrotanshinone.
Tolbutamide was used as the CYP probe while
sulfaphenazole was used as the positive control
because it is a selective inhibitor of CYP2C11
(rat) and CYP2C9 (human). For the in vivo
study, male Sprague Dawley rates were treated
with 50–200 mg/kg of danshen or saline
intraperitoneally. Thirty minutes later, a single
dose of tolbutamide 10 mg/kg was administered
intravenously and serial blood samples were
obtained over the next 6 hours. A subsequent
analysis was done in another group of rats who
were pretreated with 3 days of danshen (200 mg
intraperitoneally daily), phenobarbitone 40
mg/kg was administered intravenously for 3
consecutive days, and serial blood samples were
obtained. The in vitro analysis demonstrated
that danshen and its isolates are competitive
inhibitors or CYP2C11/CYP2C9. Furthermore,
the inhibition of 4-hydroxytolbutamide
metabolite (TOH) formation, a metabolite of
tolbutamide, by the tanshinones occurred in a
concentration-dependent manner. Acute danshen
exposure had minimal effect on the
pharmacokinetics of tolbutamide compared to
saline controls; t1/2, AUC, and clearance were not
significantly different although Cmax was decreased
by 7.4% and Vd had a reciprocal increase by the
same magnitude. In contrast, the AUC for TOH
was 15% and 20% lower in rats given danshen 50
mg/kg and 200 mg/kg, respectively (p<0.05 vs
control for 50 mg/kg, p<0.01 vs control for 200
mg/kg), confirming the inhibitory effect on
CYP2C11 by danshen. The same comparisons in
rats pretreated with danshen for three days
demonstrated similar findings with respect to the
230e PHARMACOTHERAPY Volume 31, 2011
tolbutamide AUC, clearance, C max , and V d .
However, tolbutamide t1/2 was increased by 21.4%.
Together the changes in C max, V d, and in this
experiment the t1/2 suggest alterations in either the
absorption or distribution of tolbutamide induced
by danshen. Like the acute danshen experiment,
the AUC of the TOH metabolite was decreased
(1220±48 µg/ml vs 879.8±86.84 µg/ml, p<0.05)
once again confirming the inhibitory effects on
CYP2C11/CYP2C9. The authors conclude that
danshen should be used cautiously in combination
with other drugs, particularly those metabolized
by the CPY1A2, 2C9, and 3A4 isoeznymes.
Datta P, Dasgupta A. Effect of Chinese medicines
chan su and danshen on EMIT 2000 and Randox
digoxin immunoassays: wide variation in
digoxin-like immunoreactivity and magnitude of
interference in digoxin measurement by different
brands of the same product. Ther Drug Monit
2002;24:637–44.
This study was conducted to evaluate the
effects of two traditional Chinese herbals on
digoxin immunoassays, given the structural
similarities between the compounds. Chan Su
and danshen products, from different
manufacturers, were obtained and stock
solutions of each were prepared and apparent
digoxin concentrations were measured using the
following techniques: fluorescence polarization
immunoassay (FPIA), EMIT 2000, Randox, and
chemiluminescent assay (CLIA). The changes in
digoxin concentrations due to these herbal
remedies were also studied in serum pools
prepared from leftover specimens in patients
receiving digoxin using the same assays as above.
A final experiment studied the effect of
measuring digoxin concentrations in protein-free
ultrafiltrate to eliminate the potential interference
of Chan Su on the EMIT 2000 and Randox
assays. As the focus of this section is danshen,
only the observations related to danshen and the
digoxin assays will be reported in this summary.
No digoxin-like immunoreactivity was observed
in drug-free serum supplemented with danshen
using the EMIT, Randox, and CLIA assays.
However, with FPIA, some digoxin-like
immunoreactivity was observed in two of the
three danshen products. Consistent with the
earlier findings, when danshen was added to
digoxin-containing serum pools, digoxin
concentrations were not significantly increased
using the EMIT, Randox, and CLIA assays but
moderate positive interference was observed with
FPIA. The authors concluded that CLIA is the
reference standard for measuring digoxin
concentrations because it uses a specific
monoclonal antibody against digoxin and,
therefore, is very specific for measuring digoxin
concentrations. However, the EMIT 2000 and
Randox assays are devoid of interference with
any digoxin-like immunoreactivity related to
danshen and may be suitable alternatives to
CLIA.
DEVIL’S CLAW
The active ingredient in Devil’s claw thought to
account for its effects include iridoid glycoside
constituents, primarily harpagoside, and
harpagide, and procumbide. The iridoid
constituents appear to have an anti-inflammatory
effect, inhibiting both cyclooxygenase and
lipoxygenase. Devil’s claw is used for a variety of
conditions which include arteriosclerosis,
osteoarthritis, rheumatoid arthritis, gout,
myalgia, fibrositis, lumbago, tendonitis, pleuritic
chest pain, gastrointestinal (GI) upset or
dyspepsia, fever, and migraine headache.
Cardiovascular adverse effects: Decreases HR,
alters contractility (chronotropic and inotropic
effects) (E).
Drug interactions: Inhibits CYP 2C9,
increasing levels of drugs such as warfarin (C).
Inhibits CYP 3A4, increasing levels of drugs such
as lovastatin & diltiazem (D), inhibits P-
glycoprotein, which can increase concentrations
of drugs such as digoxin and verapamil (D).
Unger M, Frank A. Simultaneous determination
of the inhibitory potency of herbal extracts on
the activity of six major cytochrome P450
enzymes using liquid chromatography/mass
spectrometry and automated online extraction.
Rapid Commun Mass Spectrom 2004;18:
2273–81. (Also applicable for feverfew.)
The purpose of this study was to test a liquid
chromatography/mass spectroscopy (LC/MS)-
based in vitro method for the identification of
herbal extracts with inhibitory potency on
human drug-metabolizing CYP450 enzymes.
Samples of red clover extract, feverfew,
peppermint oil, eucalyptus oil, kava-kava, devil’s
claw, fo-ti, and grapefruit juice (as a comparator
with known inhibitory activity in vivo and in
vitro) were analyzed on an Agilent LC/LC mass-
selective detector system. The method included
the LC/LC/MS assay which followed incubation
with a substrate/enzyme cocktail consisting of
tacrine (CYP1A2), paclitaxel (CYP2C8),
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
tolbutamide (CYP2C9), imipramine (CYP2C19,
dextromethorphan (CYP2D6), and midazolam
(CYP3A4). Herbal extracts were incubated with
CYP enzyme mixture and the substrate cocktail,
and supernatants were subsequently analyzed via
LC/LC/MS. Inhibitory activity was calculated by
dividing the metabolite to internal standard peak
area ratios by the peak area ratios obtained with
control incubations which did not contain the
inhibitor. Red clover extract reduced the activity
of various CYP enzymes with resulting IC50
values between 100–500 ug/mL. Peppermint oil
moderately inhibited all CYP enzymes except
3A4. Eucalyptus oil was a weaker inhibitor of
CYP enzymes with IC50 values > 100 ug/mL, and
inhibited 3A4 to a greater degree compared to
peppermint oil. Kava-kava inhibited all CYP
enzymes (IC50 values 20–100 ug/mL for
CYP1A2, 2C9, &2C19, and IC50 values between
100–500ug/mL for CYP2C8, 2D6, and 3A4).
Inhibitory activity of CYP1A2 and 2D6 by devil’s
claw was low (IC50 > 900 ug/mL), and CYP
enzymes 2C8, 2C9, and 2C19 were moderately
inhibited (IC50 ranges 100-350 ug/mL).
Feverfew demonstrated a stronger inhibitory
activity compared to devil’s claw (IC50 < 100
ug/mL for CYP1A2 & 2C9, and 100–200 ug/mL
for CYP2C8, 2C19, and 3A4). Due to varying
bioavailability of herbal extracts and differing
chemical forms in vivo compared to in vitro (i.e.,
sulfate conjugates), the in vivo relevance of these
results could be low. Nonetheless, identification
of in vitro inhibitory activities will help inform
the design of future clinical trials.
Romiti N, Tramonti G, Corti A, Chieli E. Effects
of Devil’s Claw (Harpagophytum procumbens)
on the multidrug transporter ABCB1/P-
glycoprotein. Phytomedicine. 2009
Dec;16(12):1095–100.
Many plant derived compounds are substrates
or inhibitors of the multidrug transporter MDR-
1/P-glycoprotein (P-gp), but there are limited
studies examining this potential drug-herb
interaction. This study investigated 3
commercial Harpagophytum procumbens (Devil’s
Claw) preparations (referred to as DC1, DC2 and
DC3, standardized on harpagoside content) and
their effects on P-glycoprotein activity.
Harpagoside content was determined by
Beckman high performance liquid
chromatography (HPLC). Immortalized human
proximal tubule cell lines (HK-2) were used as a
model for P-gp. Protein expression was
231e
evaluated via Western blotting of crude
membranes of cells cultured for 72 hours in the
presence or in the absence of the 3 compounds.
P-gp activity was evaluated by the fluorimetric
measurement of the intracellular accumulation of
calcein produced by ester hydrolysis of the Pgp
substrate calcein-AM. Cells were incubated for
one hour with or without the test compounds.
DC2 and DC3 caused statistically significant
increases in intracellular calcein fluorescence
compared to control, which equated to a
reduction in P-gp dependent efflux of calcein-
AM. This suggests that DC2 and DC3 contain
compounds that inhibit P-gp activity. P-gp
expression results showed a dose dependent
increase in P-gp immunoblottable amount in cell
culture that occurred in the presence of DC
extracts (EC50 = 169.5 mg/ml for DC3) or
harpagoside (EC 50 = 5.2 mM). For both P-gp
activity and expression, no correlations were
noted between the concentration of harpagoside
and the effects detected. This implies
involvement of other unknown compounds in
DC that could be responsible for P-gp modifying
activities.
ECHINACEA
Echinacea is most commonly used for treating
and preventing the common cold and other
upper respiratory infections. Echinacea is
thought to stimulate the immune system through
increasing phagocytosis and lymphocyte
activities. It also used orally as an
immunostimulant for fighting a variety of other
infections, including urinary tract infections
(UTIs), vaginal candidiasis (yeast infections), and
genital herpes (HSV Type 1 and 2). In vitro data
suggest that Echinacea also has anti-
inflammatory properties through inhibition of
cyclooxygenase and 5-lipogenase.
Cardiovascular adverse effects: None reported.
Drug interactions: Inhibits CYP 1A2, increasing
levels of drugs such as verapamil, clopidogrel
(B), inhibits CYP 3A4, increasing levels of drugs
such as lovastatin & diltiazem (B).
Gorski JC, Huang S, Pinto A, et al. The effect of
echinacea (Echinacea purpurea root) on
cytochrome P450 activity in vivo. Clin
Pharmacol Ther. 2004 Jan;75(1):89–100.
The purpose of this study was to examine the
effect of Echinacea administration on the in vivo
disposition of caffeine, tolbutamine,
dextromethorphan, and midazolam, which are
232e PHARMACOTHERAPY Volume 31, 2011
selective probes for CYP1A2, CYP2C9, CYP2D6,
and CYP3A4, respectively. Twelve healthy adult
subjects (6 females and 6 males) participated in
this open label study. Following baseline blood
collection, participants received oral caffeine
(200 mg), tolbutamide (500 mg), dextro-
methorphan (30 mg), and intravenous
midazolam. Blood and urine were collected
between 30 min and 72 hours after drug dosing.
After 5–7 days of completion of part 1,
participants took Echinacea 400 mg four times
daily for 8 days. Adherence was assessed by pill
counts. On day 6 (of 8 days), participants
received oral midazolam followed by blood and
urine collected as described for the first part of
the study. Serum concentrations of dextro-
methorphan and related metabolites were
determined by liquid chromatography-mass
spectrometry. Echinacea significantly reduced
caffeine oral clearance from 6.6 ± 3.8 L/hr to 4.9
± 2.3 L/hr (p=0.049), and increased maximum
caffeine concentration by 30%. The oral
clearance of tolbutamide was significantly
reduced from 0.81 ± 0.18 L/hr to 0.72 ± 0.19 L/hr
(p=0.001). Although statistically significant, the
geometric mean and 90% CIs for AUC, oral
clearance, and maximum concentration still fell
within the default no-effect boundaries of 80-
125% per FDA criteria. As such, this interaction
is unlikely to be clinically significant. A
significant increase in the half life of tolbutamide
was also observed (p=0.001). Metabolism of
dextromethorphan did not change for extensive
metabolizers, but reduced in poor metabolizers
by 28%. Finally, the clearance of midazolam was
significantly increased by 42%. Echinacea
increased the hepatic extraction of midazolam
significantly from 0.28 ± 0.04 to 0.39 ± 0.1,
suggesting an increased hepatic CYP3A4 activity.
In summary, Echinacea caused significant
changes in drug disposition through inhibition of
CYP1A2 and intestinal CYP3A4 activity and
inducing hepatic CYP3A4 activity (although
inhibition of hepatic CYP3A4 activity was noted
in other studies). Combination with substrates
of CYP1A2 and CYP3A4 could potentially
increase the risk for drug interactions.
Yale SH, Glurich I. Analysis of the inhibitory
potential of Ginkgo biloba, Echinacea purpurea,
and Serenoa repens on the metabolic activity of
cytochrome P450 3A4, 2D6, and 2C9. J Altern
Complement Med 2005;11:433–9.
In this study, investigators examined the in-
vitro potential for three herbal supplements
(Ginkgo biloba, Echinacea, and Serenoa repens) to
inhibit the metabolism of model substrates by the
CYP3A4, 2D6, and 2C9 enzymes. Inhibition of
enzyme model substrate metabolism was
measured in 96-well plates with cDNA-derived
enzymes in microsomes prepared from insect
cells infected with baculovirus. Model substrates
included 3-[2-(N, N-di-ethyl-N methyl amino)
ethyl]-7-methoxy-4-methylcoumarin (AMC) for
CYP2D6, resofurin benzyl ether (BZRes) and 7-
benzyloxy-4-trifluoromethylcoumarin (BFC) for
CYP3A4, and 7-methoxy-4-trifluoromethyl-
coumarin (MFC) for 2C9. Assays were incubated
for 30–45 minutes prior to measuring
fluorescence of the metabolites. Mean and
standard deviations of fluorescence values were
plotted to display inhibition profiles and
determine inhibitory concentration values for
each herbal extract. Echinacea did not affect
CYP2D6 enzymatic activity. Mild inhibition of
CYP3A4 was observed; IC50 for BFC was 75% of
the full test concentration. Maximum inhibition
of CYP2C9 was seen at 33% of the full test
concentration. For Ginkgo, weak inhibition of
CYP2D6 enzyme was measured at the full test
concentration, although IC50 could not be
determined due to weak enzyme inhibition. For
CYP3A4, IC50 values were 3% for BFC and 43%
for BzRes, signifying moderate and mild
inhibition, respectively. Moderate inhibition of
CYP2C9 also occurred (IC50=10% of full test
concentration). Potent inhibition of all 3 CYP
enzymes was noted with exposure to Serenoa
repens. As the three herbal preparations tested
inhibited CYP substrate metabolism, patients
should be cautioned about the risk of combining
herbal products with prescription medications
which undergo hepatic metabolism.
Abdul MM,  Jiang X,  Williams KM.
Pharmacokinetic and Pharmacodynamic
interactions of Echinacea and Policosanol with
warfarin in healthy subjects. British Journal of
Clinical Pharmacology 2010;69: 508–515(A).
The hepatic enzyme CYP2C9 is mainly
responsible for S-warfarin metabolism. The
differences in pharmacological response to
warfarin have been attributed to genetic
polymorphism in CYP2C9 and Vitamin K
epoxide reductase complex subunit 1 (VKORCI)
gene. The clinical implication of genetic
variability may explain the increased bleeding
complications and use of lower warfarin dose.
This recent study investigated the potential for
pharmacokinetic and pharmacodynamic
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
interaction of echinacea and policosanol with
warfarin of known CYP2C9 and VKORC1
genotype. This was an open-label, randomized,
three-treatment, cross-over, clinical trial in
healthy male subjects (n=12), 18–34 years of age,
(6 subjects were Caucasians and 6 were of Asian
ethnicity) who received a single oral dose of
warfarin (25 mg) alone or after 2 weeks of pre-
treatment with echinacea or policosanol (1275
mg four times daily, 10 mg twice a day
respectively). Both herbal supplements were
continued for 7 days after warfarin
administration. After a washout period of 2
weeks all subjects were crossed over to other
treatments. Plasma samples were analyzed by
chiral, HPLC assay and platelet aggregation was
measured using aggregometer. INR was
measured using BFT II analyzer. No side effects
were reported related to the study drugs.
Echinacea, when administered along with
warfarin, resulted in reduced plasma
concentration of (S)-warfarin (90% CI of ratio;
1.01, 1.18) but this did not lead to a clinically
significant change in INR (90% CI of AUC of
INR; 0.91, 1.31). Similarly, policosanol did not
significantly affect pharmacokinetics of (S)-
warfarin (90% CI of AUC of INR; 0.92, 1.33).
Coadministration of warfarin with either
policosanol or echinacea did not affect the
pharmacokinetics of (R)-warfarin. Additionally,
none of the study herbs affected warfarin
pharmacodynamics ( no effects on platelet
aggregation). Neither echinacea nor policosanol
had a significant effect on platelet aggregation
after 2 weeks of pre-treatment with the respective
herbal medicine. The current study did not
support the previously reported genotype
dependent interactions. However the results of
this study verified the lack of significant
interaction between warfarin and policosanol in
rat models, previously reported (above) by
Carbajal et al. The authors acknowledged the
relatively small size of this study, thus limiting
the further interpretation of the results.
EPHEDRA ALKALOIDS
Ephedra (ma huang) contains the alkaloids
ephedrine and pseudoephedrine which are
sympathomimetic compounds that stimulate ␣,
␤-1, and ␤-2 adrenergic receptors resulting in
vasoconstriction and bronchial relaxation.
Ephedra compounds have been utilized in a
variety of physiologic ailments, including
hypotension, allergic rhinitis, and asthma. In
233e
addition, ephedra containing compounds, usually
combined with caffeine and guarana, were widely
utilized as weight-loss supplements prior to the
FDA ban of dietary supplements containing
ephedra alkaloids in 2004 (http://www.fda.gov/
bbs/topics/NEWS/2004/NEW01021.html and
http://www.cfsan.fda.gov/-dms/ds-ephed.html).
Cardiovascular adverse effects: Hypertension
(A), tachycardia (A), palpitations (A),
arrhythmias (C), myocardial infarction (C),
cardiac arrest (C).
Drug Interactions: Stimulants (A), MAOI’s (E),
antihypertensives (E), antiarrhythmics (E),
digoxin (E), steroids (E), antidiabetic agents (E).
Haller CA, Benowitz NL. Adverse cardiovascular
and central nervous system events associated
with dietary supplements containing ephedra
alkaloids. N Engl J Med. 2000 Dec
21;343(25):1833–8.
Ephedra alkaloids are widely used in a variety
of over the counter dietary weight loss and
performance enhancing supplements. Case
reports of fatal cardiovascular and central
nervous system effects had been previously
reported. This study was an analysis of 140
adverse event reports with ephedra alkaloid
containing products submitted to the FDA
MedWatch system between 1997 and 1999.
Causation was assessed using the Blanc scoring
system. Adverse events defined as “definitely
related” only if symptoms recurred with the
reintroduction of ephedra alkaloids or if the
onset of symptoms was consistent with the
pharmacokinetics and pharmacodynamics of the
drug’s peak effect. Events defined as “probably
related” when the majority of the evidence
supported the causal link, but there existed a
minor inconsistency, or one or more aspects of
the case were unknown. Events were defined as
“possibly related” when it was equally likely an
alternate cause existed or if an event was not
previously reported but was pharmacologically
possible. Categories also existed for “possibly
unrelated” or “definitely unrelated”, correlating
with the evidence associated with the case. A
total of 43 cases (31%) were definitely or
probably related to ephedra use, whereas 24 cases
(17%) were definitely or probably unrelated and
44 cases (31%) were possibly related. Twenty-
nine cases (21%) had insufficient evidence to
make a judgment. The single most frequent
event reported in definitely, probably, or possibly
related events was hypertension (17%), followed
by palpitations or tachycardia (13%), cardiac
234e PHARMACOTHERAPY Volume 31, 2011
arrest or sudden death (8%), arrhythmia (6%),
and myocardial infarction (2%). Among adverse
events which were definitely, probably, or
possibly related, death was reported in 11% of
cases, permanent neurologic impairment in 15%,
and 48% of patients had a full recovery. The
authors concluded that due to both the frequency
and severity of events reported, routine use of
ephedra alkaloids poses a serious health risk and
should be used with extreme caution until the
individual susceptibility to these events can be
determined.
Shekelle PG, Hardy ML, Morton SC, et al.
Efficacy and safety of ephedra and ephedrine for
weight loss and athletic performance: a meta-
analysis. JAMA. 2003 Mar 26;289(12):1537–45.
This trial was a meta-analysis of 52 trials and
65 case reports of ephedra containing
compounds for weight loss or athletic
performance. Weight loss trials included in this
analysis were required to have a follow up of at
least 8 weeks whereas no minimum was
established for trials in athletic performance. In
an analysis of the 20 trials that measured weight
loss, ephedra was effective in reducing weight
with an overall combined reduction of
approximately 0.9 kg/month relative to placebo.
In a pooled analysis of all 52 trials examining
adverse events, ephedra use significantly
increased psychiatric symptoms (OR 3.64, 95%
CI 1.91–7.31), autonomic hyperactivity (OR
3.37, 95% CI 2.19–5.31), heart palpitations (OR
2.29, 95% CI 1.27–4.32), and upper GI
symptoms (OR 2.15, 95% CI 1.39–3.38).
Analysis of the case reports revealed ephedra was
associated with several deaths and other
cardiovascular sentinel events, although these
reports are inconclusive when attempting to
discern causality. The authors conclude that
while ephedra was associated with greater weight
loss than placebo, increased adverse events were
also detected.
Haller CA, Jacob P, Benowitz NL. Short-term
metabolic and hemodynamic effects of ephedra
and guarana combinations. Clin Pharmacol Ther.
2005 Jun;77(6):560–71.
This was a randomized, double-blind, three-
arm crossover trial in 18 healthy volunteers (age
18-45). Subjects were randomized to placebo,
Xenadrine RFA (a multicomponent dietary
supplement containing ephedra alkaloids and
caffeine), or ephedra plus guarana, an herbal
stimulant compound often packaged with
ephedra alkaloids. All doses were administered
at 9 A.M. and 2 P.M. on the day of the study. A 1-
week washout period occurred between study
days. Venous blood draws and hemodynamic
measurements of BP and HR (via automated
sphygmomanometer) were measured at 30, 60,
90, 120, 180, and 300 minutes after the first dose
of study drug was administered and 8, 12, 18,
and 24 hours after the second dose. Additionally,
pharmacologic comparisons were made between
the supplement and the purified forms of
ephedrine and guarana for up to 17 hours after
the first dose. Both ephedra dosing modalities
increased blood pressure, with a maximum mean
systolic blood pressure increase of 11.5±10.7
mmHg (8 hours after dosing with ephedra-
guarana, p=0.015 vs. placebo) and a maximum
diastolic blood pressure increase of 7.3±7.4
mmHg (90 minutes after ephedra-guarana,
p=0.015 vs. placebo). Maximum mean heart rate
increase was 8.9±6.5 bpm with Xenadrine and
9.4±8.6 bpm with ephedra-guarana (p=0.002 for
both relative to placebo). Postprandial glucose
concentration (maximum mean increase
41.0±18.8 mg/dL, p=0.03 vs. placebo) and
plasma insulin concentration (maximum mean
increase 41.2±47.8 µIU/mL [286.1±332 pmol/L],
p=0.005 vs. placebo) were significantly worsened
with patients receiving Xenadrine and ephedra-
guarana versus placebo. Interestingly, plasma
potassium concentrations were also significantly
lower with Xenadrine and ephedra-guarana
(maximum mean decrease 0.28±0.23 mmol/L
[0.28±0.23 mEq/L], p=0.001 vs. placebo) with 15
of the 16 patients completing the study having at
least 1 potassium measurement below the
reference range of 3.5 mmol/L (3.5 mEq/L). This
data provides mechanistic support for the
potential cardiovascular toxicity of ephedra
containing compounds.
Hallas J, Bjerrum L, Støvring H, Andersen M.
Use of a prescribed ephedrine/caffeine
combination and the risk of serious
cardiovascular events: a registry-based case-
crossover study. Am J Epidemiol. 2008 Oct
15;168(8):966-73.
This is a population registry based case-
crossover study of the cardiovascular effects of a
prescribed ephedra-containing prescription
product (Letigen, containing 20 mg of ephedrine
and 200 mg of caffeine) in Denmark. Case-
crossover analyses are similar to case-control
analyses; however, the subject’s past experiences
serve as the control, allowing confounders which
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
are stable over time to offset. The Danish National
Registry of Patients, the Prescription Database of
the Danish Medicines Agency, the Danish Register
of Death, and the Danish Person Registry were
analyzed during the period of 1995–2002. A total
of 257,364 users of the supplement were identified
with 2,316 case events. The primary composite
endpoint of index events was death outside of a
hospital, myocardial infarction, or stroke. Patients
taking the prescription compounds did not have
an increased risk of the composite endpoint in the
case-crossover analysis (2316 events, adj. OR 0.84,
95% CI 0.71–1.00) despite adjustment for
common variables. Interestingly, a trend in the
reduction of the overall composite endpoint was
observed which included a statistically significant
reduction in the incidence of death outside of a
hospital (531 events, adj. OR 0.53, 95% CI
0.36–0.79). A separate case-control analysis also
did not demonstrate increased risk. The authors
conclude that increased cardiovascular events
were not detected with the use of a combination
ephedra-caffeine prescription product and
question the ban of ephedra compounds for sale.
While inferences about the precise of ephedra
containing products cannot be made with this
observational trial, it does serve as a
counterbalance to previous observational studies
and case series’ questioning the cardiovascular
safety of ephedra. While ephedra containing
products have been removed from traditional
purchasing venues, the cardiovascular safety is still
relevant due to the ability to obtain herbal
products from a wide variety of uncontrolled
sources.
FEVERFEW
One of feverfew’s constituents, parthenolide, is
thought to reduce inflammation by inhibiting
cyclooxygenase and pro-inflammatory cytokines
such as tumor necrosis factor-alpha and
interleukin-1. Feverfew is used for fever,
headaches, prevention of migraines, and
menstrual irregularities. It is also used orally for
arthritis, psoriasis, allergies, asthma, tinnitus,
vertigo, nausea and vomiting.
Cardiovascular adverse effects: Increased risk of
bleeding (E).
Drug interactions: Inhibits platelet aggregation
(has not been demonstrated in vivo), increasing
the risk for bleeding when used with antiplatelets
and anticoagulant drugs (D).
Groenewegen WA, Heptinstall S. A comparison
of the effects of an extract of feverfew and
235e
parthenolide, a component of feverfew, on
human platelet activity in-vitro. J Pharm
Pharmacol 1990;42:553–7.
Feverfew is hypothesized to affect platelet
aggregation through inhibition of 5-HT secretion
from human platelets. This study examined the
effect of feverfew and its component parthenolide
on 5-HT secretion from platelet rich plasma
(PRP). PRP was mixed with feverfew extract,
parthenolide, or diluting media in the presence of
a platelet activating agonist. Agonists included
adrenaline, the phorbol esterPMA, ADP, AA,
collagen, and calcium ionophore A23187, the
thromoxane mimetic U46619 or the
diacylglycerol analogue OAG. 5-HT secretion
from platelets was measured in duplicate
amounts of the supernatant of the platelet
samples and expressed as a percentage of the
total amount of 5-HT taken up by the platelets.
Platelet aggregation was measured in a six
channel light absorbance aggregometer. Both
parthenolide and feverfew extract inhibited 5-HT
secretion in a dose dependent way. The extent of
inhibition varied between feverfew extract and
parthenolide based individual agonists. Upon
further experimentation, collagen-induced 5-HT
secretion was overcome by increasing its
concentration, which was the case with PMA; 5-
HT secretion was inhibited regardless of dose. Of
note, platelet aggregation via PMA was not found
to be significantly inhibited by feverfew extract
and parthenolide. This was in contrast to other
agonists whereby platelet inhibition data
matched 5-HT secretion data. Results presented
in this paper suggest that parthenolide is the
constituent in feverfew that has antiplatelet
activities; however, studies in human subjects are
needed to fully evaluate the clinical relevance of
this potential interaction.
Unger M, Frank A. Simultaneous determination
of the inhibitory potency of herbal extracts on
the activity of six major cytochrome P450
enzymes using liquid chromatography/mass
spectrometry and automated online extraction.
Rapid Commun Mass Spectrom
2004;18:2273–81.
(Refer to devil’s claw for annotated
bibliography)
FOLIC ACID
Folic acid supplementation is almost 100%
bioavailable and is used for preventing and
treating folate deficiency, megaloblastic anemia
236e PHARMACOTHERAPY Volume 31, 2011

resulting from folate or vitamin B12 deficiency, FENUGREEK

megaloblastic anemia in sickle cell disease, and
Fenugreek is primarily used for lowering blood
for folate deficiency in intestinal malabsorption
glucose in diabetics, through reducing glucose
or sprue, among other conditions. Additionally,
absorption. It can also be used for loss of
because folic acid is required to metabolize
appetite, dyspepsia, gastritis, constipation,
homocysteine, it can be used for treatment of
atherosclerosis, high serum cholesterol and
hyperhomocysteinemia and reducing the risk for
triglycerides, and for promoting lactation.
coronary heart disease.
Cardiovascular adverse effects: Antiplatelet (A).
Cardiovascular adverse effects: Folic acid (at
Drug interactions: Increased risk of bleeding
doses ≥ 0.8 mg daily) and Vitamin B6 may
when used with antiplatelets or anticoagulants
increase the risk of MI. (A).
(E).
Drug Interactions: None reported.
Bordia A, Verma SK, Srivastava KC. Effect of
Bonaa KH, Njolstad I, Ueland PM et al.
ginger (Zingiber officinale Rosc.) and fenugreek
Homocysteine lowering and cardiovascular
(Trigonella foenumgraecum L.) on blood lipids,
events after acute myocardial infarction. NEJM
blood sugar and platelet aggregation in patients
2006;354(15):1578–88.
with coronary artery disease. Prostaglandins
Plasma homocysteine can be lowered with the Leukot Essent Fatty Acids 1997;56:379–84.
B-vitamins folic acid and vitamin B12, which in
This study evaluated the effects of ginger and
epidemiologic studies was shown to reduce the
fenugreek on blood lipids, blood glucose, and
risk for cardiovascular disease. However, one
platelet aggregation, although we focus on the
large randomized, controlled trial failed to show
later effect for the purposes of this bibliography.
a benefit of such therapy for reduction of stroke,
Patients with a history of myocardial infarction
myocardial infarction, or death in individuals
(> 6 months prior to study entry) were enrolled.
with a prior stroke. This study, named the
Participants received fenugreek 5 grams daily and
Norwegian Vitamin (NORVIT) trial, examined
ginger 4 grams daily (n=30) or placebo (n=30)
the use of B vitamins on the composite endpoint
for 3 months. Blood was drawn at baseline, 45,
of new nonfatal and fatal MI, nonfatal and fatal
and 90 days for blood glucose, lipid profiles,
stroke, and CHD-related sudden death in a
fibrinogen, fibrinolytic activity, and platelet
prospective, double blind, randomized, placebo-
aggregation. Adenosine diphosphate and
controlled fashion. Adult patients with an MI
epinephrine were used as agonists for platelet
within 7 days of randomization were enrolled.
aggregation studies. Ginger dosed at 4 grams/day
Participants (n=3749) were randomized to
did not significantly affect platelet aggregation,
receive one of 4 treatments: folic acid, vitamin
fibrinogen level, and fibrinolytic activity. The
B12, and vitamin B6 daily (termed combination
single 10 gram dose of ginger significantly
therapy), folic acid plus vitamin B12 daily,
reduced platelet aggregation compared to placebo
vitamin B6 alone daily, or placebo for a median of
(p<0.05). Fenugreek did not affect platelet
40 months. The primary endpoint was not
aggregation (data were not reported in the
reduced with folic acid plus vitamin B12
manuscript). In vitro studies using arachidonic
regardless of vitamin B6 use. The folic acid
acid and adrenaline as agonists also did not
treatment groups were associated with a
demonstrate changes in platelet aggregation with
nonsignificant increase in risk compared to
fenugreek. Ginger extract demonstrated a dose-
placebo (p=0.05). The combination regimen was
dependent inhibition of thromboxane formation.
associated with a higher hazard ratio compared to
Although it is reassuring that the in vivo platelet
the other three groups (HR 1.2, 95% CI 1.02,
aggregation study results matched the in vitro
1.41, p=0.05). The power of the study was
assays, these data need to be interpreted with
slightly less than desired, but was still adequate
caution due to the small sample size and limited
to capture an 18% reduction of the primary
power to detect these differences.
endpoint. Although results differed from
previous observational studies showing a neutral
effect of folic acid in the prevention and FUMITORY
treatment of heart disease, results from this well- Fumitory has weak antispasmodic effects on
designed trial suggest that a combination of B smooth muscle in the GI tract. One of its active
vitamins, including folic acid, should be avoided ingredients, the alkaloid protopine, has
in patients in the immediate post-MI period. hypotensive, bradycardic, antihistaminic, and
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
sedative actions. Fumitory is used for a number
of GI ailments including GI spasms, irritable
bowel syndrome (IBS), and as a bile flow
stimulant. Fumitory is also used for skin
eruptions, eczema, conjunctivitis, cardiovascular
disorders, as a diuretic, and a laxative.
Cardiovascular adverse effects: None reported.
Drug Interactions: None reported.
GARLIC
Garlic (also referred to as allium sativum) is
commonly used to treat hyperlipidemia and
hypertension, for prevention of age-related
vascular changes and atherosclerosis, as well as for
chronic fatigue syndrome and menstrual disorders.
Cardiovascular adverse effects: Increased risk
for bleeding (C).
Drug Interactions: Increased risk for bleeding
with concomitant antiplatelet or anticoagulant
use (C).
Macan H, Uykimpang R, Alconcel M, et al. Aged
garlic extract may be safe for patients on warfarin
therapy. J Nutr 2006 Mar;136(3 Suppl):
793S–795S.
This prospective, randomized, double-blind,
placebo-controlled trial sought to test aged garlic
extract (AGE), a commercial garlic preparation,
with warfarin (Coumadin) in order to determine
clinically significant interaction. Fifty-two
patients were randomized for the project and 48
patients completed the study. The study
medication (AGE or placebo) was administered
at a dose of 5 mL twice a day for 12 weeks.
Potential bleeding and thromboembolic episodes
were monitored. There was no evidence of
increased hemorrhage in either the placebo or the
AGE group. Adverse events included headache,
fatigue, colds, and dizziness. However, no
significant difference was found in the incidence
of these minor adverse events between the
groups. The results suggest that AGE is relatively
safe and poses no serious hemorrhagic risk for
closely monitored patients on warfarin oral
anticoagulation therapy. Findings from this small
prospective study do not support a clinically
significant pharmacodynamic interaction
between garlic and warfarin.
Beckert BW, Concannon MJ, Henry SL, Smith
DS, Puckett CL. The effect of Herbal Medicines
on Platelet Function: An In Vivo Experiment and
review of the literature. Plast Reconstr.Surg.
2007; 120:2044-2050.
237e
Many herbal medications affect platelet
function and can potentially increase the risk of
bleeding. The objective of this study was to
examine antiplatelet effects of Ginkgo biloba,
garlic, Asian ginseng, St. John’s Wort, and
Serenoa repens (saw palmetto). The study
population was comprised of 10 adult volunteers
who received one of the herbal medications for
two weeks at recommended doses, followed by a
2 week washout period. This process was
applied to all five study drugs. At the end of two
weeks, platelet function was assessed with PFA-
100 assay. The PFA-100 is an in vitro system for
measurement of platelet function in whole blood.
A standard cuvette is used which is coated with
collagen/epinephrine or collagen/adenosine
diphosphate. The Assay results are reported as
closing times, or the time required for thrombus
to completely occlude the standard cuvette
(closer time). At the end of the initial 4 week
period each subject also received 2 weeks of
aspirin (325 mg QD), followed by a PFA-100
assay. The baseline laboratory values for
determining platelet function were within normal
limits. No significant difference was seen in the
PEA-100 results compared to baseline PFA-100
(P=0.02). However, with aspirin use the PEA-
100 closing times were prolonged compared to
baseline (p<0.001). This in vivo study did not
suggest prolonged bleeding time with the use of
saw palmetto and other study herbs.
However there are two case reports of severe
bleeding in surgery patients who were using saw
palmetto. In patients who are taking saw
palmetto and plan to undergo surgical procedure,
caution is advised to avoid the risk of bleeding.
GINGER
Ginger is thought to inhibit thromboxane
synthetase and decrease platelet aggregation.
Ginger is commonly used for motion sickness
and pregnancy-induced morning sickness. Other
uses include colic, dyspepsia, flatulence,
chemotherapy-induced nausea, rheumatoid
arthritis (RA), osteoarthritis, loss of appetite,
post-surgical nausea and vomiting, migraine
headache, and for discontinuing selective
serotonin reuptake inhibitor (SSRI) drug therapy.
Cardiovascular adverse effects: Hypotension
(D), increased risk for bleeding (B).
Drug interactions: Added bleeding risk in
combination with antiplatelet or anticoagulant
drugs (B).
238e PHARMACOTHERAPY Volume 31, 2011
Ginger may have calcium channel blocking
effects, and may have added hypotensive effects
with calcium channel blockers (D), or other
antihypertensive agents (E)
Srivastava KC. Effect of onion and ginger
consumption on platelet thromboxane
production in humans. Prostaglandins Leukot
Essent Fatty Acids 1989;35:183–5.
This study reported the effects of onion and
ginger consumption on the production of
thromboxane in human blood. Participants were
women between ages of 25 and 65 years, and
served as their own controls. The two study
groups were raw onion (70 grams/day) and fresh
ginger (5 grams/day) for 7 days. Blood was
collected prior to and following consumption of
onion or ginger (day 7). Thromboxane
production was determined in serum by
radioimmunoassay. Five participants in the
onion group and 7 participants in the ginger
group completed the study. Ginger reduced
thromboxane concentrations by 37% (782 ± 482
to 498 ± 164 pmol/mL). Statistical comparisons
between concentrations before and after ginger
consumption were not reported. Although
interesting, these results require confirmation in
a larger cohort with a longer duration of
treatment with ginger to fully assess effects on
platelet aggregation in humans.
Bordia A, Verma SK, Srivastava KC. Effect of
ginger (Zingiber officinale Rosc.) and fenugreek
(Trigonella foenumgraecum L.) on blood lipids,
blood sugar and platelet aggregation in patients
with coronary artery disease. Prostaglandins
Leukot Essent Fatty Acids 1997;56:379–84.
(Refer to fenugreek for annotated bibliography)
Ghayur MN, Gilani AH. Ginger lowers blood
pressure through blockade of voltage-dependent
calcium channels. J Cardiovasc Pharmacol
2005;45:74–80.
Ginger has been thought to have blood
pressure lowering effects through an unclear
mechanism. This study examined the mode of
action of blood pressure lowering from ginger
using rodent, guinea pig, and rabbit models.
Adult rats were anesthetized with sodium
thiopental. Drugs (ginger extract, sodium
chloride [control], acetylcholine [control], and
norepinephrine [control]) were injected through
a cannula inserted in the jugular vein. Arterial
blood pressure was measured through carotid
artery cannulation via a pressure transducer
coupled with polygraph. Guinea pig atria were
mounted in tissue baths containing krebs
solution. Following a 30 minute equilibration
period, ginger extract, verapamil, and
norepinephrine were applied and tension
changes in the tissue were recorded via a Grass
force-displacement transducer. Rabbit aorta was
prepared similarly to guinea pig atria. After a 1
hour equilibration period, tissues were stabilized
with phenylephrine (PE), followed by tested with
ginger extract to test its ability to relax PE and
potassium-induced contractions. The ability to
relax potassium contractions would indicate L-
type voltage dependent calcium channel mode of
vasodilation, whereas relaxation of PE-induced
contraction would suggest blockade of calcium
influx through receptor-operated calcium
channels. Finally, thoracic aorta were isolated
from male rats and prepared as previously
described for the guinea pig atria. Following a
30 minute incubation period, tissue was
stabilized with PE, followed by acetylcholine.
Ginger extract induced a dose dependent fall in
blood pressure in anesthetized rats, with an EC50
value of 0.9 ± 0.1 mg/kg (n=3). In guinea pig
atria, ginger extract caused a dose dependent
inhibitory effect on the spontaneous force and
beating rate of atrial contractions, as did
verapamil. For PE and potassium incubated
rabbit aorta, ginger extract produced dose-
dependent vasodilation and demonstrated
calcium dose-response curves to the right, in a
similar fashion as verapamil. In rat aorta, the
extract inhibited both high potassium ad PE-
induced contractions, and was resistant to
blockade of vasodilation by atropine. These
series of studies demonstrated that ginger
reduced arterial blood pressure via vasodilation
through voltage dependent calcium channels.
Jiang X, Williams KM, Liauw WS, et al. Effect of
ginkgo and ginger on the pharmacokinetics and
pharmacodynamics of warfarin in healthy
subjects. Br J Clin Pharmacol 2005;59:425–32.
This study investigated the possible drug
interaction between warfarin and ginkgo and
ginger as well as their effect on clotting status.
Twelve healthy male subjects were enrolled in
this randomized, open label, three-treatment,
three-period crossover study. A single dose of
warfarin 25 mg was administered to subjects with
and without pretreatment with multiple doses of
either ginkgo (EGb 761 three times daily for 1
week) or ginger (3 tablets three times daily for 1
week). Dosing of ginkgo or ginger continued for
another week following warfarin administration.
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
Two weeks of washout occurred between each
treatment phase. Blood was collected for platelet
aggregation, INR, and drug concentration assays
at multiple intervals between 48 hours prior to
warfarin to 148 days following warfarin. Urine
was also collected for measurement of S-7-
hydroxywarfarin. There were no significant
differences between treatment phases in
pharmacokinetic parameters of S- or R-warfarin,
or urinary excretion of hydroxywarfarin. Neither
treatment period affected protein binding, or INR
values with warfarin; platelet aggregation was not
significantly altered by ginkgo or ginger.
Although bleeding parameters and
pharmacokinetics of warfarin were not changed
by ginkgo or ginger, results were for a single dose
of warfarin only. As such, additional data are
required following chronic co-administration of
these agents. Similar to the previously
summarized study, the crossover design could
lead to treatment effects for the other study
phases even following a washout period.
GINKO BILOBA
Ginkgo is most known for its use in dementia,
including Alzheimer’s, vascular, and mixed
dementia. Ginkgo leaf contains flavanoids,
terpenoids, and organic acids. It is also used
orally for conditions associated with cerebral
vascular insufficiency, especially in the elderly,
including memory loss, headache, tinnitus,
vertigo, dizziness, difficulty concentrating, mood
disturbances, and hearing disorders. It is also
used orally for ischemic stroke, and peripheral
arterial disease (PAD).
Cardiovascular adverse effects: Increased risk of
bleeding (C).
Drug interactions: Decreases platelet
aggregation (A), increasing risk of bleeding when
combined with antiplatelet or anticoagulant
drugs (E). Inhibits CYP 1A2 (D), increasing
levels of drugs such as verapamil, clopidogrel
(E). Conflicting reports on Inhibiting CYP 2C9
(B); may increase levels of drugs such as warfarin
(E). Inhibits CYP 2D6 (B), increasing levels of
drugs such as flecainide and metoprolol (E).
Engelsen J, Nielsen JD, Winther K. Effect of
coenzyme Q10 and Ginkgo biloba on warfarin
dosage in stable, long-term warfarin treated
outpatients. A randomised, double blind,
placebo-crossover trial. Thromb Haemost
2002;87:1075–6.
The objective of this study was to evaluate a
239e
potential drug interaction between coenzyme Q-
10 (CoQ10) and gingko and warfarin in
outpatient individuals stable on chronic warfarin
therapy. This double blind, crossover study
enrolled 24 individuals (10 men and 14 women,
ages 33–79) taking warfarin for recurrent venous
thromboembolism, mechanical heart valves, or
chronic atrial fibrillation. The study had three 4
week treatment periods separated by a 2 week
washout period: CoQ10 (Bio-Quinone®) 100mg
+ placebo, placebo + gingko (Bio-Biloba®) 100
mg, or 2 placebo doses. The mean INR value ±
SD was 2.7 ± 0.34 during treatment with CoQ10,
2.7 ± 0.38 during treatment with gingko, and 2.7
± 0.36 during placebo treatment. Similarly, mean
doses of warfarin for each treatment arm did not
differ significantly. Differences from previous
studies and case reports finding an effect of
ginkgo on warfarin could be due to dissimilar
clinical characteristics and the chronic dosing of
warfarin used in this study.
Kohler S, Funk P, Kieser M. Influence of a 7-day
treatment with Ginkgo biloba special extract EGb
761 on bleeding time and coagulation: a
randomized, placebo-controlled, double-blind
study in healthy volunteers. Blood Coagul
Fibrinolysis 2004;15:303–9.
Several case reports raised suspicion for a
causal relationship between Ginkgo and
hemorrhagic complications based on timing
between the event and intake of the drug,
prolonged bleeding time, and absence of other
explanatory factors. This randomized, single-
center, double-blind, crossover study evaluated
the effects of a standardized formulation of
Ginkgo (EGb 761) on coagulation parameters,
platelet activity, and bleeding time. Investigators
enrolled 50 healthy male volunteers between 20
and 44 years of age. Participants received 2 x
120 mg/day EGb 761 or placebo for 7 days.
Following a 3 week washout period, treatment
assignment was reversed for a second 7 day
treatment phase. Blood was drawn at baseline
and at the end of each treatment phase for partial
thromboplastin time, thrombin time, fibrinogen,
D-dimers, Quick’s test, coagulation factors II, V,
VII, VIII, IX, X, XI, XII, and XIII, as well as
protein C and S activity. Bleeding activity was
assessed via induction of aggregation with
collagen, ADP, arachidonate, ristocetin,
epinephrine, and PAF in platelet-rich plasma.
Numerous safety labs were also measured.
Adherence was assessed by pill counts. Forty-
three participants were included in the per-
240e PHARMACOTHERAPY Volume 31, 2011
protocol analysis. Differences in coagulation
parameters were detected for Factor VII (93.4%
activity vs. 89.1% for placebo and EGb 761,
respectively, p<0.05). Epinephrine-induced
aggregation was also significantly lower in the
EGb 761 formulation (15.2% vs. 19.8%).
Statistical adjustments were not made for
multiple comparisons. Authors noted that per-
protocol results matched with full analysis
results. This study was likely underpowered to
detect meaningful differences between the groups
and it would have been desirable to include
intent-to-treat analyses in the manuscript. The
crossover design could have affected results of
the placebo group if 3 weeks was not an adequate
washout period. Moreover, results cannot be
extrapolated to other Ginkgo formulations.
Overall, this study’s findings suggest a reduced
coagulation effect with Ginkgo evidenced by
changes in epinephrine-induced coagulation and
Factor VII activity. In light of serious reports of
hemorrhagic bleeding reported with Ginkgo,
additional data are necessary to rule out harm.
Yale SH, Glurich I. Analysis of the inhibitory
potential of Ginkgo biloba, Echinacea purpurea,
and Serenoa repens on the metabolic activity of
cytochrome P450 3A4, 2D6, and 2C9. J Altern
Complement Med 2005;11:433–9.
(Refer to echinacea for annotated bibliography)
Jiang X, Williams KM, Liauw WS, et al. Effect of
ginkgo and ginger on the pharmacokinetics and
pharmacodynamics of warfarin in healthy
subjects. Br J Clin Pharmacol 2005;59:425–32.
(Refer to ginger for annotated bibliography)
Beckert BW, Concannon MJ, Henry SL, Smith
DS, Puckett CL. The effect of Herbal Medicines
on Platelet Function: An In Vivo Experiment and
review of the literature. Plast Reconstr.Surg.
2007; 120:2044–2050.
(Refer to garlic for annotated bibliography)
GINSENG
American ginseng is used as an adaptogen, for
increasing resistance to environmental stress, as a
general tonic, stimulant, diuretic, and digestive
aid. Ginseng is advocated for many uses,
including maintaining general health, combating
fatigue, and improving immune function.
Cardiovascular adverse effects: None reported.
Drug Interactions: Decreases effect of warfarin
(A).
Yuan CS, Wei G, Dey L, et al. American ginseng
reduces warfarin’s effect in healthy patients: a
randomized, controlled trial. Ann Intern Med
2004;141:23–7.
One case report demonstrated a substantial
reduction in warfarin’s anticoagulant effects with
concomitant ginseng administration. This study
evaluated this potential drug interaction in 20
individuals (9 men and 11 women) in a
randomized, double-blind, placebo-controlled
fashion. The primary endpoint was change in
peak INR between weeks 1 and 4 (before and
after ginseng or placebo). Week 1 consisted of
three doses of warfarin 5 mg on 3 consecutive
days. During week 2 participants were randomly
assigned to take either American ginseng 1000
mg, or placebo twice daily for 2 weeks, which
was at the higher end of the dosing range for
ginseng. During week 4, participants again
received warfarin 5 mg for 3 consecutive days.
Blood samples were obtained on days 1, 3, 4, 5,
and 7 of weeks 1 and to measure INR and plasma
warfarin levels. Participants were instructed to
keep a food diary to track vitamin K intake.
There was a modest reduction in the INR in the
ginseng group compared to the placebo group
(–0.16 versus –0.02, p=0.0012). Changes in INR
AUC (–0.46 vs. –0.09, p=0.025), peak plasma
warfarin level (–0.2 ug/mL vs. 0 ug/mL,
p=0.026), and warfarin AUC (–0.4 ug/mL vs.
0.18 ug/mL, p=0.007) were also statistically
significantly greater in the ginseng group.
Vitamin K intake was not statistically different
between the placebo and ginseng groups (p>0.2).
This study’s design strengths included its
randomized, double blind nature as well as
minimization of potential confounding factors
upon warfarin’s metabolism such as assessment
of vitamin K intake, and limitation of alcohol,
smoking, and caffeine. Two weeks of ginseng
was also likely an adequate amount of time to
capture the interaction. Of note, however, is that
the study sample consisted of young, healthy
adults (mean ages 30 and 24 for ginseng and
placebo groups, respectively), whose metabolism
may differ from older adults with concomitant
medical conditions that could affect warfarin and
ginseng metabolism.
Beckert BW, Concannon MJ, Henry SL, Smith
DS, Puckett CL. The effect of Herbal Medicines
on Platelet Function: An In Vivo Experiment and
review of the literature. Plast Reconstr.Surg.
2007; 120:2044–2050.
(Refer to garlic for annotated bibliography)
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
GOSSYPOL
Gossypol is known under the names
Gossypium hirsutum, Gossypium hebaceum and
other Gossypium species from the family of
Malvaceae. It is found in the cotton root, root
bark, seed, and stem, but is commercially
extracted from the cotton seed. Gossypol’s
mechanism of action as a male contraceptive is
mediated through the reduction of cellular and
microtubular tubulin content in sperm resulting
in the inhibition of the enzyme lactate
dehydrogenase X. In women gossypol results in
reduced estrogen and progesterone levels and
increases in follicle stimulating hormone and
leuteinizing hormone. Possible uses of Gossypol
are as a male contraceptive, in treatment of
uterine myomas, endometriosis, dysfunctional
uterine bleeding and metastatic carcinoma of the
endometrium or ovary.
Cardiovascular adverse effects: Fatigue (E),
hypokalemia (A), and heart failure (E).
Drug Interactions: Increased risk of digoxin
toxicity (E), hypokalemia with diuretic use (E).
Qian SZ, Jing GW, Wu XY, Xu Y, Li YQ, Zhou
ZH. Gossypol related to hypokalemia. Clinico-
pharmacological studies. Chin Med J
1980;93:477–82.
In the early 1970s gossypol was determined to
be an effective contraceptive in men in China.
These early clinical trials reported a small
increase in the cases of hypokalemia with the
administration of gossypol. There was a 0.75%
incidence of severe hypokalemia with fatigue in
these clinical trials carried out in China. An
observational study evaluating a series of
hypokalemia cases was subsequently carried out.
It was documented that there was a higher
incidence of hypokalemic paralysis in the
gossypol users than the control population, but
specific values were not reported. Individuals
with low potassium at baseline were more likely
to develop hypokalemia as well. The authors
concluded that potassium supplementation in
individuals with low potassium at baseline prior
to initiation of gossypol should be considered.
GRAPE JUICE
Proanthocyanidins are responsible for both the
antioxidant effect as well as the red color of
grapes, and a higher concentration of
proanthocyanidins appears to correlate with an
enhanced effect. Grape is used for preventing
cardiovascular disease, varicose veins,
241e
hemorrhoids, atherosclerosis, hypertension,
peripheral vascular disease, edema associated
with injury or surgery, and myocardial or cerebral
infarction. Grape is also used and as a mild
laxative for constipation.
Cardiovascular adverse effects: Increased risk
for bleeding (E).
Drug interactions: Induces CYP 1A2 (B),
decreasing levels of drugs such as verapamil,
clopidogrel (E), Increased risk for bleeding with
warfarin (E).
Xiao Dong S, Zhi Ping Z, Zhong Xiao W, et al.
Possible enhancement of the first-pass
metabolism of phenacetin by ingestion of grape
juice in Chinese subjects. Br J Clin Pharmacol
1999;48:638–40.
This open label study examined the interaction
of grape juice with phenacetin, whose oral
clearance is a marker for CYP1A2 activity.
Twelve healthy Chinese subjects (age range
29–46 years) were enrolled. Of the 12
participants, 6 currently smoked > 10 cigarettes
per day. Participants received a single 900 mg
dose of phenacetin on 2 randomized occasions
separated by one week. Each dose of phenacetin
was given concomitantly with either water or
grape juice. Blood samples were collected for up
to 12 hours following dosing for determination of
plasma concentrations of phenacetin and
metabolically derived paracetamol by HPLC.
Ingestion of grape juice associated with reduced
maximum plasma phenacetin concentrations
compared to water (1.1 ± 0.4 vs. 2.4 ± 0.6 ug/mL,
p<0.01) and delayed time to peak concentration
(2 vs 1.5 hours, p<0.01). Additionally,
phenacetin AUC (2.8 ± 0.9 vs. 5.2 ± 1.4 ug/mL,
p<0.01) and half life (0.79 ± 0.05 vs. 0.95 ± 0.07,
p<0.05) were significantly reduced by grape
juice. Since smoking induces CYP1A2, smoker
and nonsmoker participants were also compared.
Although grape juice reduced AUC and increased
oral clearance of both groups similarly, statistical
significant differences were only noted for
nonsmokers. The paracetamol AUC was
unchanged, lending weight to the hypothesis that
clearance of phenacetin was affected by grape
juice, rather than its absorption. Further
evidence is required in support of this interaction
in patients of various ages and smoking status.
Since CYP1A2 isozymes are involved in the
metabolism of a number of drugs, this interaction
may have clinical consequences.
242e PHARMACOTHERAPY Volume 31, 2011
GRAPEFRUIT JUICE
Grapefruit is known under the names Citrus
paradise, Citrus maxima, and Citrus decumana
from the family of Rutaceae. The chemistry of
grapefruit varies by the species, the growing
conditions, and the process used to extract the
juice. Grapefruit seed extract is processed
grapefruit seeds and pulp obtained from the
byproduct of grapefruit juice production.
Grapefruit juice is more commonly consumed
than other grapefruit forms (e.g., grapefruit
seeds) and is associated with the greatest number
of drug interactions. It is used for the treatment
of hyperlipidemia, atherosclerosis, reducing
hematocrit counts, cancer, psoriasis, weight loss,
and obesity.
Cardiovascular adverse effects: None reported.
Drug Interactions: Inhibits CYP 3A4, increases
levels of drugs that are metabolized via this
pathway such as calcium channel blockers (A),
carvedilol (A), lovastatin (A), simvastatin (A),
atorvastatin (A), red yeast rice (A), quinidine
(A), and reduces the effectiveness of losartan (A),
may increase warfarin effects (E), and any drug
metabolized by CYP 3A4 or undergoes P-gp
transport may be affected by grapefruit juice (E).
Bailey DG, Spence JD, Munoz C, Arnold JM.
Interaction of citrus juices with felodipine and
nifedipine. Lancet 1991;337:268–9.
A small randomized, balanced crossover study
of hypertensive (n = 6) and non-hypertensive
men (n = 6) was performed to evaluate whether
the concomitant administration of grapefruit
juice or orange juice would significantly affect
the pharmacokinetics of amlodipine and/or
nifedipine. The six hypertensive subjects
received felodipine 5 mg with 250 ml water, 250
ml double-strength grapefruit juice (’Old South’;
i.e., 125 ml frozen concentrate plus 125 ml
water), or 250 ml double-strength orange juice
(’Minute Maid’). The six healthy men received
nifedipine 10 mg with 250 ml water or 250 ml
double-strength grapefruit juice. The mean
felodipine bioavailability with grapefruit juice
was 284 (SEM 44; range 164–469%) compared to
individuals receiving water (p<0.01). At Cmax
there was a greater mean diastolic blood pressure
reduction (–20% vs –11%; p<0.01) and increase
in heart rate (22% vs. 9%; p<0.02) from baseline
(BP 129/86 mmHg, HR 79) when comparing
grapefruit juice to water. Adverse effects were
more frequent with grapefruit juice (10/12) than
orange juice (4/12) and water (3/12), which
included headaches, facial flushing, and
lightheadedness. No significant changes were
noted in the individuals who received orange
juice compared to water. In the six healthy men
who received nifedipine 10 mg with water or
grapefruit juice; the bioavailability of nifedipine
with grapefruit juice was 134% (108–169%)
greater than in the individuals receiving water.
Overall, the interaction with felodipine appears
to be much stronger than the interaction with
nifedipine although significant interactions were
observed with both calcium channel blockers.
Bailey DG, Arnold JM, Strong HA, et al. Effect
of grapefruit juice and naringin on nisoldipine
pharmacokinetics. Clin Pharmacol Ther
1993;54:589–94.
Historically, there has been documentation
showing the bioavailability of a number of
dihydropyridine calcium channel blockers can be
increased with concurrent grapefruit
administration. This study evaluated the
pharmacokinetics of nisoldipine in a small Latin
square-designed trial with healthy men (n = 12)
given nisoldipine with water, grapefruit juice, or
encapsulated naringin powder at the same
amount as that assayed in the juice. Grapefruit
juice increased the maximum concentration of
nisoldipine to 3.5 ± 0.7 ng/mL (mean ± SEM)
compared to 1.0 ± 0.2 ng/mL with water
(p<0.001). The AUC of nisoldipine was
increased to 35.0 ± 5.6 (0 to 48 hours) with
grapefruit juice compared to 19.9 ± 2.1 with
water (p<0.01). Grapefruit co-administration
resulted in a time to reach maximum nisoldipine
concentration of 3.2 ± 0.4 hours compared to 6.8
± 0.9 hours with water co-administration
(p<0.01). The proposed mechanism for these
pharmacokinetic changes is hypothesized to be
through the inhibition of nisoldipine metabolism
and possibly by increasing nisoldipine
dissolution. There were no changes in the
nisoldipine pharmacokinetics with the naringin
capsule. Adverse effects, including hypotension
and tachycardia were similar between groups.
With a four-fold increase in maximum
concentration and a two-fold increase in AUC
caution should be taken with co-administration
of grapefruit juice and nisoldipine.
Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit
juice-simvastatin interaction: effect on serum
concentrations of simvastatin, simvastatin acid,
and HMG-CoA reductase inhibitors. Clin
Pharmacol Ther 1998;64:477–83.
Simvastatin is metabolized through the CYP
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
3A4 pathway and previous studies have shown
that grapefruit juice inhibits the breakdown of
many medications that are metabolized through
this pathway. With the increased potential to
develop side effects with high dose simvastatin it
is important to determine whether there exists a
drug interaction with grapefruit juice. A
randomized, cross-over study of ten healthy
volunteers was performed to evaluate whether
drug concentrations were increased in
individuals administered 200 ml of double-
strength grapefruit juice with simvastatin. All
individuals received grapefruit juice or water
three times a day for two days and then on day
three they were given simvastatin 60 mg tablets.
The Cmax of simvastatin with grapefruit juice
group was nine times higher than the water
administered group. The AUC of the simvastatin
plus grapefruit juice arm was 16 times the water
administered arm. The active metabolite
simvastatin acid was increased as well in the
grapefruit administered patients. Based on these
findings, co-administration of grapefruit juice
with simvastatin should be avoided to minimize
any potential harm with increasing the
simvastatin drug levels in the body.
Sullivan DM, Ford MA, Boyden TW. Grapefruit
juice and the response to warfarin. Am J Health-
Syst Pharm 1998;55:1581–3.
Prior to this study there had been no studies
evaluating the potential of a drug interaction
between grapefruit juice and warfarin. Warfarin
is metabolized to a minor degree through the
CYP 3A4 pathway and mainly through the CYP
2C9 and 1A2 pathways. Most grapefruit juice
interactions are mediated through its ability to
inhibit the CYP 3A4 substrate. An open label
study of ten men receiving warfarin with a
therapeutic International Normalized Ratio
(INR) at baseline and not consuming grapefruit
juice at baseline were considered for enrollment.
Individuals were given a one week supply of
prepared frozen grapefruit juice in eight ounce
containers and were told to consume eight
ounces three times a day for one week.
Prothrombin times (PTs) and INRs were assessed
on the day prior to beginning grapefruit juice
consumption and on days two, six, and eight.
Compliance with the grapefruit consumption was
100% in seven patients and 85–90% in two other
patients. One patient withdrew from the study
secondary to diarrhea. There were no significant
changes in either PT or INR values at any time
point in the study. In conclusion, minimal or
243e
moderate amounts of grapefruit juice did not
produce significant changes in PT or INR, but
caution should still be used when larger amounts
are consumed.
Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit
juice increases serum concentrations of
atorvastatin and has no effect on pravastatin. Clin
Pharmacol Ther 1999;66:118–27.
The interaction of statins metabolized through
the CYP 3A4 pathway and grapefruit juice has
been established in multiple clinical trials. This
is the first study to evaluate whether there is a
difference in serum concentrations of statins not
metabolized through CYP 3A4 (e.g., pravastatin).
Two small randomized, crossover studies were
performed, one with atorvastatin (12 patients)
and one with pravastatin (11 patients). In both
studies individuals received double-strength
grapefruit juice 200 ml or water three times a day
for two days and then were given atorvastatin 40
mg or pravastatin 40 mg on day three. Also, on
day three individuals received another 200 ml of
grapefruit juice or water at 30 minutes and 90
minutes post drug ingestion. Serum
concentrations of drug and active metabolites
were measured. Concomitant grapefruit juice
and atorvastatin resulted in an increase of two
and a half times the AUC compared to water at
72 hours, but Cmax was not changed. A three-
fold increase in both AUC and Cmax was noted in
the metabolite atorvastatin lactone. There were
no significant changes in the pharmacokinetic
profile of pravastatin with co-administration of
grapefruit juice. Patients should be cautioned
about the drug interaction of grapefruit juice
with atorvastatin, especially at doses greater than
40 mg, but do not need to avoid consuming
grapefruit juice if taking pravastatin.
Takanaga H, Ohnishi A, Murakami H, et al.
Relationship between time after intake of
grapefruit juice and the effect on
pharmacokinetics and pharmacodynamics of
nisoldipine in healthy subjects. Clin Pharmacol
Ther 2000:67:201–14.
The drug interaction with dihydropyridine
calcium channel blockers and grapefruit juice has
been well documented prior to this study with
multiple trials and multiple drugs including
nisoldipine. The main mechanism for this
interaction is the inhibition of the CYP 3A4
pathway by grapefruit juice which subsequently
increases drug levels of calcium channel blockers
metabolized through this pathway. Eight healthy
244e PHARMACOTHERAPY Volume 31, 2011
individuals received nisoldipine 10 mg with
water or 5 mg nisoldipine with 200 ml grapefruit
juice or with water. Following 1-week of
ingesting grapefruit juice three times daily, doses
of nisoldipine were taken at 14, 38, 72, or 96
hours. Compared to control, the maximum
plasma concentration of nisoldipine was
significantly increased after grapefruit juice
intake at baseline and at 14 hours, and the
plasma concentration was significantly increased
at all time points. The model gave predicted
values in agreement with the observed values.
The author’s recommendation is to hold
grapefruit juice for at least three days prior to and
during administering nisoldipine to avoid any
potential drug interaction, but previous analyses
have recommended that close monitoring is
warranted in patients regularly consume
grapefruit juice and who are initiating or titrating
nisoldipine to avoid potentially negative
cardiovascular adverse effects.
Fuhr U, Muller-Peltzer H, Kern R, et al. Effects
of grapefruit juice and smoking on verapamil
concentrations in steady state. Eur J Clin
Pharmacol 2002;58:45–53.
The drug interaction between verapamil and
grapefruit juice was established previously with
initial therapy of verapamil, but this study sought
to evaluate verapamil effects at a steady-state
concentration. The small (n = 24) randomized
crossover study of adult healthy Caucasians
included 50% of patients who were smokers to
assess the interaction of smoking on verapamil
concentrations as well as grapefruit juice. Study
participants received 120 mg of sustained release
verapamil twice daily for seven days and then
received one liter of grapefruit juice or water
daily on days five through seven. Verapamil and
norverapamil concentrations were measured on
day seven. Grapefruit juice resulted in an
increase in verapamil AUC at steady state by a
mean of 1.45-fold (90% CI 1.29, 1.63) and Cmax
at steady state by 1.63-fold (90% CI 1.38, 1.91).
These increases in AUC fall in line with previous
studies reporting on this interaction. Overall,
smokers had lower AUC for verapamil than non-
smokers. There were no statistically significant
differences in adverse event rates; however, it is
worth noting that two individuals in the
grapefruit arm had increases above 350
milliseconds (ms) in their PR interval (median
baseline range 160 to 175 ms). This study
further supports pharmacokinetic interaction
between grapefruit juice and verapamil. The
clinical significance must be determined on an
individual basis with consideration of
concomitant drugs metabolized through the CYP
3A4 substrate.
Lim GE, Li T, Buttar HS. Interactions of
grapefruit juice and cardiovascular medications:
a potential risk of toxicity. Exp Clin Cardiol.
2003;8:99–107.
There are a number of documented drug
interactions with grapefruit juice and
cardiovascular drugs in the literature. Most
interactions are related to the inhibitory effects of
grapefruit juice on CYP 3A4 enzymes and
through P-glycoprotein transporters. Most of the
drug interactions are documented with oral drugs
and not intravenous formulations. A number of
studies have shown interactions of grapefruit
juice with cardiovascular drugs such as calcium-
channel blockers, angiotensin II receptor
antagonists, ␤-blockers, and statins. The
potential to cause unwanted side effects
secondary to these drug interactions is likely
since most of these interactions results in
increased drug concentrations in the body.
Patients who are taking drugs that are extensively
metabolized through the CYP 3A4 substrate
should be counseled on the potential drug
interaction with grapefruit juice. This review
focuses on the adverse interactions of GFJ and
cardiovascular medications, and the proposed
underlying mechanisms of such interactions.
Bailey DG, Dresser GK. Interactions between
grapefruit juice and cardiovascular drugs. Am J
Cardiovasc Drugs 2004;4:281–297.
In this review article, the authors discuss the
role of grapefruit juice and cardiovascular drug
interactions. Grapefruit juice can alter oral drug
pharmacokinetics and pharmacodynamics by a
number of different mechanisms. The primary
interaction is through the irreversible
inactivation of intestinal cytochrome P450 (CYP)
3A4. Subsequently, drugs metabolized through
this pathway have an increased oral
bioavailability which can occur as quickly as 24
hours post ingestion of grapefruit juice. Another
possible mechanism for drug interactions is
through the inhibition of P-glycoprotein (P-gp)
by grapefruit juice reducing the intestinal and/or
hepatic efflux transport and causing an increase
in the oral bioavailability of certain drugs. There
are a number of drugs used to prevent and treat
cardiovascular disease that have been shown to
interact with grapefruit juice. Based on the CYP
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
3A4 interaction atorvastatin, lovastatin, or
simvastatin have all been linked to myopathy
toxicity potential secondary to increase in statin
drug levels. This interaction has not been shown
with pravastatin, fluvastatin, or rosuvastatin.
Dihydropyridine calcium channel blockers have
the potential to cause excessive vasodilation with
concomitant grapefruit juice, with felodipine
being the most linked. Administering the non-
diyhropyridine CCB, verapamil with grapefruit
juice has resulted in increased drug
concentrations in multiple kinetic studies. The
angiotensin II type 1 receptor blocker losartan
has been shown to have a lower drug
concentration when co-administered with
grapefruit juice and a subsequent decreased effect
on blood pressure. The antiarrhythmics
amiodarone and quinidine are the most linked to
the CYP 3A4 interaction with noted increases in
drug levels. The erectile dysfunction drugs
sildenafil, tadalafil, or vardenafil can result in
systemic vasodilatation with combined with
grapefruit juice. If a patient is known to have a
baseline low oral bioavailability from presystemic
metabolism by CYP3A4 or efflux transport by P-
gp then grapefruit juice should be avoided. The
majority of interactions studies are small as well
as the predictability of altered drug response in
individuals is variable, but overall patients
should be cautioned about this interaction
especially if on a drug which is extensively
metabolized through CYP 3A4.
Merten-Talcott SU, Zadezensky I, De Castro
WV, Derendorf H, Butterweck V. Grapefruit-
drug interactions: can interactions with drugs be
avoided? J Clin Pharmacol. 2006;46:1390–416.
In a more recent review, the drug interactions
with grapefruit juice are further discussed.
Flavonoids and polyphenolic compounds
contained in grapefruit have a protective effect
against cardiovascular disease. The potential
drug interaction profile of grapefruit juice
emerged in the early 1990s and has been in
discussion and studied in a number of
cardiovascular drugs. Known drug interactions
exist through a variety of mechanisms. The most
established mechanism is the reduction of the
first-pass metabolism through the inhibition of
intestinal CYP3A4. Other studies have
demonstrated the potential influence of
grapefruit juice and other fruit juices on a
number of organic anion-transporting
polypeptides (OATPs) a group of influx
transporters and P-glycoproteins. The underlying
245e
mechanisms can be classified into two broad
categories: pharmacokinetics, including
alterations in absorption, distribution,
metabolism, and excretion, and
pharmacodynamics, describing alterations in the
drug concentration effect. Key cardiovascular
drugs with established drug interactions with
grapefruit include HMG-CoA reductase
inhibitors (statins) and calcium channel
blockers. At this time there is insufficient
evidence to support a clinically relevant
interaction between warfarin and grapefruit juice.
GUARANA AND GUAR GUM (also see
Caffeine)
Guarana is known under the names Paullinia
cupana and Paullinia sorbilis from the family of
Sapindaceae. Guarana is named for the Guarani
tribe in the Amazon who used the seeds to brew
drinks. Guar gum is known as Cyamopsis
tetragonolobus from the family Fabceae and
Leguminosae. Derived from the Indian cluster
bean, guar gum contains high dietary fiber which
is used as a therapeutic option for weight loss.
Guar gum has also been evaluated in the
treatment of diabetes, hypercholesterolemia and
atherosclerosis. Today guarana, the active
ingredient, is frequently an additive to energy
and weight loss drinks. Most of guarana’s effects
are believed to be mediated through caffeine
which stimulates the central nervous system,
heart, muscles, and can increase blood pressure.
The main uses of guarana are for weight loss,
enhanced athletic performance, reduced mental
and physical fatigue, hypotension, chronic
fatigue syndrome, as a stimulant, tonic, or
aphrodisiac, and as a diuretic.
Cardiovascular adverse effects: Tachycardia (E),
hypertension (E), diuresis (E), hypokalemia (E),
chest pain (E), premature heartbeat (E), and
arrhythmia (E) with guarana.
Drug Interactions: Decreased peak digoxin
concentrations with guar gum (B).
Huupponen R, Seppala P, Iisalo E. Effect of guar
gum, a fibre preparation, on digoxin and
penicillin absorption in man. Eur J Clin
Pharmacol 1984;26:279–81.
Because guar gum contains bulk fiber, the gut
absorption of certain medications may be
decreased. Digoxin may be of particular concern
because of its narrow therapeutic window (ie.
minimal changes in serum concentrations can
produce significant clinical effects). The
246e PHARMACOTHERAPY Volume 31, 2011
potential interaction of guar gum on the
absorption of digoxin was investigated in a
double blind study of ten healthy individuals. In
the study guar gum reduced the Cmax of digoxin
concentration by 21% compared to placebo (2.47
ng/mL vs 3.13 ng/mL). The AUC for the first six
hours was decreased by 15% in the guar gum
group compared to placebo. By 24 hours post
digoxin and guar gum administration there was
no difference in 24 hour digoxin excretion in the
urine. Although the rate of digoxin absorption
was decreased with guar gum, the extent of
absorption remained unchanged. Based on these
parameters this interaction is of minor
significance.
Pittler MH, Ernst E. Guar gum for body weight
reduction: meta-analysis of randomized trials.
Am J Med. 2001;110(9):724–730.
A meta-analysis of clinical trials was performed
evaluating the efficacy of guar gum to reduce
body weight. Out of the 34 trials preliminarily
identified for the meta-analysis, 11 trials were
considered suitable for inclusion. The average
daily dose range was between 9 and 30 g.
Following statistical pooling of the studies, guar
gum was not found to be more efficacious
compared to placebo. The safety profiles in the
clinical trials were also reported in this meta-
analysis. Based on published reports up to 2001,
no cardiac adverse drug reactions were noted
with the use of guar gum in the clinical trials
evaluated in this meta-analysis.
Haller CA, Jacob P, Benowitz NL. Short-term
metabolic and hemodynamic effects of ephedra
and guarana combinations. Clin Pharmacol Ther.
2005 Jun;77(6):560–71.
(Refer to ephedra for annotated bibliography)
GUGGULIPID (GUGGUL):
Guggulipid is known under the names of
Commiphora wightii, Commiphora mukul,
Balsamodendrum wightii, and Balsamodendrum
mukul from the family of Burseracaea. The
guggul plant has been used in Ayurvedic
medicine for centuries and has been cited in
Ayurvedic texts dating back to 600 BC for
treating atherosclerosis. Guggulipid is
commercially manufactured in India.
Mechanistically, guggulipid is thought to inhibit
the synthesis of cholesterol in the liver and block
the farnesoid X receptor which can result in
decreases in bile acid production. The main
therapeutic uses are for arthritis, to lower
cholesterol, atherosclerosis, nodulocystic acne,
skin diseases, and for weight loss.
Cardiovascular adverse effects: Increased risk of
bleed (B).
Drug Interactions: Reduces platelet aggregation
and induces fibrinolysis (B) which may increase
risk of bleeding with concomitant
anticoagulant/antiplatelet medications, induces
CYP 3A4 so can increase breakdown of drugs
metabolized through this pathway (D), can
reduce diltiazem (A) and propranolol (A)
bioavailability.
Bordina A, Chuttani SK. Effect of gum guggulu
on fibrinolysis and platelet adhesiveness in
coronary heart disease. Indian J Med Res
1979;70:992–996.
Guggulipid is a commonly used herbal in India
for atherosclerosis and its effects on coagulation
time have been observed in patients with
ischemic heart disease. Given the intense
popularity of this agent and potential benefits for
cardiovascular disease, a prospective study of 40
patients (20 healthy controls and 20 with CAD)
was conducted to investigate the effects of
guggulipid vs. placebo on fibrinolytic activity and
platelet adhesion. Guggul gum or lactose
(placebo) was administered for 30 days at 0.5 g
twice daily in gelatin capsules. Blood samples for
serum fibrinolytic activity (FA) and platelet
adhesive index (PAI) were collected at baseline
and at day 1, 15, 30, and 45. No significant
changes in FA or PAI were observed with
placebo. However in treatment groups,
guggulipid produced significant effects on FA
and PAI activity compared to baseline as seen in
the table below:
Group
All treated Day
with guggul Baseline 1 15 30a 45
FA
Healthy patients 71.8 88.2b 96.2 100.2* 70.0
CAD patients 61.0 76.1 83.7* 86.9* 57.2
PAI
Healthy patients 32.2 29.2 26.5* 26.2* 35.2
CAD patients 37.2 36.7 31.3* 31.2* 40.1
a
Discontinue
b
p<0.05 compared to baseline; units not reported in study
These data indicate that guggulipid increases
FA activity and reduces PAI activity which may
potentiate bleeding with or without concomitant
antiplatelet/anticoagulant medications. In
contrast to this study, other clinical trials using
this agent have not reported an increased
bleeding associated with chronic use. Taken
together, the potential risks of gugulipid should
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
be recognized and patients using this supplement
should be judiciously monitored for risk of
bleeding. However, further study is warranted
before any definitive conclusions can be made.
Dalvi SS, Nayak VK, Pohujani SM, Desai NK,
Kshirsagar NA, Gupta KC. Effect of gugulipid on
bioavailability of diltiazem and propranolol. J
Assoc Physicians India 1994;42(6):454–5.
A randomized cross-over study of seventeen
healthy individuals was conducted to evaluate
the effects of gugulipid on the pharmacokinetic
profiles of diltiazem and propranolol. Seven
individuals received diltiazem 60 mg or diltiazem
60 mg and gugulipid 1 gm daily in a randomized
cross-over fashion with a seven day washout
period. Ten individuals received propranolol 40
mg or propranolol 40 mg with gugulipid 1 gm
daily in a randomized cross-over fashion with a
seven day washout period. Each study arm had
nine blood samples drawn over an 8 hour period
following medication administration. Diltiazem
maximum concentration was decreased from a
baseline value of 134.3 ± 18.1 ng/ml to 79.4 ±
10.9 ng/ml co-administration with gugulipid
(p<0.01). The diltiazem half-life decreased from
a baseline value of 4.2 ± 0.9 to 2.3 ± 1.0 hours
following gugulipid co-administration (p<0.01).
Propranolol maximum concentration was
decreased from a baseline value of 180 ± 25.9
ng/ml to 102.7 ± 13.3 ng/ml with co-
administration with gugulipid (p<0.01). The
propranolol half-life was not changed following
gugulipid co-administration. Co-administration
of gugulipid with diltiazem or propranolol may
lead to diminished efficacy or nonresponsiveness
due to significant reductions in medication
concentrations achieved with concurrent use.
Caron MF, White CM. Evaluation of the
antihyperlipidemic properties of dietary
supplements. Pharmacotherapy 2001;21:481–7.
This review of dietary supplements to treat
high cholesterol specifically discusses guggulipid
and its clinical efficacy and safety data. The
review supports the lack of cardiac adverse drug
reactions with guggulipid administration in
humans. The authors note the drug interaction
of guggulipid with diltiazem and propranolol
resulting in decreased bioavailability of both
drugs. Overall, the focus of this article is on
multiple dietary supplements to treat
dyslipidemia and thus discussion on guggulipid
is only a minor part of the discussion.
Ulbricht C, Basch E, Szapary P, Hammerness P,
247e
Axentsev S, Boon H, et al. Guggul for
hyperlipidemia: a review by the natural standard
research collaboration. Complement Ther Med.
2005;13:279–90.
This is a review article evaluating the clinical
benefit of guggul for the management of
hyperlipidemia based on published clinical trials.
Guggulipid administration has been associated
with inhibition of platelet aggregation and
increased fibrinolysis, but no documented cases
of bleeding have been reported in the literature
despite this potential increased risk of bleeding.
Co-administration of guggulipid to humans has
been reported to decrease the bioavailability of
both diltiazem and propranolol. Based on
clinical studies, the additive effects of guggulipid
on the action of other lipid lowering agents is
minimal.
HAWTHORN
Hawthorn (Crataegus oxycantha) contains
flavonoids and Proanthocyanidins, which are
thought to be responsible for its cardiovascular
actions. Hawthorn is used for cardiovascular
conditions such as chronic heart failure (CHF),
coronary circulation problems, angina, and
arrhythmias. It is also used to increase cardiac
output reduced by hypertension or pulmonary
disease, to treat both hypotension and
hypertension, atherosclerosis, hyperlipidemia,
and Buerger’s disease.
Cardiovascular adverse effects: Hypotension
(D), palpitations (B), progression of heart failure
(B).
Drug interactions: Potential additive effects on
blood pressure and heart rate with ␤-blockers or
calcium channel blockers, potentiates effects of
digoxin (E).
Tankanow R, Tamer HR, Streetman DS et al.
Interaction study between digoxin and a
preparation of hawthorn (Crataegus oxyacantha).
J Clinical Pharmacol 2003;43:637–642.
Hawthorn contains flavanoids, which are
thought to be responsible for its cardiovascular
effects. Previous investigations suggested that
flavanoids may alter P-glycoprotein activities. As
hawthorn and digoxin may be administered in
the same patient this potential interaction carries
clinical significance. This open-label,
randomized, crossover study was undertaken in 8
healthy subjects (4 male, 4 female) to evaluate
the pharmacokinetic effect of hawthorn on
digoxin. Participants were randomized to receive
248e PHARMACOTHERAPY Volume 31, 2011
digoxin 0.25 mg daily for 10 days or digoxin 0.25
mg daily in addition to Crataegus special extract
WS 1442 450 mg twice daily, for 21 days. There
was a washout period of 21 days between
treatment periods, then participants were crossed
over to the other treatment arm. Pharmacokinetic
data were collected on day 10 of the digoxin only
group and day 21 of the combined treatment
group. Serial blood samples were drawn over a
12 hour period, and subjects returned for
additional blood draws at 24, 48, and 72 hours.
Urine was also collected over a 24 hour period.
Pharmacodynamic parameters included blood
pressure and ECG measurements. Overall,
digoxin concentrations (AUC, Cmax, Cmin) were
slightly lower in the combined group, but not
significantly different compared to digoxin alone.
C min values were 0.84 ± 0.2 for the digoxin
group, and 0.65 ± 0.2 for the combined group
(p=0.054). Pharmacodynamic parameters (PR
interval, heart rate) did not differ significantly
between groups. Overall, this study suggested
that there is not an interaction with hawthorn
and digoxin when the two agents are co-
administered for 21 days.
Daniele C, Mazzanti G, Pittler MH, Ernst E.
Adverse-event profile of Crataegus spp.: a
systematic review. Drug Saf. 2006;29(6):523–35.
This systematic review summarized adverse
events and drug interactions from 24 studies of
mono-preparations of Hawthorn in humans. Data
were extracted from MEDLINE, EMBASE,
AMED, The Cochrane Library, the UK National
Research Register, and the U.S. ClinicalTrials.gov
website. Additional published and unpublished
data were obtained from hand searches of
relevant journals and reference lists of studies
acquired via the search strategies outlined above.
The 24 studies included were 19 clinical trials, 2
uncontrolled studies, 2 observational studies, and
1 cohort study. The majority of studies (n=21)
used the crataegus extract WS 1442 and
crataegus extract LI 132 hawthorn preparations,
and doses ranged from 160–1800 mg daily. In
studies of WS 1442, 3 reported no adverse effects
in active treatment or control groups, and 3 did
not report adverse events. In 5 other studies
totaling 231 individuals with NYHA FC I-II heart
failure, 30 adverse events were reported such as
back pain, dizziness/vertigo, or flu-like symptoms
in the WS 1442 group, which appeared unrelated
to dose. Another study in patients with NYHA
FC III heart failure reported 2 discontinuations
out of 139 randomized to hawthorn due to
circulatory disturbance, chest pain, and
constipation. Of the 6 pooled randomized
studies of the LI 132 formulation, 15 adverse
events were reported, most commonly nausea. In
an observational study of 3664 patients using
high dose LI 132 (900 mg daily), 72 adverse
events were reported in 48 patients. Of those, 27
were attributable to hawthorn and included
palpiations (n=2), and chest pain (n=1). There
were no reports of drug interactions. Overall,
authors concluded that hawthorn was well
tolerated, although a few severe adverse events
were reported. Of note, this review published in
2006 did not include the HERB-CHF study and
the more recent SPICE trial.
Zick SM, Gillespie B, Aaronson KD. The Effect
of Crataegus oxycantha Special Extract WSS
1442 on Clinical Progression in Patients with
Mild to Moderate Symptoms of Heart Failure.
Eur J Heart Fail. 2008 June;10(6):587–593.
This was a retrospective analysis of a 6-month,
randomized, double-blind, placebo-controlled
study with Crataegus Special Extract WS 1442
(450 mg twice daily) in 120 patients with heart
failure. The main trial findings were neutral with
respect to changes in left ventricular ejection
fraction evaluated by radionuclide
ventriculogram. The primary outcome of this
post-hoc analysis was progression of heart failure,
defined as death due to HF, hospitalization due to
HF, or sustained increase in diuretic dose for HF.
Progression of HF occurred in 46.6% of
Crataegus Special Extract WS1442 patients and
43.3% of placebo patients, a difference which was
not statistically significant (p=0.86). Further
analyses revealed that participants randomized to
the Crataegus Special Extract WS 1442 were 3.9
times (95% CI = 1.1, 13.7: p=0.035) more likely
to experience HF progression at baseline
compared to placebo. This risk decreased over
time such that at 6 months it was no longer
significant (HR = 0.63, 95% CI = 0.29, 1.47:
p=0.72). A subgroup analysis of participants
with a left ventricular ejection fraction < 35% had
a sustained risk for HF progression throughout
the 6-month study period. It is possible that
these results are due to chance due to the small
number of subjects and the retrospective nature
of these analyses. Nonetheless, until further
safety data are available with Hawthorn it should
not be recommended in patients with heart
failure.
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
HORNY GOAT WEED
Horny goat weed is known under the name
Epimedium grandiflorum as well as 15 other
Epidmedium species all in the Berberidaceae
family. A perennial evergreen indigenous to
China and Japan, the herb is found growing on
hillsides, in damp shady bamboo groves, or in
cliff crevices. Epimedium is thought to increase
coronary blood flow and reduce platelet
aggregation resulting in cardiovascular disease
benefits. The leaves are used for medical
purposes which include impotence, involuntary
ejaculation, fatigue, coronary artery disease,
kidney disease, chronic hepatitis, and polio.
Cardiovascular adverse effects: Increased risk of
bleeding (E), respiratory arrest (E),
tachyarrhythmia (C) hypotension (E).
Drug Interactions: Increased risk of bleeding
with concomitant anticoagulant and/or
antiplatelet use (E), exaggerated hypotensive
effects with concomitant antihypertensive use
(E).
Cirigliano MD, Szapary PO. Horny goat weed
for erectile dysfunction. Alt Med Alert
2001;4:19–22. (E)
This is a review article on the clinical data
evaluating the role of horny goat weed in the
management of erectile dysfunction. The article
discusses safety and drug interactions in the
discussion. Horny goat weed appears to be safe
in animals when taken for short periods of time
in recommended dosages. Some traditional
Chinese medicine sources list the following
potential adverse effects: dizziness, nausea,
vomiting, dry mouth, and nosebleeds. Large
doses of Japanese epimedium have been noted to
cause respiratory arrest and exaggeration of
tendon reflexes to the point of spasm. There are
no known drug interactions identified in
humans, but the potential vasodilating effects of
horny goat weed may cause hypotension,
especially with concurrent use of other
antihypertensives.
HORSE CHESTNUT
Horse Chestnut is known under the name
Aesculus hippocastanum in the Hipoocastanaceae
family. The cardiovascular effects of horse
chestnut are thought to be mediated through
Aesculin which can increase bleeding by
increasing antithrombin activity and also may
decreases the permeability of venous capillaries.
The possible therapeutic uses are the treatment of
249e
varicose veins, hemorrhoids, diarrhea, fever,
enlarged prostate, eczema, chronic venous
insufficiency, soft tissue swelling, cough,
arthritis, and rheumatism.
Cardiovascular adverse effects: Increased risk of
bleeding (E).
Drug Interactions: Increased the risk of bleeding
with concomitant anticoagulant and/or
antiplatelet use (E).
Pittler MH, Ernst E. Horse-chestnut seed extract
for chronic venous insufficiency. A criteria-based
systematic review. Arch Dermatol
1998;134:1356–60.
This meta-analysis evaluated the horse
chestnut seed extract in trials for chronic venous
insufficiency. This evaluation looked at safety of
horse chestnut in these trials. Eight of the
studies evaluated reported adverse drug reactions
with horse chestnut which included
gastrointestinal tract symptoms, dizziness,
nausea, headache, and pruritus. There were no
reported cardiovascular adverse drug reactions in
the studies evaluated although the results of this
meta-analysis may be dated.
IRISH MOSS
Irish Moss (Carrageenan) is also known under
the names Chondrus crispus, Euchema species,
Gigartina mamillosa, Gigartina chamissoi, and
Gigartina skottsbergii in the Gigartinaceae family.
Irish moss is hypothesized to lower blood
cholesterol (mechanism unknown), reduce
gastrointestinal secretions and food absorption,
and have anticoagulant and anti-inflammatory
properties. The therapeutic uses include
soothing mucous membranes irritated by cough,
bronchitis, tuberculosis, intestinal problems, and
weight loss.
Cardiovascular adverse effects (parenteral
administration): Increased bleeding (E),
hypotension (E).
Drug Interactions (parenteral administration):
Increased anticoagulant effects possibly resulting
in increased risk of bleeding in concomitant
anticoagulant use (E), increased hypotensive
effects with concomitant antihypertensive use
(E).
KELP
Kelp is known under the names bladderwrack,
Fucus vesiculosus, and Ascophyllum nodosum in
the Fucaceae family. The mechanism by which
Kelp is believed to exhibit anticoagulant
250e PHARMACOTHERAPY Volume 31, 2011
properties is through platelet activation and
inhibitory effects on platelet adhesion by
interacting with CD62P. Kelp’s uses include
treatment of thyroid disorders, iodine deficiency,
obesity, rheumatism, arteriosclerosis, digestive
disorders, heart burn, constipation, bronchitis,
emphysema, genitourinary disorders, and
anxiety.
Cardiovascular adverse effects: Hypothyroidism
(E), palpitations (C), syncope (C), torsades de
pointes (C), increased risk of bleeding (E).
Drug Interactions: Increased risk of bleeding by
inhibitory effects on platelet adhesion (E).
KHELLA
Khella is known under the names Ammi
visnaga, Ammi daucoides, and Daucus visagna in
the Apiaceae and Umbelliferae families. Khella,
visnadin, and visnagin are all furocoumarins
which can be extracted from seeds and aerial
parts of the dry ripe fruits of Ammi visnaga. The
cardiovascular mechanism of khella is thought to
be mediated through visnadin, the most active of
all the constituents, which can inhibit vascular
smooth muscle contraction and result in
peripheral and coronary vessel dilation. The
possible therapeutic uses are for the treatment of
abdominal craps, kidney stones, menstrual pain,
premenstrual syndrome, asthma, bronchitis,
cough, hypertension, cardiac arrhythmias,
congestive heart failure, angina, atherosclerosis,
hypercholesterolemia, liver disorders, gall
bladder disorders, and diabetes.
Cardiovascular adverse effects: No known
effects.
Drug Interactions: Decreased effectiveness of
digoxin because of the negative inotropic effects
of visnadin (D), increased heart failure
exacerbations in patients with heart failure (E).
Duarte J, Torres AI, Zarzuelo A. Cardiovascular
effects of visnagin on rats. Planta Med
2000;66:35–9.
Visnagin, an active component of Khella, is
reported to produce vasodilating effects, which
are largely believed to be a result of
phosphodiesterase isozyme inhibition. Despite
these data demonstrating a local effect on the
vascular smooth muscle, it is unclear whether
visnagin would reduce systolic blood pressure
when involving the systemic response of
resistance arteries. This study evaluated the in
vivo effects of visnagin on systolic blood pressure
in a rat model. Visnagin was administered
intravenously at doses in the range of 0.3–0.5
mg/kg resulting in significant dose related
reductions in blood pressure, but no change in
heart rate. The ex vivo cardiac effects were also
studied following removal of the right and left
atria from the rat and using electrodes to
stimulate the basal rate (1 Hz) of the left atria.
Visnagin was noted to decrease the rate and
amplitude of right atria contraction and produce
a modest reduction in peak contractile force and
maximum rate of contraction. Mesenteric
arteries revealed a concentration dependent
relaxation effect with administration of visnagin.
Overall, the authors concluded that visnagin can
produce mild negative chronotropic and
inotropic actions in addition to profound
hypotensive effects. The main mechanism for
reduced blood pressure is believed to be a result
of the vasorelaxant response to visnagin seen in
resistance arteries.
L-ARGININE
L-arginine is also known as 2-amino-5-
guanidinopentanoic acid. The mechanism is
thought to occur through improvement in
endothelial function. Normal endothelial
functions require an intact L-arginine/nitric oxide
(NO) pathway and endothelium. L-arginine is
the only substrate for NO synthesis in vascular
endothelial cells, which causes blood vessel
relaxation. Therefore, L -arginine has been
evaluated in the treatment of congestive heart
failure, angina, hypertension, coronary artery
disease, intermittent claudication, dementia,
erectile dysfunction, male infertility, prevention
of common cold, interstitial cystitis, pre-
eclampsia, improving immune function, migraine
headaches, and weight gain.
Cardiovascular adverse effects: Hypotension
(E), increased mortality in patients with
myocardial infarction (A).
Drug Interactions: Potential hypotensive effects
with concomitant antihypertensive use (E),
potential additive vasodilation and hypotensive
effect with concomitant nitrates (E), and
sildenafil (E).
Huynh NT, Tayek JA. Oral arginine reduces
systemic blood pressure in type 2 diabetes: its
potential role in nitric oxide generation. J Am
Coll Nutr 2002;21:422–7.
A prospective, crossover trial was designed to
evaluate the effects of oral arginine on nitric
oxide production, counter-regulatory hormones
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
and blood pressure in mildly hypertensive
patients with type 2 diabetes mellitus. The study
included six patients who were given three grams
of arginine per hour for ten hours on day two or
three of the study. Patient’s blood pressure was
measured in their dominant arm once during the
day and once at midnight on day 2 and 3 of
arginine administration. Arginine reduced
systolic BP from 135 ± 7 to 123 ± 8 mmHg
(p<0.05). Diastolic BP was reduced from 86.9 ±
1.7 at baseline to 80.7 ± 2.4 mmHg (p<0.05). The
reduction in BP was noted to occur two hours
after starting oral arginine, and BP returned to
normal within one hour of stopping the arginine.
These data suggest arginine may temporally
reduce blood pressure in mildly hypertensive
patients with type 2 diabetes mellitus.
Schulman SP, Becker LC, Kass DA, et al. L-
arginine therapy in acute myocardial infarction:
the vascular interaction with age in myocardial
infaction (VINTAGE MI) randomized clinical
trial. JAMA 2006;295:58–64.
A double-blind, randomized, placebo
controlled, single center study was designed to
evaluate the effects of L-arginine in 153 patients
with ST-segment elevation myocardial infarctions
(MI). Patients were given L-arginine at a dose of
1 g three times a day for week 1, 2 g three times a
day for week 2, and then 3 g three times a day for
the 6-month study period. The data and safety
monitoring committee stopped patient
enrollment at 2.5 years after the start of
recruitment due to excess mortality (6 deaths) in
patients in the L -arginine study arm. The
mechanism of increased death rate in the L -
arginine group is unknown. It has been
hypothesized that it could be mediated through
L -arginine’s effects on tetrahydropbiopterin, a
cofactor for NOS. In the setting of
tetrahydropbiopterin deficiency, NOS becomes a
source of reactive oxygen species, which can be
enhanced with L -arginine supplementation.
Based on the increased mortality seen in this
study, L-arginine should not be recommended
following acute myocardial infarction.
L-CARNITINE
L-carnitine is an endogenous amino acid
synthesized in vivo from lysine and methionine. L-
carnitine may also be obtained from diet with the
highest concentrations found in red meat. Living
cells require L-carnitine to help transport fatty acids
into the mitochondria from the cytosol to support
251e
lipid metabolism and generation of energy. This
compound is used to treat primary and secondary
L-carnitine deficiency (such as those due to inborn
errors of metabolism), and L-carnitine deficiency in
patients receiving hemodialysis. On occasion it has
also been used to treat myopathies associated with
angina, myocardial infarctions, heart failure, and
myocarditis.
Cardiovascular adverse effects: No adverse drug
reactions related to cardiovascular function have
been reported in the literature.
Drug Interactions: Increased risk for bleeding
with concomitant anticoagulant use (C).
LICORICE
Orally, licorice (also known as glycyrrhiza or
alcacuz) is used for gastric and duodenal ulcers,
bronchitis, osteoarthritis, and for bacterial and
viral infections. Licorice is used as a flavoring in
foods, beverages, and tobacco.
Cardiovascular adverse effects: Hypokalemia
(C), hypertension (C), and ventricular
arrhythmias (C).
Drug Interactions: Increased blood pressure
and reduced effectiveness of antihypertensive
therapies (E), increased risk for digoxin toxicity
due to potassium loss (E), increased risk of
hypokalemia with concomitant diuretic use (E),
and increased risk for therapeutic failure with
concomitant warfarin use due to induction of
warfarin metabolism (D).
Bernardi M, D’Intino PE, Trevisani F, et al.
Effects of prolonged ingestion of graded doses of
licorice by healthy volunteers. Life Sci
1994;55(11):863–72.
This prospective randomized trial sought to
make observations about long-term licorice
supplementation in healthy volunteers. Patients
were administered graded daily doses of dried,
aqueous extract of licorice root, containing 108,
217, 380 and 814 mg of glycyrrhizin, and
randomized to 4 groups of 6 healthy volunteers
of both sexes for 4 weeks. No significant effects
occurred in groups 1 and 2. After 2 weeks, side
effects leading to withdrawal from the protocol
occurred in a female in group 3 (headache), a
male with a family history of hypertension in
group 4 (arterial hypertension), and a female also
taking oral contraceptives in group 4
(hypertension, hypokalaemia and peripheral
edema). In group 4, transient hypokalemia and
increase in body weight were found after 1 and 2
weeks, respectively. Reduced plasma renin
252e PHARMACOTHERAPY Volume 31, 2011
activity occurred in groups 3 and 4. The authors
conclude that in healthy subjects, only the
highest doses of licorice led to untoward effects.
These were related to subclinical disease or oral
contraceptives, and were less common and
pronounced than what has been reported after
the intake of glycyrrhizin taken as such or as a
flavoring agent in confectionery products. To put
these findings into perspective: licorice can
induce a hypermineralocorticoid syndrome.
Available literature usually refers to the effects of
sweets containing glycyrrhizin, but little is
known about the consequences of a prolonged
intake of “pure licorice”. These data do not
clearly establish safety of licorice
supplementation.
Sigurjonsdottir HA, Franzson L, Manhem K, et
al. Liquorice-induced rise in blood pressure: a
linear dose-response relationship. J Hum
Hypertens 2001;15:549–52.
This study sought to clarify the dose-response
and the time-response relationship between
licorice consumption and rise in blood pressure,
and to explore the inter-individual variance in
healthy, Caucasian volunteers who also served as
their own control. Licorice was administered in
various doses, 50–200 g/day, for 2–4 weeks,
corresponding to a daily intake of 75–540 mg
glycyrrhetinic acid (the active substance in
licorice). Blood pressure was measured before,
during and after licorice consumption. Systolic
blood pressure was assessed by sphygmo-
manometer by the same nurse for each patient,
and increased by 3.1–14.4 mm Hg (p<0.05 for
all), demonstrating a dose-response but not a
time-response relationship. The individual
response to licorice appeared to follow a normal
distribution. Since licorice raised the blood
pressure with a linear dose-response relationship,
even doses as low as 50 g of licorice (75 mg
glycyrrhetinic acid) consumed daily for 2 weeks
can cause a significant rise in blood pressure.
These findings suggest that exogenous licorice
supplementation is associated with increased
systolic blood pressure. These data have negative
implications for patients with hypertension or
cardiovascular disease; however, more data are
needed to characterize absolute risk in these
patient populations.
LILLY OF THE VALLEY
The plant (Convallaria majalis) contains
roughly 38 numerous digoxin like cardio-
glycosides (convallamarin, convallarin and
convallotoxin are the most active). It also
contains flavonoids and asparagin. Similar to
other glycosides lily of valley has positive
inotropic effects and is used as a cardiotonic.
The plants’ flavonoids stimulate the arteries to
dilate, and simultaneously the asparagin acts as a
diuretic. Orally, lily of the valley is used for
arrhythmias, hypertension and heart failure. It is
also used to treat urinary tract infection and
kidney stones.
Cardiovascular adverse effects: Arrhythmias (C)
potassium depletion (E)
Drug interactions: Increased risk of cardiac
glycoside toxicity with digoxin (E) and
potassium depleting diuretics such as Loop
diuretics (E)
LYCIUM
Lycium barbarum L is an herb with bright red
berries which is usually consumed as a tea.
Active ingredients are found in both Lycium
berries and bark. These include ␤-sitosterol,
kokoamine, and betaine. Kukoamine may have
significant antihypertensive effects. ␤-sitosterols
inhibit intestinal absorption of cholesterol from
the gut and reduce cholesterol levels. Lycium
root bark is believed to have antibacterial,
antipyretic and antihypertensive properties. It is
also used for improving decreased vision acuity,
erectile dysfunction, leg and back aches, diabetes,
hypertension and cancer.
Cardiovascular adverse effects: Hypotension (E)
Drug interactions: Inhibits CYP2C9 and can
increase levels of drugs that are metabolized via
this pathway such as warfarin (C), concomitant
use with antihypertensive agents may have
additive effects on blood pressure and can result
in hypotension (E).
MAGNESIUM
Magnesium is used for the treatment and
prevention of hypomagnesium. Intravenously it
is used to treat arrhythmias (torsades de point)
and acute exacerbations of asthma, migraine
headaches, neuropathic pain and tetanus. It is
also an effect laxative for constipation due to
osmotic effects of magnesium salts in the
intestine and colon. Taking magnesium as an
antacid also reduces symptoms of hyperacidity.
Cardiovascular adverse effects: Hypotension (E)
cardiac arrest (C).
Drug interaction: May have additive effects
with antihypertensive medications (E),
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
concomitant use with potassium sparing
diuretics can result in increased levels of
magnesium (E).
MANGO
Mango (Irvingia gabonensis) has many
medicinal uses in traditional Asian medicine. It
contains high vitamin A, C, and fiber content.
Mango crude seed extract is used to treat
hyperlipidemia, obesity and diabetes. The high
–soluble fiber content of the seeds might help to
reduce cholesterol. It can bind bile acids in the
gut, thus preventing reabsorption and causing
more conversion of cholesterol to bile. The oil
extract contains vitamin A, beta-carotene and
phytosterols, which might also contribute to
cholesterol lowering effects. Mango extract is
also used as an analgesic, anti-inflammatory and
antioxidant. Dried mango flowers, containing
15% tannin, serve as astringents in cases of
diarrhea, chronic dysentery, catarrh of the
bladder and chronic urethritis.
Cardiovascular adverse effects: None reported.
Drug interactions: Contains vitamin A which
inhibits CYP2C19, and can increase levels of
drugs that are metabolized via this pathway such
warfarin (C).
Monterrey-Rodriguez J, Feliu JF, Mivera-
miranda GC. Interaction between warfarin and
Mango. Ann Pharmacother 2002;36:940–41
(presented as a poster on May 10–12, 2002.).
Mango (Mangifera Indica) has been associated
with supratherapeutic INR in 13 patients who
were also receiving warfarin therapy. Patients
were consuming 1–6 mangoes per day for a
period of 2 days to a month before the INR was
tested. All other factors (compliance, alcohol
intake, dietary changes and use of other herbal
medications) that could potentially increase the
INR were ruled out. The mean baseline INR
increased from 2.79 to 3.85 after mango
ingestion (P<0.001). The average INR decreased
from 3.85 to 3.17 (18% decrease ) after
discontinuation of mango for two weeks. A
rechallenge in 2 patients showed similar results.
The proposed mechanism of this interaction is
thought to be related to high amount of Vitamin
A in mango. Human studies have shown that
Vitamin A (retinol) is a potent inhibitor of
CYP2C19 hepatic enzyme which is responsible
for warfare metabolism. The authors suggest that
future studies are required to confirm this
interaction. Until then it would be prudent to
253e
advise warfarin patients to limit their intake of
mango, or keep a consistent intake, to minimize
INR fluctuations.
NIGHT BLOOMING CERUS
The flower, stem and young shoots of Night
Blooming Cereus (Cereus grandiflorus, Cactus
grandiflorus) are used as a cardiac stimulant and
vasodilator. It contains cactine which may have
digitalis-like effects and can be used as substitute
for digitalis. Other uses include for angina
pectoris, edema, dysmenorrhea and cystitis.
Cardiovascular adverse effects: Hypotension
(E).
Drug interactions: Potentiate the effects of
cardiac glycosides such as digoxin (E), contains
tyramine and in combination with MAOIs could
potentially increase blood pressure (E).
MOTHERWORT
The leaves and flowers of Motherwort plant
(Leonurus Cardiaca) are used medicinally. The
primary chemical constituents of motherwort
include alkaloids (stachydrine, leonurinine),
ursolic acid, and flavonoids (Quercetin, Rutin).
Leonurinine is a mild vasodilator and a smooth
muscle relaxant and can potentially lower blood
pressure and strengthen cardiac function.
Stachydrine helps in stimulating contraction of
uterine muscles and may be used for female
reproductive system disorders. Ursolic acid,
appears to possess antiviral and anti-tumor
properties. The herb is particularly effective for
nervous heart palpitations, elevated heart rate
and high blood pressure due to stress. The herb
also has sedative and antispasmodic properties.
When administered intravenously, motherwort
decreases blood viscosity by decreasing
fibrinogen levels and inhibiting platelet
aggregation.
Cardiovascular adverse effects: Increased risk of
bleeding (E), Hypotension (E).
Drug interactions: Parenteral administration
may potentiate antithrombotic and antiplatelet
effects and increase the risk of bleeding when
coadministered with warfarin, aspirin (E),
decrease blood pressure when coadministered
with other antihypertensives (E).
OAT BRAN
Oat bran and whole oats are soluble fibers,
used for treating hypercholesterolemia,
hypertension and diabetes. Beta-glucan a
254e PHARMACOTHERAPY Volume 31, 2011
nonstarch polysaccharide found in oats reduces
serum cholesterol. It binds to the bile acids in
the gut and decreases enterohepatic circulation of
bile acids which increases hepatic conversion of
cholesterol to bile acids, thus lowering
cholesterol levels. Oats is also used for treating
constipation, chronic anxiety, diverticulosis,
inflammatory bowl diseases, chronic anxiety, and
prevention of colon cancer and gallstones.
Cardiovascular adverse effects: None reported.
Drug interactions: Reduces the absorption of
lovastatin (C).
OLEANDER
Oleander (Nerium oleander, Thevetia peruviana)
is an evergreen hardy shrub found in the tropical
and subtropical climates throughout the world.
Nerium oleander (pink oleander) and Thevetia
peruviana (yellow oleander) are both used in
asthma, epilepsy and dysmenorrhea. They also
have anticancer and antibacterial activity. All
parts of the plant especially seeds contain cardiac
glycosides and are poisonous, making them
potentially toxic to both animals and humans.
Topically, oleander is used to treat skin diseases
(rash, scabies, ringworm, lice and boils). In
certain cultures it is also used as a method of self
poisoning.
Cardiovascular adverse effects: Severe toxicity
produces nausea/vomiting within 6–12 hours of
ingestion, visual disturbances, bradycardia, heart
block, hyperkalemia, cardiac arrest and death
(A).
Drug interaction: May increase cardiac
glycoside toxicity when used in combination
with digoxin and potassium depleting diuretics
(E).
Eddleston M, Ariaatnam A, SJostrom L et al.
Acute Yellow Oleander (Thevetia peruviana)
poisoning: cardiac arrhythmias, electrolyte
disturbances, and serum cardiac glycoside
concentrations on presentation to hospital. Heart
2000; 83:301–306.
Accidental or intentional poisoning with
yellow oleander is very common throughout the
tropical climates. The current study describes
cardiac symptoms and electrolyte disturbances as
a result of yellow oleander ingestion in 351
patients, who were admitted to a secondary or
tertiary care facility. A majority of these patients
(n=83) presented with a normal sinus rhythm, 33
patients had sinus bradycardia, 32 had sinus
arrest or exit block, and 41 had either second
degree or third degree block. A total of 89
patients had severe cardiac toxicities. In these
patients the most common arrhythmias were
conduction defects affecting the sinus or
atrioventricular (AV) node (87% vs 53%
respectively). Fifty patients with normal EKGs
were then compared to 63 patients with marked
arrhythmias. For all patients (n=113) there was a
clear correlation between serum cardiac
glycosides and potassium concentration (r=0.70)
however no correlation was seen between
magnesium and cardiac glycoside concentrations.
The patients with marked arrhythmias were
further categorized based on AV block, sinus
block or both AV and sinus block. There was no
correlation observed between the site of
conduction and the serum cardiac glycoside or
electrolyte concentrations; however, the mean
glycoside concentrations were higher in patients
with both AV and sinus block compared to
patients with only sinus node block (p=0.016).
Also patients who were transferred to critical care
unit had higher cardiac glycoside and potassium
concentrations (p<0.0001). The authors
concluded that even though the yellow oleander
poisoning resembles digoxin poisoning,
previously healthy patients who presented with
conduction defects were younger in age than
digoxin patients. In healthy patients, atrial
fibrillation and flutter was uncommon with
oleander ingestion. However similar to digoxin
toxicity, cardiac arrhythmias were associated with
hyperkalemia and hypokalemia. Future studies
are needed to evaluate mortality as a result of
cardiac glycoside toxicity with oleander.
OMEGA III FATTY ACIDS (FISH OIL)
Omega III fatty acids (also referred to as fish
oil, eicosapentaenoic acid/docosahexaenoic acid
(EPA/DHA), or polyunsaturated fatty acids,
PUFA) are commonly used to treat
hyperlipidemia and hypertriglyceridemia, to
prevent coronary heart disease and stroke (via
reduction in triglyceride synthesis and inhibition
of fatty acid esterification), as well as to treat dry
eye syndrome, dementia, and psoriasis. The
mechanism of action of omega III fatty acids is
not completely understood; however, potential
mechanisms include inhibition of acyl-CoA:1,2-
diacylglycerol acyltransferase, increased
mitochondrial and peroxisomal ␤-oxidation in
the liver, decreased lipogenesis in the liver, and
increased plasma lipoprotein lipase activity.
Omega III fatty acids may reduce the synthesis of
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
triglycerides in the liver because EPA and DHA
are poor substrates for the enzymes responsible
for TG synthesis, and EPA and DHA inhibit
esterification of other fatty acids.
Cardiovascular adverse effects: Ventricular
dysrhythmia in patients with implanted
defibrillators (A) increase risk for bleeding (C).
Drug Interactions: Increased risk for bleeding
with concomitant antiplatelet or anticoagulant
use (E), and additive blood pressure lowering
effects with concomitant use of antihypertensives
(A).
Vandongen R, Mori TA, Burke V, et al. Effects on
blood pressure of omega 3 fats in subjects at
increased risk of cardiovascular disease.
Hypertension 1993;22:371–9.
The objective of this study was to compare the
effects of omega 3 fatty acids, taken as fish-oil
supplements in the setting of a high- or low-fat
dietary background, on blood pressure and heart
rate in men with moderate cardiovascular risks.
One hundred twenty men were randomly
allocated to five high-fat (40% of daily energy)
and two low-fat (30% of energy) groups to
undertaken a 12-week dietary intervention
period involving fish, fish oil, or a combination
of these. Sodium intake was restricted to less
than 2 gm/d. The five high-fat groups were
assigned to take either 6 or 12 fish-oil capsules
daily, fish or a combination of fish oil and fish, or
placebo capsules. The two low-fat groups took
either fish or placebo capsules. Fish meals were
devised to provide 1.3 g of eicosapentaenoic acid
daily, equivalent to that contained in 6 fish-oil
capsules. Subjects were instructed to eat a
selection of fish that provided an average of 3.65
g/d (range, 3.2 to 4.1 g/d) of total omega 3 fatty
acids. Subjects were seen at regular intervals
during the baseline and dietary intervention
periods for measurement of weight, blood
pressure, heart rate, dietary compliance, urinary
electrolyte excretion, platelet phospholipid fatty
acids, blood glucose, and insulin concentration.
There was a greater fall in both systolic and
diastolic blood pressures (absolute percentage
not reported) in subjects allocated to fish or fish
oil, particularly in the low-fat groups, compared
with control subjects. Blood pressure was
assessed automatically using the same Dynamap
1846 SX/P monitor for each patient. These
findings further support beneficial effects of fish
oil supplementation on blood pressure; albeit in
men. However, there appeared to be no
significant group effect. Data are still needed to
255e
further substantiate this effect as well as confirm
similar outcomes in women.
Toft I, Bonaa KH, Ingebretsen OC, et al. Effects
of n-3 polyunsaturated fatty acids on glucose
homeostasis and blood pressure in essential
hypertension. A randomized, controlled trial.
Ann Intern Med 1995;123:911–8.
This randomized, double-blind, placebo-
controlled study sought to determine whether
dietary supplementation with fish oil adversely
affects glycemic control in patients with
hypertension. Seventy-eight subjects with
untreated hypertension were recruited from a
population survey and were randomly assigned
to receive eicosapentaenoic and docosahexaenoic
acids, 4 g/d, or corn oil placebo, 4 g/d, for 16
weeks. The following parameters were evaluated:
an oral glucose tolerance test; assessments of
insulin release, glucose disposal, and insulin
sensitivity done using the hyperglycemic clamp
technique to keep plasma glucose levels at 180
mg/dL for 180 minutes; assessment of insulin
sensitivity done using a euglycemic hyper-
insulinemic clamp technique (infusing insulin
and glucose to keep plasma glucose levels at 90
mg/dL); assessments of lipid levels and blood
pressure. Measurements were done before and
after intervention. Changes in integrated glucose
and insulin response after the oral glucose
challenge did not differ between the fish oil and
corn oil groups after intervention (–10.8 ± 12.6
compared with –1.0 ± 10.8 mg/dL [p>0.3] for
integrated glucose and 2.7 ± 1.4 compared with
3.0 ± 1.5 pg/dL [p>0.3] for insulin response).
Changes in first-phase insulin release were 0.6 ±
1.3 pg/dL in the fish oil group compared with 3.4
± 2.0 pg/dL in the corn oil group [p>0.3], and
second-phase insulin release were 3.2 ± 1.2 pg/dL
compared with 4.6 ± 2.2 pg/dL [p>0.3]. Fish oil
lowered systolic blood pressure by 3.8 mm Hg
more than control (p=0.04) and lowered diastolic
blood pressure by 2.0 mm Hg more than control
(p=0.10). After fish oil treatment, triglyceride
levels decreased by 5.0 ± 1.4 mg/dL more than
control (P=0.01), and very-low-density
lipoprotein cholesterol levels decreased by 2.3 ±
0.7 mg/dL more than control (P=0.01). These
results suggest that fish oil, in doses that reduce
blood pressure and lipid levels in hypertensive
persons, does not adversely affect glucose
metabolism. This is an important consideration
in clinical practice and should allay any concerns
about the potential for reduced glycemic control
with supplemental fish oil use.
256e PHARMACOTHERAPY Volume 31, 2011
Prisco D, Paniccia R, Bandinelli B, et al. Effect
of medium-term supplementation with a
moderate dose of n-3 polyunsaturated fatty acids
on blood pressure in mild hypertensive patients.
Thromb Res 1998;1:105–12.
Several studies have shown that n-3
polyunsaturated fatty acids (n-3 PUFA) are able
to lower blood pressure (BP) in humans, but
large doses of fish oils have been often used. The
objective of this pilot study was to evaluate if
medium-term supplementation with a moderate
dose of highly purified eicosapentaenoic acid
(EPA) and docosahexaenoic acid (DHA) ethyl
esters is able to reduce BP in mildly hypertensive
patients. Sixteen mild essential hypertensive
(diastolic BP: 95–104 mm Hg), non-diabetic,
normolipidemic male outpatients and 16
normotensive male controls were recruited to
participate in the study. Both groups were
randomly assigned to receive either EPA and
DHA ethyl esters (2.04 g EPA and 1.4 g DHA) as
active treatment or olive oil (4 g/day) as a
placebo for a period of 4 months. Subjects
received 24-hour ambulatory BP monitoring and
blood chemistry analyses at 2 and 4 months of
treatment and 2 months after discontinuation.
The intake of n-3 PUFA was checked by red
blood cell (RBC) phosphatidylcholine (PC) fatty
acid composition. The effect of n-3 PUFA on BP
in the active group was maximum after 2
months. Both systolic (–6 mm Hg, p<0.05) and
diastolic (–5 mm Hg, p<0.05) BP significantly
decreased during the n-3 PUFA ethyl ester
supplementation. No further effect was observed
at 4 months with a return to baseline values
during the recovery period. These data indicate
that 4 g/day of highly purified EPA + DHA ethyl
esters are able to favorably affect BP in mild
hypertensives. The results of this study should
be considered hypothesis-generating; however, it
is intriguing to think that moderate fish oil
consumption is associated with statistical
reductions in both systolic and diastolic blood
pressure.
Bender NK, Kraynak MA, Chiquette E, et al.
Effects of marine fish oils on the anticoagulation
status of patients receiving chronic warfarin
therapy. J Thromb Thrombolysis 1998;5:257–61.
The purpose of this placebo-controlled,
randomized, double-blinded, parallel study was
to determine the existence and magnitude of
effect of various doses of fish oil supplements on
international normalized ratio (INR)
determinations in patients receiving chronic
warfarin therapy. Patients from anticoagulation
clinics from both the Brady Green Community
Health Center and Audie L. Murphy Veterans
Administration in San Antonio, Texas were
enrolled in the study. 5 males and 11 females
were enrolled, all of whom were receiving
chronic warfarin therapy. All patients underwent
a 4-week placebo monitoring period in which
INRs were determined on a weekly basis. If the
INRs were found to be stable, patients were
randomized to receive a 4-week treatment period
of either placebo capsules (n = 6), 3 grams of fish
oil (specific product not specified) daily (n = 5),
or 6 grams of fish oil daily (n = 5). Patients were
followed on a twice-weekly basis for INR
determinations and adverse reactions. Five
patients were discontinued from the study due to
noncompliance (2) and unstable INRs (3). There
was no statistically significant difference in INRs
between the placebo lead-in and treatment period
within each group (p=0.82). There was also no
difference in INRs found between groups
(p=0.41). One bruising episode was reported, yet
no major bleeding episodes were observed during
the study. Fish oil supplementation in doses of
3–6 grams per day does not have significant
effects on anticoagulation status of patients
receiving chronic warfarin therapy, and adds to
existing evidence (see Svaneborg N et al below)
showing no increased risk for bleeding with
other antithrombotic agents.
Svaneborg N, Kristensen SD, Hansen LM, et al.
The acute and short-time effect of
supplementation with the combination of n-3
fatty acids and acetylsalicylic acid on platelet
function and plasma lipids. Thromb Res
2002;105:311–6.
Antiplatelet therapy with acetylsalicylic acid
(ASA) is commonly used to reduce the risk of
cardiovascular and cerebrovascular events. Fish
consumption has been inversely related to
coronary disease, which has been attributed to an
inhibitory effect of n-3 polyunsaturated fatty
acids (n-3 PUFA) on platelet production of
thromboxane A2. This study sought to
determine the acute and short-time effect of
supplementation with n-3 PUFA and intravenous
ASA on platelet function, platelet fatty acid
composition and plasma lipids. Eighteen healthy
volunteers were randomly allocated to a daily
intake of 10 g n-3 PUFA or placebo. After this
supplement (14 h and 14 days), blood was
sampled before and after intravenous injection of
100 mg ASA. n-3 PUFA given for 14 days caused
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
a minor inhibition of platelet reactivity but
negligible compared to 100 mg ASA. Platelet
reactivity was assessed by measuring change in
the serum bleeding time, platelet count, and
serum thromboxane B2 concentration. No
additive effect of n-3 PUFA and ASA could be
demonstrated. These findings suggest that there
is not an additive antiplatelet effect created by
concomitant use of high-dose fish oil
supplements and low-dose aspirin.
Raitt MH, Connor WE, Morris C, et al. Fish oil
supplementation and risk of ventricular
tachycardia and ventricular fibrillation in patients
with implantable defibrillators: a randomized
controlled trial. JAMA 2005 Jun15;293(23):
2884–91.
Clinical studies of omega-3 polyunsaturated
fatty acids (PUFAs) have shown a reduction in
sudden cardiac death, suggesting that omega-3
PUFAs may have antiarrhythmic effects. This
randomized, double-blind, placebo-controlled
trial sought to determine whether omega-3
PUFAs have beneficial antiarrhythmic effects in
patients with a history of sustained ventricular
tachycardia (VT) or ventricular fibrillation (VF).
200 patients with an implantable cardioverter
defibrillator (ICD) and a recent episode of
sustained VT or VF were enrolled between 1999
and 2003. Patients were randomly assigned to
receive fish oil, 1.8 g/d, 72% omega-3 PUFAs, or
placebo and were followed up for a median of
718 days (range, 20–828 days). The primary
outcomes were time to first episode of ICD
treatment for VT/VF, changes in red blood cell
concentrations of omega-3 PUFAs, frequency of
recurrent VT/VF events, and predetermined
subgroup analyses. Patients randomized to
receive fish oil had an increase in the mean
percentage of omega-3 PUFAs in red blood cell
membranes from 4.7% to 8.3% (p<0.001), with
no change observed in patients receiving placebo.
At 6, 12, and 24 months, 46% (SE, 5%), 51%
(5%), and 65% (5%) of patients randomized to
receive fish oil had ICD therapy for VT/VF
compared with 36% (5%), 41% (5%), and 59%
(5%) for patients randomized to receive placebo
(p=0.19). In the subset of 133 patients whose
qualifying arrhythmia was VT, 61% (SE, 6%),
66% (6%), and 79% (6%) of patients in the fish
oil group had VT/VF at 6, 12, and 24 months
compared with 37% (6%), 43% (6%), and 65%
(6%) of patients in the control group (p=0.007).
Among patients with a recent episode of
sustained ventricular arrhythmia and an ICD, fish
257e
oil supplementation does not reduce the risk of
VT/VF and may be proarrhythmic in some
patients. These data are particularly concerning
since fish oil supplements are widely available
OTC and are frequently advertised by radio and
television for purported health effects.
Subsequent analysis suggests that these effects
did not uniformly occur across all studies (see
Jenkins DJ et al below), so it is important to keep
these data in perspective. For now it appears to
be reasonable to exercise caution with
recommending fish oil supplements to patients
with AICDs.
Jenkins DJ, Josse AR, Beyene J, et al. Fish oil
supplementation in patients with implantable
cardioverter defibrillators: a meta-analysis. CMAJ
2008 Jan15;178(2):157–64.
This meta-analysis of randomized controlled
trials that examined the effect of fish-oil
supplementation on ventricular fibrillation and
ventricular tachycardia sought to determine the
overall effect and to assess whether heterogeneity
exists between trials.
Randomized controlled trials of fish-oil
supplementation on ventricular fibrillation or
ventricular tachycardia in patients with
implantable cardioverter defibrillators (ICDs)
were included. The primary outcome was ICD
discharge. Three trials of 1–2 years in duration
were identified. These trials included a total of
573 patients who received fish oil and 575
patients who received a control. Meta-analysis of
data collected at one year showed no overall
effect of fish oil on the relative risk of ICD
discharge. There was significant heterogeneity
between trials. The second largest study showed
a significant benefit of fish oil (relative risk [RR]
0.74, 95% confidence interval [CI] 0.56–0.98).
The smallest showed an adverse tendency at 1
year (RR 1.23, 95% CI 0.92–1.65) and
significantly worse outcome at 2 years among
patients with ventricular tachycardia at study
entry (log rank p=0.007). These data indicate
that there is heterogeneity in the response of
patients to fish-oil supplementation. Caution
should be used when prescribing fish-oil
supplementation for patients with ventricular
tachycardia and ICDs.
Lev EI, Solodky A, Harel N, et al. Treatment of
aspirin-resistant patients with omega-3 fatty acids
versus aspirin dose escalation. J Am Coll Cardiol
2010 Jan 12;55(2):114–21.
The aim of this prospective randomized study
258e PHARMACOTHERAPY Volume 31, 2011
was to evaluate whether addition of omega-3
fatty acids or increase in aspirin dose improved
response to low-dose aspirin among patients who
are aspirin resistant based on platelet screening
with the VerifyNow Aspirin assay (Accumetrics,
San Diego, California). Aspirin resistance was
defined by ≥ 2 of 3 criteria: VerifyNow score ≥
550, 0.5-mg/ml AA-induced aggregation ≥ 20%,
and 10-micromol/l adenosine diphosphate
(ADP)-induced aggregation ≥ 70%. Patients (n =
485) with stable coronary artery disease taking
low-dose aspirin (75 to 162 mg per day) for at
least one week were screened for aspirin
response. Thirty patients (6.2%) were found to
be aspirin resistant and randomized to receive
either low-dose aspirin + omega-3 fatty acids (4
capsules daily) or aspirin 325 mg daily. After 30
days of treatment patients were re-tested. After
treatment significant reductions in AA- and ADP-
induced aggregation and the VerifyNow score
were observed in both groups. Plasma levels of
thromboxane B2 were also reduced in both
groups (56.8% reduction in the omega-3 fatty
acids group, and 39.6% decrease in the aspirin
group). Twelve patients (80%) who received
omega-3 fatty acids and 11 patients (73%) who
received aspirin 325 mg were no longer aspirin
resistant after treatment. Treatment of aspirin-
resistant patients by adding omega-3 fatty acids
or increasing the aspirin dose seems to improve
response to aspirin and effectively reduces
platelet reactivity. These findings are limited by
lack of reporting about adherence to medications,
and a control group that did not consist of
patients with aspirin resistance. The small
number of patients enrolled as well as platelet
reactivity indices as primary outcomes limit
clinical significance of this study.
Gajos G, Rostoff P, Undas A, et al. Effects of
polyunsaturated omega-3 fatty acids on
responsiveness to dual antiplatelet therapy in
patients undergoing percutaneous coronary
intervention: the OMEGA-PCI (OMEGA-3 fatty
acids after pci to modify responsiveness to dual
antiplatelet therapy) study. J Am Coll Cardiol
2010 Apr 20;55(16):1671–8.
The OMEGA-PCI (OMEGA-3 Fatty Acids After
PCI to Modify Responsiveness to Dual
Antiplatelet Therapy) study was an investigator-
initiated, prospective, single-center, double-blind,
placebo-controlled, randomized study seeking to
determine whether PUFAs are able to modify
platelet response to dual antiplatelet therapy with
aspirin and clopidogrel in patients with stable
coronary artery disease. Patients receiving
standard dual antiplatelet therapy (aspirin 75
mg/day and clopidogrel 600 mg loading dose
followed by 75 mg/day) were randomly assigned
to receive the addition of 1 g of omega-3 ethyl
esters (n = 33) or placebo (n = 30) for one
month. Platelet function was measured serially
by light transmission aggregometry (adenosine
diphosphate and arachidonic acid [AA] were
used as agonists) and assessment of the
phosphorylation status of the vasodilator-
stimulated phosphoprotein at baseline, 12 h, 3 to
5 days, and 30 days after randomization. The
P2Y(12) reactivity index was significantly lower,
by 22.2%, after 1 month of treatment with
omega-3 polyunsaturated fatty acids compared
with placebo when used in addition to dual
antiplatelet therapy (p=0.020). Maximal platelet
aggregation induced by 5 and 20 micromol/l
adenosine diphosphate was lower by 13.3%
(p=0.026) and 9.8% (p=0.029), respectively, after
1 month of treatment with omega-3 polyun-
saturated fatty acids compared with placebo.
Platelet aggregation after AA stimulation was low
and did not change significantly throughout the
study. The addition of omega-3 ethyl esters to
the combination of aspirin and clopidogrel
significantly potentiates platelet response to
clopidogrel after percutaneous coronary
intervention; however, these findings may not be
generalizable to other important patient
populations, including patients with acute
coronary syndromes. Additionally, there is
considerable controversy regarding the clinical
significance of studies using platelet function test
results as a primary outcome.
OMEGA-6 FATTY ACIDS
Omega-6 fatty acids are polyunsaturated fatty
acids and include linoleic acid (also known as
conjugated linoleic acid, or CLA), gamma-
linoleic acid, and arachidonic acid. Omega-6
fatty acids are structural components of cellular
membranes, playing a role in cell-signaling
pathways and epithelial cell function, and are
often used for reducing risk of heart disease,
lowering cholesterol levels (including LDL and
total cholesterol), and affecting HDL levels.
Cardiovascular adverse effects: (Specific to
conjugated linoleic acid, or CLA) Include
elevated triglycerides (E), increased insulin
resistance (A), and decreased HDL (A).
Drug Interactions: No specific drug interactions
have been reported.
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
Riserus U, Arner P, Brismar K, Vessby B.
Treatment with dietary trans-10,cis-12 conjugated
linoleic acid causes isomer-specific insulin
resistance in obese men with the metabolic
syndrome. Diabetes Care 2002;25:1516–21.
This randomized, double-blind, controlled trial
was designed to determine whether a specific
isomer of conjugated linoleic acid (trans-10,cis-
12) or a commercially available conjugated
linoleic acid (CLA) mixture had any detectable
effect on insulin sensitivity, lipid metabolism, or
body composition in obese men with signs of
metabolic syndrome. To put this into
perspective, it is important to note that most
commercially available preparations of CLA
contain a mixture of isomers with trans-10, cis-12
and cis-9,trans-11 being the most common.
While both isomers are present in the diet, the
cis-9,trans-11 isomer is more prevalent. Previous
studies conducted in rats suggested that the
trans-10,cis-12 isomer was responsible for
antiobesity and insulin-sensitizing properties. A
total of 60 men were randomized to receive 3.4
gm of commercial CLA mixture, purified
trans10cis12 CLA, or placebo oil. Patients
receiving the purified trans-10,cis-12 CLA had
significantly increased insulin resistance (19%;
p<0.01), blood sugar values (4%; p<0.01), and
reduced HDL concentrations (–4%; p<0.01)
compared with placebo (no SD reported). The
commercial CLA mixture did not have significant
effect on glucose metabolism, body composition,
or weight compared with placebo; however
reduced HDL concentration was also observed
(–2%; p<0.05). Unexpectedly, these data suggest
that the trans-10,cis-12 CLA isomer may promote
disease progression in men with metabolic
syndrome by decreasing HDL and increasing
insulin resistance.
Riserus U, Smedman A, Basu S, Vessby B.
Metabolic effects of conjugated linoleic acid in
humans: the Swedish Experience. Am J Clin Nutr
2004 Jun;79(6 suppl):1146s–1148s.
This review article summarizes the author’s
experience with randomized studies designed to
evaluate the effects of various preparations of
CLA (including specific isomers such as trans-
10,cis-12) on glucose and lipid metabolism in
humans with metabolic syndrome. While they
observed that CLA seemed to decrease body fat—
especially abdominal fat—there was not any
related decrease in body weight or body mass
index. Additionally, the trans-10,cis-12 isomer
appeared to increase insulin resistance and reduce
259e
HDL—although this has not been substantiated
with statistical analysis. These data indicate that
the metabolic effects of CLA supplementation in
humans are complex and further study is needed
to determine if any specific mixtures or isomers
impart clinical benefit.
PAPAYA
Papaya leaves contain 2% papain and carpain.
Papain, a proteolytic enzyme found in papaya is
used for the treatment of digestive disorders;
carpain has amebicidal properties. Papain is also
believed to have natural anti-inflammatory
properties. Topical preparations are used for the
treatment of chronic ulcers.
Cardiovascular adverse effects: None reported.
Drug interactions: Concomitant use with
warfarin can increase INR and increase risk of
bleeding (C).
PECTIN
Pectin is a complex polysaccharide found in
the primary cell walls and intercellular space of
plant cells. The dominant polysaccharides in
pectin are homogalacturonan, rhamno-
galacturonan I, rhamnogalacturonan II, and
xylogalacturonan. Consumption of pectin has
been shown to reduce blood cholesterol levels.
The mechanism appears to be an increase of
viscosity in the intestinal tract, leading to a
reduced absorption of cholesterol from bile or
food. In the large intestine and colon,
microorganisms degrade pectin and liberate
short-chain fatty acids (butyrate) and may
prevent the occurrence of colon cancer. It is also
used in combination with Kaolin for treating
diarrhea.
Cardiovascular adverse effects: None reported.
Drug interaction: can reduce absorption of
lovastatin (C) and digoxin (A).
Albert KS, Ayres JW, DiSanto AR, et al.
Influence of kaolin—pectin suspension on
digoxin bioavailability. J Pharm Sci. 1978
Nov;67(11):1582–6.
This study evaluated the effect of kaolin-pectin
suspension (27% kaolin and 0.6% pectin) on the
oral bioavailability of digoxin. This was a two
part study: in study 1, 11 subjects were
randomly given Treatment A (0.5 mg of digoxin
tablets plus kaolin-pectin suspension were given
concomitantly) or Treatment B (0.5 mg digoxin
tablets with 180 ml of water). Whereas in study
2, 15 subjects were randomly administered
260e PHARMACOTHERAPY Volume 31, 2011
Treatment A (0.5 mg digoxin tablets with 180 ml
of water), or Treatment B (90 ml of kaolin-pectin
suspension 2 hrs before zero time followed by 0.5
mg of digoxin tablets at zero time) or Treatment
C (0.5 mg digoxin at zero time and 2 hours after
zero time 90 ml kaolin- pectin suspension).
Additionally, all subjects were required to fast
from 10:00 P.M. the night before their treatment
and fast until 4 hours after administering the
medication, except in study 2, where subjects
received standardized food and beverages after
the fasting period. Blood samples were collected
at specified time intervals for each treatment.
Serum was collected during study 1 and plasma
for study 2. In study part 1, concomitant
administration of digoxin and kaolin-pectin
suspension resulted in a 77% decrease in serum
digoxin concentration. In addition AUC 0–48h
decreased to 4.98 ng/ml/hr from 12.5 ng/ml/hr
(p<0.0001) between treatment A and B
respectively. In study part 2, administration of
kaolin-pectin suspension at 2 hours after digoxin
did not affect the rate of digoxin absorption,
although the relative extent of absorption was
reduced by 20% when suspension was given 2
hours before digoxin. These findings suggest
that decreased bioavailability of digoxin could
result from alterations in the gut transit time
when antidiarrheal medication preceded the
digoxin dose, although not supported by
previous studies.
POLICOSANOL
Policosanol is a dietary supplement extracted
from sugar cane and wheat germ oil. It contains
a mixture of aliphatic alcohols. Octacosanol is
the predominant moiety (63%) and other
important constituents are triacontanol (13%)
and hexacosanol (6%). Therapeutic uses for
policasanol include cholesterol lowering by
inhibiting hepatic cholesterol synthesis and
increasing the uptake and degradation of low-
density lipoprotein (LDL) cholesterol in the
endoplasmic reticulum. Policosanol reduces
platelet aggregation by altering prostaglandin
synthesis (thromboxane A2). It is also used for
intermittent claudication.
Cardiovascular adverse effects: Increased risk of
bleeding (E), hypotension (E).
Drug interactions: Increases the risk of
bleeding due to antiplatelet effect when
coadministered with aspirin (A), warfarin (D)
and clopidogrel (E), may decrease arterial
pressure, and thus may have potential additive
effects with beta-blockers, or other blood
pressure-lowering agents.
Arruzazabala ML, Valdes S, Carbajal D, Mas R.
Fernandez L. Comparative study of Policosanol,
Aspirin and the combination therapy Policosanol
–Aspirin on platelet aggregation in healthy
volunteers. Pharmacol Res 1997;36:293–7.
This study was conducted in 43 healthy
volunteers (14 females and 29 males), who were
all non-smokers and had not consumed aspirin
or any other medications for 2 weeks prior to
enrollment. All participants randomly received
placebo (n=11), policosanol (20 mg n=11),
aspirin(ASA) (100 mg, n=11) or policosanol plus
aspirin (n=10) for a 7 day period. Blood samples
were collected before and after each treatment.
Aggregometry was performed according to the
method of Born, using Elvi-840 aggregometer.
ADP 1 µM, epinephrine1 µM and collagen 0.6 µg
ml -1 were used as aggregating agents.
Coagulation time was quantified in minutes.
Policosanol for a 7-day period significantly
reduce platelet aggregation from baseline induced
by all three reagents, ADP (37.3%, P<0.01)
epinephrine (32.3%, P<0.05), collagen (40.5%,
P<0.01). Similarly ASA also significantly lowered
platelet aggregation induced by both collagen
(61.4%) and epinephrine (21.9%), however ADP-
induced aggregation was not altered (3.8%). On
the other hand the combination therapy with
policosanol plus aspirin induced the most
antiplatelet effects. The combination therapy
reduced platelet aggregation induced by ADP,
epinephrine and collagen by 31%, 57.7% and
71.3% respectively. Also, aggregation values in
all treatment groups were significantly lower
compared to placebo. Coagulation times were
not significantly altered in all groups. However,
when compared between the groups, ASA and
the combination group had higher coagulation
time than policosanol group and placebo
(P=0.07, P<0.05 respectively). No adverse effects
were reported in the placebo and policosanol
group. Three subjects in ASA treated group and
one subject in the combination therapy
experienced adverse effects (nose bleeding, gum
bleeding). Although the study showed that dual
therapy has additive antithrombotic effects
compared to monotherapy, these incremental
antithrombotic effects could potentially be
harmful in venerable populations who are also
receiving other anticoagulants and antiplatelet
agents.
Carbajal D, Arruzazabala ML, et al. Interaction
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
policosanol—warfarin on bleeding time and
thrombosis in rats. Pharmacol Res.
1998;38:89–91.
Policosanol inhibits platelet aggregation, in
experimental models and healthy volunteers.
The proposed mechanism appears to be a
decrease in platelet aggregating thromboxane B2
with no effect on prostacyclin (PGI 2 ), and
therefore may enhance the effect of other
anticoagulant medications. This study was
specifically designed to investigate the effect of
concomitant administration of warfarin and
single or repeated doses of orally administered
policosanol on bleeding time and experimentally
induced venous thrombus in rats. The animals
were randomly assigned into four experimental
groups. The control group only received Tween-
20 vechicle and isotonoc saline. The other three
groups either received policosonal or warfarin or
both along with either isotonic saline or Tween-
20 vechicle. Both policosanol and warfarin
monotherapy produced a significant reduction in
thrombus weight (p<0.05) compared to the
control. The combination of policosanol and
warfarin and warfarin alone induced a moderate
but significant prolongation of bleeding time
when compared to control (P<0.05). However,
the addition of policosanol to warfarin therapy
did not enhance the prolongation of bleeding
time induced by warfarin alone. Additionally,
this combination therapy did not result in
reduction of thrombus weight. Although this
study suggests a lack of interaction between
policosanol and warfarin, policosanol, should not
be given concomitantly until further research can
establish its safety due to the potential to block
similar anticoagulation pathways shared by other
anticoagulants.
Castaño G, Mas R, Gámez R, et al. Concomitant
use of policosanol and ␤-blockers in older
patients. Int J Clin Pharmacol Res.
2004;24(2–3):65–77.
Policosanol decreases arterial pressure, which
has been demonstrated by several clinical trials.
Experimental models have suggested a
pharmacological interaction with concomitant
use of policosanol and ␤-blockers. This
prospective, double-blind, randomized study
investigated whether policosanol enhances the
antihypertensive effects of ␤-blockers and/or
whether this combination can potentially lead to
adverse effects in elderly hypercholesterolemic
patients. Two hundred and five patients (60-80
years of age) taking ␤-blockers were randomized
261e
to policosanol 5 mg/day (N=98) or placebo
(N=107) for 3 years. With the exception of lipid
lowering agents all other concomitant
medications were continued. Lipid profile and
safety laboratory tests (glucose, creatinine, AST,
ALT) and physical assessment (body weight,
heart rate, blood pressure) were performed at
baseline and 1, 2 and 3 years. Adverse events
(AE) were classified into mild, moderate and
serious. A serious adverse event was considered
as an AE leading to hospitalization or death.
Thirty-one patients (15.1%) discontinued the
study, 21% (n=22) in the placebo group and 9.2%
(n=9) in the policosanol group. Of these, 20
patients (16 in the placebo group and 4 in the
policosanol group) withdrew from the study due
to adverse events (P<0.01). After 1 year
policosanol significantly decreased LDL-C
(P<0.001), TC and TG, and increased HDL
(P<0.001) and these effects sustained during the
three year follow up. The frequency of serious
adverse events (SAE), mostly vascular, in
policosanol patients (3/98, 3.1%) was lower than
in the placebo group (15/107, 14.0%). However,
reductions in systolic and diastolic blood
pressure were observed in policosanol patients
compared with those in the placebo group. The
frequency of policosanol patients reporting mild
or moderate AE (18/98, 18.4%) was also lower
than in the placebo group (30/107, 28.0%).
These results provide support that policosanol
therapy added to hypercholesterolemic elderly
individuals taking ␤-blockers could provide
additional benefits in lowering blood pressure;
SAE were not more frequent in the policosanol
group than in the placebo group and there was
no increase in AE.
Abdul MM,  Jiang X,  Williams KM.
Pharmacokinetic and Pharmacodynamic
interactions of Echinacea and Policosanol with
warfarin in healthy subjects. British Journal of
Clinical Pharmacology 2010;69: 508–515(A).
(Refer to echinacea for annotated bibliography)
POMEGRANATE
The applicable parts of pomegranate are the
fruit, juice, seed, root, leaf and stem. The juice
contains polyphenols that have antioxidant
activity and can reduce the progression of
atherosclerosis. The pomegranate juice also
appears to stimulate the production of nitric
oxide. Thus it is used to treat a variety of
conditions which include hypertension,
262e PHARMACOTHERAPY Volume 31, 2011
hyperlipidemia, congestive heart failure, and
ischemic coronary heart disease. The flower of
pomegranate is used for treating diabetes because
of its alpha-glucosidase inhibiting activity.
Cardiovascular adverse effects: Hypotension
(E).
Drug interactions: Inhibits CYP3A4 and can
increase levels of drugs that are metabolized via
this pathway such as calcium channel blockers
(verapamil and diltiazem) (E) and statins
(simvastatin) (C) inhibits CYP2C9, and can
increase levels of drugs that are metabolized via
this pathway such as warfarin(C), concomitant
use with antihypertensive agents such as ACEI’s
may have additive effects on blood pressure and
can result in hypotension (B).
Aviram M, Dornfeld L. Pomegranate juice
consumption inhibits serum angiotensin
converting enzyme activity and reduces systolic
blood pressure. Atherosclerosis 2001;158:195–8.
This study tested the hypotheses that
antioxidants can reduce blood pressure and
therefore pomegranate juice (PJ), which is
considered a potent antioxidant, may also exhibit
blood pressure lowering effects. Ten hyper-
tensive individuals (7 males and 3 females) were
enrolled in the study. The mean baseline blood
pressure was 155 ±7/83 ±7mmHg. Eight subjects
were on ACE inhibitors and two were on calcium
channel blockers. Serum angiotensin II concen-
trations were measured at baseline and after 2
weeks of PJ consumption (50 ml). In seven out
of ten subjects ACE activity was significantly
reduced by 36% compared to baseline. The mean
systolic blood pressure was reduced by 5% to
147±10/82 ±5 (p<0.05). The minor change
observed in blood pressure could have resulted
from antioxidant effects of PJ and increased
availability of nitric oxide (which is a potent
vasodilator). In order to further investigate the
mechanism of inhibitory effects of PJ, increasing
concentrations of PJ were added to human serum
in vitro and incubated for 15min at 37 degrees.
ACE activity was reduced by 31%, probably due
to PJ constituents directly inhibiting ACE
activity. Thus consuming PJ with ACE inhibitors
might have some additive effects, although the
study is fairly small to draw robust conclusions.
Hidaka M, Okumura M, Fujita K, et al. Effects of
pomegranate juice on human cytochrome p450
3A (CYP3A) and carbamazepine
pharmacokinetics in rats. Drug Metab Dispos
2005;33:644–8.
This study investigated whether the
components of pomegranate juice (PJ) could
inhibit CYP3A4 activity in human liver
microsomes. In addition the authors also
investigated the in vivo pharmacokinetic
interaction between PJ and carbamazepine in
rats. Addition of 25 µl of PJ resulted in complete
inhibition of carbamazepine 10,11-epoxidase
activity of human CYP3A4(1.8%). The length of
pre-incubation altered the inhibition potency and
was similar to grapefruit juice. The residual
activities of the enzyme with PJ at pre-incubation
times 0.5, 10.15, and 30 min were 90.0%, 81.4%.
75.0%, 64.7% and 45.7% respectively, suggesting
a mechanism-based inhibition. In order to
determine the effects of PJ(2 ml) on
carbamazepine pharmacokinetic, the rats were
administered oral carbamazepine (50 mg/kg),
grapefruit juice, or water an hour following PJ
administration. PJ increased the AUC of
carbamazepine by 1.5 fold compared to rats who
were treated with water. Similar results were
observed with grapefruit juice. Conversely the
elimination half life for carbamazepine and
carbamazepine 10,11-epoxidase were not
different between the three groups. The authors
hypothesized that the increase in AUC of
carbamazepine was caused by the inhibition of
carbamazepine metabolism as well as enhanced
absorption by various components of PJ. They
further tested this hypothesis by using in situ
closed loop technique in order to determine the
absorption of PJ from various parts of the rat
intestine. Interestingly, absorption was not
different between the various segments of the rat
intestine (duodenum, jejunum, ileum, and
cecum) in the presence or absence of PJ, thus
alluding to a mechanism-based irreversible
inhibition. Furthermore, the inhibition lasted for
approximately three days which is consistent
with previously reported studies. Hence, PJ
might influence the pharmacokinetics of
carbamazepine and other drugs that use this
pathway for metabolism.
Nagata M, Hidaka M, Sekiya H, et al. Effects of
pomegranate juice on human cytochrome P450
2C9 and tolbutamide pharmacokinetics in rats.
Drug Metab Dispos. 2007;35:302–5.
This study evaluated the ability of pomegranate
juice (PJ) to inhibit CYP2C9 mediated drug
metabolism by using human liver microsomes.
Diclofenac 4¢-hydroxylase and tolbutamide were
used as the probe substrates for CYP2C9 activity
in vitro and vivo, respectively. The addition of 25
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
µL of PJ to substrate diclofenac resulted in
complete inhibition of CYP2C9 and the mean
IC50 was 4.8 µL. If the pre-incubation period
was prolonged the inhibitory potency was altered
suggesting that this could probably be a
mechanism-based inhibition rather than
proteolytic activity of the juice. Furthermore,
when boiled the inhibitory effects (IC50 was 5.03
µl) of PJ did not vary from what was observed at
physiological temperature. The authors also
investigated the effects of PJ on the
pharmacokinetics of tolbutamide in rats. The
rats were injected with 3 ml PJ one hour before
the administration of tolbutamide (20 mg/kg).
The AUC of tolbutamide was significantly
increased by 22%; however the elimination half-
life was not different from controls. The study
concluded that PJ inhibited human CYP2C9
activity and increased tolbutamide bioavailability
in rats. However, studies in human subjects are
warranted to confirm these findings.
PSYLLIUM
The applicable part of psyllium is the seed.
The seed forms a mucilaginous mass when mixed
with water and has a bulk laxative effect.
Psyllium can decrease cholesterol by absorbing
dietary fats in the gastrointestinal tract, thereby
preventing systemic absorption. It is used for
constipation, lowering cholesterol, dysentery and
to treat cancer.
Cardiovascular adverse effects: None.
Drug interactions: No effect on digoxin
absorption (A), has the potential to reduce drug
absorption of warfarin (E).
Nordstrom M, Melander A, Robertsson, Steen
B. Influence of Wheat Bran and of a Bulk-
Forming Ispaghula Cathartic on the
bioavailability of Digoxin in Geriatric In Patients.
Drug-Nutrient interactions.1987;5:67–69.
This study compared the effects of wheat bran
and psyllium-containing laxative (Vi-Siblin®) on
digoxin levels. Thirty geriatric patients were
randomized to either wheat bran(7.5 mg twice
daily) and digoxin (0.25 mg, 0.13 mg, 0.95 mg,
0.065 mg) (n=16) or psyllium(4 gm twice
daily)and digoxin (n=14) for four weeks. Most
patients received 0.13 mg digoxin. Trough levels
of digoxin did not change with psyllium
administration compared to baseline, but were
statistically significantly lower with wheat bran at
two (p<0.01) but not four weeks compared with
baseline. Psyllium-containing products may
263e
delay gastric emptying time and reduce the
absorption of some drugs. However based on the
data available, it would appear that consuming
psyllium concomitantly with digoxin would have
a minimal effect on digoxin concentrations. If
there is still a concern separating administration
times could potentially minimize this interaction.
RED YEAST RICE
Red yeast rice contains mevinic acids
(constitute about 0.4% of red rice), which
includes lovastatin, the HMG-CoA reductase
inhibitor. Red yeast is used for maintaining
desirable cholesterol levels in healthy people,
reducing cholesterol in people with
hyperlipidemia, for indigestion, diarrhea,
improving blood circulation, and for spleen and
stomach health.
Cardiovascular adverse effects: Myalgias (C),
rhabdomyolysis (C), myopathy (C), and
hepatotoxicity (C).
Drug interactions: Contains lovastatin, which is
metabolized by CYP 3A4. Drugs that inhibit CYP
3A4 can increase serum levels of lovastatin and
increase the risk for adverse effects (E), may lead
to increased risk for myopathies in combination
with gemfibrozil or other statins (E).
RESERVATROL
Resveratrol is a polyphenolic compound that
exists in nature as cis- and trans- stereoisomers.
It is primarily found in red wine, red grape skins,
purple grape juice, mulberries, and in smaller
amounts, in peanuts. Resveratrol has antioxidant
and anti-inflammatory activity. The anti-
inflammatory activity is probably due to
inhibition of cyclooxygenase-1 and 5-
lipooxygenase. It also decreases inflammatory
cytokines. By reducing lipid peroxidation
resveratrol can improve myocardial ischemia.
Orally, resveratrol is used for atherosclerosis,
lowering cholesterol levels, increasing HDL
cholesterol levels, and preventing cancer.
Cardiovascular adverse effects: Increased risk of
bleed (E).
Drug interactions: Increased risk of bleeding
when used concomitantly with antiplatelet agents
such as aspirin (B), clopidogrel and warfarin (E),
inhibits CYP3A4 and can increase levels of drugs
that are metabolized via this pathway such as
statins (D).
Stef G, Csiszar A, Lerea K, Ungvari Z, Veress G.
Resveratrol Inhibits Aggregation of Platelets from
High-risk Cardiac Patients with Aspirin
264e PHARMACOTHERAPY Volume 31, 2011
Resistance. Journal of Cardiovascular
Pharmacology 2006;48:1–5.
In animal models resveratrol can inhibit
platelet aggregation. This study investigated the
anti-platelet effects of resveratrol in a cohort of
50 high risk patients. Patients were eligible if
they were on aspirin (≥100 mg/d). Patients with
acute MI, HIV, or those on chronic oral
anticoagulants were excluded. Platelet rich
plasma was drawn to determine aspirin
sensitivity status and participants were
categorized as aspirin-sensitive (ASA-S) (n=31)
or aspirin resistant (ASA-R) (n=19). Aspirin
resistance was defined as higher-than-expected
aggregation to collagen and epinephrine (≤40%)
after oral treatment with 100 mg/d ASA. Based
on this definition, 38% of participants were ASA-
R. Platelet function was evaluated ex vivo by
optical aggregometry. In the presence of
resveratrol (10-5 mol/L) ADP-induced aggregation
at 5 µmol/L and 10 µmol/L was only slightly
affected. On the contrary maximal platelet
aggregation of ASA-R platelets to collagen 2
µmol/L was significantly decreased by resveratrol
compared to ASA-S platelets. Similar inhibitory
effects were observed with epinephrine (10
µmol/L). This study suggests that aspirin
sensitivity status affects the magnitude of platelet
aggregating effects of resveratrol in individuals
taking aspirin.
ROSEROOT
The applicable part of roseroot (Rhodiola rosea)
is the root. Roseroot contains over 30
compounds including phenlyethanoids,
phenylpropanoids, flavonoids, cyanoglycosides,
monoterpenes, and triterpenes. The
phenylpropanoid glycoside called salidroside is
thought to be responsible for many of the
stimulant or “adaptogenic” effects of roseroot.
The adaptogenic effects include neuroprotective,
cardioprotective, antidepressant, anxiolytic and
CNS stimulating activity. It is postulated that
Rooseroot extract safeguards the cardiovascular
tissue from the release of catecholamines and
helps to improve cardiac contractility. The anti-
arrhythmic effects are secondary to the
stimulation of peripheral ␬-opioid receptors. The
roseroot extract also has antioxidant and anti-
inflammatory properties.
Cardiovascular adverse effects: None reported.
Drug interactions: None reported
SAW PALMETTO
The applicable part of saw palmetto (Serenoa
repens) is the ripe fruit. The active ingredients of
saw palmetto are fatty acids, plant sterols and
flavonoids. It has antiandrogenic, antipro-
liferative and anti-inflammatory properties. It
exerts its anti-inflammatory effects by inhibiting
cyclooxygenase and 5-lipooxygenase. It is the
most popular herb supplement used to treat the
symptoms of benign prostatic hyperplasia. Other
uses include treating the common cold, sore
throat, asthma, cancer and problems with
reproductive system.
Cardiovascular adverse effects: Increased risk of
bleeding(C).
Drug interactions: May increase antiplatelet
effects of agents such as (aspirin, clopidogrel) (B)
inhibits CYP3A4 and may increase levels of drugs
that are metabolized via this pathway such as
statins (D), inhibits CYP2C9 and may increase
levels of drugs that are metabolized via this
pathway such as warfarin (D)
Markowitz JS, Donavan JL, DeVane L, Taylor
RM et al. Multiple doses of saw palmetto
(Serenoa repens ) did not alter cytochrome P450
2D6 and 3A4 activity in normal volunteers.
Clincal Pharmacology & Therapeutics.
2003;74:536–42
This study investigated if multiple doses of saw
palmetto altered the enzymatic activity of
cytochrome P450 enzymes CPY 2D6 or 3A4 in
twelve healthy volunteers. Alprazolam and
dextromethorphan were chosen as the probe
drugs for CYP3A4 and CYP2D6, respectively.
This study was conducted in three phases.
During phase one the volunteers were
administered 30 mg of dextromethorphan and 2
mg alprazolam to establish a baseline CYP2D6
and CYP3A4 activity. In phase two after a 7 day
washout period, subjects were given saw
palmetto extract for 14 days (recommended dose
of one 320 mg capsule daily). In phase three
after 14 days of exposure to saw palmetto,
subjects again received 30 mg of
dextromethorphan and 2 mg alprazolam along
with one capsule of saw palmetto for two days.
After one week blood tests were performed.
There was no significant difference in the
metabolism of dextromethorphan at baseline and
after administration of saw palmetto (P>0.05).
Similarly alprazolam metabolism was not affected
by saw palmetto. The authors concluded that at
the recommended doses it was unlikely that saw
palmetto inhibited the activity of CYP3A4 and
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
CYP2D6; however the findings cannot be
extended to other formulations of saw palmetto.
Yale SH and Glurich I. Analysis of the inhibitory
potential of Ginkgo biloba, Echinacea purpurea
and Serenoa repens on the metabolic activity of
cytochrome P450 3A4, 2D6, and 2C9. J Altern
Complementary Med. 2005;11:433–439.
(Refer to echinacea for annotated bibliography)
Beckert BW, Concannon MJ, Henry SL, Smith
DS, Puckett CL. The effect of Herbal Medicines
on Platelet Function: An In Vivo Experiment and
review of the literature. Plast Reconstr.Surg.
2007; 120:2044–2050.
(Refer to garlic for annotated bibliography)
SOY PROTEIN AND ISOFLAVONES
Orally, soy is used for hyperlipidemia,
menopausal symptoms, preventing osteoporosis,
and preventing cardiovascular disease. In foods,
soy is used as a milk substitute in infant feeding
formulas, and as an alternative to cow’s milk.
Soybeans are eaten boiled or roasted. Purported
health benefits of soy are quite variable in
published studies; however, slight decreases in
LDL, neutral effects on HDL, triglycerides,
lipoprotein A, and blood pressure have been
described.
Cardiovascular adverse effects: None reported.
Drug interactions: Decreased warfarin
anticoagulation effects possibly resulting in
increased risk for thrombosis (C), and possible
inhibition of platelet aggregation resulting in
increased risk for bleeding with concomitant use
of antiplatelet agents (E).
SAINT JOHN’S WORT
The flowers and the seeds are used to prepare
different formulations for medicinal use. St.
John’s Wort (SJW) inhibits the synaptosomal
uptake of serotonin, dopamine and
norepinephrine with approximately equal affinity.
Hence it is used in the treatment of depression,
dysthymia, anxiety, sleep disorders, mood
disturbances associated with menopause,
attention deficit-hyperactivity disorder,
obsessive-compulsive disorder, and seasonal
affective disorder. It is also used to control of
viral infections such as herpes and human
immunodeficiency virus.
Cardiovascular adverse effects: Arrhythmia,
hypertension (E).
Drug interactions: Induces P-glycoprotein and
265e
can decrease digoxin levels (A) induces intestinal
and hepatic CYP3A and can decrease levels of
drugs that are metabolized via this pathway such
as calcium channel blockers (verapamil)(B) and
statins (A), induces CYP2C9 and can decrease
levels of drugs that are metabolized via this
pathway such as warfarin (B), increases
antiplatelet effects of clopidogrel (B).
Johne A, Brockmoller J, Bauer S, Maurer A, et
al. Pharmacokinetics and drug disposition:
pharmacokinetic interaction of digoxin with
herbal extract from St. John’s Wort (hypericum
perforatum). Clin Pharmacol Ther.
1996;66:338–345.
SJW is thought to reduce serum levels of
digoxin through induction of the expression of
the MDR-1 P-glycoprotein transporter. This
study investigated the interaction between
hypericum extract LI160 and digoxin. Twenty-
five healthy subjects were enrolled (12 women,13
men). A loading dose of digoxin 0.25 mg twice a
day was initiated for two days followed by 0.25
mg/d. After 5 days the subjects were randomized
to treatment with St John’s Wort (SJW) extract
(LI160)(n=13) or placebo (n=12) for 10 days
(study day 6–15). Blood samples for
pharmacokinetic analysis were taken at days 5, 6
and 15. The primary objective was to evaluate
the influence of co-administration of digoxin
along with LI160 on digoxin trough levels and
AUC(0–24). On day 6 after a single-dose of SJW
digoxin levels were not decreased, on the
contrary there was a slight increase in digoxin
C max with LI160(p=0.057). Compared to
placebo, 10 days of co-administration of SJW
resulted in a 25% decrease in digoxin AUC(0–24)
(p=0.0035), a 26%(p=0.0095) decrease in peak
plasma digoxin concentration (C max ), a 19%
decrease in trough digoxin concentrations and a
33% (p=0.0023) decrease in digoxin
concentration at 24 hours following the last
digoxin dose. The effects on pharmacokinetic
parameters were even more pronounced when
compared within LI160 group. There was a 28%
decrease in digoxin AUC (p=0.001) and 26%
decrease in Cmax (p=0.0013) on study day 15.
Digoxin trough declined by 37% (p=0.001).
Whereas, within the placebo group, there was a
9% decrease in AUC(0–24) between day five and
day 15 (P=0.2). The terminal t 1/2 of digoxin
elimination remained constant. However, there
were no differences observed in the pharmaco-
dynamic parameters (such as: blood pressure
and heart rate) between both groups. The study
266e PHARMACOTHERAPY Volume 31, 2011
showed that multiple-dose treatment with SJW
extract LI160 resulted in a significant reduction
in digoxin trough, AUC(0–24) and C max values
compared to placebo. The increased reduction in
digoxin trough over a course of 10 day
combination therapy suggests an inducible
mechanism, probably an induction of P-
glycoprotein. Based on the significant changes
observed in the AUC, SJW can affect therapeutic
efficacy of digoxin, given the narrow therapeutic
window of the drug. In patients who are
concomitantly taking SJW and digoxin, digoxin
plasma levels should be monitored and dosage
adjustments considered when SJW is
discontinued.
Sugimoto Ki, Ohmori M, Tsuruoka S, et.al.
Different effects of St. John’s Wort on the
pharmacokinetics of simvastatin and pravastatin.
Clin Pharmacol Ther. 2001;70:518–564.
This study is comprised of two separate
studies. Study 1 (n= 8) was done with
simvastatin and study 2 (n=8) with pravastatin;
both enrolled healthy male Japanese volunteers.
All 16 subjects took one 300-mg caplet of St.
John’s Wort (SJW) or a matching placebo three
times a day for 14 days in a double blind,
crossover design with a washout period of 4
weeks. On day 14, study 1 subjects received 10
mg simvastatin and study 2 subjects received 20
mg pravastatin. Blood samples were collected
before and at 24-hour periods. SJW lowered the
plasma concentration of simvastatin lactone and
significantly decreased the concentration of its
active metabolite simvastatin hydroxyl acid
(P<0.05) when compared to placebo. The
combined AUC(0-24) for lactone and hydroxyacid
was also significantly decreased (p<0.05). On the
other hand, SJW did not influence the pravastatin
concentration, C max or AUC (0–24) . Unlike
pravastatin, simvastatin is extensively metabo-
lized by CYP3A4 and SJW is a potent inducer of
CYP3A4 in the intestinal wall and liver, thus
when ingested together can reduce the lipid
lowering effects of simvastatin,
Muller SC, Uehleke B, Woehling H, Petzsch M,
Majcher-Peszynska J, Hel E, et al. Effect of St.
John’s Wort dose and preparations on the
pharmacokinetics of digoxin. Clin Pharmacol
Ther 2004;75:546–57.
St. John’s Wort (SJW) products are
standardized with regard to hypericins but not
hyperforin. Recent studies have shown that the
degree of enzyme induction by SJW correlates
strongly with the amount of hyperforin found in
the product. Products that contain <1% amounts
of hyperforin may not produce clinically relevant
enzyme induction. SJW is commercially
marketed under numerous formulations and
dosage strengths. The purpose of this study was
to evaluate pharmacokinetic interactions between
10 different SJW products (with varying
hyperforin content) and digoxin. The
preparations included standardized extracts with
high and low hyperforin content, SJW dried herb
tea, powdered crude herb, fresh plant juice and
infused oil, as well as placebo control. This was a
randomized, placebo-controlled, parallel-group
3-part study: All parts were identical in design
except each study part had different
formulations, and doses of SJW and placebo. A
total of 97 healthy volunteers received digoxin
for an initial 7 days (loading dose with 0.2–0.3
mg 3 times a day for 3 days and then
individualized maintenance doses once daily)
followed by 14 days of co-medication with SJW
or placebo. Blood samples were taken on day 7
and on day 21 for pharmacokinetic analysis. The
high dose hyperforin-rich extract LI160 reduced
steady state AUC of digoxin by 25% (95% CI=21,
28), Cmax by 37%(95% CI= 32,42) , and Cmin by
19%(95% CI=11, 27) compared to formulations
with half the hyperforin content. Similar results
were observed with 4 g of hypericum powder
type A (which contained hyperforin content
comparable to LI160), AUC of digoxin was
reduced by 27% (95% CI=16, 37), Cmax by 38%
(95% CI= 18, 48), and Cmin by 19% (95% CI=10,
27). Furthermore both LI160 and 4g of
hypericum powder type A showed a significant
interaction based on the 90% CIs of geometric
mean ration of AUC0–24 and of Cmax, which fell
outside the range of 0.8 to 1.25 (90% CI, 0.72 to
0.78 & 0.67 to 0.81). For all other SJW
preparations a lack of interaction was seen.
These results are consistent with other
mechanism-based studies that have implicated
high-dose hyperforin-rich extracts to induce
intestinal CYP3A4 and P-glycoprotein resulting
in reduced bioavailability of substrate drugs.
Jiang X, Williams KM, Liauw WS, et al. Effect of
St. John’s Wort and ginseng on the
pharmacokinetics and pharmacodynamics of
warfarin in healthy subjects. Br J Clin
Pharmacol.2004; 57:592–599.
In vivo and vitro studies have suggested that
co-administration of St. John’s Wort (SJW)
decreases the therapeutic effects of warfarin and
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
can potentially increase the risk of
thromboembolic events. This is the first open
label, three-way crossover randomized study to
investigate this interaction. Twelve healthy male
subjects were administered a single 25 mg dose
of rac-warfarin alone or with pretreatment for 14
days, with multiple doses of either SJW or 7 day
pretreatment with Korean ginseng. There was a
14 day washout between treatment periods. Both
SJW and ginseng were further continued for one
additional week after warfarin administration.
Platelet aggregation, INR, plasma concentrations,
protein binding of warfarin enantiomers and S-7-
hydroxywarfarin urine concentration were
measured. There was a significant difference in
AUC, t1/2 and clearance for both S-warfarin and
R-warfarin following treatment with SJW. The
mean ratio and 90% CI of apparent clearance for
S- warfarin and R-warfarin was 1.29 (1.16, 1.46),
1.23 (1.11, 1.37) respectively when SJW was co-
administered. This resulted in reduced
pharmacological activity of rac-warfarin. The
mean ratio of AUC0–168 of INR was 0.79 (90% CI
0.70, 0.95) with SJW, and 1.01 (90% CI 0.88,
1.16) with ginseng. No pharmacokinetic or
pharmacodynamic changes were observed with
ginseng. Moreover, no significant changes were
seen in protein binding when warfarin was co-
administered with ginseng or SJW. S-warfarin is
metabolized by CYP2C9 while R-warfarin is
metabolized by CYP1A2 and CYP3A4. SJW is an
inducer of CY1A2 and CYP3A4 which
metabolizes R-warfarin and CYP2C9 which
metabolizes S-warfarin. Hence, SJW at
recommended doses induced the metabolism of
both R and S warfarin and affected the apparent
clearance of warfarin enantiomers with a
subsequent effect on INR. Since warfarin
response can be affected by multiple factors
(such as 2C9 polymorphisms, dietary factors,
numerous drug-drug interactions), makes it
challenging to interpret these results. However,
INR monitoring is essential when patients are on
SJW and warfarin; the potential for excessive
anticoagulation and bleeding can especially occur
in patients who have been stabilized on warfarin
and are discontinuing SJW from a stable regimen
of co-administration.
Tannergren C, Engman H, Knutson L, Headland
M et al. St John’s Wort decreases the
bioavailability of R- and S- verapamil through
induction of first pass metabolism. Clin
Pharmacol Ther. 2004;75:298–309.
Verapamil is mainly metabolized by CYP 3A4
267e
to norverapamil which has 20% of the
pharmacological activity of the parent drug.
Verapamil has low and variable bioavailability,
with high intestinal absorption. SJW which is an
inducer of CYP 3A4, when administered with
verapamil could potentially further lower the
bioavailability of verapamil. This study was
conducted in eight healthy male volunteers who
received 120 mg/racemic mixture of verapamil
(R/S-verapamil) for 100 minutes by jejunal
perfusion before and after 14 days of oral
treatment with SJW (300 mg three times a day).
SJW decreased the AUC of both enantiomers
(p<0.0001). The AUC values of norverapamil
also decreased for both R/S verapamil (51% and
63% respectively). However treatment with SJW
did not change the jejunal permeability and
terminal half-life for both enantiomers.
Compared to the enantiomers of verapamil the
AUC of norverapamil enantiomers was greater
(p<0.001) which was due to the prolonged t1/2
observed for the metabolite. Based on these
findings, SJW and verapamil interaction was a
result of CYP 3A4 induction in the gut rather
than of hepatic enzymes.
Lau WC, Carville DGM, Guyer KE, et al. St.
John’s Wort Enhances the Platelet Inhibitory
Effect of Clopidogrel in Clopidogrel “Resistant”
Healthy Volunteers. American College of
Cardiology Annual Meeting, Orlando, FL 2005:
Presentation 1043-129.
This study examined the effect of SJW on
clopidogrel’s platelet inhibitory effects. Six
research volunteers resistant to clopidogrel
(<30% platelet aggregation) were screened for
their response to 450 mg of clopidogrel, using a
platelet aggregation test. Participants received a
single dose of clopidogrel, followed by a 14-day
washout period. Thereafter, subjects were started
on St. John’s Wort, 300 mg three times a day for
two weeks followed by an additional dose of
clopidogrel, and platelet activity was monitored
for six hours. All subjects had a significant
decline in platelet aggregation, which became
more predominant at 4 hours (p=0.007). Similar
effects on platelet aggregation were also seen
after an erythromycin breath test. This study
suggests that SJW enhances the effects of
clopidogrel in patients otherwise resistant to its
benefits, and requires further confirmation in a
larger cohort.
Beckert BW, Concannon MJ, Henry SL, Smith
DS, Puckett CL. The effect of Herbal Medicines
on Platelet Function: An In Vivo Experiment and
268e PHARMACOTHERAPY Volume 31, 2011
review of the literature. Plast Reconstr.Surg.
2007; 120:2044–2050.
(Refer to garlic for annotated bibliography)
STANOL AND STEROL ESTERS
Both stanols and sterol esters are similar in
structure to cholesterol and act by inhibiting
intestinal cholesterol absorption. By lowering
LDL-C levels, plant stanols and sterols have been
shown to be useful in hyperlipidemia and
coronary heart disease, reducing the risk of
cardiovascular events.
Cardiovascular adverse effects: None reported.
Drug Interactions: Reduced plasma
concentrations of sterols with ezetimibe (A) and
pravastatin (B), but not with other statins (B);
additive effect on LDL-C reduction when
combined with statins (A).
Sudhop T, Lütjohann D, Kodal A, Igel M,
Tribble DL, Shah, S, Perevozskaya I, von
Bergmann K. Inhibition of intestinal cholesterol
absorption by ezetimibe in humans. Circulation
2002;106:1943–8.
Ezetimibe acts at the intestinal brush border
and inhibits the uptake of dietary and biliary
cholesterol. Because plant sterols share the same
route of absorption and are structurally similar to
cholesterol, an interaction with ezetimibe would
likewise reduce circulating levels of plant sterols.
While the primary focus of this study was to
evaluate the effect of the absorption and
endogenous synthesis of cholesterol under
ezetimibe therapy, important and relevant
information pertaining to plant sterols was also
included. In this randomized, double-blind,
placebo-controlled, 2-period, crossover study, the
effects of ezetimibe (10 mg/d) vs. placebo on
levels of noncholesterol plant sterols
(campesterol and sitosterol) were evaluated.
Eighteen patients between 18–55 years old with
mild to moderate hypercholesterolemia were
included in the study. Usual dietary habits and
nutritional intake were encouraged during the
study period. Plasma concentrations of
campesterol and sitosterol were collected at
baseline and after 2 weeks of treatment, which
were then analyzed by gas-liquid
chromatography selective ion monitoring.
Ezetimibe significantly lowered concentrations of
campesterol and sitosterol (–48% and –41%,
p<0.001 for both). The results after 2 weeks of
treatment with ezetimibe and placebo are listed
in the table below.
Placebo Ezetimibe
Sterol mg/dL mg/dL P-value
Campesterol 0.443±0.181 0.231±0.096 <0.001
Sitosterol 0.312±0.102 0.183±0.073 <0.001
Geometric mean±SD
Although ezetimibe has been shown to reduce
serum levels of noncholesterol plant sterols, it is
unclear whether this effect portends a worse
cardiovascular outcome. Further study is needed to
determine the clinical significance of this interaction.
STROPHANTHUS
Strophanthus is a flowering plant native to
Africa which has historically been used as a
poison in arrows. The seeds of the strophanthus
plant contain a cardiac glycoside, strophanthin-
G, which has similar effects to digoxin. Because
of its cardiac glycoside properties it has been
used for several cardiovascular disease states,
including atherosclerosis, cardiac insufficiency,
and hypertension. In addition to its theoretical
benefits, strophanthin-G may also cause cardiac
glycoside toxicity and arrhythmias.
Cardiovascular adverse effects: Cardiac
arrhythmias (C).
Drug interactions: Increased risk of cardiac
glycoside toxicity with digoxin (E) and quinidine
(E), toxicity with diuretics through potassium
depletion (E).
TAMIRIND
Tamarindus indica, or tamarind, is commonly
used as a spice in food, in herbal bowel cleanse
preparations and has been reportedly used for
several conditions including constipation,
nausea, liver and gallbladder disease. The fruit,
pod and oil contain numerous compounds like
methyl salicylate, in addition to plant acids,
vitamins and minerals. Although tamarind does
not appear to have any direct cardiovascular
effects, its components may theoretically interact
with other agents often used in coronary artery
disease.
Cardiovascular adverse effects: None reported.
Drug interactions: Increased aspirin absorption
(B)
Mustapha A, Yakasai IA, Aguye IA. Effect of
Tamarindus indica L. on the bioavailability of
aspirin in healthy human volunteers. European
Journal of Drug Metabolism and
Pharmacokinetics. 1996;21(3):223–6.
Tamarind (Tamarindus indica) is commonly
used in food preparations and therefore is often
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
consumed concomitantly with pharmaceutical
agents, allowing for the possibility for drug
interactions. This small study evaluated the
effect of tamarind fruit extract mixed in millet
porridge on the bioavailability of a single 600 mg
dose of aspirin. The study was conducted in six
healthy male volunteers after a 2-week drug-free
initiation period comparing aspirin alone, aspirin
with millet porridge without T. indica fruit
extract, and aspirin with millet porridge
containing added T. indica extract. Blood
samples were taken and analyzed for
acetylsalicylic acid and salicylic acid
concentrations with all three treatments at 0.5, 1,
2, 3, 4, 5, and 6 hours post ingestion. The mean
plasma concentrations were used to estimate and
compare the pharmacokinetic parameters of
aspirin and its metabolite. The authors found
that Cmax, AUC0–6h, and t1/2 for acetylsalicylic
acid were significantly increased with the
aspirin/T. indica combination compared to aspirin
alone (28.62 vs. 10.04 mg/mL, 86.51 vs. 14.03
mg/mL·h, and 1.50 vs.1.04 h, respectively;
p<0.05 for each comparison). Similar changes
were observed with salicylic acid. These findings
demonstrate that Tamarindus indica extract can
increase the bioavailability of aspirin. However,
aspirin at doses of 600 mg is rarely used by
current standards and therefore the applicability
of this data is limited. More importantly, it is
unclear whether an increase in the bioavailability
of aspirin would translate into greater inhibition
of platelet aggregation or increased risk of
bleeding.
TEA: BLACK AND GREEN TEA (also see
Caffeine)
Black and Green Tea are both derived from the
Camellia sinensis plant and have traditionally
been used to treat a wide variety of conditions
including coronary artery disease,
hypercholesterolemia, and hypertriglyceridemia.
The antioxidant effect of polyphenolic flavonoids
is believed to be responsible for its purported
benefits whereas other constituents, such as
caffeine, are more closely associated with adverse
effects and outcomes.
Cardiovascular adverse effects: Arrhythmia (C),
antiplatelet (D), elevated homocysteine levels
(B).
Drug interactions: Increased absorption of
green tea with ascorbic acid and sucrose (D),
increase bleeding with anti-platelet medications
(E), increased concentrations of caffeine with
269e
verapamil (E), decreased effect with warfarin (C),
reduced vasodilation associated with
dipyridamole (B).
Peters U, Poole C, Arab L. Does tea affect
cardiovascular disease? A meta-analysis. Am J.
Epidemiol 2001;154:495–503.
Because tea has constituents which are
considered to produce both beneficial and
detrimental cardiovascular effects, several
epidemiological studies have been performed to
assess outcomes with chronic tea consumption.
However, these studies have resulted in vastly
different outcomes. In this meta-analysis, the
authors provided a reasonably balanced review of
the publications related to tea consumption on
myocardial infarction. Based on the result of 7
studies, the authors estimated an incident rate of
myocardial infarction to decrease by 11% as tea
consumption increases up to 3 cups (237 mL)
per day (fixed-effects RR =0.89, 95% CI: 0.79,
1.01). However, the authors also determined that
smaller studies with adverse or neutral effects on
myocardial infarction were less likely to be
published. Of particular importance were the
differences in estimated effect between
geographic regions. While a protective effect
from tea was reported in continental Europe (rate
ratio=0.26, 95%CI: 0.15, 0.46) an increased rate
of myocardial infarction or CHD was observed in
the United Kingdom (rate ratio=1.62, 95% CI:
1.15, 2.30). Confounders such as healthy
lifestyle and heterogeneous preparations of tea
were thought to influence positive outcome
studies. Given the limitations observed in the
literature, the benefits of tea could not be clearly
established in this study. Furthermore, increased
rates of myocardial infarction or CHD were
demonstrated in select populations. However,
this meta-analysis includes older studies (up to
2001) and more recent publications, cited in part
1 of our Key Articles Related to Complementary
and Alternative Medicine in Cardiovascular
Disease series, have shown reduced rates of
cardiovascular disease and stroke, and a lower
incidence of cardiovascular death.
de Koning Gans JM, Uiterwaal CS, van der
Schouw YT, Boer JM, Grobbee DE, Verschuren
WM, Beulens JW. Tea and coffee consumption
and cardiovascular morbidity and mortality.
Arterioscler Thromb Vasc Biol. 2010
Aug;30(8):1665–71. Epub 2010 Jun 18.
(Refer to coffee for annotated bibliography.)
270e PHARMACOTHERAPY Volume 31, 2011
THIAMINE
Thiamine, water soluble Vitamin B1 is one of
the key components for carbohydrate metabolism
combining with ATP to form Thiamine
Diphosphate. Although thiamine has been used
for a variety of indications including CHD,
established benefits have been limited to patients
with genetic metabolic disorders, thiamine
deficiency, and Wernicke-Korsakoff Syndrome.
Cardiovascular adverse effects: None reported.
Drug interactions: Endogenous depletion with
furosemide (B).
Seligmann H, Halkin H, Rauchfleisch S, et al.
Thiamine deficiency in patients with congestive
heart failure receiving longterm furosemide
therapy: A pilot study. Am J Med. 1992 Dec;93
(6):705–6.
Thiamine deficiency may cause impairment of
myocardial performance affecting cardiovascular
symptoms such as edema, vasodilation, and high
output cardiac failure. Because thiamine is a
water soluble vitamin, long-term furosemide
therapy may deplete endogenous concentrations
of thiamine leading to deficiency in patients with
heart failure. In this prospective study evaluating
the effect of long-term furosemide therapy on
urinary thiamine loss, 23 patients with
congestive heart failure (CHF) receiving
furosemide therapy were compared to 16 age-
matched controls defined as patients without a
diagnosis of CHF or use of furosemide therapy.
Patients with identifiable causes of inadequate
thiamine intake, absorption, or utilization or
increased metabolic requirements were excluded.
Indicators for thiamine deficiency included a
thiamine pyrophosphate effect (TPPE) > 15% and
urinary thiamine excretion >130 µg/g creatinine.
Patients identified as having thiamine deficiency
received intravenous thiamine 100 mg twice
daily for 7 days. Preadmission furosemide dose
and duration ranged from 80 to 240 mg daily and
3 to 14 months, respectively. Thiamine
deficiency was observed in 21 of 23 furosemide-
treated patients as determined by a TTPE > 15%.
The mean TPPE in this group compared to
control was 27.7 vs. 7.1%, respectively
(p<0.001). Mean urinary excretion was also
numerically but not statistically higher in
patients receiving furosemide therapy vs. control
(410 vs 236 µg/g creatinine, respectively).
Thiamine replacement therapy was initiated in 6
patients determined to be thiamine deficient
resulting in a reduction of TTPE to normal
values. These findings suggest that chronic
furosemide therapy might cause thiamine
deficiency in patients with CHF. Thiamine
supplements in CHF patients with thiamine
deficiency may provide some benefit; however,
large prospective randomized studies are required
to determine if thiamine supplementation can
improve patient CHF symptoms and outcomes in
these patients.
TUSSILAGO FARFARA (COLTSFOOT)
Tussilago farfara, a plant commonly used in
Chinese herbal medicine, inhibits the
arachidonic acid pathway resulting in anti-
platelet and anti-inflammatory effects, in addition
to stimulation of cardiovascular and respiratory
response. It has been commonly used for
inflammatory respiratory ailments such as
bronchitis, asthma, and pertussis. Oral
preparations may contain pyrrolizidine alkaloids
(PA) which are considered to be hepatotoxic and
should be avoided unless a PA-free product.
Cardiovascular adverse effects: Hypertension by
intravenous injection (D), increased bleeding
(E).
Drug interactions: Decreased platelet
aggregation (D) and increased risk of bleeding
with with aspirin, clopidogrel, and enoxaparin
(E), CYP3A4 inducers may convert PA-containing
products to N-oxides and conjugated dienic
pyrroles, ultimately leading to hepatocellular
carcinoma and/or heptic veno-occlusive disease as
a result of toxic necine esthers and alkylating
compounds in the liver (E).
Li YP, Wang YM. Evaluation of tussilagone: A
cardiovascular-respiratory stimulant isolated
from Chinese herbal medicine. Gen Pharmacol.
1988;19(2):261–3.
Tussilagone (TUS) is derived from the flower of
the tussilago farfara plant and is believed to
produce potent pressor effects. In this small
study of 14 animals, the cardiovascular effects of
TUS was investigated in a translational model of
anesthetized dogs (n=4), cats (n=5), and rats
(n=5). TUS was prepared as an emulsion
containing soy bean phosphorlipid for
intravenous administration. A control consisting
of emulsion alone was first administered to
document an absence of effect on blood pressure.
The pressor dose-response curves were
established in all 3 animal models using arterial
pressure and the acute LD 50 dose of TUS also
determined in rats. TUS increased blood
pressure in three types of laboratory animals. In
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
cats and dogs, the doses for pressor effect were
similar, whereas in rats higher doses were
required to produce a similar pressor response.
The acute intravenous LD50 dose in rats was 28.9
± 1.8 mg/kg. This translational study described
the potential pressor effects of TUS. Therefore,
this agent may produce transient hypertension
when administered intravenously; however,
documented effects on blood pressure following
oral ingestion remain unclear.
VITAMIN C
Vitamin C is also known under the name
ascorbic acid, with therapeutic uses including
prevention and treatment of scurvy, prevention of
deficiency in patients with gastrointestinal
disease (including those on TPN), patients
requiring chronic hemodialysis (to improve oral
iron absorption from the GI tract). A Science
Advisory from the American Heart Association
also states that current evidence does not justify
use of antioxidants such as vitamin C for
reducing the risk of cardiovascular disease. More
research is needed before vitamin C can be
recommended for prevention of coronary heart
disease.
Cardiovascular adverse effects: Carotid effects
(increased rate of carotid inner wall thickening in
men)(E), increased mortality in women with
diabetes (E).
Drug interactions: Increased antiplatelet effects
possibly resulting in increased risk of bleeding
with concomitant aspirin use (E), blunted effects
on HDL with concomitant statin and niacin use
(E).
Lee DH, Folsom AR, Harnack L, et al. Does
supplemental vitamin C increase cardiovascular
disease risk in women with diabetes? Am J Clin
Nutr 2004 Nov;80(5):1194–2000.
This observational study sought to examine the
relationship between vitamin C intake and
mortality from total cardiovascular disease (n =
281), coronary artery disease (n = 175), and
stroke (n = 57) in 1,923 postmenopausal women
who reported being diabetic at baseline. Diet was
assessed with a food-frequency questionnaire at
baseline, and subjects initially free of coronary
artery disease were prospectively followed for 15
y. After adjustment for cardiovascular disease
risk factors, type of diabetes medication used,
duration of diabetes, and intake of folate, vitamin
E, and beta-carotene, the adjusted relative risks
of total cardiovascular disease mortality were 1.0,
271e
0.97, 1.11, 1.47, and 1.84 (P for trend < 0.01)
across quintiles of total vitamin C intake from
food and supplements. Adjusted relative risks of
coronary artery disease were 1.0, 0.81, 0.99, 1.26,
and 1.91 (P for trend = 0.01) and of stroke were
1.0, 0.52, 1.23, 2.22, and 2.57 (P for trend <
0.01). When dietary and supplemental vitamin
C were analyzed separately, only supplemental
vitamin C showed a positive association with
mortality endpoints. Vitamin C intake was
unrelated to mortality from cardiovascular
disease in the nondiabetic subjects at baseline.
High vitamin C intake from supplements was
associated with an increased risk of
cardiovascular disease mortality in
postmenopausal women with diabetes. However,
the following limitations prevent generalizability:
(1) findings were solely based on a baseline
dietary and health assessment; (2) diabetes was
self-reported; (3) the study was limited to
postmenopausal women; and, (4) cardiovascular
disease incidence data were not recorded.
Hansten PD, Hayton WL. Effect of antacid and
ascorbic acid on serum salicylate concentration. J
Clin Pharmacol 1980;20:326–31.
The objective of this small prospective,
observational study was to determine any effect
of antacid or ascorbic acid administration on
serum salicylate concentrations. Nine healthy
volunteers were assigned by balanced-block
design to receive the combination of choline
salicylate (equivalent of 3.76 or 5.62 gm of
aspirin per day) with magnesium-aluminum
hydroxide (120 mL/day) or with ascorbic acid (3
gm/day), or by itself. There was no significant
change in serum salicylate concentration in
patients receiving ascorbic acid. These data,
along with lack of safety concerns from existing
large randomized trials suggest that there are no
significant increases in bleeding risk when
aspirin is used with concomitant ascorbic acid.
Tardif JC, Cote G, Lesperance J, et al. Probucol
and multivitamins in the prevention of restenosis
after coronary angioplasty. N Engl J Med
1997;337:365–372.
The objective of this randomized, double-
blind, placebo-controlled study was to determine
whether drugs with antioxidant properties
reduced the severity and incidence of restenosis
after angioplasty. Patients were randomized into
four groups: 1) placebo; 2) probucol 500 mg
daily; 3) multivitamins (30,000 IU of beta
carotene, 500 mg of vitamin C, and 700 IU of
272e PHARMACOTHERAPY Volume 31, 2011
vitamin E); or, 4) both probucol and
multivitamins. All patients were treated for one
month before and 6 months after angioplasty.
The lowest restenosis rates were reported for the
patients who received probucol 500 mg daily
alone (20.7%)—suggesting that multivitamins
may blunt the response of probucol or otherwise
increase the risk for restenosis associated with
angioplasty (p=0.003 for probucol vs. no
probucol). There was no significant difference in
restenosis rates between patients who received
multivitamins containing vitamin C or placebo;
although, the absolute restenosis rate was higher
(40.3% vs. 38.9%) in the patients receiving
multivitamins, though this was not statistically
significant. This information is of scant clinical
significance due to current standards of care
since the advent and widespread adoption of
drug-eluting stents.
Brown BG, Zhao XQ, Chait A. Simvastatin and
niacin, antioxidant vitamins, or the combination
for the prevention of coronary disease. N Engl J
Med 2001;345:1583–93.
The objective of this randomized, double-
blind, placebo-controlled trial was to determine if
antioxidant vitamins (vitamin E 800 IU, vitamin
C 1,000 mg, beta carotene 25 mg, and selenium
100 µg) had beneficial effects in the prevention of
coronary heart disease compared to the
combination of simvastatin (10–20 mg daily
depending on baseline LDL) and niacin (Slo-
Niacin® 250–1,000 mg twice daily) for patients
with coronary disease, low HDL concentrations,
and normal LDL concentrations. Study
endpoints included angiographic evidence of
coronary stenosis and occurrence of first
cardiovascular event (death, MI, stroke, or
revascularization). Mean concentrations of LDL
and HDL were unchanged in the antioxidant and
placebo groups, but LDL was reduced (by 42%)
and HDL increased (26%) in the simvastatin-
niacin group. Angiographic findings confirmed
that coronary stenosis progressed at a higher rate
in the placebo (3.9%) and antioxidant (1.8%)
groups compared to the simvastatin-niacin group
(0.7%, p<0.001). The authors concluded that the
combination of simvastatin and niacin provides
significant clinical benefit and that antioxidant
use should be questioned. These data essentially
establish that antioxidants do not significantly
alter coronary disease progression; however, they
may cause harm through blunting of HDL
concentrations in vivo.
Cheung MC, Zhao XQ, Chait A, et al.
Antioxidant supplements block the response of
HDL to simvastatin-niacin therapy in patients
with coronary artery disease and low HDL.
Arterioscler Thromb Vasc Biol 2001;21:1320–6.
The objective of this randomized, double-
blind, placebo-controlled trial was to determine if
antioxidant vitamins (vitamin E 400 IU BID,
vitamin C 500 mg BID, beta carotene 12.5 mg
BID, and selenium 50 µg BID) had beneficial
effects in the prevention of coronary heart disease
compared to the combination of simvastatin
(10–20 mg daily) and niacin (niacin 1,000 mg
twice daily as tolerated) for patients with
coronary artery disease and low HDL (defined as
< 40 mg/dL) concentrations. Study endpoints
were limited to lipid concentration changes at 12
months (Total cholesterol, triglycerides, VLDL,
IDL, LDL, HDL, HDL2, HDL3, Apolipoprotein
A1, Apolipoprotein A2, Apolipoprotein B). After
12 months there were statistically significant
changes from baseline in total cholesterol,
apolipoprotein A1 and A2 particle composition,
and triglyceride levels along with LDL, IDL, and
HDL levels. The authors concluded that the
combination of simvastatin and niacin provides
significant clinical benefit and that the
combination of antioxidant use was associated
with blunted effects on HDL levels as well as
apolipoprotein composition. These data assert
that antioxidants appear to blunt beneficial
effects of combined simvastatin-niacin therapy.
The clinical significance of these findings are
questionable; however, in the context of the
study by Brown BG et al described above patients
should be counseled that taking antioxidants
may potentially lessen some of the beneficial
effects of simvastatin and niacin; although, these
results do not clearly implicate vitamin C since a
combination product was used in the study.
Bjelakovic G, Nikolova D, Gluud LL, et al.
Mortality in randomized trials of antioxidant
supplements for primary and secondary
prevention: systematic review and meta-analysis.
JAMA 2007;297:842–57.
(Refer to vitamin E for annotated bibliography)
VITAMIN D
Vitamin D is also known under the name 1,25-
dihydroxycholecalciferol, with therapeutic uses
including prevention of osteoporosis, treatment
of hypoparathyroidism, enhancement of immune
function, and prevention of vitamin D deficiency.
Cardiovascular adverse effects: There have not
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
been any reported cardiovascular adverse
reactions in clinical trials; however, there is
concern that hypercalcemia can contribute to
atherosclerosis (which may be potentiated by
high doses of vitamin D) (E).
Drug Interactions: Reduced effectiveness of
atorvastatin and other statins metabolized via the
CYP3A4 system due to induction of the enzyme
(E), increased risk for digoxin toxicity and fatal
cardiac arrhythmias due to potential for
hypercalcemia with high doses of vitamin D (E),
reduced effectiveness of verapamil (and
theoretically diltiazem) due to potential for
hypercalcemia with high doses of vitamin D, and
increased risk for hypercalcemia with
concomitant use of thiazide diuretics, which may
decrease urinary calcium excretion (E).
VITAMIN E
Orally, vitamin E (also referred to as alpha-
tocopherol or tocotrienol) is used to treat vitamin
E deficiency, treat and prevent cardiovascular
disease, as well as to treat complications
associated with diabetes mellitus due to potential
antioxidant effects.
Cardiovascular adverse effects: Increased risk
for heart failure (A).
Drug interactions: Increased risk for bleeding
with concomitant use of antiplatelet/
anticoagulant medications due to inhibition of
platelet aggregation and antagonism of vitamin K
dependent clotting factors (C), and reduced
effectiveness of simvastatin and niacin due to
blunting effects on HDL levels (B).
Steiner M, Glantz M, Lekos A. Vitamin E plus
aspirin compared with aspirin alone in patients
with transient ischemic attacks. Am J Clin Nutr
1995;62(6 Suppl):1381S–1384S.
This double-blind, randomized study sought to
compare effects of aspirin plus vitamin E [0.4 g
(400 IU)/d; n = 52] with aspirin alone (325 mg; n
= 48) in 100 patients with transient ischemic
attacks, minor strokes, or residual ischemic
neurologic deficits. The patients received study
medication for 2 years or until they reached the
primary endpoint. Preliminary results show a
reduction in the incidence of ischemic events in
patients in the vitamin E plus aspirin group
compared with patients taking only aspirin (1.9%
vs. 12.5%) although these results are
underpowered. There was no significant
difference in the incidence of hemorrhagic stroke
(although both patients who developed it were
273e
taking vitamin E). Platelet adhesion was also
measured in a randomized subgroup of both
study populations by using collagen III as the
adhesive surface. There was a highly significant
reduction in platelet adhesiveness in patients
who were taking vitamin E plus aspirin
compared with those taking aspirin only.
Measurement of ␣-tocopherol concentrations
confirmed patient adherence with the medication
schedule, showing a near doubling of serum
concentrations of ␣-tocopherol. The authors
concluded that the combination of vitamin E and
an antiplatelet agent (aspirin) significantly
enhances the efficacy of the preventive treatment
regimen in patients with transient ischemic
attacks and other ischemic cerebrovascular
problems. These findings must be tempered
against a dearth of informative knowledge about
safety of such a combination in this patient
population.
Kim JM, White RH. Effect of vitamin E on the
anticoagulant response to warfarin. Am J Cardiol
1996;77(7):545–6.
This randomized, double-blind, placebo-
controlled trial sought to clarify whether vitamin
E enhances the pharmacologic effect of warfarin.
Twenty-one subjects taking chronic warfarin
therapy were randomized to receive either
vitamin E or placebo. A possible drug effect was
defined as occurring if the subject’s INR
increased from within the target range to >1.4
times the midpoint of that target range. For
example, if the target range was INR = 2.0 to 3.0,
and the lNR then increased to >3.5 (= 1.4 x 2.5),
this was deemed a possible drug effect; for a
target range of INR = 1.7 to 2.3, the INR had to
increase to >2.8, and so forth. If a repeat INR
measurement was also elevated and if the INR
returned to within the target range after an
appropriate reduction in the dose of warfarin, the
patient was classified as having aprobable drug-
induced effect. A definite drug effect required:
(1) return of the INR and warfarin dose to initial
values after discontinuation of the study drug,
and (2) reoccurrence of the observed drug effect
on rechallenge. None of the subjects who
received vitamin E had a significant change in the
international normalized ratio, and thus it
appears that vitamin E can safely be given to
patients who require chronic warfarin therapy.
The findings from this small prospective study
indicate that there are no significant
pharmacodynamic interactions between warfarin
and vitamin E supplementation; however, data
274e PHARMACOTHERAPY Volume 31, 2011
are underpowered have limited clinical
significance.
Tardif JC. Probucol and multivitamins in the
prevention of restenosis after coronary
angioplasty. N Engl J Med 1997;337:365–372.
The objective of this randomized, double-
blind, placebo-controlled study was to determine
whether drugs with antioxidant properties
reduced the severity and incidence of restenosis
after angioplasty. Patients were randomized into
four groups: 1) placebo; 2) probucol 500 mg
daily; 3) multivitamins (30,000 IU of beta
carotene, 500 mg of vitamin C, and 700 IU of
vitamin E); or, 4) both probucol and
multivitamins. All patients were treated for one
month before and 6 months after angioplasty.
The lowest restenosis rates were reported for the
patients who received probucol 500 mg daily
alone—suggesting that multivitamins may blunt
the response of probucol or otherwise increase
the risk for restenosis associated with angioplasty
(p=0.003 for probucol vs. no probucol). There
was no significant difference in restenosis rates
between patients who received multivitamins
containing vitamin E or placebo; although, the
absolute restenosis rate was higher (40.3% vs.
38.9%) in the patients receiving multivitamins,
though this was not statistically significant. This
information is of scant clinical significance due
to current standards of care since the advent and
widespread adoption of drug-eluting stents.
Liede KE, Haukka JK, Saxen LM, Heinonen OP.
Increased tendency towards gingival bleeding
caused by joint effect of ␣-tocopherol
supplementation and acetylsalicylic acid. Ann
Med 1998;30:542–6.
The objective of this cross-sectional study was
to assess the effect of ␣-tocopherol
supplementation on gingival bleeding either in
combination with acetylsalicylic acid (ASA) or
without it. This study was an end-point
examination of a random sample of male
smokers who had participated in a controlled
clinical trial, the Alpha-Tocopherol, Beta-
Carotene Cancer Prevention Study (ATBC Study)
for 5–7 years. The study included 409 men aged
55–74 years of whom 191 received ␣-tocopherol
supplementation (50 mg/day); 56 used ASA, 30
received both and 132 received neither. Gingival
bleeding was examined by probing with a WHO
probe and reported as a percentage of bleeding
sites adjusted by the logistic regression model.
Gingival bleeding was more common in those
who received ␣-tocopherol compared with
nonreceivers among subjects with a high
prevalence of dental plaque (p<0.05). ASA alone
increased bleeding only slightly. The highest risk
of gingival bleeding was among those who took
both ␣-tocopherol and ASA (33.4% of probed
sites bleeding vs 25.8% among subjects taking
neither ␣-tocopherol nor ASA, p<0.001). Results
of the present study suggest that ␣-tocopherol
supplementation may increase the risk of
clinically important bleeding, particularly when
combined with ASA. Clinicians and patients
should be aware of these potential risks.
Brown BG, Zhao XQ, Chait A. Simvastatin and
niacin, antioxidant vitamins, or the combination
for the prevention of coronary disease. N Engl J
Med 2001;345:1583–93.
(Refer to vitamin C for annotated
bibliography)
Cheung MC, Zhao XQ, Chait A, et al.
Antioxidant supplements block the response of
HDL to simvastatin-niacin therapy in patients
with coronary artery disease and low HDL.
Arterioscler Thromb Vasc Biol 2001;21:1320–6.
(Refer to vitamin C for annotated
bibliography)
Booth SL, Golly I, Sacheck JM, et al. Effect of
vitamin E supplementation on vitamin K status
in adults with normal coagulation status. Am J
Clin Nutr 2004;80:143–8.
The objective of this randomized trial was to
assess the effect of 12 weeks of supplementation
with 1,000 IU ␣-tocopherol per day on
biochemical measures of vitamin K status in men
and women not taking oral anticoagulants.
Vitamin K status, was assessed with the use of
plasma phylloquinone concentrations, the degree
of under-␥-carboxylation of prothrombin
(proteins induced by vitamin K absence-factor II,
PIVKA-II), and the percentage of
undercarboxylated osteocalcin (ucOC), was
determined in 38 men and women with
rheumatoid arthritis (study A) and in 32 healthy
men (study B) participating in 2 independent,
12-wk randomized clinical trials of vitamin E
supplementation (1,000 IU per day). Mean (±
SD) PIVKA-II increased from 1.7 ± 1.7 to 11.9 ±
16.1 ng/mL (p<0.001) in study A and from 1.8 ±
0.6 to 5.3 ± 3.9 ng/mL (p<0.001) in study B in
response to 12 wk of vitamin E supplementation.
An increase in PIVKA-II is indicative of poor
vitamin K status. In contrast, the other measures
of vitamin K status (i.e., plasma phylloquinone
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
concentration and percentage of ucOC) did not
change significantly in response to the
supplementation. High-dose vitamin E
supplementation increased PIVKA-II in adults
not receiving oral anticoagulant therapy. The
clinical significance of these changes warrants
further investigation, but high doses of vitamin E
may antagonize vitamin K. Future research is
needed to determine if such an interaction is
beneficial or harmful. Patients receiving
anticoagulation with warfarin should be advised
to alert their pharmacist or provider if they are
taking vitamin E supplements.
Lonn E, Bosch J, Yusuf S, et al. Effects of long-
term vitamin E supplementation on
cardiovascular events and cancer: a randomized
controlled trial. JAMA 2005;293(11):1338–47.
This secondary analysis of the HOPE (the
initial Heart Outcomes Prevention Evaluation
[HOPE] trial conducted between December 21,
1993, and April 15, 1999) and HOPE-TOO
(HOPE-The Ongoing Outcomes [HOPE-TOO])
trials sought to evaluate whether long-term
supplementation with vitamin E decreases the
risk of cancer, cancer death, and major
cardiovascular events. Approximately 9,541
patients (4,761 receiving vitamin E 400 IU daily,
4,780 receiving placebo) were included in the
analysis. Among all HOPE patients, there were
no significant differences in the primary analysis
for major cardiovascular events, 1022 (21.5%) vs.
985 (20.6%), respectively (RR, 1.04; 95% CI,
0.96–1.14; P=0.34). Patients in the vitamin E
group had a higher risk of HF (RR, 1.13; 95% CI,
1.01–1.26; P=0.03) and hospitalization for HF
(RR, 1.21; 95% CI, 1.00–1.47; P=0.045).
Similarly, among patients enrolled at the centers
participating in the HOPE-TOO trial, there were
no differences in major cardiovascular events, but
higher rates of HF and hospitalizations for HF. In
patients with vascular disease or diabetes
mellitus, long-term vitamin E supplementation
does not prevent major cardiovascular events and
may increase the risk for HF and hospitalization
for HF.
Bjelakovic G, Nikolova D, Gluud LL, et al.
Mortality in randomized trials of antioxidant
supplements for primary and secondary
prevention: systematic review and meta-analysis.
JAMA 2007;297:842–57.
This systematic review sought to assess the
effect of antioxidant supplements on mortality in
randomized primary and secondary prevention
275e
trials. All randomized trials involving adults
comparing beta carotene, vitamin A, vitamin C
(ascorbic acid), vitamin E, and selenium either
singly or combined vs. placebo or vs. no
intervention were included in the analysis. Sixty-
eight randomized trials with 232,606 participants
(385 publications) were included. When all low-
and high-bias risk trials of antioxidant
supplements were pooled together there was no
significant effect on mortality (RR, 1.02; 95% CI,
0.98–1.06). Multivariate meta-regression
analyses showed that low-bias risk trials (RR,
1.16; 95% CI, 1.04[corrected]–1.29) and
selenium (RR, 0.998; 95% CI, 0.997–0.9995)
were significantly associated with mortality. In 47
low-bias trials with 180 938 participants, the
antioxidant supplements significantly increased
mortality (RR, 1.05; 95% CI, 1.02–1.08). In low-
bias risk trials, after exclusion of selenium trials,
beta carotene (RR, 1.07; 95% CI, 1.02–1.11),
vitamin A (RR, 1.16; 95% CI, 1.10–1.24), and
vitamin E (RR, 1.04; 95% CI, 1.01–1.07), singly
or combined, there was significantly increased
mortality. Vitamin C and selenium had no
significant effect on mortality. Treatment with
beta carotene, vitamin A, and vitamin E may
increase mortality. The potential effects of
vitamin C and selenium on mortality are not
clear and require further study.
WINTERGREEN
Wintergreen is also known under the names
boxberry, Canada Tea, and Oil of Wintergreen,
with therapeutic uses including treatment of
headache, stomach ache, flatulence, and to
stimulate gastric secretions and aid digestion.
Topically, wintergreen oil is used as a
counterirritant for musculoskeletal pain and as
an antiseptic. Wintergreen oil contains methyl
salicylate and may cause additive salicylate
toxicity when used with concomitant aspirin.
Cardiovascular adverse effects: None reported.
Drug interactions: Increased risk for bleeding
with concomitant antithrombotic use due to
systemic absorption of methyl salicylate (E).
Tanen DA, Danish DC, Reardon JM, et al.
Comparison of oral aspirin versus topical applied
methyl salicylate for platelet inhibition. Ann
Pharmacother 2008;42(10):1396–401.
This randomized, prospective, blinded,
crossover study sought to assess the ability of
topically applied methyl salicylate (MS) to inhibit
systemic platelet aggregation for patients who are
276e PHARMACOTHERAPY Volume 31, 2011
unable to tolerate oral drug therapy. Nine
healthy men, aged 30–46 years participated in
the study. All subjects ingested 162 mg of aspirin
or applied 5 g of 30% MS preparation to their
anterior thighs. There was a minimum 2-week
washout period between study arms. Blood and
urine were collected at baseline and at 6 hours.
An aggregometer measured platelet aggregation
over time against 5 standard concentrations of
epinephrine, and a mean area under the curve
(AUC) was calculated. Urinary metabolites of
thromboxane B(2) were measured by a standard
enzyme immunoassay. Baseline platelet
aggregation did not differ significantly between
the 2 arms of the study (median AUC [%
aggregation(*)min]; binominal confidence
intervals): aspirin 183; 139 to 292 versus MS
197; 118 to 445 (p=0.51). Both aspirin and MS
produced statistically significant platelet
inhibition; aspirin decreased the AUC from 183;
139 to 292 to 85; 48 to 128 (p=0.008) and MS
decreased the AUC from 197; 118 to 445 to 112;
88 to 306 (p=0.011). No significant difference
was detected between baseline and 6-hour
thromboxane levels for either aspirin (p=0.779)
or MS (p=0.327). Oral acetylsalicylic acid
(aspirin) is the primary antiplatelet therapy in
the treatment of acute myocardial infarction and
acute coronary syndrome. Methyl salicylate (MS;
oil of wintergreen) is compounded into many
over-the-counter antiinflammatory muscle
preparations and has been shown to inhibit
platelet aggregation locally and to be absorbed
systemically. Patients requiring chronic
antiplatelet therapy with aspirin should avoid MS
supplementation due to potential additive
antiplatelet effects.
YOHIMBINE
Orally, yohimbine (also referred to as 11-
hydroxy yohimbine or Johimbi) is used as an
aphrodisiac and to treat impotence as well as
generalized male and female sexual dysfunction.
Yohimbine bark is also smoked or snuffed for its
hallucinogenic effects.
Cardiovascular adverse effects: Increased blood
pressure (A).
Drug interactions: Interference with blood
pressure control with concomitant use of
antihypertensives (E).
Musso NR, Vergassola C, Pende A, Lotti G.
Yohimbine effects on blood pressure and plasma
catecholamines in human hypertension. Am J
Hypertens 1995;8(6):565–71.
The purpose of this study was to test the
hypothesis of an ␣2-adrenoreceptor alteration in
human essential hypertension. This small
randomized study involved the oral
administration of 10 mg yohimbine, an ␣2-
adrenergic antagonist, to 25 healthy volunteers
and 29 sex- and age-matched untreated
hypertensive patients. Volunteers and patients
were studied twice in random order, after placebo
or yohimbine treatment, in supine and upright
positions. Arterial pressure and heart rate were
monitored by servoplethy-smomanometry, and
venous plasma catecholamines were determined
by HPLC with electrochemical detection.
Yohimbine induced a significant increase in
diastolic pressure only in the hypertensive
patients (94.1 mm Hg vs. 78.3 mm Hg; p=0.05).
Plasma norepinephrine was increased
significantly in both yohimbine-treated groups,
but the percent increase of plasma
norepinephrine after the standing test was
decreased significantly only in the healthy
yohimbine-treated subjects. Plasma dopamine
was increased significantly only in the healthy
yohimbine-treated subjects. The response of
plasma dopamine to the upright position was
modified only in the healthy yohimbine-treated
subjects. The decrease observed after 2 min of
standing was abolished, showing the involvement
of ␣2-adrenoreceptors in the physiologic
response of plasma catecholamines in healthy
volunteers. These data provide evidence of an
␣2-adrenoreceptor desensitization or alteration
in the balance of ␣-adrenoreceptors in human
hypertension; however, the clinical significance
of these findings remains to be determined with
future study.
Ernst E, Pittler MH. Yohimbine for erectile
dysfunction: a systematic review and meta-
analysis of randomized clinical trials. J Urol
1998;159(2):433–6.
This study used computerized literature
searches and standardized data extraction to rate
methodological quality in a meta-analysis using
computer statistical software. Seven trials met
inclusion criteria. Serious adverse reactions
(most commonly GI upset, altered mental status)
were infrequent and reversible. The authors
conclude that benefit of yohimbine for erectile
dysfunction seems to outweigh risks. Erectile
dysfunction is a common problem, particularly in
diabetics. It is associated with a considerable
burden of suffering; however, given the current
availability of alternatives with more widely
 CAM AND CARDIOVASCULAR DISEASE: PART 2 Chow et al
established safety profiles (sildenafil, vardenafil,
and tadalafil), yohimbine is not considered a
first-line agent.
ZINC
Zinc is an essential element in our body and
important cofactor in many biological processes
including DNA, RNA and protein synthesis. As
an oral supplement, zinc is used for the
prevention and treatment of deficiency; however,
benefits have also been reported for other
conditions including respiratory tract infections,
hypertension and thalassemia.
Cardiovascular adverse effects: Reduced HDL-C
in younger patients consuming doses above RDA
(B).
Drug interactions: Reduced excretion with
amiloride > 10 mg per day (A).
Foster M, Petocz P, Samman S. Effects of Zinc on
plasma lipoprotein cholesterol concentrations in
humans: meta-analysis of randomized controlled
trials. Atherosclerosis. 2010 Jun; 210(2): 344–52.
Zinc supplementation has been reported to
adversely influence cholesterol metabolism in
animal studies. The proposed mechanism is
related to the ability of zinc to produce copper
deficiency, which may lead to greater activity of
HMG-CoA reductase thereby raising plasma
cholesterol levels. Despite this established
relationship in animals, the clinical impact of
zinc on lipoprotein metabolism is less certain.
Therefore, a meta-analysis was performed to
determine the effect of zinc supplementation on
plasma cholesterol and triglycerides. A total of
277e
421 potentially relevant studies containing zinc
supplement with documented lipid outcomes
were considered for inclusion. Out of these
studies, only 20 (14,238 participants) were used
in the meta-analysis. The primary analyses were
conducted to determine the effects of zinc on
plasma concentrations of total cholesterol, LDL
cholesterol, HDL cholesterol, and triglycerides.
The secondary analysis evaluated additional
variables thought to influence the effect of zinc
on cholesterol including health status (healthy,
type 2 DM, hemodialysis, other), element zinc
dose (<30 mg/d, 30–100 mg/d, >100 mg/d),
gender, age, and duration. The mean dose of
elemental zinc used in the trials was 58 mg/d
(RDA 40 mg/d). Although the age range of study
participants was varied (18–106 years), most
(90%) were between 35–65 years. The primary
analyses demonstrated no significant effects of
zinc on total cholesterol, LDL cholesterol, HDL
cholesterol, and triglyceride concentrations.
However, adverse effects were detected in specific
subgroups. Compared to baseline, plasma HDL
concentrations were significantly reduced in
healthy subjects (n=13215, –3.86 ± 0.77 mg/dL,
p<0.01) and age <40 years (n=150, –6.17±1.93
mg/dL, p=0.001). Therefore, caution is
warranted in young healthy patients who may
use zinc supplementation in excess of the
recommended daily allowance.
Acknowledgements
The authors recognize Toby Trujillo, PharmD, Kalee
Foreman, B.S. and Tae Gun Kim, B.S., for their
contributions and assistance.