3. Umbruch 4.4..2005 - Online Pot

Cannabinoids in appetite and obesity 223
tor. In both ob/ob and db/db obese mice with unrestricted access to food, acute
administration of SR-141716 (3 mg/kg i.p.) produced a significant reduction
of food intake [35]. In Zucker (fa/fa) rats, SR-141716 induced a transient
decrease in food intake and body-weight gain when administered orally for 4
weeks [36].
These encouraging results have stimulated the search for cannabinoid
antagonists. Both publications and patent literature suggest that new cannabinoid
antagonists with chemical structures distinct from that of SR-141716 may
exhibit anti-obesity activity in animal models. The pyrazole derivative
SR-147778 (Fig. 1) was able to reduce sucrose consumption in mice and rats,
and food intake in fasted and non-deprived rats [37]. A new imidazole derivative
acting as a potent cannabinoid CB 1 inverse agonist (Fig. 1, compound 1)
was recently shown to be effective in reducing body weight in DIO rats following
14 days treatment (3–10 mg/kg p.o.) [38] . Similar compounds are
claimed in a Bayer patent application which describes significant reduction in
food intake in normal rats and weight loss following chronic treatment in
Zucker obese rats [39].
Following the results obtained in animal models of obesity,
Sanofi-Synthelabo advanced SR-141716 (rimonabant) into clinical trials
involving obese patients. Rimonabant was tested in obese male subjects with
a body mass index (BMI = weight/height 2 ) of >27 kg/m 2 in a double-blind
cross-over study (20 mg once a day versus placebo). The patients were treated
for 7 days with a 28-days wash out. Rimonabant had no effect on taste and spit
tests, yet induced a significant decrease in hunger (visual analogue scale),
caloric intake and weight [40]. Moreover, in a subsequent study involving 287
obese patients (BMI values of between 29 and 41 kg/m 2 ) treated for 16 weeks
with either placebo or rimonabant (5, 10 and 20 mg once daily), rimonabant
was able to significantly reduce body weight as well as waist circumference.
In the 20-mg group the mean decrease in body weight was 3.8 kg (versus
0.9 kg in the placebo group) and the mean decrease in waist circumference was
3.9 cm (versus 1.1 cm in the placebo group). The observed decrease in weight
did not reach a plateau during the 4-month duration of the study and the tolerance
of SR-141716 was excellent [41].
Rimonabant is currently being evaluated in multi-centre, randomized, double-blind
phase III studies in order to assess its efficacy and long-term safety.
The results of one of these studies, the RIO-Lipids trial, which enrolled 1036
overweight or obese patients (BMI values between 27 and 40 kg/m 2 ) with
untreated dyslipidemia [high triglycerides and/or low high-density lipoprotein
(HDL)-cholesterol] were presented at the 2004 American College of
Cardiology annual meeting [42]. Patients were randomized to receive either a
daily, fixed dose of rimonabant (5 or 20 mg) or placebo along with a mild
hypocaloric diet for 1 year. Patients treated for 1 year with rimonabant
20 mg/day lost 8.6 kg (versus 2.3 kg in the placebo group). Over 72% of
patients treated for one year with rimonabant (20 mg/day) lost over 5% of their
body weight (versus 27.6% in the placebo group). Moreover, 44.3% of the