Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Therapeutic strategies currently available for the management of cardiometabolic risk factors focus mainly on individual factors, and do not target the underlying cause of cardiovascular and metabolic diseases. The Rimonabant-in-Obesity (RIO) programme consists of four 1-2 yr Phase III trials, RIO-Europe, RIO-Lipids, RIO-North America (NA), and RIO-Diabetes, designed to assess the efficacy and safety of rimonabant in the treatment of multiple cardiometabolic risk factors in 6600 overweight/obesity patients. After 1 yr, results from the RIO-NA anci RIO-Europe trials, showed that treatment with rimonabant 20mg/day improved HDL-C (p< 0.001), triglycerides (p< 0.001), fasting insulin (p< 0.001) and insulin resistance (p=0.002 and p< 0.001 for RIO-Europe and RIO-NA, respectively) compared to placebo. The results of both studies also showed significant and sustained mean reductions in waist circumference (p< 0.001), and weight (p< 0.001) for rimonabant 20 mg/day compared with placebo. Similar improvements were seen in the RIO-Lipids trial at 1 yr and these results were consistently maintained over 2 yr in RIO-NA. The RIO-Europe and RIO-NA trials showed that improvements in HDL-C and TG levels with rimonabant over 1 yr, compared with bodyweight, were beyond that attributable to weight loss alone [40 and 55% for HDL-C and triglyceride (TG), respectively for RIO-Europe and 58 and 47%, respectively for RIO-NA]. Additionally, in RIO-NA, changes in fasting insulin and homeostasis model assessment insulin resistance (HOMA-IR), were beyond weight loss alone (50 and 51%, respectively). Rimonabant was well tolerated and the majority of adverse events reported were mild and transient, and occurred early in the treatment period. Rimonabant, the first cannabinoid receptor type 1 (CB1) receptor blocker, reduces weight and waist circumference, and improves lipid and glucose metabolism.
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PMID:New approaches for the management of patients with multiple cardiometabolic risk factors. 1675 12

Endocannabinoid system, the complex of specific cannabinoid receptors (CB1 and CB2 subtypes) and their endogenous agonistic ligands (endocannabinoids) plays, besides others, an important role in the central and peripheral regulation of food intake, fat accumulation, and lipid and glucose metabolism. Alterations of these functions are associated with endocannabinoid system hyperactivity. The cannabinoid receptor CB1 antagonist rimonabant normalizes the over activated endocannabinoid system which contributes to the regulation of energy homeostasis, and improves lipid and glucose metabolism--decreases body weight, waist circumference, intra-abdominal obesity and triglycerides, increases HDL-C, improves insulin sensitivity according to HOMA index. Results of the international multicentric clinical trials confirm that rimonabant is well tolerated and show antiatherogenic effects (increased adiponectin, decreased marker of inflammation CRP and improvement of LDL profile) as well as decreased percentage of subjects with NCEP/ATPIII (National Cholesterol Education Program Adult Treatment Panel III) defined metabolic syndrome. Thus, the CB1 cannabinoid receptor antagonist rimonabant is suggested to be a prospective drug decreasing cardiometabolic risk factors.
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PMID:[Impact of endocannabinoid system in modulation of cardiometabolic risk factors]. 1687 57

Rimonabant is the first of a new class of selective cannabinoid receptor-1 blockers. It reduces the overactivity of the endocannabinoid system, improving lipid and glucose metabolism and regulating food intake and energy balance. In four randomised, double-blind clinical trials in overweight or obese adults with or without type 2 diabetes and/or dyslipidaemia, oral rimonabant 20mg once daily reduced weight and waist circumference to a significantly greater extent than placebo. A significantly greater proportion of rimonabant than placebo recipients achieved the clinically significant weight-loss target of > or =5% or > or =10% of initial weight. Rimonabant was associated with significant improvements in glycaemic control relative to placebo, with approximately equal to 57% of the reduction in glycosylated haemoglobin being independent of the effects of weight loss in one trial. Improvements in other cardiometabolic risk factors (i.e. increases in high-density lipoprotein-cholesterol [HDL-C] and decreases in triglyceride [TG] levels) were significantly greater with rimonabant than with placebo. The improvement in lipid profile also demonstrated a weight-independent effect, with approximately equal to 47-58% of the improvement in HDL-C and TG being beyond that expected through weight loss alone. Rimonabant was generally well tolerated, with most adverse events considered mild to moderate in severity.
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PMID:Rimonabant. 1711 4

The molecular basis for the control of energy balance by the endocannabinoid anandamide (AEA) is still unclear. Here, we show that murine 3T3-L1 fibroblasts have the machinery to bind, synthesize and degrade AEA, and that their differentiation into adipocytes increases by approximately twofold the binding efficiency of cannabinoid receptors (CBR), and by approximately twofold and approximately threefold, respectively, the catalytic efficiency of the AEA transporter and AEA hydrolase. In contrast, the activity of the AEA synthetase and the binding efficiency of vanilloid receptor were not affected by the differentiation process. In addition, we demonstrate that AEA increases by approximately twofold insulin-stimulated glucose uptake in differentiated adipocytes, according to a CB1R-dependent mechanism that involves nitric oxide synthase, but not lipoxygenase or cyclooxygenase. We also show that AEA binding to peroxisome proliferator-activated receptor-gamma, known to induce differentiation of 3T3-L1 fibroblasts into adipocytes, is not involved in the stimulation of glucose uptake.
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PMID:Endocannabinoids in adipocytes during differentiation and their role in glucose uptake. 1718 72

The metabolic syndrome or cardiovascular dysmetabolic syndrome is characterized by obesity, central obesity, insulin resistance, atherogenic dyslipidemia, and hypertension. The major risk factors leading to this syndrome are physical inactivity and an atherogenic diet and cornerstone clinical feature is abdominal obesity or adiposity. In addition, patients usually have elevated triglycerides, low HDL cholesterol, elevated LDL cholesterol, other abnormal lipid parameters, hypertension, and elevated fasting blood glucose. Impaired fibrinolysis, increased susceptibility to thrombotic events, and raised inflammatory markers are also observed. Given that India has the largest number of subjects with type-2 diabetes in the world it can be extrapolated that this country also has the largest number of patients with the metabolic syndrome. Epidemiological studies confirm a high prevalence. Therapeutic approach involves intervention at a macro-level and control of multiple risk factors using therapeutic lifestyle approaches (diet control and increased physical activity, pharmacotherapy - anti-obesity agents) for control of obesity and visceral obesity, and targeted approach for control of individual risk factors. Pharmacological therapy is a critical step in the management of patients with metabolic syndrome when lifestyle modifications fail to achieve the therapeutic goals. Anti-obesity drugs such as sibutramine and orlistat can be tried to reduce weight and central obesity and jointly control the metabolic syndrome components. Other than weight loss, there is no single best therapy and treatment should consist of treatment of individual components of the metabolic syndrome. Newer drugs such as the endocannabinoid receptor blocker,rimonabant, appear promising in this regard. Atherogenic dyslipidemia should be controlled initially with statins if there is an increase in LDL cholesterol. If there are other lipid abnormalities then combination therapy of statin with fibrates, nicotinic acid, or ezetimibe should be considered. For insulin resistance, drugs such as thiazolidinediones and renin-angiotensin system blockers are available. Available evidence suggests that angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBS) may be more beneficial for treatment of hypertension in patients with metabolic syndrome compared to others as these drugs also prevent development of diabetes. Patients with metabolic syndrome also have elevations in fibrinogen and other coagulation factors leading to prothrombotic state and aspirin may be beneficial for primary prevention in these patients. The new developments in the treatment of metabolic syndrome with drugs, such as peroxisome proliferator-activated receptor (PPAR) agonists and cannabinoid receptor-1 antagonists, will broaden the horizons of the current treatment options. Fixed-dose combination polypharmacy using a single pill is an interesting concept that needs to be evaluated in long-term prospective trials in such patients.
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PMID:Management issues in the metabolic syndrome. 1721 77

Excessive adipose tissue is associated with increased expression or suppression of cytokines and hormones, leading to inflammation and chronic disease. In particular, abdominal adiposity, as evidenced by a high waist circumference, is a component of the metabolic syndrome, a constellation of risk factors (e.g., high waist circumference, high blood pressure, elevated triglycerides, low high-density lipoprotein cholesterol, elevated fasting glucose) that increases the risk for type 2 diabetes and cardiovascular disease. Lifestyle modification is the first-line approach to the management of obesity and the metabolic syndrome. However, for patients who cannot achieve a reduction in weight (5% to 10% of initial body weight) and cardiometabolic risk factors with lifestyle modification alone, physicians should consider adjunctive long-term pharmacotherapy. A variety of approved and investigational pharmacologic agents have been shown to reduce weight and modify metabolic syndrome components, including sibutramine, orlistat, metformin, and rimonabant. Data from four phase 3 trials suggest that rimonabant, the first cannabinoid receptor inhibitor, modulates cardiometabolic risk factors, both through its impact on body weight and through direct pathways that are not related to weight loss.
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PMID:Therapeutic options for modifying cardiometabolic risk factors. 1732 May 19

Endocannabinoids released during cerebral ischemia have been implicated as neuroprotective agents. We assessed the role of cannabinoid receptors in modulating the response of neurons to oxygen/glucose deprivation (OGD), a model for in vitro ischemia, in rat hippocampal slices using extracellular recording techniques. Under control conditions, 15 min OGD resulted in only 50% recovery of CA1 field excitatory postsynaptic potentials (fEPSPs) 60 min post-insult. This post-OGD depression of function was primarily NMDA receptor-dependent as the NMDA receptor antagonist MK-801 (50 microM) promoted recovery of synaptic transmission to 76% of the baseline. Treatment with the CB1 receptor antagonist AM251 (1 microM), which prevented the depression of excitatory synaptic transmission caused by WIN55,212-2 (1 microM), also markedly enhanced recovery of function (71% of control). The enhanced recovery after OGD in the presence of AM251 was independent of both GABA(A) receptors and NMDA receptors since co-application of AM251 with either bicuculline (10 microM) or MK-801 (50 microM) did not alter recovery, or further improved recovery, respectively. These results suggest endocannabinoids released during OGD may modulate synaptic transmission and post-OGD neuronal outcome via activation of an AM251-sensitive cannabinoid receptor.
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PMID:Cannabinoid modulation of neuronal function after oxygen/glucose deprivation in area CA1 of the rat hippocampus. 1738 73

Clinical reports (RIO trials) have shown that chronic administration of a CB-cannabinoid receptor antagonist (rimonabant) provides improvements of disturbed metabolic parameters observed in overweight and obese patients with type 2 diabetes. The production of endocannabinoid and the expression of CB1-cannabinoid receptors are largely distributed in the different organs aside from the brain. It is now clearly established that endocannabinoids act both through orexigenic effects and peripheral metabolic effects in various tissues involved in the control of metabolism and energy expenditure (i.e. adipose tissue, liver, gastrointestinal tract, skeletal muscle and pancreas). This review will consider: i) the disturbances of glucose and lipid metabolisms in obese type 2 diabetics; ii) an overview of the pharmacological properties of rimonabant and iii) the various mechanisms involved in tissues and organs to explain the therapeutic efficacy of rimonabant. A special attention will be paid to its utilization in obese type 2 diabetics. The emerging concept of endocannabinoids acting as metabolic regulators is the more likely explanation of the success of rimonabant treatments in phase III studies.
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PMID:Effects of CB1 antagonist on the control of metabolic functions in obese type 2 diabetic patients. 1741 7

Despite intervention with effective oral glucose-lowering agents, most patients with type 2 diabetes will experience a gradual loss of glycaemic control. Irrespective of underlying levels of insulin resistance, the progressive failure and loss of beta-cells are ultimately responsible for the onset of frank type 2 diabetes. The mechanisms responsible for loss of beta-cell function are likely to be multifactorial, but may involve toxicity because of elevated glucose and/or lipid levels, increased secretory demand because of insulin resistance, amyloid deposition and altered levels of cytokines. Preservation of beta-cell function is now gaining recognition as a critical target in the management of type 2 diabetes. For patients with frank type 2 diabetes, preservation of beta-cell function has the potential to reduce or stabilise the progression of type 2 diabetes and to decrease the need for additional oral glucose-lowering agents and/or insulin therapy. There is a growing body of animal/preclinical evidence for improved and preserved beta-cell function with current glucose-lowering agents, such as the thiazolidinediones, metformin and the glucagon-like peptide-1 analogue, exenatide. Clinical studies incorporating indirect measures of beta-cell function also support a protective effect with some agents. A number of novel therapies that are currently under investigation may also offer beta-cell structural and functional protection, including dipeptidyl peptidase IV inhibitors and cannabinoid receptor type 1 blockers. Emerging evidence from interventional trials suggests that both intensive lifestyle changes and pharmacotherapy can delay or possibly prevent the onset of type 2 diabetes in high-risk individuals. For patients newly diagnosed with type 2 diabetes, early and aggressive intervention strategies that combine maximal glucose-lowering efficacy alongside potential beta-cell preserving properties may provide an opportunity to delay or prevent progression of the disease.
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PMID:The importance of beta-cell management in type 2 diabetes. 1759 89

Tobacco smoking and obesity are worldwide important health problems with a growing impact in adolescent and young adults. One of the consequences of nicotine withdrawal is an increase in body weight that can act as a risk factor to relapse. Experimental therapies with a cannabinoid receptor antagonist have been recently proposed for both cigarette smoking and complicated overweight. In the present study, we aimed to investigate metabolic and hormonal effects of chronic nicotine treatment (during treatment and in abstinence) in an animal model of adolescence as well as to address the pharmacological effects of the novel selective CB1 cannabinoid receptor antagonist, SR 147778 (Surinabant). Adolescence (postnatal days 37-44) and/or post-adolescence (postnatal days 45-59) administration of Surinabant reduced body weight gain, as well as plasma glucose levels and triglycerides. The drug also reduced insulin and leptin secretion, and increased adiponectin and corticosterone levels. The effects showed sexual dimorphisms and, in general, were more pronounced in females. Chronic exposure to nicotine (0.8 mg/kg), from postnatal days 30-44 did not result in overt effects on food intake or body weight gain. However, it altered certain responses to the administration of Surinabant, both when the two drugs were given simultaneously and when Surinabant was administered during the post-adolescence period, along nicotine withdrawal. The present results indicate that the endogenous cannabinoid system is active as a metabolic modulator during adolescence and that nicotine exposure can induce long-lasting effects on metabolic regulation, altering cannabinoid modulation of energy expenditure and metabolism.
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PMID:Effects of adolescent nicotine and SR 147778 (Surinabant) administration on food intake, somatic growth and metabolic parameters in rats. 1772 Feb 6


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