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Microsoft word - cmr-ejournal- vol 1- no 3 - v1.95.doc

December 2008 (Vol. 1, Issue 3, pages 47-50)

HISTORY OF THE DEVELOPMENT AND CLINICAL USE
OF CB1 RECEPTOR INVERSE AGONISTS/ANTAGONISTS

By Gérard Le Fur, PhD Sanofi-aventis, Paris, France Introduction
In 1964, the structure of delta-9-tetrahydrocannabinol, the main psychoactive ingredient in mari-juana, was identified [1]. The breakthrough was given impetus by the discovery of cannabinoid re-ceptors and their endogenous ligands, the endocannabinoids. The endocannabinoid system (ECS) is a physiological system with an impor-tant regulatory role in numerous bio- Key Points
■ CB1 receptors may be involved in the motivational aspects ■ Rimonabant can reduce the appetitive and rewarding properties of food and drink in animal models. ■ An activation of peripheral metabolic processes contrib- utes to the weight-reducing effect of rimonabant. ■ Preclinical studies have shown the potential of rimonabant ligands and systems for their transport, in the specific treatment of dyslipidemia, glycemia, and atherosclerosis and in reducing the risk of major cardio- ■ Rimonabant in the RIO studies achieved clinically signifi- Discovery
cant improvements in body weight, HbA1c levels in type 2 In the late 80s and early 90s, scientists ■ Subsequent clinical studies have demonstrated that ri- monabant improves glycemic control in type 2 diabetes tion of appetite and thus be a potential across a range of patient populations while improving weight loss and lipid parameters, thereby addressing mul- tiple cardiometabolic risk factors commonly observed in type 2 diabetes. ■ CB1 receptor antagonism with rimonabant represents a novel approach to the treatment of abdominal obesity and years later by the characterization of a other cardiovascular and cardiometabolic risk factors. second cannabinoid receptor (CB2). A high throughput screening was then performed on the cannabinoid receptors. These studies led, after optimization, to the selection of SR141716 (rimonabant). Rimonabant was found to be highly selective for the central CB1 receptor (at nM levels), exhibiting only very weak activity (at mM levels) for the cloned peripheral CB2 re- ceptor [3]. The compound was then examined in an in vivo environment and, at low doses adminis-tered by the oral or intraperitoneal routes, it antagonized in a dose-dependent way the behavioural responses elicited by the cannabinoid receptor agonist WIN 55212-2 in rodents. In addition, other tests established the good bioavailability of the compound and its long duration of action. Preclinical Profile
Numerous preclinical studies have shown that rimonabant selectively reduces the intake of palatable food or drink [4], and it is also able to diminish the intake of a high-fat diet preferred by the obese Zucker rats, without modifying the intake of a high-carbohydrate diet. Rimonabant has been studied in different models of obesity in rodents. The anti-obesity effect of rimonabant has also been studied in a model of obesity (DIO) induced by a high-fat diet in mice. In this model, rimonabant adminis-tered at a dose of 10mg/kg/day during 6 weeks produced a marked reduction in eating, which was transitory during the first weeks of treatment. Afterwards this effect tended to disappear. However, rimonabant produced a marked loss in body weight that was maintained up to the end of the 6-week treatment [5]. The initial loss in body weight was probably due to the reduction in food intake ob-served at the beginning of treatment. However, the fact that this effect persisted even when the mice increased their food intake to normal levels suggested a metabolic effect involving the peripheral tis-sues. It has been demonstrated that the CB1 receptors are also expressed in the adipose tissue of rodents and humans and also in the cultured mouse 3T3 F442A adipose cells. This expression is increased in the adipose tissue of obese Zucker rats compared to nonobese rats [6]. Rimonabant at a dose of 10 mg/kg/day for 10 days in Zucker rats stimulated the expression of adiponectin mRNA in the adipose tissue of the obese animals. This effect was mediated by the blockade of the CB1 receptors, as ri-monabant did not modify the expression in the adipose tissue of CB1 knockout mice. These results demonstrate that rimonabant, in blocking the adipocyte CB1 receptors, regulates the expression of this adiponectin protein. The increase in the levels of adiponectin could therefore be partially re-sponsible for the peripheral metabolic effects of rimonabant. A follow-up study in Zucker rats dem-onstrated that rimonabant had a definite hepatoprotective effect with a reduced hepatomegaly asso-ciated with reduced elevated plasma levels of enzyme markers of hepatic damage as well as reduced local hepatic tumor necrosis factor-α levels indicative of steatohepatitis [7]. Further long-term studies in obese Zucker rats that developed chronic renal failure showed that ri-monabant preserved renal function and increased survival [8]. When rimonabant was administered to Zucker diabetic rats, it prevented the development of hypoglycemia and improved β-cell function, while maintaining a normal profile of insulin secretion with a much lower impact on body weight compared to rosiglitazone treatment [9]. In addition, rimonabant positively modulates the lipid profile, reduces circulating neutrophils and monocytes, attenuates platelet activation as well as the release of proatherosclerotic chemokines, re-ducing cardiovascular risk in the process [10]. Clinical Studies
The preclinical studies confirmed the potential of rimonabant as a CB1 receptor antagonist as well as its potential therapeutic application in the treatment of obesity. Initial phase II clinical studies con-firmed the potential of the compound in reducing body weight in obese patients. In 4 large random-ized phase III clinical studies in obese or overweight patients (RIO program in over 6,600 patients) [11-14], rimonabant has shown the ability to reduce body weight and waist circumference, increase HDL cholesterol levels, reduce triglyceride and HbA1c levels and other cardiometabolic risk factors, and is thus considered a novel treatment in conjunction with diet and exercise for obese and over-weight patients with cardiometabolic diseases such as type 2 diabetes or dyslipidemia. After the RIO program, different clinical studies were initiated to assess the therapeutic potential of the compound in the treatment of type 2 diabetes and other cardiovascular risk factors. These in-cluded the SERENADE study, where the drug was found to improve glycemic control in newly di-agnosed naive type 2 diabetic patients [15]. More recently, the ARPEGGIO study demonstrated an improvement in glycemic control in a difficult population of type 2 diabetic patients inadequately controlled by insulin alone, with a significant decrease in HbA1c levels being observed [16]. In the ADAGIO-Lipids study, rimonabant was active against certain biomarkers indicative of atherogenic dyslipidemia in abdominally obese patients, e.g., fatty acid index, alanine transaminase, high-sensitivity C-reactive protein, and adiponectin [17]. Further studies included the STRADIVARIUS study, where the effect of rimonabant over 18 months on the progression of atherosclerosis was measured by IVUS endpoints. Rimonabant failed to show a statistically significant effect on the primary endpoint, but did show encouraging results across 4 IVUS endpoints [18]. Current/Future Clinical Studies
In the cardiovascular area, as a follow-up to the STRADIVARIUS study, the AUDITOR study will specifically look for an effect on the inhibition of atherosclerosis progression as assessed by carotid artery intima-media thickness (CIMT) in overweight patients. In addition, the ongoing RAPSODI study will assess the efficacy and safety of long-term administration of rimonabant to delay the onset of type 2 diabetes in patients with a pre-diabetic status. Finally, the CRESCENDO study (~17,000 patients), due to be completed in 2011, will see whether rimonabant treatment can reduce cardiovas-cular events in abdominally obese patients with high cardiovascular risk factors. References
1. Mechoulam R and Gaoni Y. Isolation, structure, and partial synthesis of an active constituent of hashish. J Am 2. Matsuda LA, Lolait SJ, Brownstein MJ, et al. Structure of a cannabinoid receptor and functional expression of the 3. Rinaldi-Carmona M, Barth F, Heaulme M, et al. SR141716A, a potent and selective antagonist of the brain can- nabinoid receptor. FEBS Lett 1994; 350: 240-4. 4. Arnone M, Maruani J, Chaperon F, et al. Selective inhibition of sucrose and ethanol intake by SR 141716, an an- tagonist of central cannabinoid (CB1) receptors. Psychopharmacology (Berl) 1997; 132: 104-6. 5. Ravinet Trillou C, Arnone M, DelGeorge C, et al. Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am J Physiol Regul Integr Comp Physiol 2003; 284: R345-R53. 6. Bensaid M, Gary-Bobo M, Esclangon A, et al. The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol Pharmacol 2003; 63: 908-14. 7. Gary-Bobo M, Elachouri G, Gallas JF, et al. Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. Hepatology 2007; 46: 122-9. 8. Janiak P, Poirier B, Bidouard JP, et al. Blockade of cannabinoid CB1 receptors improves renal function, metabolic profile, and increased survival of obese Zucker rats. Kidney Int 2007; 72: 1345-57. 9. Chamiot-Clerc P, Duquenne C, Ludop-Maignel J, et al. Effects of rimonabant on metabolic parameters and pancre- atic function in male ZDF rats: comparison with rosiglitazone. Diabetologia 2007; 50: S343 (abstract). 10. Schafer A, Pfrang J, Neumuller J, et al. The cannabinoid receptor-1 antagonist rimonabant inhibits platelet activa- tion and reduces pro-inflammatory chemokines and leukocytes in Zucker rats. Br J Pharmacol 2008; 154: 1047-54. 11. Després JP, Golay A and Sjöström L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005; 353: 2121-34. 12. 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: 761-75. 13. Scheen AJ, Finer N, Hollander P, et al. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 2006; 368: 1660-72. 14. Van Gaal LF, Rissanen AM, Scheen AJ, et al. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005; 365: 1389-97. 15. Rosenstock J, Hollander P, Chevalier S, et al. SERENADE: the Study Evaluating Rimonabant Efficacy in Drug- naive Diabetic Patients: effects of monotherapy with rimonabant, the first selective CB1 receptor antagonist, on gly-cemic control, body weight, and lipid profile in drug-naive type 2 diabetes. Diabetes Care 2008; 31: 2169-76. 16. Hollander PA, Amod A and Litwak LE. Rimonabant improves glycemic control in insulin-treated type 2 diabetes: the ARPEGGIO trial. Diabetes 2008; 57: A95 (abstract). 17. Després JP, Ross R, Boka G, et al. Rimonabant reduces both intra-abdominal adiposity and liver fat and improves cardiometabolic risk factors: the ADAGIO-Lipids trial. Presented at the late breaking session of the 77th European Atherosclerosis Society meeting, Istanbul, Turkey, 2008. 18. Nissen SE, Nicholls SJ, Wolski K, et al. Effect of rimonabant on progression of atherosclerosis in patients with ab- dominal obesity and coronary artery disease: The STRADIVARIUS randomized controlled trial. JAMA 2008; 299: 1547-60.

Source: http://www.myhealthywaist.org/cmrejournal/pdf/vol1/v1i3a12.pdf

Ne02:.pdf

Interpersonelle Psychotherapie: Stand der Wirksamkeitsüberprüfung (April Elisabeth Schramm Die Interpersonelle Psychotherapie (IPT) gehört zu den wenigen psychologischen Verfahren, deren Wirksamkeit bei affektiven Störungen nachgewiesen wurde. Der Ansatz wurde Ende der 60ziger Jahre von Klerman und Weissman ((Klerman et al. 1984, Weissman et al., 2000; dt. Version: Schramm 1998, 2

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