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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical trial data are beginning to emerge with respect to the therapeutic efficacy of cannabis extracts for the treatment of chronic pain. Although there is some evidence of efficacy, a major issue concerns the narrow margin between doses producing therapeutic effects and those producing the "highs" associated with cannabis misuse. In addition, long-term use is associated with an increased risk of psychiatric illness. These negative aspects constrain the doses of cannabis extracts and psychoactive cannabinoids that can be given to patients, and raise the risk that properly conducted clinical trials with too low dosages will impact negatively on subsequent drug development in this field. However, recent research has opened up a number of avenues whereby compounds acting directly upon cannabinoid (CB) receptors may have therapeutic potential. In this review, two such areas are discussed, namely a) the possible use of peripherally acting CB agonists and CB2 receptor-selective agonists for the treatment of pain, and b) the possible utility of CB2 receptor agonists for the prevention of stress-induced exacerbations of skin disorders such as psoriasis. A second area of drug development at present is that of CB1 receptor antagonists/inverse agonists, spearheaded by rimonabant, for the treatment of obesity and as an aid for smoking cessation. An important aspect of these compounds is their efficacy and selectivity, and this is discussed in detail in the present review.
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PMID:Pharmacological properties and therapeutic possibilities for drugs acting upon endocannabinoid receptors. 1637 86

Rimonabant is the first selective blocker of the cannabinoid CB1 receptors being developed for the treatment of obesity, tobacco smoking and cardiometabolic risk factors. Following 1 year of treatment, rimonabant 20 mg/day leads to greater weight loss compared with placebo. Therapy with rimonabant is also associated with favourable changes in serum lipids and an improvement in glycaemic control in Type 2 diabetics. At the same dose, rimonabant significantly increases the cigarette smoking quit rates compared with placebo. Rimonabant appears to be generally well tolerated, with primary side effects of mild nausea, diarrhoea, anxiety and depression. As an agent with a novel mechanism of action, rimonabant has the potential to be a useful adjunct to lifestyle modification in the treatment of obesity, metabolic syndrome and cigarette smoking.
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PMID:Rimonabant: a selective blocker of the cannabinoid CB1 receptors for the management of obesity, smoking cessation and cardiometabolic risk factors. 1650 66

The CB1 cannabinoid receptor has attracted much recent interest because of the observation that CB1 receptor antagonists have efficacy in treating metabolic syndrome and obesity. CB1 receptors also mediate most of the psychotropic effects of Delta9-tetrahydrocannabinol (Delta9THC), the principal psychoactive component of cannabis. In addition, they are one component of an interesting and widespread paracrine signaling system, the endocannabinoid system. The endocannabinoid system is comprised of cannabinoid receptors, endogenous cannabinoids, and the metabolic pathways responsible for their synthesis and degradation. The details of the endocannabinoid system have been most thoroughly studied in the brain. Here it has been shown to be intimately involved in several forms of neuronal plasticity. That is, activation of CB1 receptors by endocannabinoids produces either short- or long-term changes in the efficacy of synaptic transmission. The behavioral consequences of these changes are many, but some of the most striking and relevant to the current symposium are those associated with endogenous reward and consumptive behavior.
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PMID:Mechanisms of CB1 receptor signaling: endocannabinoid modulation of synaptic strength. 1657 Jan

Presentations in this symposium addressed effects and modes of action of endocannabinoids in various tissues in relation to metabolic disorders. Endocannabinoids are produced and exert their effect in various brain sites, including the mesolimbic reward circuitry and the hypothalamus. Both of these regions have direct ties to energy metabolism regulation, particularly food intake and energy expenditure. These data clearly suggest that the observed beneficial effects of CB1 (cannabinoid receptor 1) receptor antagonists on obesity may be related to the central endocannabinoid system. On the other hand, data presented on cannabinoid action in the liver and white adipose tissues clearly indicate that CB1-mediated events in affecting metabolic phenotype may occur in peripheral tissues as well. This together with the reported results from human trials on CB1 antagonists showing that the initial anorectic effect of rimonabant is diminished after the first weeks while longer lasting weight loss is achieved do indicate that peripheral action of cannabinoids are very important in body weight regulation. Should this hold true in the long run, antagonizing CB1 receptors with compound not crossing the blood-brain barrier could revolutionize pharmaceutical approaches to obesity by offering a tool that short cuts the central nervous system.
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PMID:The unfolding cannabinoid story on energy homeostasis: central or peripheral site of action? 1657 Jan 2

The worldwide increase in the prevalence of type 2 diabetes represents a tremendous challenge for our healthcare system, especially if we consider that this phenomenon is largely explained by the epidemic of obesity. However, despite the well-recognized increased morbidity and mortality associated with an elevated body weight, there is now more and more evidence highlighting that abdominal adipose tissue is the fat depot that conveys the greatest risk of metabolic complications. This cluster of metabolic abnormalities has been referred to as the metabolic syndrome and this condition is largely the consequence of abdominal obesity, especially when accompanied by a high accumulation of visceral adipose tissue. This cluster of metabolic complications has also been found to be predictive of a substantially increased risk of coronary heart disease beyond the presence of traditional risk factors. Moreover, a moderate weight loss in initially abdominally obese patients is associated with a selective mobilization of visceral adipose tissue, leading to improvements in the metabolic risk profile predictive of a reduced risk of coronary heart disease and of type 2 diabetes. The recent discovery of the endocannabinoid-CB1 receptor system and of its impact on the regulation of energy metabolism represents a significant advance, which will help physicians target abdominal obesity and its related metabolic complications. In this regard, studies have shown that rimonabant therapy (the first developed CB1 blocker) could be useful for the management of clustering cardiovascular disease risk factors in high-risk abdominally obese patients through its effects not only on energy balance but also on adipose tissue metabolism. For instance, the presence of CB1 receptors in adipose tissue and the recently reported effect of rimonabant on adiponectin production by adipose cells may represent a key factor responsible for the weight loss-independent effect of this CB1 blocker on cardiometabolic risk variables.
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PMID:Contribution of CB1 blockade to the management of high-risk abdominal obesity. 1657 Jan 6

The present study evaluates the pharmacological profile of the new neutral cannabinoid CB1 receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole -LH-21- on feeding behavior and alcohol self-administration in rats, two behaviors inhibited by cannabinoid CB1 receptor antagonists. Administration of LH-21 (0.03, 0.3 and 3 mg/kg) to food-deprived rats resulted in a dose-dependent inhibition of feeding. Subchronic administration of LH-21 reduced food intake and body weight gain in obese Zucker rats. Acute effects on feeding were not associated with anxiety-like behaviors, or induction of complex motor behaviors such as grooming or scratching sequences, usually observed after central administration of cannabinoid receptor blockers with inverse agonist properties. LH-21 did not markedly reduce alcohol self-administration (30% reduction observed only at a high dose of 10 mg/kg). This pharmacological pattern partially overlaps that of the reference cannabinoid CB1 receptor antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, SR141716A, (0.3, 1 and 3 mg/kg) that reduced feeding and alcohol self-administration with similar efficacy. In vitro analysis of blood-brain barrier permeability using a parallel artificial membrane permeation assay demonstrated that LH-21 has lower permeation through membranes than SR141716A. That was confirmed in vivo by studies showing lower potency of peripherally injected LH-21 when compared to SR141716A to antagonize motor depression induced by intracerebroventricular administration of the CB1 agonist CP55,940. The neutral antagonist profile and the lower penetration into the brain of LH-21 favour this class of antagonists with respect to reference inverse agonists for the treatment of obesity because they potentially will display reduced side effects.
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PMID:Antiobesity effects of the novel in vivo neutral cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole--LH 21. 1675 May 44

In the past two decades, cannabinoids have emerged as crucial mediators in a variety of pathophysiological conditions. Awareness of their critical functions in liver pathophysiology is only recent, probably given the low level of expression of cannabinoid receptor type 1 (CB1 receptor) and type 2 (CB2 receptor) in normal liver. However, it has been shown that non-alcoholic fatty liver disease and cirrhosis are associated to a marked upregulation of the hepatic endocannabinoid system, including increases in endocannabinoids and in hepatic CB receptors, both in humans and in rodents. Consequently, a growing number of cannabinoid-related hepatic effects are being unravelled. Hence, hepatic CB1 receptors enhance liver steatogenesis in a mouse model of high fat-induced obesity, and contribute to peripheral arterial vasodilation in cirrhosis, thereby promoting portal hypertension. In addition, CB1 and CB2 receptors elicit dual opposite effects on fibrogenesis associated to chronic liver injury, by promoting pro- and antifibrogenic effects, respectively. Therefore, endocannabinoid-based therapies may open novel therapeutic avenues in the treatment of chronic liver diseases.
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PMID:Endocannabinoids as novel mediators of liver diseases. 1675 9

The prevalence of Type 2 diabetes is showing a rapid progression worldwide, a phenomenon largely resulting from the epidemic proportions reached by obesity in various populations of the world. However, physicians have been puzzled by the heterogeneity of obesity as not every obese patient is characterized by chronic complications. In this regard, body fat distribution, especially intra-abdominal adipose tissue accumulation, has been found to be a key correlate of a cluster of diabetogenic, atherogenic, prothrombotic and inflammatory metabolic abnormalities increasing the risk of Type 2 diabetes and cardiovascular disease. In this regard, it has been recently demonstrated that abdominal obesity was independently associated with an increased risk of coronary heart disease and Type 2 diabetes independently of overall adiposity. Lifestyle modification programs have shown the benefits on cardiometabolic risk variables of a moderate weight loss as it has been found to be associated with a substantial loss of intra-abdominal fat in viscerally obese patients. However, to be successful, such programs require the support of a multidisciplinary team not available to most clinicians. In this context, it is proposed that pharmacotherapy of obesity should target abdominally obese patients at high risk of Type 2 diabetes and cardiovascular disease, such risk being encompassed by the notion of "cardiometabolic risk". The recent discovery of the endocannabinoid-cannabinoid receptor type 1 (CB1 receptor) system and of its impact on the regulation of energy metabolism represents a significant advance which could help physicians to target abdominal obesity and its related metabolic complications. In this regard, studies have shown that rimonabant (the first CB1 blocker developed) therapy could be useful for the management of clustering cardiovascular disease risk factors in high-risk abdominally obese patients through its marked effects on both abdominal adiposity and related metabolic risk factors.
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PMID:Intra-abdominal obesity: an untreated risk factor for Type 2 diabetes and cardiovascular disease. 1675 11

Energetic balance is a fundamental homeostasis mechanism, which contributes to the species' survival. The endocannabinoid system is a new and important component among such mechanisms. Its receptors and endogenous agonists are expressed in central nervous system (CNS) and at various peripheral organs, establishing a CNS-periphery net communication. A relevant aspect is its expression in the adipose tissue, where it regulates lipogenesis and increases the expression of influent genes on lipids and carbohydrate metabolism. Interestingly, it seems to be upregulated in human and animal obesity, although it is activated on demand and rapidly deactivated. Its activation increases food intake and promotes weight gain, contributing to Metabolic Syndrome (MS). Rimonabant is a specific antagonist to the main endocannabinoid receptor (CB1). In animal models of obesity and MS, as well as in humans, Rimonabant has demonstrated to be a useful tool in controlling weight and metabolic aspects. Indeed, some new human trials suggest a possible role for this substance in controlling cardiovascular risk factors related to MS.
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PMID:[The endocannabinoid system: a new paradigm in the metabolic syndrome treatment]. 1676 5

Research into the endocannabinoid 'system' has grown exponentially in recent years, with the discovery of cannabinoid receptors and their endogenous ligands, such as anandamide and 2-arachidonoylglycerol (2-AG). Important advances have been made in our understanding of endocannabinoid transduction mechanisms, their metabolic pathways, and of the biological processes in which they are implicated. A decade of endocannabinoid studies has promoted new insights into neural regulation and mammalian physiology that are as revolutionary as those arising from the discovery of the endogenous opioid peptides in the 1970s. Thus, endocannabinoids have been found to act as retrograde signals: released by postsynaptic neurons, they bind to presynaptic heteroceptors to modulate the release of inhibitory and excitatory neurotransmitters through multiple G-protein-coupled receptor (GPCR)-linked effector mechanisms. The metabolic pathways of anandamide and 2-AG have now been been characterised in great detail, and we can anticipate that these pathways -- together with endocannabinoid uptake mechanisms -- will complement cannabinoid receptors as targets for the pharmacological analysis of the physiological functions of these substances. Specific insights into the potential role of endocannabinoid-CB1 receptor systems in central appetite control, peripheral metabolism and body weight regulation herald the clinical application of CB1 receptor antagonists in the management of obesity and its associated disorders.
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PMID:Endocannabinoids in appetite control and the treatment of obesity. 1678 29


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