3. Umbruch 4.4..2005 - Online Pot

224 F. Barth and M. Rinaldi-Carmona
patients in the 20-mg rimonabant group lost more than 10% of their body
weight (versus 10.3% in the placebo group). In addition to weight loss, the
study was designed to assess a number of important associated cardiovascular
risk factors. Study findings for rimonabant 20 mg include:
• a waist-circumference reduction of 9.1 cm in patients treated for 1 year
(completers);
• an average increase in HDL-cholesterol (+23%) and a reduction in triglycerides
(–15%) in completers;
• reduction of C-reactive protein (CRP), an important inflammatory marker
predictive of cardiovascular risk (–27% versus –11% in the placebo group);
• and improved insulin sensitivity (oral glucose tolerance test) [42, 43].
These robust data were replicated in another phase III study (RIO-Europe)
involving 1507 obese patients with or without comorbidities [44].
Rimonabant, which was well tolerated, could therefore become an important
agent in the management of cardiovascular risk in obese patients.
Mechanism of action of cannabinoid ligands on food intake and energy
balance
The mechanisms that control food-intake and energy homeostasis in mammals
are particularly complex. Leptin and insulin, two hormones secreted by
adipocytes and the pancreas cells respectively, are key elements of this process.
Leptin and insulin are released from peripheral organs and interact with specific
brain receptors in the hypothalamus in order to adapt food intake to body fat
mass. However, it would appear that more than 16 other hypothalamic neuropeptides
are involved in the precise control of energy homeostasis and act to
either stimulate or inhibit food intake [45]. Moreover, monoamine neurotransmitters
such as noradrenaline, serotonin and dopamine have also been shown to
affect food intake, with noradrenaline and serotonin uptake being the pharmacological
mechanism of sibutramine, one of the only two prescription drugs
approved by the FDA for the treatment of obesity. How the endogenous and synthetic
cannabinoids interact with all these systems remains largely unknown.
The involvement of cannabinoid CB 1 receptors in both the agonist-induced
hyperphagia and antagonist-induced food-intake reduction has been demonstrated
by several authors.
The involvement of cannabinoid CB 1 receptors in food consumption
induced by anandamide and 2-AG was confirmed by its sensitivity to the specific
CB 1 antagonist SR-141716, which reversed for example the hyperphagia
induced by anandamide [20] and 2-AG [23]. On the other hand, the CB 2 antagonist
SR-144528 [46] did not affect the ∆ 9 -THC-induced feeding in pre-satiated
rats, excluding the participation of the CB 2 subtype in this effect [28]. The
involvement of CB 1 receptors in the food-intake reduction induced by the