physiological need to eat and the energy storage state. Thus, the EC system ... migrant are the global leaders in Diabetes and Metabolic syndrome. 41 million ...
Review Article
Endocannabinoid System - A Novel Target for Cardiometabolic Risk Shashank R Joshi
Abstract The endocannabinoid system (EC) plays a significant role in appetite drive and associated behaviours. Therefore attenuation of the activity of the EC system would have therapeutic benefit in treating disorders that might have a component of excess appetite drive or over-activity of the endocannabinoid system, such as obesity, ethanol and other drug abuse, and a variety of central nervous system and other disorders. Antagonists of cannabinoid receptors have been designed through rational drug discovery essential to exploit these novel targets for potential in obesity, metabolism, addiction, pain and neurologic disorders. Rimonabant is the only compound in this group which along this pathway is now approved as a selective CB (1) (cannabinoid receptor subtype 1) antagonist, or inverse agonist, in the European Union and India and under regulatory review in the United States for the treatment of obesity and associated cardiometabolic risk. ©
INTRODUCTION History: The Journey from Cannabis to Anandamide ince 4500 years Hemp –Cannabis sativa has been cultivated all over the world with the basic plant being used a fiber and oil source but more notoriously abused as an recreational drug (viz marihuana, ganja and hashish). The ability of these recreational compounds to stimulate appetite (the munchies) generated scientific interest in studying the use of endogenous cannbinod agents for weight related disorders. The primary natural psychoactive alkaloid of Cannabis is 9-tertahydrocannbinol (THC) with more than 60 cannabinod compounds now isolated. The synthetic THC is Dronabinol a drug now used in post chemotherapy induced nausea and emesis as well as HIV associated anorexia.1 The Endocannabinoid (EC) system is a physiological system that acts centrally as well as peripherally and plays a key role in regulating body weight and metabolic processes. The EC system regulates food intake and hedonic reward through central mechanism located within the hypothalamus and limbic forebrain. The EC system also plays a role in tobacco dependence. Endocannabinoids (ECBs), are the chemical messengers of the EC system, which bind and activate the G-protein coupled cannabinoid (CB) receptors namely two known subtypes of cannabinoid receptors namely, CB1 and
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Cons. Endocrinologist, Lilavati Hospital and Bhatia Hospital. Dept. of Endocrinology, Seth G.S. Medical College and KEM Hospital, Mumbai. © JAPI • VOL. 55 • JUNE 2007
CB2. Its two major ligands are “Anandamide” (derived from Sanskrit word “anand” meaning bliss) and “ 2-arachidonoyl-glycerol (2-AG)”. Endocannabinoids are PUFA (Polyunsaturates) omega 6 metabolites of arachidonic acid derivatives which are produced on demand that elicit many biological responses namely food deprivation, pain etc. CB1 receptors are found predominantly at nerve terminals where they mediate inhibition of transmitter release. CB2 receptors occur mainly on immune cells, one of their roles being to modulate cytokine release. Endogenous agonists for cannabinoid receptors also exist, and are all eicosanoids. The first-discovered of these ‘endocannabinoids’ was arachidonoylethanolamide and there is convincing evidence that this ligand and some of its metabolites can activate vanilloid VRI (TRPV1) receptors. CB1 is expressed in the brain, adipose tissue, liver, muscle and GI tract and CB2 is mainly expressed in the immune system. CB1 receptors in the brain as well as those in some peripheral tissues of the body such as adipocytes (or ‘fat cells’) are associated with lipid and glucose metabolism. CB1 receptors in the CNS, are necessary to stimulate food intake after a short period of food deprivation. When activated, they also preferentially stimulate the ingestion of palatable food.1-3 The endocannabinoids, particularly after stress and brief food deprivation, act in turn as local modulators of the expression and action of neurotransmitters, hormones and adipokines involved in metabolic control. Endocannabinoid overactivity seems to accompany metabolic and eating disorders and to contribute to the development of abdominal obesity, dyslipidemia and
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hyperglycemia. Accordingly, clinical trials have shown that CB1 receptor antagonists are efficacious at reducing not only food intake, but also abdominal adiposity and its metabolic sequelae. It is now well-known that endocannabinoids play a specific role in appetite control. This is achieved by modulating the expression and release of appetite suppressing and appetite stimulating chemical messengers in the hypothalamus region of the brain. At the peripheral level the activation of the CB1 receptor has been shown to stimulate lipogenesis in adipocytes that results in fat accumulation and modulation of the expression of adiponectin, a hormone that regulates the metabolism of lipids and glucose.1-3 Through its effects on the multiple components of the energy balance system, the EC system helps regulate the physiological need to eat and the energy storage state. Thus, the EC system plays a major role in helping to maintain energy balance by regulating what and how much we eat and how much fat we store or use. These, as well as other proposed endocannabinoids, derive from the nonoxidative metabolism of arachidonic acid, an essential v6-polyunsaturated fatty acid. The endocannabinoids, similarly to D9-THC and synthetic cannabinoid receptor agonists, trigger several intracellular pathways following the stimulation of CB1 and CB2 receptors and their associated G proteins. It is well established that AEA and 2-AG are not prestored in secretory vesicles but are biosynthesized de novo following an increase in the intracellular concentration of calcium, within a framework of metabolic reactions involving phospholipid precursors. In fact, both the formation of the two direct and distinct biosynthetic precursors of AEA and 2-AG and their conversion into the two endocannabinoids are catalysed by calciumsensitive enzymes. This means that the whole cascade of endocannabinoid production is triggered ‘on demand’, thus leading to endocannabinoid levels that will ultimately also depend on the availability of arachidonic acid on the sn-1 or -2 position of phosphoglycerides for AEA and 2-AG, respectively. Endocannabinoids are then released from the cell immediately after their biosynthesis to activate their targets, and then rapidly removed from the extracellular space by a rapid and selective cellular reuptake mechanism (the exact molecular identity of which has not yet been elucidated) followed by intracellular enzymatic hydrolysis. The cannabinoid receptors, the endocannabinoids and the proteins catalysing endocannabinoid biosynthesis and inactivation constitute the endocannabinoid system (ECS). This signalling system, after little more than a decade from its discovery, has recently afforded an entirely new class of drugs for the treatment of obesity and related metabolic disorders. 1-5
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Sufficient data in humans now indicates that higher levels of cannabinoids are present in obese individuals. In fact the circulating levels of anandamide and 2-AG were significantly increased (35% and 52%, respectively, in obese compared with lean women. In addition, some forms of human obesity are associated with a mutation in fatty acid amide hydrolase (FAAH), the enzyme that degrades ECs. Sipe and colleagues observed that an FAAH gene mutation was associated with overweight and obesity in both white and black subjects . In whites, genetically defective FAAH expression was correlated with increasing body mass index (BMI) and obesity, and a similar trend was observed in black subjects. These data suggest that a genetic defect in FAAH, the enzyme that inactivates ECs, renders some individuals more susceptible to obesity and supports the use of CB1 blockade as a therapeutic strategy. Important questions remain regarding the use of CB1 receptor antagonists to treat cardiometaboilc risks. For example, since none of the clinical data published to date have included patients being treated for depression, it is unknown how rimonabant may interact with antipsychotic therapeutics such as some selective serotonin reuptake inhibitors that tend to cause weight gain. Likewise, there are no data yet on possible interactions of rimonabant with specific dietary nutrients, such as low-fat diets, or the consumption of omega-3 fats; and studies combining rimonabant with exercise have not yet been reported. In summary, hyperactivity of the EC system in obesity involves several factors, including a high-fat diet, insulin resistance, and genetic malfunctioning of EC inactivation mechanisms. CB1 receptor blockade appears to represent a viable therapeutic strategy that addresses the underlying mechanisms of obesity.1-4
OBESITY AND ENDOCANNABINOID SYSTEM:RELEVANCE TO ASIAN INDIANS The explosive worldwide growth of obesity is due to alteration in our nutritional habits and sedentary lifestyle. Furthermore, the modern high-fat, highcarbohydrate diet has also contributed to the increase in the incidence of obesity. The combination of a sedentary lifestyle and a calorie-dense diet can disrupt the energy balance system, leading to obesity and chronic overstimulation of the EC system. This overactivity of the EC system not only promote fat storage in the adipocytes, but can also be associated with insulin resistance, glucose intolerance, elevated triglycerides and the low HDL cholesterol levels, all of which are risk factors for cardiovascular disease. Therefore, regulating the EC system is important in the control of food/energy storage and release in the body. Asian Indian both native and migrant are the global leaders in Diabetes and Metabolic syndrome. 41 million Asian Indians have Diabetes and 22 million of them are either obese or abdominally obese.7 They confer a huge cardiometabolic risk and are a vulnerable population in urban affluent metros of
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India which can threaten to hamper India's economic grown.7-9 Preventive strategies related to lifestyle are necessary on an emergency basis. Tobacco dependence as well as smoking also plagues Indians so the dual impact of smoking and lifestyle can be sinister on health indicators.10 Agents which can modulate weight, waist, glucose, lipids and potentially reduce motivation to smoke or nicotine deaddiction can have direct impact on the health of the affluent vulnerable Asian Indian. It is likely that the Asian Indian phenotype represents a state of overactivity of the EC system which needs restorations to every possible available measure. The blockade of CB1 receptor which modulates overactivity of the EC system results in the restoration of energy balance. Such blockage of the CB1 receptor eliminates the part of obesity that is controlled by the EC system such as increased appetite, excessive hunger and food intake. It also increases adiponectin levels, which is though to result in increased fat metabolism and an improvement in glucose metabolism. This may result in reducing cardiovascular risk factors through weight loss and an improvement in metabolic risk factor profile. It has been demonstrated that chronic nicotine consumption results in persistent over-stimulation of the EC system. The blockade of CB1 receptor may reduces motivation to self-administer nicotine.
ENDOCANNABIOD AGENTS (CB1 AND CB2 AGENTS) Several CB 1 - and CB 2 -selective agonists and antagonists have been developed. Agonists( Antiemetics and Apetite stimulants) : Two cannabinoid CB1 receptor agonists are already used clinically, as antiemetics or as appetite stimulants. These are D 9 - tetrahydrocannabinol (THC) and nabilone. Other possible uses for CB1 receptor agonists include the suppression of muscle spasm/spasticity associated with multiple sclerosis or spinal cord injury, the relief of chronic pain and the management of glaucoma and bronchial asthma. So too may CB2 receptor ligands and drugs that activate cannabinoid receptors indirectly by augmenting endocannabinoid levels at cannabinoid receptors. When taken orally, THC seems to undergo variable absorption and to have a narrow ‘therapeutic window’ (dose range in which it is effective without producing significant unwanted effects). This makes it difficult to predict an oral dose that will be both effective and tolerable to a patient and indicates a need for better cannabinoid formulations and modes of administration. For the therapeutic potential of cannabis or CB1 receptor agonists to be fully exploited, it will be important to establish objectively and conclusively (a) whether these agents have efficacy against selected symptoms that is of clinical significance and, if so, whether the benefits outweigh the risks, (b) whether cannabis has therapeutic advantages over individual cannabinoids, (c) whether © JAPI • VOL. 55 • JUNE 2007
there is a need for additional drug treatments to manage any of the disorders against which cannabinoids are effective, and (d) whether it will be possible to develop drugs that have reduced psychotropic activity and yet retain the ability to act through CB1 receptors to produce their sought-after effects Antagonists: CB1 receptor antagonists may also have clinical applications, e. g. as appetite suppressants and in the management of schizophrenia or disorders of cognition and memory. The antagonists include the CB1selective SR141716A, AM251, AM281 and LY320135, and the CB2-selective SR144528 and AM630. These all behave as inverse agonists, one indication that CB1 and CB2 receptors can exist in a constitutively active state. ‘Neutral’ cannabinoid receptor antagonists have also been developed. CB1 and/or CB2 receptor activation appears to ameliorate inflammatory and neuropathic pain and certain multiple sclerosis symptoms. This might be exploited clinically by using CB1, CB2 or CB1/ CB2 agonists, or inhibitors of the membrane transport or catabolism of endocannabinoids that are released in increased amounts, at least in animal models of pain and multiple sclerosis.1-5 Some French scientist have recently demonstrated that CB1 and CB2 receptors display opposite effects in the regulation of liver fibrogenesis during chronic liver injury.6 Indeed, both receptors are up-regulated in the liver of cirrhotic patients, and expressed in liver fibrogenic cells. Moreover, CB1 receptors are profibrogenic and accordingly, the CB1 antagonist rimonabant reduces fibrosis progression in three experimental models. In keeping with these results, daily cannabis smoking is a risk factor for fibrosis progression in patients with chronic hepatitis C. In contrast, CB2 display antifibrogenic effects, by a mechanism involving reduction of liver fibrogenic cell accumulation. These results may offer new perspectives for the treatment of liver fibrosis, combining CB2 agonist and CB1 antagonist therapy. 6 More than a decade has elapsed since the discovery by Sanofi of SR141716A(Rimonabant) the first selective CB1 cannabinoid receptor antagonist. Shortly after, Sanofi also reported the synthesis of the first selective CB2 cannabinoid receptor antagonist, SR144528. Since these two milestones in the cannabinoid field, many other compounds, more or less related to the Sanofi compounds, or based on a completely different scaffold appeared. Several of these compounds are currently involved in clinical trials for diseases such as obesity, nicotine and alcohol addictions, or allergies. Further, the cannabinoid receptors knock-out mice production strengthened the hypothesis of the existence of several other “cannabinoid” receptors for which the first antagonists begin to appear. The large amount of patents taken by many different pharmaceutical companies prove, if necessary, the great therapeutic potential expected for the cannabinoid receptors antagonists. SR
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147778 is a new CB1 cannabinoid receptor antagonist, SR147778, which has effection ethanol preference and alcoholism which sounds exciting area of work The best survivor among these agents is “Rimonabant” a selective CB1 antagonist which has a lot of interest due to its weight loss and pleurimetabolic effects which can impact cardiovascular risk.1-5
RIMONABANT (SR141716) Rimonabant is the first of a new class of selective cannabinoid 1 (CB1) receptor blockers. Rimonabant is a selective cannabinoid receptor (CB1) blocker that inhibits the pharmacological effects of Endocannabinoids. By selectively blocking the CB1 receptor, rimonabant modulates over-activity of the EC system, which results in weight loss and improvement of metabolic risk factors (i.e. HDL, triglycerides and insulin resistance) in obesity.1 By acting centrally Rimonabant decreases food intake leading to weight loss. Acting peripherally rimonabant increases adiponectin levels thereby increasing fatty acid oxidation. Rimonabant increases the fatty acid clearance leading to weight loss and metabolic effects such as decrease in hyperinsulinemia, restoring insulin sensitivity, decrease in triglycerides and increase highdensity lipoprotein levels.4-5 The various sites of action of Rimonabant are shown in Figure 1. Pharmacokinetics : The pharmacokinetics data of rimonabant is summarized below Pharmacokinetic Properties of Rimonabant Tmax Bioavailability Protein binding Metabolism Half life
Excretion
2 hours Undetermined >99.9% Hepatic, CYP3A involved Variable: 6-9 days with normal BMI 16 days if BMI >30 Fecal (86%) and renal (3%)
It is used as an adjunct to diet and exercise for the treatment of obese patients (BMI 30 kg/m 2), or overweight patients (BMI 27 kg/m2) with associated risk factor(s), such as type 2 diabetes or dyslipidemia. In adults, the recommended dosage is one 20 mg tablet daily to be taken in the morning before breakfast. The treatment should be introduced with a mildly reduced
Fig. 1 : Pleurimetabolic impact of rimonabant. 442
calorie diet. It has to be used with caution (preferably avoided) in people over 75 years of age, People with moderately decreased liver function, People with moderately decreased kidney function, People who have had a heart attack or stroke in the last six months (this medicine has not been studied in this group of people). It is contraindicated in people with severely decreased liver function, severely decreased kidney function, Uncontrolled serious psychiatric and uncontrolled depression and rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucosegalactose malabsorption, pregnancy, breastfeeding and children and adolescents under 18 years of age. Rimonabant should be used with caution in combination with CYP 3A4 inhibitors namely Clarithromycin, Itraconazole, Ketoconazole, Nefazodone, Ritonavir, Telithromycin (these drugs may increase the blood level of rimonabant) and CYP 3A4 inducers namely Carbamazepine, Phenobarbital, Phenytoin, Rifampicin (these drugs decrease the blood level of Rimonabant & so could make it less effective).4-5 Safety and Adverse effects: Rimonabant has been evaluated for safety in approximately more than 10,000 patients enrolled in studies that examined the metabolic and weight loss effects in overweight and obese patients and in approximately more than 5000 patients in other indications. The common adverse reactions were: nausea, diarrhoea, mood alteration symptoms, anxiety and dizziness.4-5 Safety remains the prime concern in all obesity medications from the dubious history of the old agents. Currently the available safety and pharmacovigilance data suggest that the adverse events are comparable to that of the placebo. Adverse effects mentioned in published clinical trials of rimonabant include mental disorders (anxiety, depression), neurological disorders (dizziness) and gastrointestinal disorders (nausea, diarrhoea). No postmarketing safety data are available. The possible long-term adverse effects of rimonabant are unknown The concerns especially of psychosis, depression and unmasking of immunological disorders remain speculative and ongoing data appears safe as long as they are kept in mind and avoided in people with major depression or psychiatric co-morbidities
RIMONABANT: CLINICAL EVIDENCE AND RIO PROGRAMS Table 1 lists the various mega trails in the RIO program which are published which lead to most of the regulatory approvals.11-14 These programs enrolled more than 13,000 patients of which RIO-Obesity enrolled more than 6,600 patients. RIO North America and Europe had 2 year treatment and RIO Lipids and Diabetes had 1 year treatment arms. The RIO programs were Phase III clinical programs which not only established efficacy but proved the plurimetabolic effects and
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Table 1 : RIO Trials Summary for efficacy and safety of Rimonabant
Obese patients Number Patient characteristics
Weight (≥, kg) Waist (≥, cm) Triglycerides (% decrease) HDL (% increase) Glucose (≥, mmol/l) Insulin (≥, ¼U/ml) Main adverse events (≥ between the % observed in the rimonabant and placebo groups)
RIO-Europe11
RIO-Lipids12
RIO-North America13
RIO-Diabetes14
n = 1507 BMI ≥ 30 kg/m2 or BMI >27 kg/m2 with untreated hyperlipidemia ≥ 4.7 ≥ 4.2 15.1 8.9 ≥ 0.11 ≥ 2.8 Dizziness: +3.8 Nausea: +8.6 Diarrhoea: +4.2 Insomnia: +2.4 Anxiety: +1.9 Depression: “0.3
n = 1036 BMI 34 kg/m2 with untreated
n = 3045 BMI ≥ 30 kg/m2 or BMI >27 kg/m2 with untreated hyperlipidemia ≥ 4.7 ≥ 3.6 13.2 7.2 ≥ 0.04 ≥ 2.8 Dizziness: +1.6 Nausea: +5.4 Diarrhoea: +0.2 Insomnia: +1.4 Anxiety: +4.0 Depression: +2.1
n = 1047 BMI ≥ 30 kg/m2 with type 2 diabetes mellitus and treated hyperglycaemia ≥ 3.9 ≥ 3.3 16.4 8.4 ≥ 0.97 ≥ 1.1 Dizziness: +4.0 Nausea: +6.0 Diarrhoea: +0.0 Insomnia: +0.0 Anxiety: +2.0 Depression: +2.1
hyperlipidemia ≥ 5.4 4.7 12.4 8.1 ≥ 0.02 ≥ 2.6 Dizziness: +3.7 Nausea: +9.5 Diarrhoea: +3.1 Insomnia: +3.8 Anxiety: +4.9 Depression: +0.2
ensured the safety profile. The data clearly establish it as a pleotropic agent which has multiple impact on lipids and glucose independent of weight loss by direct novelmechanisms. Ongoing Rimonabant Trials of the future : There are several other non RIO trials which shall address several other issues. The STRATUS Studies with Rimonabant and Tobacco Use (STRATUS) namely the STRATUS – United States study, STRATUS – Europe study and STRATUS – Worldwide study shall look at the Nicotine effects of Rimonabant. There are numerous phase IIIB Clinical Trials to Assess the Potential Role of Rimonabant in Risk Reduction. Of these there are eight studies to assess the potential role of rimonabant in reducing the risk of heart attacks or strokes in patients with abdominal obesity and other risk factors and to explore the use of Rimonabant in preventing and treating type 2 diabetes. Among them the phase IIIb Trials involving Cardiovascular Disease are CRESCENDO: Comprehensive Rimonabant Evaluation Study of Cardiovascular END points and Outcomes trial, AUDITOR: Atherosclerosis Underlying Development Assessed by Intima-Media Thickness In Patients On Rimonabant trial, STRADIVARIUS: Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant – The Intravascular Ultrasound Study trial,VICTORIA: Visceral Fat Reduction Assessed by CT-Scan on Rimonabant trial, and the ADAGIOLipids: An International Study of Rimonabant in Dyslipidemia with Athero Genic Risk in Abdominally Obese Patients trial. The phase IIIb Trials involving Type 2 Diabetes which are ongoing are SERENADE: Study Evaluating Efficacy in Drug Naïve Diabetic Patients, ARPEGGIO: A Multicenter, Randomized, Placebocontrolled, Double-Blind, Parallel-Group, Fixed-Dose Study Evaluating the Effect of One Dose of Rimonabant 20 mg/day on Glycemic Control in Type 2 Diabetic Patients Inadequately Controlled with Insulin trial and © JAPI • VOL. 55 • JUNE 2007
RAPSODI: Rimonabant in Pre-Diabetic Subjects to Delay Onset of Type 2 Diabetes. These eight studies involving more than 22,000 patients to assess the potential role of Rimonabant in reduction in risk of cardiovascular disease and stroke include CRESCENDO – Four to five year study (n=17,000), AUDITOR – Two year study (n=600), STRADIVARIUS – Eighteen month study (n=800), VICTORIA – One year study (n=250), ADAGIOLipids – Two year study (n=740), Ongoing studies to assess the potential role of the Rimonabant in prevention and treatment of Type 2 diabetes, SERENADE – Sixmonth study (n=281), ARPEGGIO – Two-year study (n=300) and RAPSODI – Two-year study (n=2,100). The STRATUS Program in Smoking Cessation has enrolled more than 6,500 patients with STRATUS-US 10-week treatment, STRATUS-Europe 10-week treatment and STRATUS-Worldwide 1-year treatment. Thus the emerging evidence base of Rimonabant is one of the largest in the world supporting the various indications will allow us to know the real world clinical use of this novel compound.Several other novel CB 1 agents will also be discovered in forthcoming years but Rimonbant shall remain the signature drug of the EC system.The impact of Rimonbant both in India and USA will be intersting to observe this decade.
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