Title: PharmaNote
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Permanent Link: http://ufdc.ufl.edu/UF00087345/00043
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Title: PharmaNote
Series Title: PharmaNote
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Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: August 2006
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Bibliographic ID: UF00087345
Volume ID: VID00043
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David Kleynberg, Pharm.D. Candidate

Until recently, sexual health has not been at the
forefront of medical research. Over the last 8 years,
new medications have been introduced that are safe
and effective for the treatment of erectile dysfunction
(ED). ED is defined as the recurrent inability to ob-
tain and/or maintain an erection sufficient for sexual
activity for at least 3 months.1 Due to the ambiguity
of the definition, the exact estimate of its prevalence
is unknown. ED is a common disorder affecting over
150 million men worldwide. Approximately 52% of
men between 40 and 70 years of age suffer from ED.
In addition, the risk of ED increases 2-3 fold with
each decade of life.2 Unfortunately, 70-90% of men
with ED do not receive treatment. ED not only af-
fects the patient's quality of life, but also their part-
ner. For example, it is estimated that ED is at least
partially responsible for 20% of marriage failures.3
Any condition which impairs blood-flow to the
penis may cause ED, while vascular disorders ac-
count for the majority of physiological causes.4 Ta-
ble 1 lists possible etiologies of ED. According to
the MMAS (Massachusetts Male Aging Study), ED
has a strong correlation to cardiovascular disease
(CVD) and patients with CVD should be routinely
screened for ED and vice versa. In fact, ED may be

the initial manifestation of underlying vascular dis-
ease.5 Regardless of the etiology, phosphodiesterase-
5 inhibitors (PDE5i) are safe and effective oral
agents routinely used for treatment of ED. This sum-
mary will focus on the similarities and differences
between commercially available PDE-5 inhibitors:
sildenafil (Viagra), vardenafil (Levitra), and ta-
dalafil (Cialis).

Obtaining an erection involves a complex cas-
cade of neurovascular events modulated by hormonal
and psychological factors. An erection is maintained
by smooth-muscle tone of the corpora cavernosa. In
the absence of sexual stimulation, contractile factors,
endothelin-1 and PGF2a, are favored. These factors
induce vasoconstriction and limit blood flow to the
Upon sexual stimulation, penile vasculature and
tissues change from a contracted to a blood-filled,
relaxed state. The parasympathetic pathways ampli-
fies the relaxant effects of nitric oxide (NO), which
causes the corpora caversona to swell with blood.
Cyclic guanosine monophosphate (cGMP) [second
messenger of nitric oxide], through downstream me-
rIa U I






Volume 21, Issue 11, August 2006


Table 1. Etiologies of erectile dysfunction
Lifestyle Disease states Psychogenic Medications
Thiazide diu-
Smoking Hypertension Stress
Obesity Dyslipidemia Relationship Beta-blockers
High-fat Diabetes Mel- Performance RIs
diet litus anxiety
Sedentary CVD Anti-
drug abuse Depression
drug abuse

diators, leads to reduced cytosolic concentrations of
calcium. Decreased availability of calcium leads to
smooth muscle relaxation. Premature degradation of
cGMP by PDE5 is key in detumescence.3 Selective
inhibition of PDE5 by sildenafil, vardenafil and ta-
dalafil increases the availability of cGMP; thus, pro-
moting smooth muscle relaxation and a sustained
PDE5 is part of a protein superfamily of nucleo-
tides which are divided into at least 11 families of
related enzymes. Although structurally and function-
ally related, they show some differences in primary
structure as well as tissue distribution. PDE5-
inhibitors show a high selectivity towards PDE5,
with minor selectivity differences between agents.
Localization and reduced selectivity account for cer-
tain adverse effects of PDE5i. For example, PDE-6
is localized in photoreceptor cells in the rods and
cones of the eye. When inhibited, visual distur-
bances, such as color changes, blurred vision, and
loss of vision, may occur. Tadalafil's increased
PDE5 selectivity may account for a reduced inci-
dence of visual side effects.6-8

The pharmacokinetics of sildenafil, vardenafil,
and tadalafil are summarized in table 2. Subtle dif-
ferences exists between agents with half-life and pe-
riod of response with tadalafil being clinically sig-

Sildenafil, vardenafil and tadalafil are highly
effective in enhancing erectile function in a wide
range of patients with many co-morbidities. Due to
differences in study designs, comparisons of the
three agents are difficult. Each agent improves gen-
eral scores on function, intercourse satisfaction by
the patient and partner, and overall satisfaction with
therapy.9 Night-time erections in men with and with-

out ED, rigidity, and orgasmic function also show
significant improvement. However, several random-
ized controlled trials (RCTs) show no improvement
in libido when compared to placebo.10' 11
Each agent is effective in treating patients with a
history of diabetes mellitus (DM). Tadalafil is an ef-
fective treatment for those DM patients with mi-
crovascular complications, such as diabetic retinopa-
thy, or microabuminuria. RCTs for sildenafil and
vardenafil excluded DM patients with a history of
microvascular problems.12-14 Although usually taken
on demand, there is recent data to support daily ad-
ministration of sildenafil. This type of administration
seems to have a beneficial effect on endothelial func-
tion in diabetic patients due to amplification of tissue
oxygenation during more frequent nocturnal erec-
In an open label study, authors investigated
whether 50 mg of sildenafil at bedtime would have
long-term improvements over "as-needed" use. After
1 year of treatment, both groups had similar erectile
function domain scores. After a 4 week washout pe-
riod, 59% of patients dosed nightly continued to have
erectile domain scores in the normal range compared
to only 9% of the on-demand group. Extended func-
tionality after drug discontinuation may be secondary
to improved endothelial function.15 Future studies
are needed to determine the role of daily administra-
tion for ED.


Table 2. Pharmacokinetics of PDE inhibitors 68
Sildenafil Vardenafil Tadalafil

Dosing (mg) 25, 50, 100 2.5 5 10, 5, 10, 20

Bioavalability (%)

Onset (min)

Half-life (h)

Period of re-
sponse (h)

A Cmax with
high-fat meal





No change

NR = none reported, V = decrease

PharmaNote Volume 21, Issue 11, August 2006

Volume 21, Issue 11, August 2006


Safety of all three PDE5 inhibitors has been es-
tablished through large clinical trials. Most adverse
effects may be attributed to the inhibition of PDE5 in
nonpenile tissues. Common adverse effects include
rhinitis, myalgia/back pain, flushing, dyspepsia,
headache, and abnormal vision. In an recent review,
flushing was more common in patients taking varde-
nafil and sildenafil, while back pain and myalgia
were more common with tadalafil. All adverse ef-
fects were typically transient and abated with time.
Discontinuation rates were low with each agent at
less than 3%.
Clinical trials of sildenafil, vardenafil and tadala-
fil included patients with stable cardiovascular dis-
ease (CVD) and DM. Trials did not include patients
with unstable CVD, unstable angina, recent myocar-
dial infarction, uncontrolled arrhythmias, uncon-
trolled hypertension, and heart failure. Guidelines
exist for risk-stratification and counseling of ED pa-
tients with CVD. Patients who experience cardiac
symptoms during sexual activity should seek imme-
diate medical attention.

Drug Interactions
CYP 3A4 is the predominant enzyme responsible
for metabolism of PDE5 inhibitors. Any potent in-
hibitor of 3A4 may increase the systemic exposure
by 2-16 fold, which may increase adverse effects.6-8
Concomitant use of organic nitrates and PDE5 in-
hibitors constitutes an absolute contraindication due
to a PDE5 inhibitor's ability to potentiate the hy-
potensive/vasodilator effects of NO donors. Postural
hypotension has been reported when sildenafil was
administered together with doxazosin, an a-blocker
commonly used for treating BPH and hypertension.
According to the package insert (PI), sildenafil doses
greater than 25 mg should not be taken within 4 h of
an a-blocker.6 Co-administration of an a-blocker is a
precaution for patients taking vardenafil and tadala-
fil.7'8 When co-administered with alcohol (a mild,
systemic vasodilator), both sildenafil and vardenafil
did not show an increase in hypotensive side effects

in healthy patients with mean maximum blood alco-
hol levels of 0.08%.6,7
Treatment Success
Incorrect use of any of the PDE5 inhibitors could
lead to treatment failure. To optimize treatment suc-
cess, providers should educate patients that sexual
arousal as well as multiple attempts may be required
to obtain an erection. The majority of patients re-
spond to treatment after 1 or 2 doses; however, some
patients may need to undergo 6-8 separate attempts
prior to success. Practitioners should educate patients
not to be discouraged or give up before a sufficient
number of attempts on the maximum dose is at-
tempted. If a PDE5 inhibitor fails, an alternative
PDE5 inhibitor should be attempted. In a review of
patients with ED, investigators found the cumulative
chance of successful intercourse increased from 54%
on the first attempt to 86% after 7-8 attempts.16

ED is a consequence of aging. With several
available treatments and additional emerging op-
tions, PDE5 inhibitors continue to be the most
widely prescribed agents. Overall, PDE5 inhibitors
are relatively safe and efficacious in about two-thirds
of patients. Treatment success depends on the dose
of medication, number of attempts, and, if necessary,
switching drugs. Most often, patient preference is
the key determinant to predict successful treatment.

1. NIH Consensus Development Panel on Impo-
tence. NIH Consensus Conference: impotence.
JAMA 1993;270:83-90.
2. Feldman HA, Goldstein I, et al. Impotence and
its medical and psychosocial correlates: results of
the Massachusetts Male Aging Study. J Urol
1994; 151:54-61.
3. Carson CC and Lue TF. Phosphodiesterase type-
5 inhibitors for erectile dysfunction. BJU Int
2005; 96:257-80.

Table 3. Cost of therapy2
Sildenafil Avg price' Range' Vardenafil Avg price' Range' Tadalafil Avg price' Range'
25 mg 116 107-131 2.5 mg 107 98-115 5 mg 134 126-148
50 mg 116 107-131 5 mg 107 98-116 10 mg 134 126-148
100 mg 116 107-131 10 mg 114 107-127 20 mg 134 126-148
20 mg 114 107-128
'Rounded to the nearest dollar 2 Prices obtained for 10 tablets from 4 community pharmacies in Gainesville, FL
Phara~ot Volme 2, Isue 1, Agust200

Volume 21, Issue 11, August 2006


4. Esposito K, Giugliano F, et al. Effect of lifestyle
changes on erectile dysfunction in obese men; a
randomized controlled trial. JAMA.
5. Araujo AB, Johannes CB, et al. The prospective
relation between psychosocial factors and inci-
dent erectile dysfunction: results from the Massa-
chusetts Male Aging Study. Am J Epidemiol.
2000; 15:533-541.
6. Bayer. Vardenafil hydrochloride (Levitra). US
prescriving information 2005. Available at http:
Accessed March 29, 2006.
7. Pfizer. Sildenafil citrate (Viagra). US prescribing
information 2005. Available at http://
www.pfizer.com/download/uspi viagra.pdf Ac-
cessed March 30, 2006.
8. Lilly ICOS LLC. Tadalafil (Cialis). US prescrib-
ing information 2005. Available at http:
pi.lilly.com/us/cialis-pi.pdf Accessed March 30,
9. Brock GB, McMahon CG et al. Efficacy and
safety of Tadalafil for the treatment of erectile
dysfunction: results of integrated analyses. J Urol
2002; 168:1332-6.
10. Goldstein I, Lue TF, et al. Oral Sildenafil in
treatment of erectile dysfunction. Sildenafil
Study Group. NEnglJMed 1998; 338:1397-404.
11. Hellstrom WJ, Gittelman M, et al. Vardenafil for
treatment of men with erectile dysfunction: effi-
cacy and safety in a randomized, double-blind,
placebo-controlled trial. J Androl 2002; 23:763-
12. Goldstein I, Young JM, Fischer J, et al. Varde-
nafil, a highly selective PDE5 inhibitor, improves
erectile function in patients with diabetes melli-
tus. Diabetes 2001; 50:924.
13. Rendell MS, Rajfer J, el at. Sildenafil for treat-
ment of erectile dysfunction in men with diabe-
tes: a randomized controlled trial. Sildenafil Dia-
betes Study Group. JAMA 1999; 281:421-6.
14. Saenz de Tejada I, Anglin G, et al. Effects of Ta-
dalafil on erectile dysfunction in men with diabe-
tes. Diabetes Care 2002; 25:2159-64.
15. Sommer F and Schulze W. Treating erectile dys-
function by endothelial rehabilitation with phos-
phodiesterase 5 inhibitors. World J Urol 2005;
16. McCullough AR, Barada JH, et al. Achieving
treatment optimization with sildenafil citrate


Devon R Mueller, Pharm.D. Candidate

Globally there are over 1 billion adults who are
overweight; as many as 300 million are obese. Obe-
sity is considered a major risk factor for developing
chronic diseases, such as type 2 diabetes, cardiovas-
cular diseases, hypertension, stroke, and certain
forms of cancer.1 While genetics play a role in obe-
sity, societal influence and nutritional habits, such as
increased consumption of saturated fats and sugars,
also contribute. The prevalence of health risks asso-
ciated with obesity pose an extensive economic bur-
den on society. It is estimated that obesity costs the
United States over $117 billion each year including
both direct and indirect costs, such as diagnosis,
treatment, hospitalizations, and loss of productivity.2
Costs associated with obesity are now estimated to
be comparable to that associated with smoking.
The cannabinoid-1 (CB1) receptor is one of two
known receptors of the endocannabinoid system as-
sociated with the intake of food and tobacco depend-
ency. Preliminary evidence indicates that blocking
the CB1 receptor increases satiety resulting in weight
reduction.3 Currently, there are only a few FDA ap-
proved medications for treatment of obesity: a lipase
inhibitor (i.e. orlistat) and a central nervous system
agents (i.e. sibutramine, phentermine, diethyl-
propion). However, adverse effects limit the use of
these agents.4 Development of investigational
weight loss agents has concentrated on serotonin and
noradrenaline reuptake inhibitors, lipase inhibitors,
and leptin sensitizers. In addition, development
should focus not only on reducing fat mass
adiposityy), but also on correcting adipose tissue dys-
function (adiposopathy).5
Rimonabant (Acomplia [a k6m' plE a]) is the first
selective cannabinoid-1 (CB1) receptor blocker with
an approvable letter from the FDA.6 The European
Union approved rimonabant on June 21, 2006 for the

PharmaNote Volume 21, Issue 11, August 2006

Volume 21, Issue 11, August 2006


treatment of obesity in addition to diet and exercise.
This paper will review the efficacy, safety, cost, and
convenience of rimonabant.

Pharmacology and Pharmacokinetics
High concentrations of endocannabinoid recep-
tors are synthesized in the GI tract. Endocannabinoid
receptors found in the brain and intestine are respon-
sible for integrating feeding behavior, metabolism,
and energy balance. Specifically, CB1 receptors are
found throughout the enteric system, in spinal and
vagal afferents from the gut, and in adipocytes. En-
docannabinoid concentration in the hypothalamus
increases during short-term fasting and declines dur-
ing feeding.7 Rimonabant works on the premise that
if endocannabinoids induce hunger, antagonists at
the CB1 receptor will help reduce appetite and
stimulate weight loss.
Absorption of rimonabant exhibits linear kinetics
up to a 20 mg dose, or target dose, after which there
is a decline in absorption. In healthy and obese sub-
jects, mean peak plasma concentrations (Cmax) were
similar and ranged from 188 ng/mL in obese volun-
teers to 196 ng/mL in healthy volunteers. Time to
maximum concentration (tmax) occurred 2 hours af-
ter oral administration. Steady-state concentration
was achieved in 25.5 days. The terminal elimination
half-life of rimonabant is 6-9 days in healthy subjects
and 16 days in obese subjects due to a larger periph-
eral volume of distribution.8 Gender has no impact
on the pharmacokinetics of rimonabant.9 No dosage
adjustment is required for renal impairment or mild
to moderate hepatic disease. Of note, rimonabant has
not been studied in severe hepatic disease.

Clinical Trials
There are numerous trials investigating the ef-
fects of rimonabant on weight loss, lipids, atheroscle-
rosis, smoking cessation, diabetes, alcoholism, and
other cardiometabolic factors. Three trials are com-
plete and published, while others are currently en-
rolling patients.

Rimonabant in treatment of obesity in North America
The Rimonabant in Obesity-North America
(RIO-NA) trial was a two year, randomized, multi-
center, placebo-controlled, double-blinded study that
evaluated the effects of rimonabant on overall weight
reduction from baseline.10 RIO-NA is the largest

clinical trial of rimonabant to date with over 3,000
subjects, and is the most recent segment completed
for the rimonabant phase III trials. After a 4 week,
placebo plus diet (600kcal/d deficit) run-in period,
patients were randomized to receive either 5 mg or
20 mg of rimonabant or placebo once daily. In the
second year, patients were re-randomized to either
the same dose of rimonabant or switched to placebo.
The main outcome measures included body weight
change in the first year, and prevention of weight
gain over the second year. Secondary outcome meas-
ures were changes in waist circumference, plasma
lipid levels, and other cardiometabolic risk factors.
All patients lost a mean of 1.9 kg in the 4 week
placebo run-in period. After randomization to 5 mg,
20 mg, or placebo, weight loss in the rimonabant
groups was significantly greater than those random-
ized to placebo. The percentage of patients achiev-
ing 5% or greater weight loss at one year was 26.1%
in the 5 mg rimonabant group (P=0.004), 48.6% in
the 20 mg rimonabant group (p<0.001), and 20% in
the placebo group. Patients achieving or exceeding
10% weight loss was 25.2% of patients in the 20 mg
rimonabant group and 8.5% of placebo patients
(p<0.001). In the second year of the study, patients
were re-randomized to either rimonabant 20 mg or
placebo. Patients treated with rimonabant 20 mg
once daily for 2 years achieved an average 7.9 lbs
greater weight loss than the placebo group (p<0.001).
In contrast, patients switched from active drug to pla-
cebo for the second year of treatment regained the
majority of weight lost in the previous year.

Rimonabant effects on metabolic risk factors
The Rimonabant in Obesity-Lipids (RIO-Lipids)
trial was a 12 month, double-blinded, randomized,
placebo-controlled trial that evaluated the effects of
rimonabant on body mass index (BMI).11 The trial
also measured secondary effects, including changes
in cholesterol, insulin resistance, glucose tolerance,
and the prevalence of metabolic syndrome. Patients
were obese (BMI of 27 to 40 kg/m2), had untreated
dyslipidemia, and were non-diabetic. Study subjects
were randomized to receive 5 mg or 20 mg of ri-
monabant, or placebo, in addition to a hypocaloric
diet (600kcal/d deficit). Follow up with a dietician
occurred every 2 weeks for the first two visits, then
monthly for the duration of the study. Clinical end-
points included 5% and 10% weight loss from base-
line. Each group lost 2 kg initially. The placebo

PharmaNote Volume 21, Issue 11, August 2006

Volume 21, Issue 11, August 2006


Table 2. RIO-Lipids: Changes from Baselinetfor Secondary Endpoints in the Intention to Treat Population (Last-
Observation-Carried-Forward Method)12
End point Placebo Rimonabant 5mg Rimonabant 20mg

HDL cholesterol (mgO%)
Total cholesterol:HDL ratio
Fasting glucose (mmol/L)
Fasting insulin (microunits/ml)
Adiponectin (mcg/ml)
Leptin (ng/ml)
C-reactive protein (mg/L)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
QTc (msec)*

11.0+ 15.8
-0.14 + 0.68
-0.05 + 0.62
0.09 + 15.9
0.7 + 1.9
-0.3 + 6.0
-0.3 + 10.1
-0.2 + 7.4
-1.8 + 15.3
0.2 2.7
0.1 2.7

14.2 + 17.6
-0.23 + 0.82
-0.01 + 0.62
0.04 + 10.3
1.0 2.0
-2.3 + 7.9
0.4 + 11.8
0.1 8.3
-3.7 + 16.9
-0.2 + 2.8
-0.1 + 3.5

t Plus-minus values are means SD, NS = Not significant, ND = Not determined
* No statistical test was performed; measured according to the institution's anxiety and depression scales

group had a further 2.3 kg weight loss over the entire
12 months compared to a weight loss of 4.2 kg in the
5 mg group and 8.6 kg in the 20 mg group(p<0.001).
The proportion of patients who reached or exceeded
the weight loss endpoint of 5% was 19.5% in the pla-
cebo group and 58.4% in the 20 mg group (p<0.001).
The proportion of patients who achieved or exceeded
10% weight reduction was 7.2% in the placebo group
and 32.6% in the 20 mg group (p<0.001). Weight
loss occurred in the first 9 months and stabilized
without regain for the duration of the study.
In addition to decreased weight and waist cir-
cumference, there was also a wide array of cardiome-
tabolic risk factors that improved in RIO-Lipids
(Table 2).

Overall discontinuation rates were similar among
the three treatment groups in each trial, but more pa-
tients discontinued treatment due to adverse events in
the 20 mg rimonabant group than in other groups. In
the first year of the RIO-Lipids trial when compared
with placebo, adverse effects that were reported in
5% or greater of patients receiving 20 mg rimona-
bant included upper respiratory tract infection, naso-
pharyngitis, nausea, influenza, diarrhea, arthralgia,
anxiety, insomnia, viral gastroenteritis, dizziness,


depressed mood, and fatigue.8 In the second year,
study withdrawals, and adverse event-related study
withdrawal were lower than in the first year and
there were no differences among the treatment
In Rio-NA, serious adverse events occurred in
5.2% of the 5 mg group, 4.0% in the 20 mg group,
and 2.3% in the placebo group. Adverse events that
occurred in 5% or greater of each treatment group, in
decreasing order of frequency, were nausea, dizzi-
ness, influenza, anxiety, diarrhea, and insomnia, and
occurred more often in the 20 mg treatment group.
The most common adverse events in the treatment
groups compared with placebo that resulted in dis-
continuation included depression, anxiety, and nau-
sea.9 Other safety measures were similar in all
groups except for blood pressure which was de-
creased in the rimonabant 20 mg group, and occurred
more often in patients that were hypertensive at base-

Dosing and Cost
Rimonabant is in phase III clinical trials and is
not currently marketed in the United States. If ap-
proved, rimonabant will be available as 20 mg tablets
with once daily administration. Long term effects are
unknown at this time. Information regarding the du-

Volume 21, Issue 11, August 2006

p value

19.1 20.9
-0.72 + 0.93
-0.08 + 0.58
-1.7 + 12.4
2.2 + 2.5
-4.1 7.4
-2.1 12.3
-1.7 8.5
-4.6 + 15.7
0.1 3.1
0.3 + 3.0

p value

ration of therapy is pending further investigation.
Pricing information from Europe projects the cost of
rimonabant to be about $82 for 28 days of therapy.
Rimonabant is projected to be available in late 2006.

Rimonabant is the first endocannabinoid receptor
antagonist for treatment of obesity. It increases sati-
ety and causes weight reduction through activity at
the CB1 receptor. Phase III clinical trials (RIO-NA
and RIO-LIPIDS) demonstrated positive results of
rimonabant-induced weight loss and decreased waist
circumference, as well as improvements in other car-
diometabolic risk factors. At high concentrations,
rimonabant blocks calcium and potassium channels,
and may directly affect cellular gap junctions
through the CB2 receptor. Actions through this alter-
native mechanism may soon initiate human clinical
trials for myocardial infarction, endotoxemia, and
attenuating shock due to hemorrhage. Ongoing clini-
cal trials are currently investigating the effects of ri-
monabant on smoking cessation, diabetes, and reduc-
tion of alcohol consumption.
The use of current weight loss agents is limited
due to their significant side effect profile. Rimona-
bant may be an alternative to these agents in obese
patients. In addition to a limited side effect profile,
rimonabant's effect on weight loss and cardiome-
tabolic risks may prove useful in patients with meta-
bolic syndrome.

1. World Health Organization. Global Strategy on
Diet, Physical Activity & Health: Obesity and
Overweight [cited 2006 June 2]. Available from:
2. Stein and Colditz. Epidemic of Obesity. J Clin
Endocrineol Metab 2004; 89(6): 2522-2525.
3. Acomplia (Rimonabant) Investigational Agent
for the Management of Obesity. [serial online]
Sanofi-Aventis. [Cited 2006 June 2]. Available
from: www.drugdeveopment-technology.com/
proj ects/rimonabant
4. Vastag B. Experimental Drugs Take Aim at Obe-
sity. JAMA 2003; 289: 1763-1764.
5. Bays HE. Current and Investigational Anti-
obesity Agents and Obesity Therapeutic Treat-
ment Targets. Obesity Research 2004;12(8):

6. Boyd ST. Update on Rimonabant- A Selective
Cannabinoid CB 1 Antagonist. Annals of Pharma-
cotherapy 2006; 40: 994.
7. Sharkey K and Pittman Q. Central and Peripheral
Signaling Mechanisms Involved in Endocannabi-
noid Regulation of Feeding. Science. STKE,
2005; 277: 15.
8. Turpault S, Kanamaluru V, Lockwood G, et al.
Rimonabant Pharamcokinetics in Healthy and
Obese Subjects. Clin Pharmacol Ther 2006; 79
9. Ferron GM, Grandison M, Lockwood G. Popula-
tion pharmacokinetic analysis of Rimonabant in
Healthy Subjects. Abstracts of the 2006 Annual
Meeting of the American Society for Clinical
Pharmacology and Therapeutics (ASCPT), Balti-
more, Maryland. March 2006. Clin Pharmacol
Ther 2006;77(2):43.
10. Pi-Sunyer FX, Aronne LJ, Heshmati HM, et al.
Effect of Rimonabant, a Cannabinoid-1 Receptor
Blocker on Weight and Cardiometabolic Risk
Factors in Overweight or Obese Patients: RIO-
North America: A Randomized Controlled Trial.
JAMA 2006;295:761-775.
11. Despres JP, et al. Effects of Rimonabant on
Metabolic Risk Factors in Overweight Patients
with Dyslipidemia. NEJM 2005; 353: 2121-34.
12. Gelfand E and Cannon C. Rimonabant: A Can-
nabinoid Receptor Type 1 Blocker for Manage-
ment of Multiple Cardiometabolic Risk Factors. J
Am Col Cardiology 2006;47(10):1919-26.

The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida

John G. Gums, Editor

R. Whit Curry, M.D. Associate Editor

Shawn D. Anderson, Assistant Editor

Phrm~oe olme21 sse 1,Auus 20

Volume 21, Issue 11, August 2006


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