piperidines and Weight-Loss

All major guidelines on antihypertensive therapy recommend weight loss; anti-obesity drugs may be able to help in this respect.. To assess the long-term effects of pharmacologically induced reduction in body weight in adults with essential hypertension on all-cause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total non-serious adverse events).. To assess the long-term effects of pharmacologically induced reduction in body weight in adults with essential hypertension on change from baseline in systolic blood pressure, change from baseline in diastolic blood pressure, and body weight reduction.. We obtained studies using computerised searches of the Cochrane Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Ovid EMBASE, the clinical trials registry ClinicalTrials.gov, and from handsearches in reference lists and systematic reviews (status as of 13 April 2015).. Randomised controlled trials in hypertensive adults of at least 24 weeks' duration that compared long-term pharmacologic interventions for weight loss with placebo. . Two review authors independently selected studies, assessed risk of bias, and extracted data. Where appropriate and in the absence of significant heterogeneity between studies (P > 0.1), we pooled studies using fixed-effect meta-analysis. When heterogeneity was present, we used the random-effects method and investigated the cause of heterogeneity.. After updating the literature search, which was extended to include four new weight-reducing drugs, we identified one additional study of phentermine/topiramate, bringing the total number of studies to nine that compare orlistat, sibutramine, or phentermine/topiramate to placebo and thus fulfil our inclusion criteria. We identified no relevant studies investigating rimonabant, liraglutide, lorcaserin, or naltrexone/bupropion. No study included mortality and cardiovascular morbidity as predefined outcomes. Incidence of gastrointestinal side effects was consistently higher in those participants treated with orlistat versus those treated with placebo. The most frequent side effects were dry mouth, constipation, and headache with sibutramine, and dry mouth and paresthaesia with phentermine/topiramate. In participants assigned to orlistat, sibutramine, or phentermine/topiramate body weight was reduced more effectively than in participants in the usual-care/placebo groups. Orlistat reduced systolic blood pressure as compared to placebo by -2.5 mm Hg (mean difference (MD); 95% confidence interval (CI): -4.0 to -0.9 mm Hg) and diastolic blood pressure by -1.9 mm Hg (MD; 95% CI: -3.0 to -0.9 mm Hg). Sibutramine increased diastolic blood pressure compared to placebo by +3.2 mm Hg (MD; 95% CI: +1.4 to +4.9 mm Hg). The one trial that investigated phentermine/topiramate suggested it lowered blood pressure.. In people with elevated blood pressure, orlistat and sibutramine reduced body weight to a similar degree, while phentermine/topiramate reduced body weight to a greater extent. In the same trials, orlistat and phentermine/topiramate reduced blood pressure, while sibutramine increased it. We could include no trials investigating rimonabant, liraglutide, lorcaserin, or naltrexone/bupropion in people with elevated blood pressure. Long-term trials assessing the effect of orlistat, liraglutide, lorcaserin, phentermine/topiramate, or naltrexone/bupropion on mortality and morbidity are unavailable and needed. Rimonabant and sibutramine have been withdrawn from the market, after long-term trials on mortality and morbidity have confirmed concerns about the potential severe side effects of these two drugs. The European Medicines Agency refused marketing authorisation for phentermine/topiramate due to safety concerns, while the application for European marketing authorisation for lorcaserin was withdrawn by the manufacturer after the Committee for Medicinal Products for Human Use judged the overall benefit/risk balance to be negative.

Topics: Adult; Anti-Obesity Agents; Appetite Depressants; Blood Pressure; Cyclobutanes; Diet, Reducing; Female; Fructose; Humans; Hypertension; Lactones; Male; Middle Aged; Orlistat; Phentermine; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Safety-Based Drug Withdrawals; Time; Topiramate; Weight Loss

Effective, evidence-based management of type 2 diabetes (T2D) requires the integration of the best available evidence with clinical experience and patient preferences.. Studies published from 2000 to 2012 evaluating glucagon-like peptide-1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) were identified using PubMed. The author contextualized the study findings with his clinical experience.. Incretin-based therapy targets multiple dysfunctional organs in T2D. Injectable GLP-1RAs provide substantial glycemic control and weight reduction; while oral DPP-4 inhibitors provide moderate glycemic control and weight neutrality. Both classes are effective, well tolerated, and associated with a low incidence of hypoglycemia when used alone or in combination with other antidiabetes agents. GLP-1RAs are associated with transient nausea and, like DPP-4 inhibitors, rare pancreatitis.. Data indicate and clinical experience confirms that incretins are well tolerated in appropriate patients and provide sustained glycemic control and weight loss or weight neutrality throughout T2D progression.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Linagliptin; Liraglutide; Peptides; Piperidines; Purines; Pyrazines; Quinazolines; Receptors, Glucagon; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Uracil; Venoms; Weight Loss

All major guidelines for antihypertensive therapy recommend weight loss; anti-obesity drugs might be a helpful option.. To assess the long-term effects of pharmacologically induced reduction in body weight with orlistat, sibutramine or rimonabant on:- all cause mortality - cardiovascular morbidity - adverse events. - changes in systolic and/or diastolic blood pressure - body weight reduction even though sibutramine and rimonabant have been withdrawn from the market.. Studies were obtained from computerised searches of Ovid MEDLINE, EMBASE, CENTRAL and from hand searches in reference lists and systematic reviews (status as of 17(th) August, 2012).. Randomized controlled trials in adult hypertensive patients with a study duration of at least 24 weeks comparing pharmacologic interventions (orlistat, sibutramine, rimonabant) for weight loss with placebo.. Two authors independently assessed risk of bias and extracted data. Studies were pooled using fixed-effect meta-analysis in the absence of significant heterogeneity between studies (p>0.1). Otherwise, we used the random effects method and investigated the cause of heterogeneity.. After the updated literature search, the number of studies remained the same, with eight studies comparing orlistat or sibutramine to placebo fulfilling our inclusion criteria. No relevant studies investigating rimonabant for weight loss were identified. No study included mortality and cardiovascular morbidity as a pre-defined outcome. Incidence of gastrointestinal side effects was consistently higher in orlistat treated vs. placebo treated patients. Most frequent side effects with sibutramine were dry mouth, constipation and headache. Patients assigned to weight loss diets, orlistat or sibutramine reduced their body weight more effectively than patients in the usual care/placebo groups. Blood pressure reduction in patients treated with orlistat was for systolic blood pressure (SBP): weighted mean difference (WMD): -2.5 mm Hg; 95% CI, -4.0 to -0.9 mm Hg and for diastolic blood pressure (DBP): WMD -1.9 mm Hg; 95% CI, -3.0 to -0.9 mm Hg. Meta-analysis showed DBP increase under therapy with sibutramine: WMD +3.2 mm Hg; 95%CI +1.4 to +4.9 mm Hg.. In patients with elevated blood pressure, orlistat and sibutramine reduced body weight to a similar degree. In the same trials, orlistat reduced blood pressure and sibutramine increased blood pressure. No trials investigating rimonabant in people with elevated blood pressure could be included. Long-term trials assessing the effect of orlistat, sibutramine and rimonabant on mortality and morbidity are lacking. Rimonabant and sibutramine have been withdrawn from the market for the time being.

Topics: Adult; Anti-Obesity Agents; Blood Pressure; Cyclobutanes; Diet, Reducing; Female; Humans; Hypertension; Lactones; Male; Middle Aged; Orlistat; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Safety-Based Drug Withdrawals; Time; Weight Loss

The study aims to compare anti-obesity interventions in a single evidence synthesis framework. Electronic databases were searched for randomized controlled trials of orlistat, rimonabant or sibutramine reporting weight or body mass index (BMI) change from baseline at 3, 6 or 12 months. A mixed treatment comparison was used to combine direct and indirect trial evidence. Ninety-four studies involving 24,808 individuals were included; 83 trials included data on weight change and 41 on BMI change. All results are in comparison with placebo. The active drugs were all effective at reducing weight and BMI. At 3 months, orlistat reduced weight by -2.65 kg (95% credibility interval -4.00 kg, -1.31 kg). For sibutramine, 15 mg gave a greater reduction than 10 mg at 12 months, -6.35 kg versus -5.42 kg, respectively. Rimonabant reduced weight by -11.23 kg at 3 months and -4.55 kg at 12 months. Lifestyle advice alone also reduced weight at 6 and 12 months, but was less effective than the pharmacological interventions. In conclusion, modest weight reductions were seen for all pharmacological interventions. Those interventions which have now been withdrawn from use (sibutramine and rimonabant) seem to be the most effective, implying that there may be a place in clinical practice for similar drugs if side effects could be avoided.

Topics: Anti-Obesity Agents; Body Mass Index; Cyclobutanes; Humans; Lactones; Life Style; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Treatment Outcome; Weight Loss

Obesity is a world wide epidemic; it is becoming more usual to be overweight or obese than to be normal weight. Obesity increases the risk of an extensive range of diseases such as cardiovascular disease, diabetes mellitus type 2, hypertension, depression and some types of cancer. Adipose tissue is more than a storage organ for surplus energy - it is also a setting for complex metabolic processes and adipose tissue releases substances that interact with other parts of the body to influence several systems including food intake and energy metabolism. The endocannabinoid system (ECS) is one of the signalling systems that control feeding behaviour. The ECS is implicated in many functions, such as pain, memory, addiction, inflammation, and feeding, and could be considered a stress recovery system. It also seems to integrate nutrient intake, metabolism and storage maintaining homeostatic balance. The ECS is a recently discovered system, and research indicates hyperactivity in obesity. The aim of this thesis is to elaborate on the relationships of this widespread system and its elements in adipose tissue in obesity. Study I is a 4 weeks rat intervention study to investigate whether weight independent effect of Rimonabant treatment exists. We found that food intake-tolerance development could be circumvented by cyclic administration of Rimonabant and implications of weight independent effects of treatment. Study II is a cross-sectional study to establish the expression of cannabinoid receptor 1 from various adipose tissue depots of lean and obese persons. In this study we conclude, that the subcutaneous adipose tissue express more CBR1 than the visceral depot in lean, but comparable levels in obese. Study III is a 10 weeks human intervention study to asses the effects on the ECS of 10% weight loss. We found reduction in the ECS in obesity that normalised with weight loss. Our results clearly show the presence of all the components of the ECS in human adipose tissue, and suggest that the ECS is reduced in adipose tissue in obesity. Our results do not support the hypothesis of hyperactivity of the ECS in human obesity. Possible future treatment of obesity with CBR1 antagonist could involve cyclic treatment of specific peripheral compounds.

Topics: Adiponectin; Adipose Tissue; Animals; Body Mass Index; Body Weight; C-Reactive Protein; Cannabinoid Receptor Modulators; Case-Control Studies; Endocannabinoids; Fatty Acids, Nonesterified; Feeding Behavior; Female; Genetic Variation; Humans; Inflammation; Male; Obesity; Piperidines; Pyrazoles; Rats; Rats, Wistar; Reference Values; Rimonabant; Risk Factors; Weight Loss

Obesity is one of the greatest public health challenges of the twenty-first century. The World Health Organization (WHO) reports that in 2005 approximately 1.6 billion adults were overweight and at least 400 million adults were obese. The prevalence of obesity is still continuing to increase dramatically. Overweight and obese people carry a higher risk for a variety of cardiovascular diseases including hypertension, coronary heart disease, stroke and peripheral occlusive artery disease. Weight loss is considered to be the initial step which helps to prevent or to control the clinical consequences of obesity. In a great number of patients who are not able to reduce weight by means of non-pharmacological measures, drug therapy can assist in reaching the weight management targets. Drug treatment should only be considered as part of a systematic weight management program including dietary and lifestyle changes. This review summarizes current pharmacotherapeutic concepts for the treatment of obesity in adults focusing on efficacy and safety of anti-obesity drugs.

Topics: Adult; Anti-Obesity Agents; Appetite Depressants; Combined Modality Therapy; Cyclobutanes; Enzyme Inhibitors; Humans; Lactones; Lipase; Obesity; Orlistat; Piperidines; Prevalence; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Reduction Behavior; Treatment Outcome; Weight Loss

Obesity is considered as a major health problem, as its prevalence continuously rises worldwide. One of the common health consequences of obesity is type 2 diabetes mellitus. Therefore, antiobesity management is a prerequisite in treating diabetic patients. Lifestyle modifications combined with pharmacological agents appear to be an effective approach. Sibutramine is a serotonin-noradrenaline reuptake inhibitor, which acts centrally by promoting the feeling of satiety and decreasing caloric intake, thus resulting in weight loss. A potential association with cardiovascular side effects has been noted. Orlistat, a gastric and pancreatic lipase inhibitor, also achieves significant weight loss and improves glycaemic status, but it has gastrointestinal side effects. Rimonabant, the first endocannabinoid CB1 antagonist, is associated with weight reduction and it improves diabetic parameters; nevertheless, it is associated with psychiatric disorders; indeed, a recently conducted safety review led to the temporal suspension of its commercialization. The above-mentioned medications seem to be currently useful agents for treating obesity in patients with type 2 diabetes mellitus. Other medications used for diabetes management, such as exenatide, liraglutide and pramlintide, have also shown body weight reduction. Ongoing research is needed to scrutinize the precise impact of these agents in the daily clinical practice of management of obesity in patients with type 2 diabetes mellitus.

Topics: Adolescent; Adult; Aged; Anti-Obesity Agents; Appetite Depressants; Body Weight; Cyclobutanes; Diabetes Mellitus, Type 2; Female; Humans; Lactones; Male; Middle Aged; Obesity; Orlistat; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Rimonabant; Treatment Outcome; Weight Loss; Young Adult

All major guidelines for antihypertensive therapy recommend weight loss; anti-obesity drugs might be a helpful option.. To assess the long-term effects of pharmacologically induced reduction in body weight with orlistat, sibutramine or rimonabant on:- all cause mortality - cardiovascular morbidity - adverse events. - changes in systolic and/or diastolic blood pressure - body weight reduction. Studies were obtained from computerised searches of Ovid MEDLINE, EMBASE, CENTRAL and from hand searches in reference lists and systematic reviews.. Randomized controlled trials in adult hypertensive patients with a study duration of at least 24 weeks comparing pharmacologic interventions (orlistat, sibutramine, rimonabant) for weight loss with placebo.. Two authors independently assessed risk of bias and extracted data. Studies were pooled using fixed-effect meta-analysis in the absence of significant heterogeneity between studies (p>0.1). Otherwise, we used the random effects method and investigated the cause of heterogeneity.. Eight studies comparing orlistat or sibutramine to placebo fulfilled our inclusion criteria. No relevant studies investigating rimonabant for weight loss were identified. No study included mortality and cardiovascular morbidity as a pre-defined outcome. Incidence of gastrointestinal side effects was consistently higher in orlistat treated vs. placebo treated patients. Most frequent side effects with sibutramine were dry mouth, constipation and headache. Patients assigned to weight loss diets, orlistat or sibutramine reduced their body weight more effectively than patients in the usual care/placebo groups. Blood pressure reduction in patients treated with orlistat was for systolic blood pressure (SBP): weighted mean difference (WMD): -2.5 mm Hg; 95% CI, -4.0 to -0.9 mm Hg and for diastolic blood pressure (DBP): WMD -1.9 mm Hg; 95% CI, -3.0 to -0.9 mm Hg. Meta-analysis showed DBP increase under therapy with sibutramine: WMD +3.2 mm Hg; 95%CI +1.4 to +4.9 mm Hg.. In patients with elevated blood pressure, orlistat and sibutramine reduced body weight to a similar degree. In the same trials, orlistat reduced blood pressure and sibutramine increased blood pressure. No trials investigating rimonabant in people with elevated blood pressure could be included. Long-term trials assessing the effect of orlistat, sibutramine and rimonabant on mortality and morbidity are needed.

Topics: Adult; Anti-Obesity Agents; Blood Pressure; Cyclobutanes; Female; Humans; Hypertension; Lactones; Male; Middle Aged; Orlistat; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Time; Weight Loss

This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of rimonabant for the treatment of obese or overweight patients based upon a review of the manufacturer's submission to the National Centre for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submission's main evidence came from four randomised controlled trials. Rimonabant resulted in a significantly greater benefit than placebo for all primary weight loss outcomes. At 1 year, rimonabant had a statistically significant beneficial effect on systolic blood pressure, high-density lipoprotein cholesterol, triglycerides and fasting plasma glucose in diabetics and non-diabetics, and glycosylated haemoglobin in diabetics. Improvements were maintained over 2 years with rimonabant; withdrawal of rimonabant at 1 year resulted in a reduction in weight loss until there was no difference from placebo at 2 years. Psychiatric adverse events were experienced by 26% and 14% of rimonabant and placebo patients respectively; figures for symptoms of depression were 9% and 5% respectively. Pairwise comparisons of orlistat, sibutramine and rimonabant showed beneficial effects of rimonabant over orlistat and sibutramine for weight loss outcomes; however, response hurdles imposed on orlistat or sibutramine in clinical practice may not have been applied in the orlistat and sibutramine trials. The manufacturer's Markov cohort model evaluated rimonabant versus orlistat, sibutramine and diet and exercise alone for three base-case populations. The incremental cost-effectiveness ratio (ICER) of rimonabant varied from 10,534 pounds to 13,236 pounds per quality-adjusted life-year (QALY) versus diet and exercise, to 8977 pounds to 12,138 pounds per QALY versus orlistat, to 1463 pounds to 3908 pounds per QALY versus sibutramine. In subgroup analysis there was a wider variation in the ICER estimates although none exceeded 20,000 pounds per QALY. The ICER of rimonabant remained under 20,000 pounds per QALY in reanalyses by the manufacturer and the ERG, with the results sensitive to the source of health-related quality of life (HRQoL) benefits in the model. Four treatment strategies were modelled in comparisons of rimonabant versus diet and exercise alone and orlistat and sibutramine in which rimonabant was continued only in patients achieving 5% weight loss at 3, 6, 9 or 12 months. In pairwise comparisons rimonabant remained bel

Topics: Anti-Obesity Agents; Cost-Benefit Analysis; Humans; Obesity; Overweight; Piperidines; Pyrazoles; Rimonabant; Weight Loss

The prevalence of obesity and the metabolic syndrome (MS) is on the rise, and subsequently the hepatic manifestation of MS, nonalcoholic fatty liver disease (NAFLD), has become a common entity in clinical practice. Most patients with NAFLD face medical complications related to their underlying MS in other organ systems; however, a small but significant group of patients with the more aggressive form of fatty liver, nonalcoholic steatohepatitis (NASH), are at risk of developing cirrhosis and hepatocellular carcinoma. As patients are generally asymptomatic, often their disease goes unrecognized. This is particularly true for NASH, where liver biopsy is currently required to make the diagnosis. Once diagnosed, no one treatment has been shown to be universally efficacious and those that are of benefit are not without side effects. Effective treatment regimens directed at both decreasing insulin resistance as well as the processes leading to necroinflammation and hepatic fibrosis have been investigated and include lifestyle modification, surgical therapies, and pharmacotherapy. This review focuses on current and potential future therapies for NASH.

Topics: Animals; Antioxidants; Bariatric Surgery; Body Mass Index; Cannabinoids; Cholagogues and Choleretics; Comorbidity; Fatty Liver; Glucagon-Like Peptide 1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Insulin Resistance; Lactones; Life Style; Metformin; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Thiazolidinediones; Treatment Outcome; Ursodeoxycholic Acid; Weight Loss

It has been long known that the frequency of overweight and obese people is higher among depressed and bipolar patients than in the general population. The marked alteration of body weight (and appetite) is one of the most frequent of the 9 symptoms of major depressive episode, and these symptoms occur during recurrent episodes of depression with a remarkably high consequence. According to studies with representative adult population samples, in case of obesity (BMI over 30) unipolar or bipolar depression is significantly more frequently (20-45%) observable. Since in case of depressed patients appetite and body weight reduction is observable during the acute phase, the more frequent obesity in case of depressed patients is related (primarily) not only to depressive episodes, but rather to lifestyle factors, to diabetes mellitus also more frequently occurring in depressed patients, to comorbid bulimia, and probably to genetic-biological factors (as well as to pharmacotherapy in case of medicated patients). At the same time, according to certain studies, circadian symptoms of depression give rise to such metabolic processes in the body which eventually lead to obesity and insulin resistance. According to studies in unipolar and bipolar patients, 57-68% of patients is overweight or obese, and the rate of metabolic syndrome was found to be between 25-49% in bipolar patients. The rate of metabolic syndrome is further increased by pharmacotherapy. Low total and HDL cholesterol level increases the risk for depression and suicide and recent studies suggest that omega-3-fatty acids possess antidepressive efficacy. Certain lifestyle factors relevant to healthy metabolism (calorie reduction in food intake, regular exercise) may be protective factors related to depression as well. The depression- and possibly suicide-provoking effect of sibutramine and rimonabant used in the pharmacotherapy of obesity is one of the greatest recent challenges for professionals and patients alike.

Topics: Anti-Obesity Agents; Antidepressive Agents; Appetite Depressants; Appetite Regulation; Bipolar Disorder; Circadian Rhythm; Cyclobutanes; Depression; Depressive Disorder, Major; Dietary Carbohydrates; Energy Intake; Ghrelin; Humans; Hypothalamo-Hypophyseal System; Insulin Resistance; Leptin; Obesity; Piperidines; Pituitary-Adrenal System; Pyrazoles; Rimonabant; Seasonal Affective Disorder; Sleep Wake Disorders; Surveys and Questionnaires; Weight Gain; Weight Loss

The prevalence of obesity in the developed world is increasing. Approximately 23% of adult Canadians (5.5 million people) are obese. Obesity is associated with an increased risk of developing several comorbid diseases, ranging from cardiovascular diseases to cholelithiasis and nonalcoholic fatty liver disease. The etiology of obesity is multifactorial, involving a complex interaction among genetics, hormones and the environment. The available evidence and recommendations for nonpharmacological management of obesity, including dietary therapy, physical activity and behavioural therapy, in addition to pharmacotherapy are discussed. A brief discussion on endoscopic and surgical procedures is undertaken. Several antiobesity treatment options are available and may be indicated in appropriate situations. Selecting obesity therapy may be guided by body mass index measurements, comorbid illnesses and patient preference.

Topics: Anti-Obesity Agents; Bariatric Surgery; Behavior Therapy; Caloric Restriction; Cyclobutanes; Dietary Carbohydrates; Dietary Fats; Exercise; Humans; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Weight Loss

The increase of obesity and type 2 diabetes on a global scale has increased the interest in how to counteract this epidemic. Improved lifestyle in general is a fundamental approach, but other remedies such as specific weight reduction or diabetes preventive drugs and surgery have also been tested. One problem to understand is what really happens after weight loss. Ongoing studies will try to address this question, such as the Swedish Obese Subjects (SOS) surgery study, the Look AHEAD (Action for Health in Diabetes) trial in the U.S. (recruiting obese type 2 diabetic patients), and the Comprehensive Rimonabant Evaluation Study of Cardiovascular End Points and Outcomes (CRESCENDO) trial (by use of rimonabant versus placebo). This is very important, since previously, several observational studies in large population-based cohorts have indicated some detrimental effects of weight loss, even after intentional weight loss, with increased morbidity and mortality rates.

Topics: Bariatric Surgery; Cannabinoids; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Life Style; Multicenter Studies as Topic; Obesity; Piperidines; Power, Psychological; Pyrazoles; Rimonabant; Self Concept; Weight Loss

Obesity and cardiometabolic risk, or the metabolic syndrome, continue to be major public health concerns. To date, treatment with lifestyle and pharmacotherapy interventions has resulted in limited efficacy in reversing the upward trend in this present-day health crisis. Research reveals that a modest 5% to 10% weight loss results in substantial improvement in health. While obtaining modest weight loss is often achievable, maintaining lost weight is challenging. Research has recently improved our understanding of several endogenous pathways that influence body weight regulation and disease risk. The endocannabinoid system has been found to regulate appetite and energy expenditure, as well as lipid and glucose metabolism. Interest in blocking stimulation of this pathway to aid weight loss and reduce cardiometabolic risk factor development is an area of interest and research. This article reviews the mechanisms by which the endocannabinoid system is believed to influence body weight regulation and cardiometabolic risk factors, as well as the results of clinical trials investigating the safety and efficacy of a selective cannabinoid-1 receptor antagonist (rimonabant). Clinical trials investigating rimonabant treatment resulted in substantial reductions in body weight and markers for cardiometabolic risk in study participants. However, increases in adverse events were reported in the drug-treated group. Data regarding long-term benefit and adverse events from rimonabant treatment are being collected in several ongoing clinical trials. Rimonabant is currently available in 42 countries, but has not received United States Food and Drug Administration approval. Food and nutrition professionals play a pivotal role in tackling the current obesity crisis; it is essential that they understand the many physiological mechanisms regulating body weight. Emerging research data reveals pathways that influence appetite and energy metabolism, and this knowledge may form the foundation for new clinical treatment options for obese individuals.

Topics: Appetite Regulation; Blood Glucose; Cannabinoid Receptor Modulators; Drug Approval; Endocannabinoids; Energy Metabolism; Humans; Lipid Metabolism; Obesity; Piperidines; Pyrazoles; Rimonabant; United States; United States Food and Drug Administration; Weight Loss

Antiobesity treatment is recommended for selected patients in whom lifestyle modification is unsuccessful. Two antiobesity drugs are currently licensed for long-term use. Orlistat, a gastrointestinal lipase inhibitor, reduces weight by around 3 kg on average and decreases progression to diabetes in high-risk patients; adverse gastrointestinal effects are common. Sibutramine, a monoamine-reuptake inhibitor, results in mean weight losses of 4-5 kg, but is associated with increases in blood pressure and pulse rate. Rimonabant, the first of the endocannabinoid receptor antagonists, reduces weight by 4-5 kg on average and improves waist circumference and concentrations of HDL cholesterol and triglyceride; however, an increased incidence of mood-related disorders has been reported. To date, all antiobesity drug trials have been limited by their high attrition rates and lack of long-term morbidity and mortality data. Other promising antiobesity drugs, including those acting within the central melanocortin pathway, are in development, but are years away from clinical use. In light of the lack of successful weight-loss treatments and the public-health implications of the obesity pandemic, the development of safe and effective drugs should be a priority. However, as new drugs are developed we suggest that the assessment processes should include both surrogate endpoints (ie, weight loss) and clinical outcomes (ie, major obesity-related morbidity and mortality). Only then can patients and their physicians be confident that the putative benefits of such drugs outweigh their risks and costs.

Topics: Anti-Obesity Agents; Blood Pressure; Cholesterol, HDL; Cyclobutanes; Half-Life; Humans; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Weight Loss

Topics: Adrenal Gland Neoplasms; Bradykinin; Carotid Stenosis; Clinical Trials as Topic; Contrast Media; Endarterectomy, Carotid; Esophageal and Gastric Varices; Female; Heart Failure; Humans; Hyperglycemia; Hypertension; Hyperthyroidism; Internal Medicine; Male; Middle Aged; Osteitis Deformans; Piperidines; Pulmonary Disease, Chronic Obstructive; Pyrazoles; Renal Insufficiency; Rimonabant; Risk Factors; Stents; Stethoscopes; Weight Loss

Rimonabant (Acomplia) is the first selective CB1 receptor blocker of the endocannabinoid system. It has been evaluated in the RIO ("Rimonabant In Obesity and related disorders") programme including above 6.600 overweight/obese patients with or without comorbidities followed for 1 to 2 years. Compared to placebo, rimonabant 20 mg/day consistently increases weight loss, reduces waist circumference, increases HDL cholesterol, lowers triglyceride levels, diminishes insulin resistance, and reduces the prevalence of metabolic syndrome. In patients with type 2 diabetes, rimonabant also diminishes HbA1c levels, an effect confirmed in the recent SERENADE trial. Almost half of the metabolic effects occurs beyond weight loss, suggesting direct peripheral effects of rimonabant. Rimonabant is indicated in Europe as an adjunct to diet and exercise for the treatment of obese patients, or overweight patients with associated risk factor(s), such as type 2 diabetes or dyslipidaemia.

Topics: Anti-Obesity Agents; Bradykinin; Cannabinoids; Cholesterol, HDL; Diabetes Mellitus, Type 2; Dyslipidemias; Follow-Up Studies; Glycated Hemoglobin; Heart; Humans; Insulin Resistance; Metabolic Syndrome; Obesity; Overweight; Piperidines; Placebos; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Triglycerides; Waist-Hip Ratio; Weight Loss

Rimonabant (Acomplia - Sanofi-Aventis) has been licensed in the UK since June 2006 for the treatment of obese and certain overweight adults. Advertisements claim the drug has beneficial effects on "cardiometabolic risk factors", and that "an estimated 50% of the effects. . .on cardiometabolic risk factors are beyond those expected from weight loss alone". Here we review the role of rimonabant in managing patients with obesity.

Topics: Anti-Obesity Agents; Cardiovascular Diseases; Drug Costs; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Treatment Outcome; Weight Loss

The increasing prevalence of overweight and obesity counteracts the favorable advances of risk factor management achieved for cardiovascular disease (CVD) prevention. Obese and overweight individuals are at increased risk for CVDs and diabetes mellitus, a risk pattern called "cardiometabolic risk." There is a growing interest concerning the role of the endocannabinoid system in energy metabolism and how blockade of cannabinoid receptors (CB(1)) may optimize fat distribution, insulin sensitivity, and blood lipids to improve cardiovascular risk profile.

Topics: Abdominal Fat; Adipokines; Animals; Cannabinoid Receptor Modulators; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus; Endocannabinoids; Humans; Insulin Resistance; Lipids; Obesity; Overweight; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Weight Loss

Modification of lifestyle is the main therapeutical approach in the treatment of obesity, but use to fail on long terms of time. Addition of anti-obesity drugs allows keeping the weight loss during years and improving obesity-related comorbidities.. This review is an actualisation on efficacy, safety and tolerability of the approved drugs on the long-term treatment of obesity (orlistat and sibutramine). New indications and effects of their use far beyond the weight loss are as well commented. Finally, potential benefits of the administration of CB1 antagonist rimonabant on the weight loss and cardiometabolic risk factors are analysed in detail.. A decade of experience on the use of orlistat and sibutramine has demonstrated their higher efficacy on the weight loss when compared to placebo either on adult or teenage population as well as safety and tolerability on long-term administration. Beneficial effects on the lipid profile, glycosilated haemoglobin on diabetic patients, blood pressure and levels of inflammatory cytokines, contribute to decrease the cardiovascular risk on obese patients. Phase III clinical trials using rimonabant show additional benefits to the expected weight loss, mainly reducing visceral fat and cardiometabolic risk factors.. Pharmacological treatment of obesity must be considered as a therapeutical tool that has to be used together with long-term lifestyle changes, contributing to the body weight reduction as well as to the improvement of the cardiometabolic risk related to obesity.

Topics: Anti-Obesity Agents; Cyclobutanes; Humans; Lactones; Life Style; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Safety; Treatment Outcome; Weight Loss

The growing prevalence of obesity is associated with a dramatic increase in a number of related risk factors for cardiovascular disease and diabetes, including high triglyceride and fasting glucose levels, reduced high-density lipoprotein cholesterol, and increased blood pressure. For many patients, lifestyle interventions (eg, exercise and a reduced-calorie diet) are insufficient for overcoming obesity, and pharmacotherapy becomes necessary. Unfortunately, the currently available agents are associated with side effects such as gastrointestinal distress and increased blood pressure. A new class of drugs targeting the cannabinoid receptors is poised to join the obesity-management armamentarium, with one agent-rimonabant-demonstrating efficacy in 4 recent phase III multinational trials. Patients randomized to rimonabant 20 mg/d showed significant reductions in weight and significant improvements in lipid profiles and other measures of cardiometabolic risk factors.

Topics: Anti-Obesity Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diet; Dyslipidemias; Exercise; Humans; Insulin Resistance; Life Style; Lipids; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rimonabant; Risk Assessment; Risk Factors; Treatment Outcome; Weight Loss

Factors derived from adipose tissue are believed to play a central role in the development and progression of diabetes and its vascular complications. Insulin resistance and vascular function are directly affected these factors, i.e., by free fatty acids, inflammatory adipocytokines, thrombotic and antifibrinolytic factors and by adiponectin, and adipokine with insulin sensitizing and anti-inflammatory actions. Targeting these factors by antidiabetic agents should result in improved metabolism and in a reduction of vascular risk. We therefore analyzed antidiabetic treatment strategies with regard to improvements of adipose tissue derived risk factors. This shows that weight loss remains an extremely powerful tool to reduce all of these risk factors. Thiazolidinediones and rimonabant are most potent in improving numerous adipose derived risk factors but studies demonstrating reduced mortality are not yet available. Metformin has little effect on any of the adipose tissue derived factors but appears to reduce diabetes related mortality according to limited evidence. Sulfonylureas and insulin have rather limited effects on adipose tissue derived factors and are likely to exert beneficial effects mainly by improved glucose metabolism and its consequences.

Topics: Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Drug Delivery Systems; Humans; Hypoglycemic Agents; Insulin; Metformin; Models, Biological; Piperidines; Pyrazoles; Rimonabant; Sulfonylurea Compounds; Thiazolidinediones; Weight Loss

Topics: Adult; Aged; Anti-Obesity Agents; Appetite Depressants; Bariatric Surgery; Body Mass Index; Cyclobutanes; Diagnosis, Differential; Enzyme Inhibitors; Humans; Lactones; Male; Middle Aged; Obesity; Obesity, Morbid; Orlistat; Overweight; Piperidines; Prognosis; Pyrazoles; Rimonabant; Time Factors; Weight Loss

Since the prevalence of obesity continues to increase, there is a demand for effective and safe anti-obesity agents that can produce and maintain weight loss and improve comorbidity. We did a meta-analysis of all published randomised controlled trials to assess the efficacy and safety of the newly approved anti-obesity agent rimonabant.. We searched The Cochrane database and Controlled Trials Register, Medline via Pubmed, Embase via WebSpirs, Web of Science, Scopus, and reference lists up to July, 2007. We collected data from four double-blind, randomised controlled trials (including 4105 participants) that compared 20 mg per day rimonabant with placebo.. Patients given rimonabant had a 4.7 kg (95% CI 4.1-5.3 kg; p<0.0001) greater weight reduction after 1 year than did those given placebo. Rimonabant caused significantly more adverse events than did placebo (OR=1.4; p=0.0007; number needed to harm=25 individuals [95% CI 17-58]), and 1.4 times more serious adverse events (OR=1.4; p=0.03; number needed to harm=59 [27-830]). Patients given rimonabant were 2.5 times more likely to discontinue the treatment because of depressive mood disorders than were those given placebo (OR=2.5; p=0.01; number needed to harm=49 [19-316]). Furthermore, anxiety caused more patients to discontinue treatment in rimonabant groups than in placebo groups (OR=3.0; p=0.03; number needed to harm=166 [47-3716]).. Our findings suggest that 20 mg per day rimonabant increases the risk of psychiatric adverse events--ie, depressed mood disorders and anxiety-despite depressed mood being an exclusion criterion in these trials. Taken together with the recent US Food and Drug Administration finding of increased risk of suicide during treatment with rimonabant, we recommend increased alertness by physicians to these potentially severe psychiatric adverse reactions.

Topics: Anti-Obesity Agents; Anxiety Disorders; Depression; Double-Blind Method; Female; Humans; Male; Multicenter Studies as Topic; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Weight Loss

--Obesity is an important healthcare issue. --Recent research has led to insights into the role of the endocannabinoid system in the regulation of body weight. --Rimonabant is a CB1-endocannabinoid-receptor antagonist. --Four trials were published recently on the efficacy and safety of rimonabant in the treatment of people with obesity. --When combined with a hypocaloric diet, rimonabant 20 mg/day was more effective than placebo in achieving and maintaining weight loss. In addition, treatment with rimonabant had beneficial effects on insulin resistance, HDL-cholesterol and hypertriglyceridaemia. --There is concern regarding the increased incidence of depression during treatment. --Whether the beneficial effects of rimonabant on weight reduction and cardiovascular risk factors translate into a reduction in cardiovascular morbidity and mortality remains to be established in large phase III trials.

Topics: Cardiovascular Diseases; Depression; Diet, Reducing; Humans; Lipids; Obesity; Obesity, Morbid; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Weight Loss

Acceptable adverse effects and a clinical relevant weight loss of 3 to 5 kilograms have been found in long-term randomized clinical trials for sibutramine (Reductil) and orlistat (Xenical); these drugs may be prescribed for treatment of obesity for a duration of one and four years, respectively. This also seems to be the case for rimonabant (Acomplia), which is expected to receive approval in 2005 or 2006. However, until data on morbidity and mortality are available from RCTs, there is no absolute indication for prescribing drugs for treatment of obesity.

Topics: Anti-Obesity Agents; Appetite Depressants; Cyclobutanes; Diethylpropion; Enzyme Inhibitors; Humans; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Time Factors; Weight Loss

Currently, the substances orlistat and sibutramine are approved drugs for the pharmacotherapy of obesity. Used in combination with increased exercise and dietary measures, both are capable of significantly reducing weight. In the USA and Europe, official approval for the selective cannabinoid receptor antagonist, rimonabant has been applied for.

Topics: Anti-Obesity Agents; Appetite Depressants; Cannabinoid Receptor Antagonists; Clinical Trials as Topic; Cyclobutanes; Enzyme Inhibitors; Exercise; Humans; Lactones; Lipase; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Time Factors; Weight Loss

This review offers an overview of physiological agents, current therapeutics, as well as medications, which have been extensively used and those agents not currently available or non-classically considered anti-obesity drugs. As obesity - particularly that of central distribution - represents an important triggering factor for insulin resistance, its pharmacological treatment is relevant in the context of metabolic syndrome control. The authors present an extensive review on the criteria for anti-obesity management efficacy, on physiological mechanisms that regulate central and/or peripheral energy homeostasis (nutrients, monoamines, and peptides), on beta-phenethylamine pharmacological derivative agents (fenfluramine, dexfenfluramine, phentermine and sibutramine), tricyclic derivatives (mazindol), phenylpropanolamine derivatives (ephedrin, phenylpropanolamine), phenylpropanolamine oxytrifluorphenyl derivative (fluoxetine), a naftilamine derivative (sertraline) and a lipstatine derivative (orlistat). An analysis of all clinical trials - over ten-week long - is also presented for medications used in the management of obesity, as well as data about future medications, such as a the inverse cannabinoid agonist, rimonabant.

Topics: Amphetamines; Anti-Obesity Agents; Appetite Depressants; Clinical Trials as Topic; Cyclobutanes; Energy Metabolism; Homeostasis; Humans; Lactones; Mazindol; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Topics: Anti-Obesity Agents; Clinical Trials as Topic; Cyclobutanes; Drug Therapy, Combination; Humans; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Worldwide, the prevalence of obesity and overweight in industrialized countries and in a substantial number of developing countries is increasing at an alarming rate. Rimonabant is a selective cannabinoid-1 receptor antagonist that has been investigated for its efficacy in reducing body weight and associated risk factors in obese people. Phase III trials are now under way to test the use of rimonabant for long-term weight-loss. Given the prevalence of overweight and obesity, it is important to establish the efficacy and safety of rimonabant.. To assess the effects of rimonabant in overweight and obese people.. MEDLINE, EMBASE, The Cochrane Library, LILACS, databases of ongoing trials and reference lists were used to identify relevant trials. The last search was conducted in June 2006.. Randomised controlled trials comparing rimonabant with placebo or other weight loss interventions in overweight or obese adults.. Two reviewers independently assessed all potentially relevant citations for inclusion and methodological quality. The primary outcome measures were weight loss change, morbidity and adverse effects occurrence.. Four studies evaluating rimonabant 20 mg versus rimonabant 5 mg versus placebo in addition to a hypocaloric diet lasting at least one year were included. Compared with placebo, rimonabant 20 mg produced a 4.9 kg greater reduction in body weight in trials with one-year results. Improvements in waist circumference, high-density lipoprotein cholesterol, triglyceride levels and systolic and diastolic blood pressure were also seen. However, the results with rimonabant 5 mg demonstrated a weight reduction which was only 1.3 kg greater when compared with placebo. No clinically relevant effects on plasma lipids and blood pressure were found. Rimonabant 20 mg caused significant more adverse effects both of general and serious nature, especially of nervous system, psychiatric or gastro-intestinal origin. Attrition rates were approximately 40% at the end of one year.. The use of rimonabant after one year produces modest weight loss of approximately 5%. Even modest amounts of weight loss may be potentially beneficial. The observed results should be interpreted with some caution, though, since the evaluated studies presented some deficiencies in methodological quality. Studies with longer follow-ups after the end of treatment and of more rigorous quality should be done before definitive recommendations can be made regarding the role of this new medication in the management of overweight or obese patients.

Topics: Adult; Anti-Obesity Agents; Diet, Reducing; Humans; Obesity; Overweight; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Weight Loss

The primary goal of managing patients with metabolic syndrome is to decrease their cardiovascular risk by individualizing treatment strategies according to the patient's specific risk factors. Treatment options for patients with metabolic syndrome include lifestyle modification and drug therapy. Lifestyle modification can be summarized as dietary changes, exercise, and smoking cessation. Drug therapy indicated for cardiometabolic risk reduction includes antihypertensives, insulin sensitizers, and cholesterol-lowering agents. In addition, two drugs-sibutramine and rimonabant-have been evaluated and produced promising outcomes in the overall management of high-risk patients with metabolic syndrome.

Topics: Appetite Depressants; Cardiovascular Diseases; Cyclobutanes; Exercise; Humans; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Weight Loss

Development of the metabolic syndrome results from the interaction of genetic and environmental factors. Metabolic syndrome together with smoking represents risk factors for the development of cardiovascular complications. They may result from the hyperstimulation of the endocannabinoid system. The CB1 receptor has been assumed to play an important role in the endocannabionoid system. It is abundantly expressed in the brain, and in other parts of human body such as in the fat tissue. Rimonabant is a selective blocker of cannabinoid-1 (CB1) receptors and participates in the regulation of impaired endocannabinoid system. In the overweight humans, it stimulates sustained reduction of the body weight, girth size and it improves lipid and glucose metabolism. Rimonabant also reduces nicotine self-administration and may be effective not only as an aid for smoking cessation but also in the prevention of body weight increase related to the smoking cessation as it was documented in Rio-Lipids and Stratus-us studies.

Topics: Arachidonic Acids; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Endocannabinoids; Humans; Metabolic Syndrome; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rimonabant; Smoking; Smoking Cessation; Weight Loss

Overweight and obesity are recognised as significant risk factors for coronary heart disease (CHD). Weight reduction leads to reduction in associated CHD risk factors. The discovery that endocannabinoid system is involved in regulation of food intake and other reward behaviours has led to development of cannabinoid receptor antagonists. Recent studies with rimonabant, a cannabinoid type 1 receptor (CB(1)) antagonist, demonstrate clinically significant weight loss as well as reduction in metabolic syndromme burden in obese patients.

Topics: Cannabinoid Receptor Antagonists; Humans; Models, Biological; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Cholinesterase (ChE) inhibitors, which prevent the hydrolysis of acetylcholine, have been approved for the symptomatic treatment of Alzheimer's disease (AD) for over a decade. However, the first ChE inhibitors were associated with a high incidence of side-effects and general tolerability concerns, including hepatotoxicity. Side-effects associated with increased cholinergic activity, particularly in the gastrointestinal (GI) system, can prevent patients from achieving effective doses of drug. In addition, the advanced age and frail nature of patients with AD mean that poor tolerability is a serious concern. The potential for drug-drug interactions is also an important consideration, due to the high prevalence of comorbid disease in these patients. Data both from clinical trials and studies in routine clinical practice have shown that donepezil is associated with a low incidence of GI adverse events (AEs) that is comparable with placebo. Donepezil is a potent, selective inhibitor of acetylcholinesterase, and selective inhibition of central as opposed to peripheral ChEs might be expected to reduce the incidence of AEs, thus this may explain the lower incidence of cholinergic AEs observed following treatment with donepezil, compared with nonselective ChE inhibitors. There are no differences in cardiovascular AEs, including bradycardia, between placebo and donepezil groups in the clinical trials published to date, even in a very sick vascular dementia population with high rates of comorbidity and concomitant medication use. Data from single- and multiple-dose studies of donepezil in patients with hepatic impairment and with moderately to severely impaired renal function indicate that donepezil is safe and well tolerated in these groups. Furthermore, both in vitro and clinical studies have shown that donepezil is not associated with drug-drug interactions. The incidence of weight loss is very similar between donepezil- and placebo-treated patients. Although insomnia and other sleep disorders have been reported following administration of donepezil, lengthening the time period before increasing the dose of donepezil from 5 to 10 mg day(-1) or switching to morning dosing can reduce these events to the levels of placebo-treated patients. Over 770 million days of patient use and an extensive publication database demonstrate that donepezil has a good tolerability and safety profile.

Topics: Alzheimer Disease; Cardiovascular Diseases; Cholinesterase Inhibitors; Donepezil; Drug Interactions; Humans; Indans; Piperidines; Sleep Wake Disorders; Weight Loss

Evidence suggests that endocannabinoid system activation through the cannabinoid receptor 1 (CB1) is associated with enhanced liver injury, and CB1 antagonism may be beneficial. The aim of this study was to determine the impact of rimonabant (CB1 antagonist) on alanine aminotransferase (ALT), a hepatocellular injury marker, and a hepatic inflammatory cytokine profile.. Post hoc review of 2 studies involving 50 obese women with PCOS and well matched for weight, randomised to weight reducing therapy; rimonabant (20 mg od) or orlistat (120 mg tds), or to insulin sensitising therapy metformin, (500 mg tds), or pioglitazone (45 mg od). No subject had non-alcoholic fatty liver disease (NAFLD).. Treatment with rimonabant for 12 weeks reduced both ALT and weight (p < 0.01), and there was a negative correlation between Δ ALT and Δ HOMA-IR (p < 0.001), but not between Δ ALT and Δ weight. There was a significant reduction of weight with orlistat (p < 0.01); however, orlistat, metformin and pioglitazone had no effect on ALT. The free androgen index fell in all groups (p < 0.05). The inflammatory marker hs-CRP was reduced by pioglitazone (p < 0.001) alone and did not correlate with changes in ALT. The inflammatory cytokine profile for IL-1β, IL-6, IL-7, IL-10, IL12, TNF-α, MCP-1 and INF-γ did not differ between groups. None of the interventions had an effect on biological variability of ALT.. Rimonabant through CB1 receptor blockade decreased serum ALT that was independent of weight loss and hepatic inflammatory markers in obese women with PCOS without NAFLD.. ISRCTN58369615 (February 2007; retrospectively registered) ISRCTN75758249 (October 2007; retrospectively registered).

Topics: Alanine Transaminase; Anti-Obesity Agents; Body Mass Index; Cannabinoid Receptor Antagonists; Case-Control Studies; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Insulin Resistance; Lactones; Liver Diseases; Metformin; Obesity; Orlistat; Pioglitazone; Piperidines; Polycystic Ovary Syndrome; Prognosis; Pyrazoles; Receptor, Cannabinoid, CB1; Retrospective Studies; Rimonabant; Thiazolidinediones; Weight Loss

Animal studies suggest that cannabinoid receptor-1 (CB-1) blockade reduces inflammation and neovascularization by decreasing vascular endothelial growth factor (VEGF) levels associated with a reduction in inflammatory markers, thereby potentially reducing cardiovascular risk.. To determine the impact of CB1 antagonism by rimonabant on VEGF and inflammatory markers in obese PCOS women.. Randomized, open-labelled parallel study.. Endocrinology outpatient clinic in a referral centre.. Twenty patients with PCOS (PCOS) and biochemical hyperandrogenaemia with a body mass index of ≥30 kg/m. Post hoc review to detect VEGF and pro-inflammatory cytokines TNF-α, IL-1β, IL-1ra, IL-2, IL6, IL-8, IL-10 and MCP-1 before and after 12 weeks of treatment.. After 12 weeks of rimonabant treatment, there was a significant increase in VEGF (99·2 ± 17·6 vs 116·2 ± 15·8 pg/ml, P < 0·01) and IL-8 (7·4 ± 11·0 vs 18·1 ± 13·2 pg/ml, P < 0·05) but not after metformin (VEGF P = 0·7; IL-8 P = 0·9). There was no significant difference in the pro-inflammatory cytokines TNF-α, IL-1β, IL-1ra, IL-2, IL6, IL-8, IL-10 and MCP-1 following either treatment.. This study suggests that rimonabant CB-I blockade paradoxically raised VEGF and the cytokine IL-8 in obese women with PCOS that may have offset the potential benefit associated with weight loss.

Topics: Biomarkers; Cannabinoid Receptor Antagonists; Cytokines; Female; Humans; Hyperandrogenism; Inflammation; Interleukin-8; Metformin; Obesity; Piperidines; Polycystic Ovary Syndrome; Pyrazoles; Rimonabant; Vascular Endothelial Growth Factor A; Weight Loss

This study was designed to compare the effects of metformin and repaglinide on the fasting plasma glucose (FPG) and glycated haemoglobin (HbA1c) in newly diagnosed type 2 diabetes in China.. A total of 107 newly diagnosed type 2 diabetic patients (46 women and 61 men) participated in the study. All patients received 3-month treatment of metformin or repaglinide. Fasting blood glucose and HbA1c were determined at baseline and at the end of the 3-month of treatment.. FPG and HbA1c decreased in both metformin and repaglinide groups after 3 months treatment (P < 0.01). The reduction of HbA1c was significantly greater in the repaglinide group (P < 0.01). Metformin decreases fasting insulin concentration and HOMA-IR (P < 0.01), and repaglinide improves HOMA-β(P < 0.01). Triglycerides (TG) were reduced in both groups (P < 0.01 in metformin group; P < 0.05 in repaglinide group), but total cholesterol (TC) and low-density lipoprotein (LDL) were decreased only after metformin treatment (P < 0.05).. Both repaglinide and metformin were effective in glycaemic control in new onset patients with type 2 diabetes in China. Repaglinide had no effect on insulin sensitivity, but it improved β-cell function.

Topics: Body Mass Index; Carbamates; China; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Diabetic; Diet, Reducing; Drug Monitoring; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hyperlipidemias; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Overweight; Piperidines; Weight Loss

Studies in mice have suggested that endocannabinoid blockade using the cannabinoid receptor type 1 (CB1) blocker rimonabant prevents obesity-induced hepatic steatosis.. To determine effects of rimonabant on liver fat in humans, we measured liver fat content by proton magnetic resonance spectroscopy in 37 subjects who used either a CB1 blocker rimonabant or placebo in a double-blind, randomized manner. This was retrospectively compared with a historical hypocaloric diet weight loss group (n=23).. Weight loss averaged 8.5±1.4 kg in the rimonabant, 1.7±1.0 kg in the placebo and 7.5±0.2 kg in the hypocaloric diet group (P<0.001, rimonabant vs placebo; NS, rimonabant vs hypocaloric diet). Liver fat decreased more in the rimonabant (5.9% (2.5-14.6%) vs 1.8% (0.9-3.5%), before vs after) than in the placebo group (6.8% (2.2-15.7%) vs 4.9% (1.6-7.8%), before vs after, P<0.05). The percentage change in body weight correlated closely with the percentage loss of liver fat (r=0.70, P>0.0001). The decreases in liver fat were comparable between the rimonabant and the young historical hypocaloric diet groups.. We conclude that, unlike in mice, in humans rimonabant decreases liver fat in proportion to weight loss.

Topics: Adult; Aged; Cannabinoid Receptor Antagonists; Double-Blind Method; Fatty Liver; Female; Finland; Humans; Liver; Male; Metabolic Syndrome; Middle Aged; Obesity; Piperidines; Pyrazoles; Retrospective Studies; Rimonabant; Treatment Outcome; Weight Loss

In obesity, a dysregulation of the endocannabinoid system has been shown. The endocannabinoid receptor blockage by rimonabant demonstrated interesting metabolic effects. However, the role of rimonabant in weight loss of patients with binge eating disorder has not been investigated. Thus, our aim was to evaluate the effects of rimonabant on body weight in obese patients with binge eating disorders. This multicenter, randomized, double-blind, placebo-controlled study included 289 obese subjects (age 18-70 years, body mass index 30-45 kg/m(2)) with binge eating disorders. Subjects were randomized (1:1) to receive rimonabant 20 mg/day or placebo for 6 months. In total, 289 participants (age: 43.2±10.5 yrs, 91% of women) were randomized. The completer rate was similar (71%) in both treatment and placebo groups. Participants treated with rimonabant lost 4.7±5.2% of their initial body weight, vs. 0.4±4.5% in the placebo group (difference between both groups: 4.4±0.6 kg, p<0.0001). The rimonabant group showed a greater reduction on the binge eating scale total score (mean±SD  - 40.9±35.2%) vs. placebo ( - 29.9±34.6%, p=0.02). The incidence of treatment emergent adverse events was comparable in both the rimonabant (82.5%) and placebo (76.0%) group. Discontinuations due to treatment emergent adverse events occurred in 13.3% rimonabant-treated vs. 6.2% placebo-treated participants. In conclusion, this is the only randomised, placebo-controlled, double-blind trial having assessed the effect of rimonabant in patients with binge eating disorders. The rimonabant treatment reduced body weight significantly more than placebo in obese subjects with binge eating. Trial registration number (clinicaltrials.gov): NCT00481975.

Topics: Adolescent; Adult; Aged; Binge-Eating Disorder; Cannabinoid Receptor Antagonists; Double-Blind Method; Female; Humans; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

This randomized, double blind, placebo-controlled, 8 week trial assessed the efficacy on metabolic changes produced by a consumption of a combination of bioactive food ingredients (epigallocatechin gallate, capsaicins, piperine and L-carnitine) versus a placebo, as part of a therapeutic 'lifestyle change' diet, in 86 overweight subjects. Forty-one patients (2/14 F/M; age 43.7 ± 8.5; BMI 30.3 ± 3.5 kg/m(2)) were randomized to the supplemented group and 45 (29/16; age 40.7 ± 10.2; BMI 30.0 ± 2.7) to the control group. We observed that consumption of the dietary supplement was associated with a significantly greater decrease in insulin resistance, assessed by homostasis model assessment (p < 0.001), leptin/adiponectin ratio (p < 0.04), respiratory quotient (p < 0.008). LDL-cholesterol levels (p < 0.01). Moreover, statistically significant differences were recorded between the two groups in relation to urinary norepinephrine levels (p < 0.001). Leptin, ghrelin, C-reactive protein decreased and resting energy expenditure increased significantly in the supplemented group (p < 0.05, 0.03, 0.02 and 0,02 respectively), but not in the placebo group; adiponectin decreased significantly in the placebo group (0.001) but not in the supplemented group, although no statistical significance between the groups was elicited. BMI, fat mass (assessed by DXA) and vascular endothelial growth factor significantly decreased, whilst the resting energy expenditure/free fat mass significantly increased in both groups. In general, a greater change was recorded in the supplemented group compared to the placebo, although no statistically significant difference between the two groups was recorded. These results suggest that the combination of bioactive food ingredients studied might be useful for the treatment of obesity-related inflammatory metabolic dysfunctions.

Topics: Adipokines; Adult; Alkaloids; Benzodioxoles; Capsaicin; Carnitine; Catechin; Diet, Reducing; Dietary Supplements; Double-Blind Method; Female; Humans; Inflammation Mediators; Insulin Resistance; Male; Middle Aged; Overweight; Piperidines; Polyunsaturated Alkamides; Time Factors; Weight Loss; Young Adult

Endocannabinoid receptor 1 blockade is proposed to improve metabolic complications of obesity via central and peripheral effects.. Our objective was to test whether rimonabant improves insulin regulation of free fatty acid and glucose metabolism after controlling for fat loss.. This was a double-blind, placebo-controlled substudy of the visceral fat reduction assessed by computed tomography scan on rimonabant (VICTORIA) trial.. Sixty-seven abdominally obese, metabolic syndrome volunteers age 35-70 yr participated at academic medical center general clinical research centers.. Intervention included a 12-month lifestyle weight management program plus rimonabant 20 mg/d or placebo.. Body composition and two-step euglycemic, hyperinsulinemic clamp before and after intervention were performed. Insulin sensitivity was assessed as insulin concentration needed to suppress by 50% palmitate concentration [IC50(palmitate)], flux [IC50(palmitate)f], and hepatic glucose output [IC50(HGO)] and as insulin-stimulated glucose disposal (Δ glucose disappearance per Δ insulin concentration--glucose slope).. Body fat decreased by 4.5±2.9% (SD) in the rimonabant and 1.9±4.5% in the placebo group (P<0.005). The primary [improvement in IC50(palmitate) and IC50(palmitate)f] and secondary [improvement in IC50(HGO) and glucose slope] outcomes were not significantly different between the rimonabant and placebo groups. Post hoc analyses revealed that 1) changes in body mass index (BMI) and IC50(palmitate) were correlated (P=0.005) in the rimonabant group; this relationship was not significantly different from placebo when controlling for greater BMI loss (P=0.5); 2) insulin-regulated glucose disposal improved in both groups (P=0.002) and correlated with changes in BMI.. Improvements observed in insulin regulation of free fatty acid and glucose metabolism with rimonabant treatment in humans was not greater than that predicted by weight loss alone.

Topics: Adult; Aged; Behavior Therapy; Body Composition; Cannabinoid Receptor Antagonists; Diet, Reducing; Double-Blind Method; Fatty Acids, Nonesterified; Female; Glucose; Glucose Clamp Technique; Humans; Insulin; Intra-Abdominal Fat; Life Style; Male; Metabolic Syndrome; Middle Aged; Obesity; Piperidines; Pyrazoles; Rimonabant; Treatment Outcome; Weight Loss

The objectives of this study is to evaluate the efficacy and safety of alogliptin versus very low fat/calorie traditional Japanese diet (non-inferiority trial) as an initial therapy for newly diagnosed, drug naïve subjects with type 2 diabetes (T2DM). Study design was prospective, randomized, non-double-blind, controlled trial. The study was conducted at outpatient units of municipal hospital. Patients were newly diagnosed, drug naïve patients who visited the outpatient units. The patients randomly received 12.5-25 mg/day alogliptin (n = 25) or severe low calorie traditional Japanese diet (n = 26). The procedure of this trial was assessed by the consolidated standards of reporting trials statement. The primary end point was the change of HbA1c at 3 months. Secondary end points included the changes of fasting blood glucose, insulin, homeostasis model assessment-R (HOMA-R), HOMA-B, body mass index (BMI), and lipid parameters. Similar, significant reductions of HbA1c levels were observed in both groups (from 10.51 to 8.74% for alogliptin and from 10.01 to 8.39% for traditional Japanese diet) without any clinically significant adverse events. In the alogliptin group, some subjects (16%) had mild hypoglycemic evens which could be managed by taking glucose drinks by themselves. HOMA-B significantly increased in both groups with varying degrees, whereas HOMA-R significantly decreased only in the Japanese diet group. Atherogenic lipids, such as, total cholesterol, non-high density lipoprotein cholesterol, and low density lipoprotein cholesterol levels significantly decreased in both groups. BMI had no change in the alogliptin group, whereas it significantly decreased in the Japanese diet group. (1) Concerning its glycemic efficacy, alogliptin is effective and non-inferior to traditional Japanese diet as an initial therapeutic option for newly diagnosed T2DM. However, regarding the reductions of body weight and insulin resistance, traditional Japanese diet is superior. (2) Both alogliptin and traditional Japanese diet have favorable effects on atherogenic lipid profiles.

Topics: Adult; Diabetes Mellitus, Type 2; Diet, Diabetic; Diet, Fat-Restricted; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Hospitals, Municipal; Humans; Hyperglycemia; Hyperlipidemias; Hypoglycemia; Insulin Resistance; Japan; Male; Middle Aged; Outpatient Clinics, Hospital; Patient Dropouts; Piperidines; Uracil; Weight Loss

This study aimed to determine in obese women if endocannabinoid receptor antagonism has effects on fatty acid and triglyceride metabolism and insulin sensitivity which are independent from the metabolic effects of weight loss. Fourteen obese (BMI=33.0±0.5 kg/m(2)) (mean±SEM) Caucasian post-menopausal women, aged 57.8±4.7 years were studied. The women were randomised to 2 groups, one group received the endocannabinoid receptor antagonist rimonabant (20 mg/d) for 12 weeks. A control group achieved the same weight loss by a hypocaloric dietary intervention over 12 weeks. Palmitate production rate (Ra), a measure of lipolysis, and palmitate oxidation rate, and VLDL(1) and VLDL(2) triglyceride (TG) kinetics, were measured using isotopic tracers before and after the intervention. Weight loss was not different in the 2 groups; 2.6±0.5 kg with rimonabant and 3.1±1.0 kg in the control group. Palmitate Ra increased with rimonabant with no change in the control group (p=0.03 between groups). Palmitate oxidation rate increased with rimonabant but decreased in the control group (p=0.005 between groups). VLDL(1) TG secretion rate decreased in the control group and increased in the rimonabant group (p=0.008 between groups). There was no significant effect on insulin sensitivity. This study suggests that endocannabinoid receptor antagonism for 12 weeks in obese women increased lipolysis and fatty acid oxidation. The increase in VLDL(1) TG secretion rate may be due to the increase in lipolysis which exceeded the increase in fatty acid oxidation.

Topics: Adiponectin; Aged; Breath Tests; Cannabinoid Receptor Antagonists; Cholesterol; Diet, Reducing; Energy Intake; Energy Metabolism; Fatty Acids; Female; Humans; Insulin Resistance; Leptin; Lipolysis; Lipoproteins, VLDL; Middle Aged; Obesity; Oxidation-Reduction; Palmitic Acids; Piperidines; Pyrazoles; Rimonabant; Triglycerides; United Kingdom; Weight Loss

Three double-blind, placebo-controlled, three-parallel-group, multicenter phase 3 trials were conducted to assess the efficacy and safety of CP-945,598 for weight loss and weight-loss maintenance. Two trials were designed to be 2 years in duration (in obese and overweight patients) and one as a 1-year study (in obese and overweight patients with type 2 diabetes). However, the 2-year trials and the CP-945,598 development program were terminated before completion due to changing regulatory perspectives of CB1 receptor-related drugs. In total, 1,253 and 2,536 participants in the two 2-year multinational and North American studies were randomized to 10-mg CP-945,598 (n = 360; 718); 20-mg CP-945,598 (n = 534, 1,084) and placebo (n = 359, 734), respectively; and 975 participants were randomized to 10-mg CP-945,598 (n = 318); 20-mg CP-945,598 (n = 320); and placebo (n = 337) in the 1-year multinational diabetes trial. Baseline demographics were similar between treatment groups within each trial. One year of treatment with CP-945,598 resulted in a dose-related mean percentage reduction from baseline body-weight in all trials. A significant proportion of all participants also achieved 5% and 10% weight loss after 1 year. In participants with mainly well-controlled type 2 diabetes, the combination of lifestyle and CP-945,598 induced substantial improvements in glycemic control. The most frequent adverse events (AEs) for CP-945,598 were: diarrhea, nausea, nasopharyngitis, and headache. Self-reported experiences of anxiety and suicidal thoughts were higher with CP-945,598 than placebo, as were the incidence of depression and depressed mood. However, the reported increases in psychiatric symptoms were not consistently dose dependent.

Topics: Adolescent; Adult; Aged; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drugs, Investigational; Early Termination of Clinical Trials; Female; Humans; Male; Middle Aged; Obesity; Overweight; Patient Dropouts; Piperidines; Purines; Receptor, Cannabinoid, CB1; Secondary Prevention; Weight Loss; Young Adult

The aim of this trial was to determine whether obese patients benefit from treatment with rimonabant in terms of progression of carotid atherosclerosis. Rimonabant, a selective cannabinoid-1 receptor blocker, reduces body weight and improves cardiometabolic risk factors in patients who are obese.. A prospective, double-blind, placebo-controlled trial (Atherosclerosis Underlying Development assessed by Intima-media Thickness in patients On Rimonabant (AUDITOR)) randomised 661 patients with abdominal obesity and metabolic syndrome to rimonabant or placebo for 30 months of treatment. The absolute change in the average value for six segments of far wall carotid intima-media thickness from baseline to month 30 was 0.010 ± 0.095 mm in the rimonabant group and 0.012 ± 0.091 mm in the placebo group (p=0.67). The annualised change was an increase of 0.005 ± 0.042 mm for the rimonabant-treated group and 0.007 ± 0.043 mm for the placebo-treated group (p=0.45).. There was no difference in atherosclerosis progression between patients receiving rimonabant for 30 months and those receiving placebo for the primary efficacy measure (absolute change in carotid intima-media thickness). These findings are consistent with a similar study using coronary intravascular ultrasound and another study evaluating the occurrence of cardiovascular events. Our findings suggest that a 5% loss of body weight over a 30-month period with rimonabant is insufficient to modify atherosclerosis progression in the carotid artery in obese patients with metabolic syndrome. Clinical trial registration information clinicaltrials.gov Identifier: NCT00228176.

Topics: Anti-Obesity Agents; Canada; Carotid Arteries; Carotid Artery Diseases; Chi-Square Distribution; Disease Progression; Double-Blind Method; Europe; Female; Humans; Kaplan-Meier Estimate; Male; Metabolic Syndrome; Obesity, Abdominal; Piperidines; Placebo Effect; Prospective Studies; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Time Factors; Treatment Outcome; Tunica Intima; Tunica Media; Ultrasonography; United States; Waist Circumference; Weight Loss

Weight loss and hypolipidemic drugs can improve lipid and adipokine levels. We assessed the effects of rimonabant, alone and in combination with fenofibrate or ezetimibe, on adipokine levels in obese/overweight patients with dyslipidemia. Overweight/obese patients (n = 60, body mass index = 27-40 kg/m(2)) with mixed dyslipidemia were recruited. Patients received a hypocaloric diet and were randomized to rimonabant 20 mg/d (group R, n = 20), rimonabant 20 mg/d plus fenofibrate 200 mg/d (group RF, n = 20), or rimonabant 20 mg/d plus ezetimibe 10 mg/d (group RE, n = 20). After 3 months, leptin concentration was significantly reduced in all groups (-38%, P < .005; -40%, P < .005; and -44%, P < .001 in the R, RF, and RE groups, respectively). Total adiponectin remained unaltered. Visfatin concentration decreased significantly only in the RE and RF groups (-18% and -38%, respectively; P < .047). Treatment with rimonabant may improve adipokine levels in overweight/obese patients with dyslipidemia. The addition of fenofibrate or ezetimibe may reinforce this effect.

Topics: Adipokines; Adult; Aged; Azetidines; Body Mass Index; Diet, Reducing; Drug Therapy, Combination; Dyslipidemias; Ezetimibe; Female; Fenofibrate; Humans; Hypolipidemic Agents; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Rimonabant has been shown to reduce weight, free androgen index (FAI) and insulin resistance in obese patients with polycystic ovary syndrome (PCOS) compared to metformin. Studies have shown that significant weight regain occurs following the cessation of rimonabant therapy. This study was undertaken to determine if subsequent metformin treatment after rimonabant would maintain the improvement in weight, insulin resistance and hyperandrogenaemia in PCOS.. An extension study for 3 months with the addition of metformin to the randomised open labelled parallel study of metformin and rimonabant in 20 patients with PCOS with a body mass index >or= 30 kg/m(2). Patients who were on 3 months of rimonabant were changed over to metformin for 3 months, whereas those on 3 months of metformin were continued on metformin for another 3 months.. The primary end-point was a change in weight; secondary end-points were a change in FAI and insulin resistance.. The mean weight loss of 6.2 kg associated with 3 months of rimonabant treatment was maintained by 3 months of metformin treatment (mean change +0.2 kg, P = 0.96). Therefore, the percentage reduction in weight remained significantly higher in the rimonabant/metformin group compared to metformin only subjects at 6 months compared to baseline (-6.0 +/- 0.1%vs. -2.8 +/- 0.1%, P = 0.04). The percentage change in testosterone and FAI from baseline to 6 months was also greater in the rimonabant/metformin group. [Testosterone (-45.0 +/- 5.0%vs. -16 +/- 2.0%, P = 0.02); FAI (-53.0 +/- 5.0%vs. -17.0 +/- 12.2%, P = 0.02)]. HOMA-IR continued to fall significantly in the rimonabant/metformin group between 0, 3 and 6 months (4.4 +/- 0.5 vs. 3.4 +/- 0.4 vs. 2.7 +/- 0.3, respectively, P < 0.01) but not at all in the metformin only group (3.4 +/- 0.7 vs. 3.4 +/- 0.8 vs. 3.7 +/- 0.8, respectively, P = 0.80). Total cholesterol and LDL reduced significantly in both groups, but improvements in triglycerides and HDL were limited to the rimonabant/metformin group.. In these obese patients with PCOS, metformin maintained the weight loss and enhanced the metabolic and biochemical parameters achieved by treatment with rimonabant, compared to 6 months of metformin treatment alone.

Topics: Adult; Androgens; Female; Humans; Insulin Resistance; Metformin; Piperidines; Polycystic Ovary Syndrome; Pyrazoles; Rimonabant; Testosterone; Weight Loss

Rimonabant, the first selective cannabinoid type 1 (CB1) receptor blocker, has been shown to improve multiple cardiometabolic risk factors in overweight/obese patients. This analysis assessed the impact of rimonabant on blood pressure in the pooled population from four large trials with similar design - the Rimonabant-In-Obesity (RIO) programme.. RIO-Europe (n = 1507) and RIO-North America (n = 3040) recruited overweight/obese patients, and RIO-Lipids (n = 1033) and RIO-Diabetes (n = 1045) recruited overweight/obese patients with untreated dyslipidaemia or type 2 diabetes, respectively. At study entry (screening), 37.2% (n = 2463) of patients had hypertension, 71.4% (n = 1757) of whom were taking an antihypertensive treatment.. After 1 year of treatment, mean change in systolic blood pressure (SBP) from baseline was -0.8 mmHg for rimonabant 20 mg versus +0.3 mmHg for placebo (P = 0.007); diastolic blood pressure (DBP) decreased by -0.8 versus -0.3 mmHg (P = 0.029) respectively. In the subgroup of patients with high blood pressure at baseline, SBP change was -7.5 mmHg for rimonabant 20 mg versus -4.7 mmHg for placebo (P = 0.005); DBP change was -5.2 versus -3.0 mmHg (P < 0.001). Reductions were more pronounced in patients with dyslipidaemia and type 2 diabetes. There was no effect of rimonabant 20 mg on blood pressure beyond that expected from weight loss alone. Overall, there was a similar incidence of adverse events (AEs) at 1 year in the placebo (81.8%) and rimonabant 20 mg (86.0%). The most common AEs occurring with rimonabant were nausea, dizziness, arthralgia and diarrhoea. A slightly higher proportion of patients in the rimonabant 20 mg group discontinued as a result of AEs (13.8%) versus placebo (7.2%).. Rimonabant 20 mg led to modest, but significant SBP and DBP reductions in overweight/obese patients. The effect of rimonabant on blood pressure appears to be mediated by weight loss.

Topics: Adult; Blood Pressure; Cannabinoid Receptor Antagonists; Diabetes Mellitus, Type 2; Double-Blind Method; Dyslipidemias; Female; Humans; Hypertension; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Weight loss and metformin therapy are reported to be beneficial in improving the biochemical hyperandrogenaemia and insulin resistance of polycystic ovary syndrome (PCOS). Rimonabant has been found to reduce weight and improve the metabolic profile in patients with obesity, type 2 diabetes and metabolic syndrome.. To compare the effects of insulin sensitization with metformin to weight reduction by rimonabant on biochemical hyperandrogenaemia and insulin resistance in patients with PCOS.. A randomized, open-label parallel study.. Endocrinology outpatient clinic in a referral centre.. Twenty patients with PCOS and biochemical hyperandrogenaemia with a body mass index (BMI) >or= 30 kg/m(2) were recruited.. Patients were randomized to 1.5 g daily of metformin or 20 mg daily of rimonabant.. The primary end-point of the study was a change in total testosterone.. After 12 weeks of rimonabant there was a significant reduction (mean +/- SEM) in weight (104.6 +/- 4.6 vs. 98.4 +/- 4.7 kg, P < 0.01), waist circumference (116.0 +/- 3.3 vs. 109.2 +/- 3.7 cm, P < 0.01), hip circumference (128.5 +/- 4.0 vs. 124.1 +/- 4.2 cm, P < 0.03), waist-hip ratio (0.90 +/- 0.02 vs. 0.88 +/- 0.01, P < 0.01) free androgen index (FAI) (26.6 +/- 6.1 vs. 16.6 +/- 4.1, P < 0.01), testosterone [4.6 +/- 0.4 vs. 3.1 +/- 0.3 nmol/l (132.7 +/- 11.5 vs. 89.4 +/- 8.65 ng/dl), P < 0.01] and insulin resistance as measured by the homeostasis model assessment (HOMA) method (4.4 +/- 0.5 vs. 3.4 +/- 0.4, P = 0.05). There was no change in any of these parameters in the metformin-treated group.. This study suggests that the weight loss through rimonabant therapy may be of use in patients with PCOS and appears superior to insulin sensitization by metformin in reducing the FAI and insulin resistance in obese PCOS patients treated over a 12-week period.

Topics: Adult; Female; Humans; Hyperandrogenism; Insulin Resistance; Metformin; Piperidines; Polycystic Ovary Syndrome; Pyrazoles; Rimonabant; Testosterone; Weight Loss

Rimonabant, the first selective cannabinoid type 1 receptor blocker, has been shown to produce weight loss and improvements in several cardiometabolic risk factors over 1 year. We report the 2 year efficacy and tolerability data of rimonabant.. Patients with a body mass index > or =30 or >27 kg/m(2) with treated/untreated hypertension, dyslipidaemia, or both, were randomized to double-blind treatment with placebo, rimonabant 5 or 20 mg once daily plus a calorie-restricted diet for 2 years. Weight loss from baseline to 2 years in the intention-to-treat population was significantly greater with rimonabant 20 mg (mean +/- SD: -5.5 +/- 7.7 kg; P < 0.001) and 5 mg (-2.9 +/- 6.5 kg; P = 0.002) than placebo (-1.2 +/- 6.8 kg). Rimonabant 20 mg produced significantly greater improvements than placebo in waist circumference, high-density lipoprotein cholesterol, triglycerides, fasting glucose and insulin levels, insulin resistance, and metabolic syndrome prevalence. Rimonabant 20 mg produced clinically meaningful improvements in all Impact of Weight on Quality of Life-Lite questionnaire domain scores at 2 years. Rimonabant was generally well tolerated and rates of adverse events, including depressed mood disorders and disturbances were similar to placebo during year 2. Proportions of patients with clinically significant depression (Hospital Anxiety and Depression Scale score >11) were similar in all treatment groups.. Rimonabant 20 mg over 2 years promoted clinically relevant and durable weight loss and improvements in cardiometabolic risk factors.

Topics: Adult; Anti-Obesity Agents; Blood Glucose; Body Mass Index; Cannabinoid Receptor Antagonists; Cardiovascular Diseases; Cholesterol, HDL; Dose-Response Relationship, Drug; Epidemiologic Methods; Female; Humans; Insulin; Male; Metabolic Syndrome; Middle Aged; Obesity; Piperidines; Pyrazoles; Rimonabant; Treatment Outcome; Triglycerides; Weight Loss

Rimonabant (Acomplia) is the first selective CB1 receptor blocker of the endocannabinoid system. It has been evaluated in the RIO ("Rimonabant In Obesity and related disorders") programme including above 6.600 overweight/obese patients with or without comorbidities followed for 1 to 2 years. Compared to placebo, rimonabant 20 mg/day consistently increases weight loss, reduces waist circumference, increases HDL cholesterol, lowers triglyceride levels, diminishes insulin resistance, and reduces the prevalence of metabolic syndrome. In patients with type 2 diabetes, rimonabant also diminishes HbA1c levels, an effect confirmed in the recent SERENADE trial. Almost half of the metabolic effects occurs beyond weight loss, suggesting direct peripheral effects of rimonabant. Rimonabant is indicated in Europe as an adjunct to diet and exercise for the treatment of obese patients, or overweight patients with associated risk factor(s), such as type 2 diabetes or dyslipidaemia.

Topics: Anti-Obesity Agents; Bradykinin; Cannabinoids; Cholesterol, HDL; Diabetes Mellitus, Type 2; Dyslipidemias; Follow-Up Studies; Glycated Hemoglobin; Heart; Humans; Insulin Resistance; Metabolic Syndrome; Obesity; Overweight; Piperidines; Placebos; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Triglycerides; Waist-Hip Ratio; Weight Loss

Topics: Appetite Depressants; Cannabinoids; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Male; Obesity; Overweight; Patient Dropouts; Piperidines; Placebos; Pyrazoles; Rimonabant; Treatment Outcome; Weight Loss

Rimonabant, a selective cannabinoid-1 receptor blocker, may reduce body weight and improve cardiometabolic risk factors in patients who are overweight or obese.. To compare the efficacy and safety of rimonabant with placebo each in conjunction with diet and exercise for sustained changes in weight and cardiometabolic risk factors over 2 years.. Randomized, double-blind, placebo-controlled trial of 3045 obese (body mass index > or =30) or overweight (body mass index >27 and treated or untreated hypertension or dyslipidemia) adult patients at 64 US and 8 Canadian clinical research centers from August 2001 to April 2004.. After a 4-week single-blind placebo plus diet (600 kcal/d deficit) run-in period, patients were randomized to receive placebo, 5 mg/d of rimonabant, or 20 mg/d of rimonabant for 1 year. Rimonabant-treated patients were rerandomized to receive placebo or continued to receive the same rimonabant dose while the placebo group continued to receive placebo during year 2.. Body weight change over year 1 and prevention of weight regain during year 2. Additional efficacy measures included changes in waist circumference, plasma lipid levels, and other cardiometabolic risk factors.. At year 1, the completion rate was 309 (51%) patients in the placebo group, 620 (51%) patients in the 5 mg of rimonabant group, and 673 (55%) patients in the 20 mg of rimonabant group. Compared with the placebo group, the 20 mg of rimonabant group produced greater mean (SEM) reductions in weight (-6.3 [0.2] kg vs -1.6 [0.2] kg; P<.001), waist circumference (-6.1 [0.2] cm vs -2.5 [0.3] cm; P<.001), and level of triglycerides (percentage change, -5.3 [1.2] vs 7.9 [2.0]; P<.001) and a greater increase in level of high-density lipoprotein cholesterol (percentage change, 12.6 [0.5] vs 5.4 [0.7]; P<.001). Patients who were switched from the 20 mg of rimonabant group to the placebo group during year 2 experienced weight regain while those who continued to receive 20 mg of rimonabant maintained their weight loss and favorable changes in cardiometabolic risk factors. Use of different imputation methods to account for the high rate of dropouts in all 3 groups yielded similar results. Rimonabant was generally well tolerated; the most common drug-related adverse event was nausea (11.2% for the 20 mg of rimonabant group vs 5.8% for the placebo group).. In this multicenter trial, treatment with 20 mg/d of rimonabant plus diet for 2 years promoted modest but sustained reductions in weight and waist circumference and favorable changes in cardiometabolic risk factors. However, the trial was limited by a high drop-out rate and longer-term effects of the drug require further study. Clinical Trials Registration ClinicalTrials.gov Identifier: NCT00029861.

Topics: Adult; Aged; Anti-Obesity Agents; Blood Pressure; Cannabinoid Receptor Antagonists; Cardiovascular Diseases; Cholesterol, HDL; Diet, Reducing; Double-Blind Method; Female; Humans; Male; Metabolic Syndrome; Middle Aged; Obesity; Overweight; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Weight Loss

Rimonabant, a selective cannabinoid-1 receptor (CB1) blocker, has been shown to reduce body weight and improve cardiovascular risk factors in obese patients. The Rimonabant in Obesity-Lipids (RIO-Lipids) study examined the effects of rimonabant on metabolic risk factors, including adiponectin levels, in high-risk patients who are overweight or obese and have dyslipidemia.. We randomly assigned 1036 overweight or obese patients (body-mass index [the weight in kilograms divided by the square of the height in meters], 27 to 40) with untreated dyslipidemia (triglyceride levels >1.69 to 7.90 mmol per liter, or a ratio of cholesterol to high-density lipoprotein [HDL] cholesterol of >4.5 among women and >5 among men) to double-blinded therapy with either placebo or rimonabant at a dose of 5 mg or 20 mg daily for 12 months in addition to a hypocaloric diet.. The rates of completion of the study were 62.6 percent, 60.3 percent, and 63.9 percent in the placebo group, the group receiving 5 mg of rimonabant, and the group receiving 20 mg of rimonabant, respectively. The most frequent adverse events resulting in discontinuation of the drug were depression, anxiety, and nausea. As compared with placebo, rimonabant at a dose of 20 mg was associated with a significant (P<0.001) mean weight loss (repeated-measures method, -6.7+/-0.5 kg, and last-observation-carried-forward analyses, -5.4+/-0.4 kg), reduction in waist circumference (repeated-measures method, -5.8+/-0.5 cm, and last-observation-carried-forward analyses, -4.7+/-0.5 cm), increase in HDL cholesterol (repeated-measures method, +10.0+/-1.6 percent, and last-observation-carried-forward analyses, +8.1+/-1.5 percent), and reduction in triglycerides (repeated-measures method, -13.0+/-3.5 percent, and last-observation-carried-forward analyses, -12.4+/-3.2 percent). Rimonabant at a dose of 20 mg also resulted in an increase in plasma adiponectin levels (repeated-measures method, 57.7 percent, and last-observation-carried-forward analyses, 46.2 percent; P<0.001), for a change that was partly independent of weight loss alone.. Selective CB1-receptor blockade with rimonabant significantly reduces body weight and waist circumference and improves the profile of several metabolic risk factors in high-risk patients who are overweight or obese and have an atherogenic dyslipidemia.

Topics: Adiponectin; Adult; Aged; Anti-Obesity Agents; Blood Glucose; Cannabinoid Receptor Antagonists; Cholesterol; Double-Blind Method; Dyslipidemias; Female; Humans; Insulin; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Overweight; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Triglycerides; Weight Loss

Cannabinoid CB1 receptor (CB1R) inverse agonists reduce appetite and body weight (BW) gain in various species. Exercise is thought to be a natural reward process and the cannabinoid system is also believed to influence reward. We tested the hypothesis that voluntary exercise would augment the effects of AM251, a CB1R inverse agonist, on food intake (FI) and BW loss in murine genetic models of obesity. ob/ob, agouti yellow (A(y)), and lean C57BL/6J mice were treated via oral gavage with vehicle or AM251 (1, 3, or 10 mg/kg) 1 h before the dark cycle. The suppressive effects of 3 and 10 mg/kg AM251 on overnight FI, BW gain, and water intake (WI) were significant in ob/ob mice. In contrast, in A(y) mice, 10 mg/kg AM251 decreased FI and BW gain while it did not influence WI. Food consumption of ob/ob and A(y) mice, as evidenced by feeding frequency (FF) and feeding duration (FD), was reduced by AM251 for 4-6 h. AM251 at these doses had no impact on the appetitive behavior or BW gain of lean mice. After a 1-week wash-out period, mice were given running wheels in their home cages. With running wheel exercise, lean and obese mice exhibited increased sensitivity to AM251. Low voluntary wheel running activity of ob/ob mice precluded detection of combined effects of AM251 and exercise in this genetic model of obesity. Lean and agouti mice given AM251 combined with exercise lost a greater amount of BW than with AM251 alone. Our data suggest that voluntary exercise can enhance CB1R inverse agonist effects on appetite and BW loss in both lean and agouti obese mice.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Eating; Female; Mice; Mice, Inbred C57BL; Mice, Obese; Physical Conditioning, Animal; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Thinness; Weight Loss

Anorexia is a common problem in cancer patients who receive radiotherapy. In this current study, we attempt to determine the effect of megestrol acetate and prepulsid on appetite and nutritional improvement in patients with head and neck cancers undergoing radiotherapy.. One hundred twenty-nine consecutive patients with head and neck cancers treated between July 1993 and June 1994 were prospectively randomized to receive either megestrol acetate, 40 mg qid (megace group), prepulsid, 5 mg tid (cisapride group), or a placebo treatment (control group) during radiotherapy. Before radiotherapy, body weight (kg), appetite score, performance status, biochemical parameters and hematological parameters were evaluated, and the above-noted clinical and biochemical parameters were assessed and recorded every other week. All patients received 6- 10 MV X-rays or Co-60 gamma-ray to head and neck region for a full course of radiotherapy, 61.2-75.6 Gy/7-9 weeks.. Forty-eight patients were enrolled in the megace group, 41 patients in the cisapride group, and 40 patients in the control group. At the 2nd, 4th, 6th and 8th week, as the radiation dose escalated, the megace group had significantly less body weight loss than did the cisapride and control groups (P = 0.045, 0.024, 0.006, 0.003, respectively). The appetite scores of the megace group were significantly higher than those of the cisapride and control groups (P = 0.0001). However, there were no statistically significant differences in the change of albumin level among these three groups at the 2nd, 4th, 6th and 8th week (P > 0.05, respectively).. Megestrol acetate can significantly decrease the degree of body weight loss, and can prevent the deterioration of appetite in patients with head and neck cancers receiving radiotherapy. However, prepulsid lacks the above-mentioned clinical benefits.

Topics: Adult; Aged; Appetite Stimulants; Cisapride; Female; Head and Neck Neoplasms; Humans; Male; Megestrol Acetate; Middle Aged; Nutritional Physiological Phenomena; Piperidines; Prospective Studies; Weight Loss

Patients with type 2 diabetes (T2D) may experience frequent body weight changes over time. The prognostic impact of these weight changes (gains or losses) requires further study.. To study the associations between changes in body weight (intentional or unintentional) with subsequent outcomes.. The EXAMINE trial included 5380 patients with T2D and a recent acute coronary syndrome, who were randomized to alogliptin or placebo. Time-updated Cox models and mixed effects models were used to test the associations between changes in body weight and subsequent outcomes over a median follow-up of 1.6 (1.0-2.1) years.. During the post-randomization follow-up period, 1044 patients (19.4%) experienced a weight loss ≥ 5% of baseline weight, 2677 (49.8%) had a stable weight, and 1659 (30.8%) had a ≥ 5 % weight gain. Patients with weight loss were more frequently women and had more co-morbid conditions. In contrast, patients who gained ≥ 5% weight were more frequently men with less co-morbid conditions. A weight loss ≥ 5% was independently associated with a higher risk of subsequent adverse outcomes, including all-cause mortality: adjusted HR (95% CI) = 1.79 (1.33-2.42), P < 0.001. Similar associations were found for cardiovascular mortality, the composite of cardiovascular mortality or heart failure hospitalization, and the primary outcome. A weight gain ≥ 5% was independently associated with an increase in the risk of subsequent cardiovascular mortality or heart failure hospitalization only: adjusted HR (95% CI) = 1.34 (1.02-1.76), P = 0.033.. In patients with T2D who had a recent ACS/MI, a ≥ 5% loss of body weight was associated with a higher risk of subsequent cardiovascular events and mortality.

Topics: Acute Coronary Syndrome; Aged; Body Mass Index; Comorbidity; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Incidence; Male; Middle Aged; Piperidines; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Uracil; Weight Gain; Weight Loss

To develop an evidence-based guideline for the pharmacologic and nonpharmacologic treatment of psoriatic arthritis (PsA), as a collaboration between the American College of Rheumatology (ACR) and the National Psoriasis Foundation (NPF).. We identified critical outcomes in PsA and clinically relevant PICO (population/intervention/comparator/outcomes) questions. A Literature Review Team performed a systematic literature review to summarize evidence supporting the benefits and harms of available pharmacologic and nonpharmacologic therapies for PsA. GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to rate the quality of the evidence. A voting panel, including rheumatologists, dermatologists, other health professionals, and patients, achieved consensus on the direction and the strength of the recommendations.. The guideline covers the management of active PsA in patients who are treatment-naive and those who continue to have active PsA despite treatment, and addresses the use of oral small molecules, tumor necrosis factor inhibitors, interleukin-12/23 inhibitors (IL-12/23i), IL-17 inhibitors, CTLA4-Ig (abatacept), and a JAK inhibitor (tofacitinib). We also developed recommendations for psoriatic spondylitis, predominant enthesitis, and treatment in the presence of concomitant inflammatory bowel disease, diabetes, or serious infections. We formulated recommendations for a treat-to-target strategy, vaccinations, and nonpharmacologic therapies. Six percent of the recommendations were strong and 94% conditional, indicating the importance of active discussion between the health care provider and the patient to choose the optimal treatment.. The 2018 ACR/NPF PsA guideline serves as a tool for health care providers and patients in the selection of appropriate therapy in common clinical scenarios. Best treatment decisions consider each individual patient situation. The guideline is not meant to be proscriptive and should not be used to limit treatment options for patients with PsA.

Topics: Abatacept; Adalimumab; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Psoriatic; Comorbidity; Diabetes Mellitus; Enthesopathy; Etanercept; Evidence-Based Medicine; Exercise; Glucocorticoids; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Interleukin-12; Interleukin-17; Interleukin-23; Occupational Therapy; Physical Therapy Modalities; Piperidines; Pyrimidines; Pyrroles; Rheumatology; Smoking Cessation; Societies, Medical; Spondylitis; Tumor Necrosis Factor-alpha; Ustekinumab; Weight Loss

Among gliomas types, glioblastoma is considered the most malignant and the worst form of primary brain tumor. It is characterized by high infiltration rate and great angiogenic capacity. The presence of an inflammatory microenvironment contributes to chemo/radioresistance, resulting in poor prognosis for patients. Recent data show that thiazolidinones have a wide range of pharmacological properties, including anti-inflammatory and antiglioma activities. Nanocapsules of biodegradable polymers become an alternative to cancer treatment since they provide targeted drug delivery and could overcome blood-brain barrier. Therefore, here we investigated the in vitro antiglioma activity and the potential in vivo toxicity of 2- (2-methoxyphenyl) -3- ((piperidin-1-yl) ethyl) thiazolidin-4-one-loaded polymeric nanocapsules (4L-N). Nanocapsules were prepared and characterized in terms of particle size, polydispersity index, zeta potential, pH, molecule content and encapsulation efficiency. Treatment with 4L-N selectively decreased human U138MG and rat C6 cell lines viability and proliferation, being even more efficient than the free-form molecule (4L). In addition, 4L-N did not promote toxicity to primary astrocytes. We further demonstrated that the treatment with sub-therapeutic dose of 4L-N did not alter weight, neither resulted in mortality, toxicity or peripheral damage to Wistar rats. Finally, 4L as well as 4L-N did not alter makers of oxidative damage, such as TBARS levels and total sulfhydryl content, and did not change antioxidant enzymes SOD and CAT activity in liver and brain of treated rats. Taken together, these data indicate that the nanoencapsulation of 4L has potentiated its antiglioma effect and does not cause in vivo toxicity.

Topics: Animals; Apoptosis; Astrocytes; Biomarkers, Tumor; Brain; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Liberation; Glioma; Humans; Light; Liver; Male; Nanocapsules; Oxidative Stress; Piperidines; Polymers; Rats, Wistar; Thiazolidines; Thiobarbituric Acid Reactive Substances; Toxicity Tests; Weight Loss

Epoxyeicosatrienoic acids (EETs), the metabolites of arachidonic acid derived from the cytochrome P450 (CYP450) epoxygenases, are mainly metabolized by soluble epoxide hydrolase (sEH) to their corresponding diols. EETs but not their diols, have anti-inflammatory properties and inhibition of sEH might provide protective effects against inflammatory fibrosis. We test the effects of a selected sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), on bleomycin-induced pulmonary fibrosis (PF) in mice. A mouse model of PF was established by intratracheal injection of bleomycin and TPPU was administered for 21 days after bleomycin injection. We found TPPU treatment improved the body weight loss and survival rate of bleomycin-stimulated mice. Histological examination showed that TPPU treatment alleviated bleomycin-induced inflammation and maintained the alveolar structure of the pulmonary tissues. TPPU also decreased the bleomycin-induced deposition of collagen and the expression of procollagen I mRNA in lung tissues of mice. TPPU decreased the transforming growth factor-β1 (TGF-β1), interleukin-1β (IL-1β) and IL-6 levels in the serum of bleomycin-stimulated mice. Furthermore, TPPU inhibited the proliferation and collagen synthesis of mouse fibroblasts and partially reversed TGF-β1-induced α-smooth muscle actin expression. Our results indicate that the inhibition of sEH attenuates bleomycin-induced inflammation and collagen deposition and therefore prevents bleomycin-induced PF in a mouse model.

Topics: Animals; Bleomycin; Cell Death; Cell Differentiation; Cell Proliferation; Collagen; Eicosanoids; Epoxide Hydrolases; Fibroblasts; Interleukin-1beta; Interleukin-6; Lung; Male; Mice; Mice, Inbred C57BL; NIH 3T3 Cells; Phenylurea Compounds; Piperidines; Pulmonary Fibrosis; S Phase; Solubility; Transforming Growth Factor beta1; Weight Loss

Multiple studies suggest a pivotal role of the endocannabinoid system in regulating the reinforcing effects of various substances of abuse. Rimonabant, a CB. Rats were trained to self-administer nicotine under a fixed-ratio 5 or progressive-ratio schedules of reinforcement. A control group was trained to self-administer food. The acute/chronic effects of AM4113 pretreatment were evaluated on nicotine taking, motivation for nicotine, and cue-, nicotine priming- and yohimbine-induced reinstatement of nicotine-seeking. The effects of AM4113 in the basal firing and bursting activity of midbrain dopamine neurons were evaluated in a separate group of animals treated with nicotine. Anxiety/depression-like effects of AM4113 and rimonabant were evaluated 24h after chronic (21 days) pretreatment (0, 1, 3, and 10mg/kg, 1/d).. AM4113 significantly attenuated nicotine taking, motivation for nicotine, as well as cue-, priming- and stress-induced reinstatement of nicotine-seeking behavior. These effects were accompanied by a decrease of the firing and burst rates in the ventral tegmental area dopamine neurons in response to nicotine. On the other hand, AM4113 pretreatment did not have effects on operant responding for food. Importantly, AM4113 did not have effects on anxiety and showed antidepressant-like effects.. Our results indicate that AM4113 could be a promising therapeutic option for the prevention of relapse to nicotine-seeking while lacking anxiety/depression-like side effects.

Topics: Animals; Anxiety; Behavior, Addictive; Behavior, Animal; Cannabinoid Receptor Antagonists; Cues; Depression; Disease Models, Animal; Dopaminergic Neurons; Dose-Response Relationship, Drug; Drug Inverse Agonism; Drug-Seeking Behavior; Male; Maze Learning; Mesencephalon; Motivation; Motor Activity; Piperidines; Pyrazoles; Rats, Long-Evans; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Signal Transduction; Swimming; Time Factors; Tobacco Use Cessation Devices; Tobacco Use Disorder; Weight Loss

The individual weight loss response to obesity treatment is diverse. Here we test the hypothesis that the weight loss response to the CB1 receptor antagonist rimonabant is influenced by endogenous levels of receptor agonists. We show that baseline anandamide levels and body weight independently contribute to predict the treatment response to rimonabant in rodents, demonstrating that addition of biomarkers related to mode of action is relevant for a personalized health care approach to obesity treatment.

Topics: Animals; Arachidonic Acids; Body Weight; Cannabinoid Receptor Antagonists; Endocannabinoids; Male; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Weight Loss

To investigate the in vivo metabolic effects of treatment with BPR0912, a novel and potent peripheral cannabinoid receptor 1 (CB1R) antagonist, on both normal mice and diet-induced obese (DIO) mice.. The acute peripheral effects of BPR0912 administration on gastrointestinal transit and energy metabolism in normal mice were investigated. The effects of chronic BPR0912 treatment were compared with those of rimonabant using DIO mice. Alterations to body weight and biochemical and metabolic variables were determined.. Acute treatment with BPR0912 did not alter food intake or energy metabolism, but efficiently reversed CB1R-mediated gastrointestinal delay. Chronic treatment of DIO mice with BPR0912 showed that BPR0912 exerts a food intake-independent mechanism, which contributes to weight loss. Genes involved in β-oxidation and thermogenesis were upregulated in white adipose tissue (WAT) in addition to increased lipolytic activity, whereas Ucp1 expression was induced in brown adipose tissue (BAT) and body temperature was elevated. Expression of the β2-adrenoceptor was specifically elevated in both WAT and BAT in a manner dependent on the BPR0912 dose. Lastly, chronic BPR0912 treatment was more efficacious than rimonabant in reducing hepatic triglycerides in DIO mice.. BPR0912 exhibits significant in vivo efficacy in inducing food intake-independent weight loss in DIO mice, while tending to reduce their hepatic steatosis. The thermogenic effects of BPR0912, as well as its modulation of protein and gene expression patterns in WAT and BAT, may enhance its efficacy as an anti-obesity agent. The results of the present study support the benefits of the use of peripheral CB1R antagonists to combat metabolic disorders.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Anti-Obesity Agents; Cannabinoid Receptor Antagonists; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Eating; Energy Metabolism; Fatty Liver; Ion Channels; Lipolysis; Male; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Thermogenesis; Thiophenes; Uncoupling Protein 1; Weight Loss

Anorexia nervosa (AN) is an eating disorder characterized by severe hypophagia and weight loss, and an intense fear of weight gain. Activity-based anorexia (ABA) refers to the weight loss, hypophagia and paradoxical hyperactivity that develops in rodents exposed to running wheels and restricted food access, and provides a model for aspects of AN. The atypical antipsychotic olanzapine was recently shown to reduce both AN symptoms and ABA. We examined which component of the complex pharmacological profile of olanzapine reduces ABA. Mice received 5-HT(2A/2C), 5-HT3, dopamine D1-like, D2, D3 or D2/3 antagonist treatment, and were assessed for food intake, body weight, wheel running and survival in ABA. D2/3 receptor antagonists eticlopride and amisulpride reduced weight loss and hypophagia, and increased survival during ABA. Furthermore, amisulpride produced larger reductions in weight loss and hypophagia than olanzapine. Treatment with either D3 receptor antagonist SB277011A or D2 receptor antagonist L-741,626 also increased survival. All the other treatments either had no effect or worsened ABA. Overall, selective antagonism of D2 and/or D3 receptors robustly reduces ABA. Studies investigating the mechanisms by which D2 and/or D3 receptors regulate ABA, and the efficacy for D2/3 and/or D3 antagonists to treat AN, are warranted.

Topics: Amisulpride; Animals; Anorexia Nervosa; Benzodiazepines; Disease Models, Animal; Dopamine D2 Receptor Antagonists; Eating; Female; Indoles; Mice; Mice, Inbred BALB C; Motor Activity; Nitriles; Olanzapine; Piperidines; Receptors, Dopamine D3; Salicylamides; Sulpiride; Tetrahydroisoquinolines; Weight Loss

Current anti-obesity monotherapies have proven only marginally effective and are often accompanied by adverse side effects. The cannabinoid 1 (CB1) receptor antagonist rimonabant, while effective at producing weight loss, has been discontinued from clinical use owing to increased incidence of depression. This study investigates the interaction between the cannabinoid and melanin-concentrating hormone (MCH) systems in food intake, body weight control, and mood.. Lean male C57BL/6 mice were injected i.p. with rimonabant (0.0, 0.03, 0.3 and 3.0 mg kg(-1)) or the MCH1-R antagonist SNAP-94847 (0.0, 1.0, 5.0 and 10.0 mg kg(-1)) to establish dose response parameters for each drug. Diet-induced obese (DIO) mice were given either vehicle, sub-threshold dose of rimonabant and SNAP-94847 alone or in combination. Impact on behavioral outcomes, food intake, body weight, plasma metabolites and expression of key metabolic proteins in the brown adipose tissue (BAT) and white adipose tissue (WAT) were measured.. The high doses of rimonabant and SNAP-94847 produced a reduction in food intake after 2 and 24 h. Combining sub-threshold doses of rimonabant and SNAP-94847 produced a significantly greater loss of body weight in DIO mice compared with vehicle and monotherapies. In addition, combining sub effective doses of these drugs led to a shift in markers of thermogenesis in BAT and lipid metabolism in WAT consistent with increased energy expenditure and lipolysis. Furthermore, co-administration of rimonabant and SNAP-94847 produced a transient reduction in food intake, and significantly reduced fat mass and adipocyte size. Importantly, SNAP-94847 significantly attenuated the ability of rimonabant to reduced immobility time in the forced swim test.. These results provide proof of principle that combination of rimonabant and a MCH1 receptor antagonist is highly effective in reducing body weight below that achieved by rimonabant and SNAP-94847 monotherapies. In addition, the combination therapy normalizes the rimonabant-induced behavioral changes seen in the forced swim test.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Affect; Animals; Anti-Obesity Agents; Body Weight; Drug Therapy, Combination; Hypothalamic Hormones; Lipolysis; Male; Melanins; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Physical Conditioning, Animal; Piperidines; Pituitary Hormones; Pyrazoles; Rimonabant; Thermogenesis; Weight Loss

Binge eating disorder (BED) is characterized by excessive food intake during short periods of time. Recent evidence suggests that alterations in the endocannabinoid signalling could be involved in the pathophysiology of BED. In this study, we investigated whether pharmacological manipulation of endocannabinoid transmission may be effective in modulating the aberrant eating behaviour present in a validated rat model of BED.. Binge-type eating was induced in female rats by providing limited access to an optional source of dietary fat (margarine). Rats were divided into three groups, all with ad libitum access to chow and water: control (C), with no access to margarine; low restriction (LR), with 2 h margarine access 7 days a week; high restriction (HR), with 2 h margarine access 3 days a week.. Compared with the LR group, the HR group consumed more margarine and this was accompanied by an increase in body weight. The cannabinoid CB₁/CB₂ receptor agonist Δ⁹-tetrahydrocannabinol significantly increased margarine intake selectively in LR rats, while the fatty acid amide hydrolase inhibitor URB597 showed no effect. The CB₁ receptor inverse agonist/antagonist rimonabant dose-dependently reduced margarine intake in HR rats. Notably, in HR rats, chronic treatment with a low dose of rimonabant induced a selective long-lasting reduction in margarine intake that did not develop tolerance, and a significant and persistent reduction in body weight.. Chronic pharmacological blockade of CB₁ receptors reduces binge eating behaviour in female rats and may prove effective in treating BED, with an associated significant reduction in body weight.

Topics: Animals; Behavior, Animal; Binge-Eating Disorder; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Disease Models, Animal; Dose-Response Relationship, Drug; Dronabinol; Drug Inverse Agonism; Drug Tolerance; Endocannabinoids; Energy Intake; Feeding Behavior; Female; Margarine; Piperidines; Pyrazoles; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Signal Transduction; Weight Loss

Pharmacologic inhibition of the cannabinoid-1 receptor (CB1R) in rodent models leads to weight loss and time-dependent changes in energy balance. This study evaluated the effects of CB1R inhibition on weight loss, energy expenditure (EE), and food intake (FI) in an obese canine model following 4 weeks of treatment. Eighteen maintenance-fed obese beagles were evenly and randomly allocated to a CB1R inverse agonist (AM251) (2 mg/kg), a 70% food-restricted (FR) diet, or a control group (C). Evaluations included body weight and composition (dual-energy x-ray absorptiometry scan), EE (doubly labeled water), and FI. Change in body mass at week 4 was significantly greater (P < .050) in the AM251 (-1476.7 g) and FR groups (-1100.0 g) than in the C group (-228.3 g). Food intake was decreased from week 2 onward in the FR and AM251 groups (P < .05). Absolute and lean mass-adjusted EEs were decreased only in the FR group (P < .01); EE in the AM251 group was greater (P < .05) than that in the FR group. Pharmacologic inhibition of CB1R in a canine model led to sustained effects on FI and EE. Weight loss was greater with AM251 than could be accounted for by food restriction (∼25%), an effect likely mediated by the EE response to CB1R inhibition.

Topics: Absorptiometry, Photon; Animals; Disease Models, Animal; Dogs; Eating; Energy Metabolism; Female; Glucose Tolerance Test; Obesity; Piperidines; Pyrazoles; Random Allocation; Receptor, Cannabinoid, CB1; Weight Loss

The endocannabinoids have been recognized as an important system involved in the regulation of energy balance. Rimonabant (SR141716), a selective inverse agonist of cannabinoid receptor 1 (CB1), has been shown to cause weight loss. However, its suppressive impact on food intake is transient, indicating a likely additional effect on energy expenditure. To examine the effects of rimonabant on components of energy balance, we administered rimonabant or its vehicle to diet-induced obese (DIO) C57BL/6 mice once daily for 30 days, by oral gavage. Rimonabant induced a persistent weight reduction and a significant decrease in body fatness across all depots. In addition to transiently reduced food intake, rimonabant-treated mice exhibited decreased apparent energy absorption efficiency (AEAE), reduced metabolizable energy intake (MEI), and increased daily energy expenditure (DEE) on days 4-6 of treatment. However, these effects on the energy budget had disappeared by days 22-24 of treatment. No chronic group differences in resting metabolic rate (RMR) or respiratory quotient (RQ) (P > 0.05) were detected. Rimonabant treatment significantly increased daily physical activity (PA) levels both acutely and chronically. The increase in PA was attributed to elevated activity during the light phase but not during the dark phase. Taken together, these data suggested that rimonabant caused a negative energy balance by acting on both energy intake and expenditure. In the short term, the effect included both reduced intake and elevated PA but the chronic effect was only on increased PA expenditure.

Topics: Adipose Tissue; Administration, Oral; Animals; Anti-Obesity Agents; Cannabinoid Receptor Antagonists; Eating; Energy Intake; Energy Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Translational animal models are essential in the prediction of the efficacy and side effects of new chemical entities. We have carried out a thorough study of three distinct disease-modifying antirheumatic drugs (DMARDs) in an adjuvant-induced arthritis (AIA) model in the rat and critically appraised the results in the context of the reported clinical experience in rheumatoid arthritis (RA) patients.. Teriflunomide - a dihydroorotate dehydrogenase (DHODH) inhibitor; AL8697 - a selective p38 MAPK inhibitor; and tofacitinib - a Janus kinase (JAK) inhibitor; were selected as representatives of their class and dose-response studies carried out using a therapeutic 10-day administration scheme in arthritic rats. Paw swelling and body weight were periodically monitored, and joint radiology and histology, lymph organ weight and haematological and biochemical parameters evaluated at study completion.. All three drugs demonstrated beneficial effects on paw swelling, bone lesions and splenomegalia, with p38 inhibition providing the best anti-inflammatory effect and JAK inhibition the best DMARD effect. Leukopenia, body weight loss and gastrointestinal toxicity were dose-dependently observed with teriflunomide treatment. p38 MAPK inhibition induced leukocytosis and increased total plasma cholesterol. JAK inhibition, normalized platelet, reticulocyte and neutrophil counts, and alanine aminotransferase (ALT) levels while inducing lymphopenia and cholesterolemia.. This multiparametric approach can reveal specific drug properties and provide translational information. Whereas the complex profile for p38 inhibition in AIA is not observed in human RA, immunosuppressants such as DHODH and JAK inhibitors show DMARD properties and side effects seen in both AIA and RA.

Topics: Animals; Antirheumatic Agents; Arthritis, Experimental; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Crotonates; Dihydroorotate Dehydrogenase; Dose-Response Relationship, Drug; Edema; Enzyme Inhibitors; Gastrointestinal Tract; Half-Life; Hydroxybutyrates; Hypercholesterolemia; Immunosuppressive Agents; Janus Kinases; Joints; Leukocyte Disorders; Male; Nitriles; Oxidoreductases Acting on CH-CH Group Donors; p38 Mitogen-Activated Protein Kinases; Piperidines; Pyrimidines; Pyrroles; Rats; Rats, Wistar; Splenomegaly; Toluidines; Weight Loss

Leukocyte infiltration, up-regulation of proinflammatory cytokines and severe oxidative stress caused by increased amounts of reactive oxygen species are characteristics of inflammatory bowel disease. The catechin (2R,3R)-2-(3,4,5-Trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol-3-(3,4,5-trihydroxybenzoate), named epigallocatechin-3-gallate, EGCG, has been demonstrated to exert anti-inflammatory and antioxidative properties, reducing reactive oxygen species in the inflamed tissues. The aim of this study was to evaluate the therapeutic effects of EGCG in a murine model of colitis induced by oral administration of dextran sodium sulfate.. Mice received a daily oral administration of 6.9 mg/kg body weight EGCG or Piper nigrum (L.) alkaloid (2E,4E)-5-(1,3-benzodioxol-5-yl)-1-piperidin-1-ylpenta-2,4-dien-1-one, named piperine (2.9 mg/kg body weight) or the combination of the both - piperine was used in this combination to enhance the bioavailability of EGCG.. In vivo data revealed the combination of EGCG and piperine to significantly reduce the loss of body weight, improve the clinical course and increase overall survival in comparison to untreated groups. The attenuated colitis was associated with less histological damages to the colon and reduction of tissue concentrations of malondialdehyde, the final product of lipid peroxidation. Neutrophils accumulation indicator myeloperoxidase was found to be reduced in colon tissue, while antioxidant enzymes like superoxide dismutase and glutathione peroxidase showed an increased activity. In vitro, the treatment with EGCG plus piperine enhanced the expression of SOD as well as GPO and also reduced the production of proinflammatory cytokines.. These data support the concept of anti-inflammatory properties of EGCG being generally beneficial in the DSS-model of colitis, an effect that may be mediated by its strong antioxidative potential.

Topics: Alkaloids; Analysis of Variance; Animals; Antioxidants; Benzodioxoles; Catechin; Colitis; Dextran Sulfate; Female; Glutathione Peroxidase; HT29 Cells; Humans; Interleukin-8; Malondialdehyde; Mice; Mice, Inbred C57BL; Oxidative Stress; Peroxidase; Piperidines; Polyunsaturated Alkamides; Reactive Oxygen Species; Superoxide Dismutase; Weight Loss

New cholecystokinin-1 receptor (CCK1R) agonist 'triggers' were identified using iterative library synthesis. Structural activity relationship studies led to the discovery of compound 10e, a potent CCK1R agonist that demonstrated robust weight loss in a diet-induced obese rat model with very low systemic exposure. Pharmacokinetic data suggest that efficacy is primarily driven through activation of CCK1R's located within the intestinal wall.

Topics: Amides; Animals; Cells, Cultured; Disease Models, Animal; Drug Discovery; Humans; Inhibitory Concentration 50; Male; Mice; Mice, Obese; Piperidines; Protein Binding; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin A; Structure-Activity Relationship; Weight Loss

Inflammatory bowel diseases, primarily Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract with unknown etiology. The majority of current therapeutic agents focus on controlling proinflammatory molecules. The neuropeptide nociceptin/orphanin FQ (N/OFQ) has been described as a potential immunomodulator for inflammatory bowel diseases. In this study, we asked whether the small molecule N/OFQ antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB612111) would inhibit the development of dextran sodium sulfate-induced colitis in C57BL/6 mice. Inhibition of the N/OFQ receptor (NOP) by SB612111 significantly ameliorated the clinical disease course in these animals, as indicated by reduced fecal bleeding, improved recovery from diarrhea and weight loss, and a reduction in histopathological alterations. In addition, the inflammatory response in the colon was diminished, as demonstrated by reduced cytokine protein and messenger RNA expression for CXCL1/keratinocyte-derived chemokine, interferon-γ, interleukin-1β, interleukin-6, and tumor necrosis factor-α, some of which are known targets for the treatment of this devastating disease. Our results strongly support a role for the receptor-ligand pair NOP-N/OFQ in the pathogenesis of colitis. We conclude that inhibition of NOP receptors with small molecule inhibitors may constitute a novel, urgently needed approach for the treatment of inflammatory bowel diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Colon; Cycloheptanes; Cytokines; Dextran Sulfate; Diarrhea; Female; Gastrointestinal Hemorrhage; Gene Expression Regulation; Intestinal Mucosa; Mice; Mice, Inbred C57BL; Molecular Targeted Therapy; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Opioid Peptides; Piperidines; Receptors, Opioid; RNA, Messenger; Signal Transduction; Weight Loss

G-protein coupled receptor 26 (GPR26) is a brain-specific orphan GPCR with high expression in the brain region that controls satiety. Depletion of GPR26 has been shown to increase fat storage in C. elegans, whereas GPR26 deficiency in the hypothalamus is associated with high genetic susceptibility to the onset of obesity in mice. However, the metabolic function of GPR26 in mammals remains elusive. Herein, we investigated a role of GPR26 in regulating energy homeostasis by generating mice with targeted deletion of the GPR26 gene. We show that GPR26 deficiency causes hyperphagia and hypometabolism, leading to early onset of diet-induced obesity. Accordingly, GPR26 deficiency also caused metabolic complications commonly associated with obesity, including glucose intolerance, hyperinsulinemia, and dyslipidemia. Moreover, consistent with hyperphagia in GPR26 null mice, GPR26 deficiency significantly increased hypothalamic activity of AMPK, a key signaling event that stimulates appetite. In further support of a regulatory role of GPR26 in satiety, GPR26 knockout mice also demonstrate hypersensitivity to treatment of rimonabant, an endocannabinoid receptor-1 antagonist commonly used to treat obesity by suppressing appetite in humans. Together, these findings identified a key role of GPR26 as a central regulator of energy homeostasis though modulation of hypothalamic AMPK activation.

Topics: Adiposity; AMP-Activated Protein Kinases; Animals; Diet; Dyslipidemias; Energy Metabolism; Enzyme Activation; Gene Silencing; Gene Targeting; Glucose Intolerance; Hyperinsulinism; Hyperphagia; Hypothalamus; Mice; Mice, Inbred C57BL; Obesity; Phosphorylation; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Rimonabant; Weight Loss

Weight loss is often difficult to achieve in individuals with type 2 diabetes and anti-obesity drugs are often advocated to support dietary intervention. Despite the extensive use of centrally acting anti-obesity drugs, there is little evidence of how they affect dietary composition. We investigated changes in energy intake and dietary composition of macro- and micronutrients following therapy with the endocannabinoid receptor blocker, rimonabant.. 20 obese patients with type 2 diabetes were studied before and after 6 months dietary intervention with rimonabant. Dietary intervention was supervised by a diabetes dietician. Five-day food diaries were completed at baseline and at 6 months and dietary analysis was performed using computer software (Dietplan 6).. After 6 months, (compared with baseline) there were reductions in weight (107 ± 21Kg versus 112 ± 21, p < 0.001, 4% body weight reduction), and improvements in HbA1c (7.4 ± 1.7 versus 8.0 ± 1.6%, p < 0.05) and HDL cholesterol. Intake of energy (1589 ± 384 versus 2225 ± 1109 kcal, p < 0.01), carbohydrate (199 ± 74 versus 273 ± 194 g, p < 0.05), protein (78 ± 23 versus 98 ± 36 g, p < 0.05), fats (55 ± 18 versus 84 ± 39 g, p < 0.01) and several micronutrients were reduced. However, relative macronutrient composition of the diet was unchanged. Improvement in blood glucose was strongly correlated with a reduction in carbohydrate intake (r = 0.76, p < 0.001).. In obese patients with type 2 diabetes, rimonabant in combination with dietary intervention led to reduced intake of energy and most macronutrients. Despite this, macronutrient composition of the diet was unaltered. These dietary changes (especially carbohydrate restriction) were associated with weight loss and favourable metabolic effects.

Topics: Adult; Aged; Blood Glucose; Cannabinoid Receptor Antagonists; Diabetes Mellitus, Type 2; Diet; Dietary Carbohydrates; Dietary Fats; Energy Intake; Female; Humans; Male; Micronutrients; Middle Aged; Obesity; Piperidines; Pyrazoles; Regression Analysis; Rimonabant; Weight Loss

Topics: Antipsychotic Agents; Dibenzothiazepines; Female; Homeostasis; Humans; Insulin Resistance; Piperazines; Piperidines; Quetiapine Fumarate; Schizophrenia; Waist Circumference; Weight Loss; Young Adult

3,4-Methylenedioxymethamphetamine (MDMA) abuse is a substantial problem in young adults. Due to a high focus on body image in this population, two main factors that may encourage MDMA use are the appetite suppressant and locomotor stimulant effects of this drug. The nucleus accumbens (NAc) is a brain region associated with the regulation of motivated and locomotor behaviours, and recent evidence suggests that NAc 5-HT4 receptors are likely to be involved in the appetite suppressant effect of MDMA. It has not yet been shown whether 5-HT4 receptors of the NAc are involved in the locomotor stimulant effects of MDMA, which may also contribute to a reduction in food intake.. This study aimed to investigate the effect of local antagonism of serotonin 5-HT4 receptors in the NAc in the appetite suppressant and locomotor stimulant effects of MDMA.. Male hooded Wistar rats underwent surgery for the implantation of bilateral NAc microinjection cannulae under isofluorane anesthesia. Following 5-7 days of recovery, the rats received bilateral microinjections of the 5-HT4 antagonist RS39604 into the NAc immediately prior to either saline or MDMA administration. Food intake, water intake, body weight and locomotor activity were measured.. RS39604 significantly increased food intake and increased weight loss in MDMA-treated but not saline-treated rats. Measures of MDMA-induced water intake or locomotor activity were not altered by antagonist administration.. These results demonstrate that 5-HT4 receptors in the NAc specifically regulate the appetite suppressant effects of MDMA but not MDMA-induced water intake or locomotor activity.

Topics: Animals; Appetite Depressants; Drinking; Eating; Male; Microinjections; Motor Activity; N-Methyl-3,4-methylenedioxyamphetamine; Nucleus Accumbens; Piperidines; Propane; Rats; Rats, Wistar; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Antagonists; Weight Loss

We studied whether cannabinoid receptor (CB1) blockade with rimonabant has an anti-inflammatory effect in obese mice, and whether this effect depends on weight loss and/or diet consumption. High-fat diet (HFD)-induced obese mice were treated orally with rimonabant (HFD-R) or vehicle (HFD-V) for 4 weeks. Paired-feeding was conducted in two additional groups of obese mice to achieve either the same body weight (HFD-BW) or the same HFD intake (HFD DI) as HFD-R. All these groups of mice were maintained on HFD throughout, with mice on normal diet (ND) throughout as lean controls. Rimonabant treatment of obese mice induced marked diet-intake reduction and weight loss during the first week, which was followed by maintenance of low body weight but not diet-intake reduction. Lower HFD intake was required to reach the same degree of weight loss in HFD-BW. HFD-DI had similar weight loss initially, but then started to gain weight, reaching a higher body weight than HFD-R. Despite the same degree of weight loss, HFD-R had less fat mass and lower adipogenic gene expression than HFD-BW. Compared to HFD-V or HFD-DI, HFD-R had reduced inflammation in adipose tissue (AT) and/or liver indicated primarily by lower monocyte chemoattractant protein-1 (MCP-1) levels. However, MCP-1 levels were not significantly different between HFD-R and HFD-BW. In vitro incubation of rimonabant with AT explants did not change MCP-1 levels. Thus, rimonabant induced weight loss in obese mice by diet-intake-dependent and -independent fashions. Rimonabant decreased inflammation in obese mice, possibly through a primary effect on weight reduction.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Chemokine CCL2; Diet; Dietary Fats; Disease Models, Animal; Energy Intake; Inflammation; Liver; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Weight Gain; Weight Loss

Topics: Humans; Hypoglycemic Agents; Metformin; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

In eight studies included in the present Cochrane review the effects of orlistat or sibutramine versus placebo on mortality, cardiovascular mortality and adverse events were investigated in obese people with hypertension. No studies with rimonabant fulfilled the inclusion criteria. The weight loss was larger in the groups treated with orlistat or sibutramine compared with placebo therapy. Orlistat reduced systolic and diastolic blood pressure more than placebo, while blood pressure increased during treatment with sibutramine. The studies were too small and of too short duration to allow an evaluation of the effect on cardiovascular mortality and morbidity.

Topics: Adult; Anti-Obesity Agents; Appetite Depressants; Blood Pressure; Cardiovascular Diseases; Cyclobutanes; Evidence-Based Medicine; Humans; Hypertension; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Time Factors; Treatment Outcome; Weight Loss

We hypothesized that a combination of low doses of rimonabant and leptin would markedly reduce body weight through the modulation of neuronal activity within the hypothalamus. To this end, high fat diet-induced obese rats were randomized to receive either leptin (0.5mg/kg subcutaneously), rimonabant (3mg/kg), the combination of both, or vehicle, daily for a duration of 2 weeks. A subset of rats was pair-fed to the combination-treated animals and received either vehicle or leptin. At the end of the weight loss phase, leptin treatment was maintained for 7 days while rimonabant was discontinued to assess changes in body weight during the rebound phase. The combination of rimonabant and leptin resulted in a marked inhibition of food intake and a profound reduction in body weight that was greater than achieved with either leptin or rimonabant alone. Treatment with leptin during the rebound phase inhibited compensatory increases in body weight associated with restitution of ad libitum feeding in previously pair-fed rats. Moreover, leptin partially blunted the rebound in food intake and body weight associated with cessation of rimonabant therapy.To investigate the effect of the combination on neuronal firing in the rat hypothalamus, single unit activity was recorded from brain slices containing the ventromedial and arcuate nuclei. The combination of rimonabant and leptin synergistically increased and decreased neuronal firing in the ventromedial and arcuate nuclei, respectively. Overall, these data demonstrate profound anti-obesity effects of combining cannabinoid type 1 receptor antagonists and leptin.

Topics: Animals; Anti-Obesity Agents; Dose-Response Relationship, Drug; Drug Synergism; Leptin; Male; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Recurrence; Rimonabant; Ventromedial Hypothalamic Nucleus; Weight Loss

Topics: Adult; Biomarkers; Cannabinoid Receptor Modulators; Cholesterol; Fatty Liver; Female; Humans; Hypercholesterolemia; Insulin Resistance; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity, Morbid; Piperidines; Pyrazoles; Retrospective Studies; Rimonabant; Safety-Based Drug Withdrawals; Triglycerides; Weight Loss

The use of retroviral drugs in the treatment of infection by human immunodeficiency virus (HIV) is associated, especially for first generations, with side effects such as lipodystrophy, fatty liver and insulin resistance, which may trigger secondary diabetes or worsen existing diabetes. The use of Glucagon-Like Peptide-1 in obese patients with type 2 diabetes on HIV retroviral as an alternative to insulin therapy is not documented; we report the case of a 47-year-old treated with exenatide when insulin was discontinued. During the first year of treatment, exenatide, in combination with metformin and repaglinide, led to a weight loss of 14 kg and fat mass and waist circumference were respectively reduced from 31 to 25.5% and from 114 to 103 cm. Homeostatic model assessment (HOMA) was used to calculate β-cell secretion which increased from 50 to 78% and insulin sensitivity which increased from 28 to 51%, reflecting a decrease in HbA(1c) by 1.9%. Exenatide may be a new therapeutic option for HIV-infected type 2 diabetes patients undergoing retroviral therapy.

Topics: Adipose Tissue; Antiretroviral Therapy, Highly Active; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; HIV Infections; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Peptides; Piperidines; Venoms; Waist Circumference; Weight Loss

Δ(9)-Tetrahydrocannbinol (THC), the primary active constituent of Cannabis sativa, has long been known to reduce opioid withdrawal symptoms. Although THC produces most of its pharmacological actions through the activation of CB(1) and CB(2) cannabinoid receptors, the role these receptors play in reducing the variety of opioid withdrawal symptoms remains unknown. The endogenous cannabinoids, N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), activate both cannabinoid receptors but are rapidly metabolized by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. The objective of this study was to test whether increasing AEA or 2-AG, via inhibition of their respective hydrolytic enzymes, reduces naloxone-precipitated morphine withdrawal symptoms in in vivo and in vitro models of opioid dependence. Morphine-dependent mice challenged with naloxone reliably displayed a profound withdrawal syndrome, consisting of jumping, paw tremors, diarrhea, and weight loss. THC and the MAGL inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) dose dependently reduced the intensity of most measures through the activation of CB(1) receptors. JZL184 also attenuated spontaneous withdrawal signs in morphine-dependent mice. The FAAH inhibitor N-(pyridin-3-yl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)benzyl)-piperdine-1-carboxamide (PF-3845) reduced the intensity of naloxone-precipitated jumps and paw flutters through the activation of CB(1) receptors but did not ameliorate incidence of diarrhea or weight loss. In the final series of experiments, we investigated whether JZL184 or PF-3845 would attenuate naloxone-precipitated contractions in morphine-dependent ilea. Both enzyme inhibitors attenuated the intensity of naloxone-induced contractions, although this model does not account mechanistically for the autonomic withdrawal responses (i.e., diarrhea) observed in vivo. These results indicate that endocannabinoid catabolic enzymes are promising targets to treat opioid dependence.

Topics: Amidohydrolases; Animals; Arachidonic Acid; Behavior, Animal; Benzodioxoles; Brain Chemistry; Cannabinoid Receptor Modulators; Diarrhea; Dronabinol; Electric Stimulation; Endocannabinoids; Hydrolysis; Ileum; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Monoacylglycerol Lipases; Morphine Dependence; Muscle Contraction; Naloxone; Narcotic Antagonists; Piperidines; Prostaglandins; Pyridines; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Substance Withdrawal Syndrome; Weight Loss

We recently reported that compounds created around a dipiperidine scaffold demonstrated activity against Mycobacterium tuberculosis (Mtb) (Bogatcheva, E.; Hanrahan, C.; Chen, P.; Gearhart, J.; Sacksteder, K.; Einck, L.; Nacy, C.; Protopopova, M. Bioorg. Med. Chem. Lett.2010, 20, 201). To optimize the dipiperidine compound series and to select a lead compound to advance into preclinical studies, we evaluated the structure-activity relationship (SAR) of our proprietary libraries. The (piperidin-4-ylmethyl)piperidine scaffold was an essential structural element required for antibacterial activity. Based on SAR, we synthesized a focused library of 313 new dipiperidines to delineate additional structural features responsible for antitubercular activity. Thirty new active compounds with MIC 10-20 μg/ml on Mtb were identified, but none was better than the original hits of this series, SQ609, SQ614, and SQ615. In Mtb-infected macrophages in vitro, SQ609 and SQ614 inhibited more than 90% of intracellular bacterial growth at 4 μg/ml; SQ615 was toxic to these cells. In mice infected with Mtb, weight loss was completely prevented by SQ609, but not SQ614, and SQ609 had a prolonged therapeutic effect, extended by 10-15 days, after cessation of therapy. Based on in vitro and in vivo antitubercular activity, SQ609 was identified as the best-in-class dipiperidine compound in the series.

Topics: Adamantane; Animals; Antitubercular Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Macrophages; Mice; Mice, Inbred C3H; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Piperidines; Small Molecule Libraries; Structure-Activity Relationship; Weight Loss

We examined the physiological mechanisms by which cannabinoid receptor 1 (CB1) antagonism improves glucose metabolism and insulin sensitivity independent of its anorectic and weight-reducing effects, as well as the effects of CB1 antagonism on brown adipose tissue (BAT) function.. Three groups of diet-induced obese mice received for 1 month: vehicle; the selective CB1 antagonist SR141716; or vehicle/pair-feeding. After measurements of body composition and energy expenditure, mice underwent euglycaemic-hyperinsulinaemic clamp studies to assess in vivo insulin action. In separate cohorts, we assessed insulin action in weight-reduced mice with diet-induced obesity (DIO), and the effect of CB1 antagonism on BAT thermogenesis. Surgical denervation of interscapular BAT (iBAT) was carried out in order to study the requirement for the sympathetic nervous system in mediating the effects of CB1 antagonism on BAT function.. Weight loss associated with chronic CB1 antagonism was accompanied by increased energy expenditure, enhanced insulin-stimulated glucose utilisation, and marked activation of BAT thermogenesis. Insulin-dependent glucose uptake was significantly increased in white adipose tissue and BAT, whereas glycogen synthesis was increased in liver, fat and muscle. Despite marked weight loss in the mice, SR141716 treatment did not improve insulin-mediated suppression of hepatic glucose production nor increase skeletal muscle glucose uptake. Denervation of iBAT blunted the effect of SR141716 on iBAT differentiation and insulin-mediated glucose uptake.. Chronic CB1 antagonism markedly enhances insulin-mediated glucose utilisation in DIO mice, independent of its anorectic and weight-reducing effects. The potent effect on insulin-stimulated BAT glucose uptake reveals a novel role for CB1 receptors as regulators of glucose metabolism.

Topics: Adipose Tissue, Brown; Animals; Body Composition; Diet, High-Fat; Energy Metabolism; Gluconeogenesis; Glucose; Glycogen; Insulin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle, Skeletal; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Thermogenesis; Weight Loss

Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of lipid and glucose metabolism. PPARgamma agonists improve insulin sensitivity and hyperglycemia and are effective in treating type 2 diabetes mellitus (T2DM), whereas PPARalpha agonists are used to treat dyslipidemia and atherosclerosis. The goal here was to examine the efficacy of a selective PPARalpha agonist {(S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP-900691} on lipid, glycemic, and inflammation indices in 14 cynomolgus monkeys with spontaneous T2DM maintained on daily insulin therapy. Monkeys were dosed orally with either vehicle (n = 7) or CP-900691 (3 mg/kg, n = 7) daily for 6 weeks. CP-900691 treatment increased plasma high-density lipoprotein cholesterol (HDLC) (33 +/- 3 to 60 +/- 4 mg/dL, p < 0.001) and apolipoprotein A1 (96 +/- 5 to 157 +/- 5 mg/dL, p < 0.001), reduced plasma triglycerides (547 +/- 102 to 356 +/- 90 mg/dL, p < 0.01), and apolipoprotein B (62 +/- 3 to 45 +/- 3 mg/dL, p < 0.01), improved the lipoprotein index (HDL to non-HDLC ratio; 0.28 +/- 0.06 to 0.79 +/- 0.16, p < 0.001), decreased body weight (p < 0.01) and C-reactive protein (CRP) (1700 +/- 382 to 304 +/- 102 ng/ml, p < 0.01), and increased adiponectin (1697 +/- 542 to 4242 +/- 1070 ng/ml, p < 0.001) compared with baseline. CP-900691 treatment reduced exogenous insulin requirements by approximately 25% (p < 0.04) while lowering plasma fructosamine from 2.87 +/- 0.09 to 2.22 +/- 0.17 mM (p < 0.05), indicative of improved glycemic control. There were no changes in any of the aforementioned parameters in the vehicle group. Because low HDLC and high triglycerides are well established risk factors for cardiovascular disease, the marked improvements in these parameters, and in glycemic control, body weight, and CRP, suggest that CP-900691 may be of benefit in diabetic and obese or hyperlipidemic populations.

Topics: Adiponectin; Animals; Area Under Curve; Blood Glucose; C-Reactive Protein; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Glucose Tolerance Test; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Lipids; Lipoproteins; Macaca fascicularis; Piperidines; PPAR alpha; Propionates; Weight Loss

Brain-derived neurotrophic factor (BDNF) regulates food intake and body weight, but is not useful as a therapeutic because of its short half-life. Chronic activation of its receptor, tyrosine kinase receptor B (TrkB), represents an alternative strategy for lowering body weight. However, because BDNF can raise blood pressure (BP) acutely, it is possible that chronic TrkB activation will produce adverse cardiovascular effects.. We used radiotelemetry to test whether treatment with a TrkB agonist antibody (Ab) causes adverse cardiovascular effects in mice with diet-induced obesity.. High-dose (1 mg/kg) TrkB Ab reduced body weight and significantly increased BP, whereas low-dose (0.3 mg/kg) treatment lowered body weight without adverse cardiovascular effects. Rimonabant, through a different mechanism of action, lowered body weight in this model more than TrkB activation, but showed no adverse effects on heart rate (HR) or BP. These data suggest that elevated BP was a direct effect of high-dose TrkB Ab treatment rather than secondary to substantial weight loss.. Overall, high-dose TrkB Ab lowered body weight and increased BP, whereas low-dose TrkB Ab treatment caused therapeutic weight loss without adverse cardiovascular effects. We conclude that TrkB activation dose-dependently lowers body weight and transiently raises BP in mice with diet-induced obesity.

Topics: Animals; Anti-Obesity Agents; Antibodies, Monoclonal; Blood Pressure; Body Weight; Brain-Derived Neurotrophic Factor; Diet; Dietary Fats; Hypertension; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Pyrazoles; Receptor, trkB; Rimonabant; Telemetry; Weight Loss

Tesofensine, a novel triple monoamine reuptake inhibitor, produces a significant weight loss in humans. The present study aimed at characterizing the weight-reducing effects of tesofensine in a rat model of diet-induced obesity. Sibutramine and rimonabant were used as reference comparators. Compared to baseline, long-term treatment with tesofensine (28 days, 1.0 or 2.5mg/kg, p.o.) resulted in a significant, dose-dependent and sustained weight loss of 5.7 and 9.9%, respectively. Sibutramine (7.5mg/kg, p.o.) treatment caused a sustained weight loss of 7.6%, whereas the employed dose of rimonabant (10mg/kg, p.o.) only produced a transient weight reduction. While all compounds exhibited a significant inhibitory effect on food intake which gradually wore off, the hypophagic effect of tesofensine was longer lasting than sibutramine and rimonabant. In contrast to tesofensine, the body weight of pair-fed rats returned to baseline at the end of the study, which may indicate that tesofensine stimulated energy expenditure. The differential efficacy on weight reduction was also reflected in lowered body fat depots, as tesofensine and sibutramine most efficiently reduced abdominal and subcutaneous fat mass which was paralleled by reduced plasma lipid levels. In an oral glucose tolerance test, only tesofensine significantly suppressed the plasma insulin response below the level that could be obtained by paired feeding, indicating that tesofensine further improved glycemic control. In conclusion, the robust weight loss with long-term tesofensine treatment is likely due to a combined synergistic effect of appetite suppression and increased energy expenditure.

Topics: Adipose Tissue; Animals; Appetite; Biogenic Monoamines; Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Cyclobutanes; Diet; Eating; Glucose Tolerance Test; Lipids; Male; Neurotransmitter Uptake Inhibitors; Obesity; Piperidines; Pyrazoles; Rats; Rimonabant; Time Factors; Weight Loss

The increase in adiponectin levels in obese patients with untreated dyslipidemia and its mRNA expression in adipose tissue of obese animals are one of the most interesting consequences of rimonabant treatment. Thus, part of rimonabant's metabolic effects could be related to an enhancement of adiponectin secretion and its consequence on the modulation of insulin action, as well as energy homeostasis. The present study investigated the effects of rimonabant in adiponectin knockout mice (Ad(-/-)) exposed to diet-induced obesity conditions. Six-week-old Ad(-/-) male mice and their wild-type littermate controls (Ad(+/+)) were fed a high-fat diet for 7 mo. During the last month, animals were administered daily either with vehicle or rimonabant by mouth (10 mg/kg). High-fat feeding induced weight gain by about 130% in both wild-type and Ad(-/-) mice. Obesity was associated with hyperinsulinemia and insulin resistance. Treatment with rimonabant led to a significant and similar decrease in body weight in both Ad(+/+) and Ad(-/-) mice compared with vehicle-treated animals. In addition, rimonabant significantly improved insulin sensitivity in Ad(+/+) mice compared with Ad(+/+) vehicle-treated mice by decreasing hepatic glucose production and increasing glucose utilization index in both visceral and subcutaneous adipose tissue. In contrast, rimonabant failed to improve insulin sensitivity in Ad(-/-) mice, despite the loss in body weight. Rimonabant's effect on body weight appeared independent of the adiponectin pathway, whereas adiponectin seems required to mediate rimonabant-induced improvement of insulin sensitivity in rodents.

Topics: Adiponectin; Animals; Anti-Obesity Agents; Dietary Fats; Disease Models, Animal; Eating; Glucose; Glucose Tolerance Test; Hyperinsulinism; Insulin; Insulin Resistance; Intra-Abdominal Fat; Lipids; Liver; Male; Mice; Mice, Knockout; Obesity; Piperidines; Pyrazoles; Rimonabant; Subcutaneous Fat; Weight Loss

Continuing medicinal chemistry studies to identify spiropiperidine-derived NPY Y5 receptor antagonists are described. Aryl urea derivatives of a variety of spiropiperidines were tested for their NPY Y5 receptor binding affinities. Of the spiropiperidines so far examined, spiro[3-oxoisobenzofurane-1(3H),4'-piperidine] was a useful scaffold for producing orally active NPY Y5 receptor antagonists. Oral administration of 5c significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 3mg/kg. In addition, this compound was efficacious in decreasing body weight in diet-induced obese mice.

Topics: Administration, Oral; Animals; Anti-Obesity Agents; Eating; Humans; Mice; Piperidines; Rats; Receptors, Neuropeptide Y; Spiro Compounds; Urea; Weight Loss

The aim of this study was to investigate the effect of rimonabant treatment on hepatic mitochondrial function in rats fed a high-fat diet. Sprague-Dawley rats fed a high-fat diet (35% lard) for 13 wk were treated with rimonabant (10 mg·kg(-1)·day(-1)) during the last 3 wk and matched with pair-fed controls. Oxygen consumption with various substrates, mitochondrial enzyme activities on isolated liver mitochondria, and mitochondrial DNA quantity were determined. Body weight and fat mass were decreased in rats treated with rimonabant compared with pair-fed controls. Moreover, the serum adiponectin level was increased with rimonabant. Hepatic triglyceride content was increased, while serum triglycerides were decreased. An increase of mitochondrial respiration was observed in rats treated with rimonabant. The increase of mitochondrial respiration with palmitoyl-CoA compared with respiration with palmitoyl-l-carnitine stating that the entry of fatty acids into mitochondria via carnitine palmitoyltransferase I was increased in rats treated with rimonabant. Moreover, rimonabant treatment led to a reduction in the enzymatic activity of ATP synthase, whereas the quantity of mitochondrial DNA and the activity of citrate synthase remained unchanged. To summarize, rimonabant treatment leads to an improvement of hepatic mitochondrial function by increasing substrate oxidation and fatty acid entry into mitochondria for the β-oxidation pathway and by increasing proton leak. However, this increase of mitochondrial oxidation is regulated by a decrease of ATP synthase activity in order to have only ATP required for the cell function.

Topics: Adiponectin; Animals; Body Composition; Diet, High-Fat; Dietary Fats; DNA; DNA, Mitochondrial; Eating; Energy Metabolism; Glucose; Insulin Resistance; Liver Function Tests; Male; Mitochondria, Liver; Oxygen Consumption; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Triglycerides; Weight Loss

Topics: Animals; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Clinical Trials as Topic; Delusions; Drug Administration Schedule; Humans; Lipogenesis; Mice; Mice, Knockout; Models, Biological; Nerve Endings; Obesity; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant; Schizophrenia; Waist-Hip Ratio; Weight Loss

Topics: Anti-Obesity Agents; Depression; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; Safety; Treatment Outcome; Weight Loss

Replacing the conventional pyrazole 5-aryl substituent of 1 (SR141716A) with the 2-thienyl moiety appended with an appropriate alkynyl unit, a novel class of 5-(5-alkynyl-2-thienyl)pyrazole derivatives, behaving as highly potent CB1 receptor antagonists with good CB1/2 selectivity, was discovered, many of which, as typified by compound 18, showed significant weight reduction in diet-induced obese mouse model, thus pharmacologically validating that the bioisosteric replacement described above is viable. Also encouraging was the finding that a subtle structural modification of the newly developed series could result in a distinct difference in the intrinsic property, as demonstrated by compounds 12 (NA) and its methylated structural isomers 15 (PA) and 18 (IA). Moreover, current structure-activity relationship studies revealed that around the pyrazole 5-position of 1, a deep and flat crevice surrounded by a sequence of hydrophobic/aromatic residues as indicated by the CB1-receptor homology model might exist in the binding site.

Topics: Animals; Binding Sites; Hydrophobic and Hydrophilic Interactions; Mice; Mice, Obese; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Structure-Activity Relationship; Thiophenes; Weight Loss

Obesity is reaching epidemic proportions worldwide and it is correlated with various comorbidities, among which the most relevant are diabetes mellitus, arterial hypertension, and cardiovascular diseases. Obesity management is a modern challenge because of the rapid evolution of unfavorable lifestyles and unfortunately there are no effective treatments applicable to the large majority of obese/overweight people. The current medical attitude is to treat the complications of obesity (e.g. dyslipidemia, hypertension, diabetes, and cardiovascular diseases). However, the potential of treating obesity is enormous, bearing in mind that a volitional weight loss of 10 kg is associated with important risk factor improvement: blood pressure -10 mmHg, total cholesterol -10%, LDL cholesterol -15%, triglycerides -30%, fasting glucose -50%, HDL cholesterol +8%. Drug treatment for obesity is an evolving branch of pharmacology, burdened by severe side effects and consequences of the early drugs, withdrawn from the market, and challenged by the lack of long-term data on the effect of medications on obesity-related morbidity and mortality, first of all cardiovascular diseases. In Europe three antiobesity drugs are currently licensed: sibutramine, orlistat, and rimonabant; important trials with clinical endpoints are ongoing for sibutramine and rimonabant. While waiting for their results, it is convenient to evaluate these drugs for their effects on body weight and cardiometabolic risk factors. Sibutramine is a centrally acting serotonin/noradrenaline reuptake inhibitor that mainly increases satiety. At the level of brown adipose tissue, sibutramine can also facilitate energy expenditure by increasing thermogenesis. The long-term studies (five) documented a mean differential weight reduction of 4.45 kg for sibutramine vs placebo. Considering the principal studies, attrition rate was 43%. This drug not only reduces body weight and waist circumference, but it decreases triglycerides and uric acid as well and it increases HDL cholesterol; in diabetics it improves glycated hemoglobin. Sibutramine has conflicting effects on blood pressure: in some studies there was a minimal decrease, in some others a modest increase. In all the studies this drug increased pulse rate. Sibutramine is not recommended in patients with uncontrolled hypertension, or in case of history of cardio- and cerebrovascular disease. Orlistat is a pancreatic lipase inhibitor that reduces fat absorption by parti

Topics: Anti-Obesity Agents; Appetite Depressants; Body Mass Index; Bradykinin; Cannabinoid Receptor Antagonists; Cannabinoids; Cyclobutanes; Diabetes Mellitus, Type 2; Double-Blind Method; Economics, Pharmaceutical; Humans; Lactones; Lipase; Meta-Analysis as Topic; Obesity; Orlistat; Piperidines; Practice Guidelines as Topic; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Risk Factors; Time Factors; Weight Loss

The CB1 receptor antagonist, rimonabant, affects the endocannabinoid system and causes a sustained reduction in body weight (BW) despite the transient nature of the reduction in food intake. Therefore, in a multiple-dose study, female candy-fed Wistar rats were treated with rimonabant (10 mg/kg) and matched with pair-fed rats to distinguish between hypophagic action and hypothesized effects on energy expenditure. Within the first week of treatment, rimonabant reduced BW nearly to levels of standard rat chow-fed rats. Evaluation of energy balance (energy expenditure measured by indirect calorimetry in relation to metabolizable energy intake calculated by bomb calorimetry) revealed that increased energy expenditure based on increased fat oxidation contributed more to sustained BW reduction than reduced food intake. A mere food reduction through pair feeding did not result in comparable effects because animals reduced their energy expenditure to save energy stores. Because fat oxidation measured by indirect calorimetry increased immediately after dosing in the postprandial state, the acute effect of rimonabant on lipolysis was investigated in postprandial male rats. Rimonabant elevated free fatty acids postprandially, demonstrating an inherent pharmacological activity of rimonabant to induce lipolysis and not secondarily postabsorptively due to reduced food intake. We conclude that the weight-reducing effect of rimonabant was due to continuously elevated energy expenditure based on increased fat oxidation driven by lipolysis from fat tissue as long as fat stores were elevated. When the amount of endogenous fat stores declined, rimonabant-induced increased energy expenditure was maintained by a re-increase in food intake.

Topics: Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Candy; Diet; Eating; Energy Metabolism; Fatty Acids, Nonesterified; Female; Liver Glycogen; Male; Photoperiod; Piperidines; Pyrazoles; Rats; Rats, Wistar; Rimonabant; Time Factors; Weight Loss

Rimonabant is a novel drug for treatment of obesity. Four randomised studies have shown a significant effect of 20 mg rimonabant on bodyweight and other cardiovascular risk factors. The weight loss is modest, approximately 5 %, and the patients regain their baseline weight within 9 months after withdrawal. There is no evidence that rimonabant reduces morbidity or mortality, and no comparative studies with orlistat or sibutramine have been performed. Long-term effects of blocking the endocannabinoid system are not known. Side effects are nausea, depressive symptoms, anxiety and dizziness. There are reports on increased suicidality, and rimonabant is contraindicated in depressed patients.

Topics: Animals; Anti-Obesity Agents; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Weight Loss

Diabetes mellitus (DM) is a worldwide epidemic. Its prevalence is rapidly increasing in both developing and developed countries. Coronary heart disease (CHD) is highly prevalent and is the major cause of morbidity and mortality in patients with diabetes. Individuals with prediabetes states, with or without known CHD, should undergo lifestyle modifications aimed at preventing DM. In patients with CHD and DM, routine use of aspirin and an angiotensin-converting enzyme inhibitor, along with strict glycemic, blood pressure, and lipid control, is strongly recommended. Intense insulin therapy may be needed for glycemic control, and high-dose statin therapy may be needed for lipid control. For blood pressure control, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are considered first-line therapy. Noncompliance with medications and/or lifestyle measures and underprescription of evidence-based therapies remain important unsolved problems.

Topics: Antihypertensive Agents; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Diabetes Mellitus; Diabetic Angiopathies; Humans; Hyperglycemia; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Life Style; Myocardial Infarction; Obesity; Pioglitazone; Piperidines; Platelet Aggregation Inhibitors; Prediabetic State; Pyrazoles; Ramipril; Rimonabant; Risk Assessment; Thiazolidinediones; Triglycerides; Weight Loss

Topics: Cannabinoid Receptor Antagonists; Diabetes Mellitus, Type 2; Humans; Obesity; Piperidines; PPAR gamma; Pyrazoles; Rimonabant; Weight Loss

Topics: Depression; Diabetes Mellitus, Type 2; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Too many adverse effects for a minor effect on weight loss, without reduced rates of complications.

Topics: Anti-Obesity Agents; Clinical Trials as Topic; Diabetes Mellitus; Humans; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Treatment Outcome; Weight Loss

Ghrelin, through action on its receptor, GH secretagogue receptor type 1a (GHS-R1a), exerts a variety of metabolic functions including stimulation of appetite and weight gain and suppression of insulin secretion. In the present study, we examined the effects of novel small-molecule GHS-R1a antagonists on insulin secretion, glucose tolerance, and weight loss. Ghrelin dose-dependently suppressed insulin secretion from dispersed rat islets. This effect was fully blocked by a GHS-R1a antagonist. Consistent with this observation, a single oral dose of a GHS-R1a antagonist improved glucose homeostasis in an ip glucose tolerance test in rat. Improvement in glucose tolerance was attributed to increased insulin secretion. Daily oral administration of a GHS-R1a antagonist to diet-induced obese mice led to reduced food intake and weight loss (up to 15%) due to selective loss of fat mass. Pair-feeding experiments indicated that weight loss was largely a consequence of reduced food intake. The impact of a GHS-R1a antagonist on gastric emptying was also examined. Although the GHS-R1a antagonist modestly delayed gastric emptying at the highest dose tested (10 mg/kg), delayed gastric emptying does not appear to be a requirement for weight loss because lower doses produced weight loss without an effect on gastric emptying. Consistent with the hypothesis that ghrelin regulates feeding centrally, the anorexigenic effects of potent GHS-R1a antagonists in mice appeared to correspond with their brain exposure. These observations demonstrate that GHS-R1a antagonists have the potential to improve the diabetic condition by promoting glucose-dependent insulin secretion and promoting weight loss.

Topics: Animals; Appetite; Appetite Depressants; Cells, Cultured; Drug Evaluation, Preclinical; Ghrelin; Glucose Intolerance; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Models, Biological; Piperidines; Quinazolinones; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Ghrelin; Weight Loss

Topics: Anti-Obesity Agents; Cannabinoid Receptor Antagonists; Cannabinoids; Central Nervous System; Central Nervous System Diseases; Drug Approval; Germany; Humans; Mental Disorders; Metabolic Syndrome; Piperidines; Pyrazoles; Rimonabant; United States; United States Food and Drug Administration; Weight Loss

Despite a large and consistent literature on the suppressant effects of cannabinoid CB1 receptor antagonists/inverse agonists (e.g. rimonabant, AM 251) on food intake and weight gain in rodents, surprisingly little is known about the behavioural selectivity of such effects. In this study, ethological scoring was used to characterize the acute behavioural effects of the rimonabant analogue AM 251 (1.5 and 3.0 mg/kg, intraperitoneally) in nondeprived male rats during a 1-h test with palatable mash. Data were also collected on daily weight gain and on retest food intake 7 days after dosing. Results showed that the higher dose of AM 251 significantly inhibited mash consumption (32% decrease relative to vehicle control), reduced time spent feeding during the test and suppressed body weight gain over the 48-h period that followed acute dosing. No effects on mash consumption were observed when the animals were retested drug-free 1 week after drug treatment. Detailed video analysis of the test sessions showed that, over the dose range tested, AM 251 did not significantly interfere with the vast majority of noningestive behaviours. Both doses of the compound, however, significantly increased the incidence of and the time spent on scratching, whereas the higher dose additionally increased both the number and duration of grooming episodes. The latter effect in particular disrupted the normal structure of behaviour (behavioural satiety sequence) with atypically high levels of grooming displacing feeding during the middle part of the test session. Overall, the behavioural profile of AM 251 in a free-feeding context is very similar to (but approximately two-fold less potent than) that recently reported for the parent molecule, rimonabant. Together, these data strongly suggest that the acute anorectic response to CB1 receptor antagonists/inverse agonists is indirectly mediated via major alterations to other components of the behavioural repertoire.

Topics: Animals; Appetite Depressants; Dose-Response Relationship, Drug; Drug Inverse Agonism; Eating; Feeding Behavior; Grooming; Injections, Intraperitoneal; Male; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Satiety Response; Weight Gain; Weight Loss

Topics: Depression; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Suicide; United States; United States Food and Drug Administration; Weight Loss

The endocannabinoid system controls the regulation of food intake and appetite in the brain and lipogenesis in adipose tissue. Rimonabant belongs to the new drug class of cannabinoid-1 receptor antagonists. It can decrease appetite and food intake and thus stimulate weight loss. Rimonabant is indicated for severe obesity and as an adjunct to lifestyle modifications for obese patients with type 2 diabetes or hyperlipidaemia. Safety concerns limit the clinical applicability of the drug. The drug has not been approved in the US due to its neurological and psychiatric adverse effects. Rimonabant is approved in Europe but is contraindicated in patients with major depression and those taking antidepressants.

Topics: Appetite Regulation; Cardiovascular Diseases; Depression; Diet, Reducing; Energy Intake; Humans; Lipids; Lipogenesis; Obesity; Obesity, Morbid; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Weight Loss

Topics: Anti-Obesity Agents; Appetite Depressants; Cyclobutanes; Depression; Drug Therapy, Combination; Evidence-Based Medicine; Humans; Lactones; Obesity, Morbid; Orlistat; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Suicide; Weight Loss

Topics: Anti-Obesity Agents; Cannabinoid Receptor Antagonists; Depression; Drug Approval; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Weight Loss

Topics: Appetite Depressants; Drug Evaluation; Drug Industry; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

In the present paper, the age-related changes in the vasoconstrictive endothelin-mediated response to insulin in aortas of normal and hypertensive, hypertriglyceridemic, hyperinsulinemic (HTG) rats were studied. To develop HTG rats, weanling male Wistar animals were given 30% sucrose in their drinking water for 4, 6, 12 and 18 months. Blood pressure was increased in HTG rats for up to 12 months showing a maximum at 6 months (138.9+/-0.8 mmHg). In vitro contractions were elicited with 40 mM KCl in the presence and absence 50 microU/ml insulin and of endothelin-receptor antagonists BQ123 and BQ788. Tension development to KCl was not modified during aging in control rats but was increased at 4 and 6 months in HTG rats. Increased endothelin release induced by insulin remained constant in normal rats, while in HTG rats it was higher than in controls at all ages. ET(A) blocker participation alone increased during aging in control rats while both receptor blockers participated in HTG rats. Our results suggest that the vasoconstrictive capacity to KCl plus insulin decreases during aging and that this decrease is greater in HTG rats. The participation of endothelin receptors in the aging process differs in control and HTG rats.

Topics: Aging; Animals; Antihypertensive Agents; Aorta; Blood Glucose; Blood Pressure; Endothelin Receptor Antagonists; Endothelins; Hypertension; Hypertriglyceridemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Potassium Chloride; Rats; Rats, Wistar; Triglycerides; Vasoconstriction; Weight Loss

Topics: Adolescent; Adult; Appetite Depressants; Body Mass Index; Cardiovascular Diseases; Child; Cyclobutanes; Female; Humans; Life Style; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Risk Factors; Surveys and Questionnaires; Weight Loss

Topics: Anti-Obesity Agents; Cardiovascular Diseases; Dyslipidemias; Glucose Intolerance; Humans; Obesity; Overweight; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Topics: Cannabinoids; Cholesterol; Humans; Piperidines; Pyrazoles; Rimonabant; Smoking Prevention; Weight Loss

Topics: Anti-Obesity Agents; Humans; Life Style; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk; Weight Loss

(1) The treatment of obesity is based on calorie reduction and moderate physical activity. (2) Rimonabant, a CB1 cannabinoid receptor antagonist, is marketed in Europe for the adjuvant treatment of obesity, in combination with a low-calorie diet and physical exercise. (3) Four double-blind placebo-controlled trials involving about 6500 patients show that, when combined with a low-calorie diet, rimonabant 20 mg/day leads to an average weight loss of 4 or 5 kg more than placebo after one year of treatment. This is similar to the weight loss reported with orlistat (indirect comparison). Effects on the lipid profile are similar to those reported with sibutramine. (4) Rimonabant has not been shown to reduce morbidity or mortality. Patients regain the weight they lost within about 9 months after rimonabant withdrawal. (5) Three placebo-controlled trials have evaluated rimonabant in smoking cessation. The available results (a single conference abstract) are inconclusive. In early 2006 the FDA and the European Medicines Agency refused to approve rimonabant for this use. (6) 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. (7) In practice, when drug therapy is considered for weight loss, it seems unwise to prescribe rimonabant: this new drug has only limited symptomatic effects and its adverse effects, especially in the long term, are poorly documented.

Topics: Anti-Obesity Agents; Cholesterol, HDL; Diet, Reducing; Double-Blind Method; Drug Approval; Europe; Exercise; Glycated Hemoglobin; Humans; Lactones; Lipase; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Smoking; Treatment Outcome; United States; Weight Loss

Topics: Adolescent; Adult; Age Factors; Aged; Blood Glucose; Body Mass Index; Cardiovascular Diseases; Cholesterol, HDL; Clinical Trials, Phase III as Topic; Contraindications; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Time Factors; Triglycerides; Weight Loss

Topics: Anti-Obesity Agents; Cannabinoid Receptor Antagonists; Clinical Trials as Topic; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Blocking the endocannabinoid system is an option that substantially reduces cardiovascular risk beyond reducing body weight. Endocannabinoids and their receptors are expressed in the central nervous system as well as in the peripheral organs and regulate the central circuits for food uptake and peripheral metabolic circuits. Within the context of food uptake the cannabinoid receptors 1 (CB (1)-receptor) is of crucial importance. Its stimulation with Delta (9)-tetrahydrocannabiol (Delta (9)-THC) or its blockade with rimonabant are clinically relevant therapeutic means to maintain body weight. Rimonabant is the first of a new class of drugs, that interferes with the endocannabinoid system by blocking the CB (1)-Receptor. In recent clinical studies a substantial reduction of body weight and waist circumference was associated with an improvement of the cardiovascular risk profile, which was marked by increased HDL-cholesterol, serum triglycerides and improved insulin sensivity.

Topics: Cannabinoid Receptor Modulators; Cardiovascular Diseases; Clinical Trials as Topic; Endocannabinoids; Humans; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Treatment Outcome; Weight Loss

Topics: Cannabinoid Receptor Antagonists; Cannabinoids; Controlled Clinical Trials as Topic; Diabetes Mellitus; Glycated Hemoglobin; Humans; Metabolic Syndrome; Piperidines; Placebos; Pyrazoles; Rimonabant; Time Factors; Weight Loss

Topics: Appetite; Appetite Depressants; Clinical Trials as Topic; Diabetes Mellitus; Drug Approval; Drug Industry; Europe; France; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; United States; United States Food and Drug Administration; Weight Loss

Topics: Anti-Obesity Agents; Appetite Depressants; Cannabinoid Receptor Antagonists; Cyclobutanes; Dyslipidemias; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Topics: Diabetes Mellitus, Type 2; Humans; Piperidines; Pyrazoles; Rimonabant; United States; Weight Loss

Cannabinoid withdrawal has been indicated in both human and animal subjects. One of pathways proposed to facilitate cannabinoid action is the arachidonic acid cascade. Previously, we have shown that prostaglandin attenuated the expression of withdrawal signs in tetrahydrocannabinol-dependent mice. It follows that the cascade might participate in the expression of cannabinoid withdrawal. We utilized a quasi abstinence approach (the induction of a state of cannabinoid withdrawal without giving any cannabinoid substances in a naïve animal) to describe the relationship between the change in prostaglandin level, an end product of the arachidonic acid cascade, and the expression of cannabinoid withdrawal. Administration of 10 mg/kg diclofenac, a prostaglandin synthesis inhibitor, i.p. 30 min before SR 141716A induced cannabinoid withdrawal signs in naïve mice, which were comparable to the true abstinence in cannabinoid-tolerant mice. In turn, 10 mg/kg Delta(8)-THC i.p., given 15 min prior to SR 141716A, blocked the expression of these signs. These results suggested that the decrease in prostaglandin level is a prerequisite for the expression of cannabinoid withdrawal.

Topics: Animals; Behavior, Animal; Cannabinoids; Cyclooxygenase Inhibitors; Diclofenac; Dronabinol; Male; Mice; Piperidines; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pyrazoles; Rimonabant; Substance Withdrawal Syndrome; Weight Loss

We have investigated the effect of 0.001 mg/kg delta(8)-tetrahydrocannabinol (THC) on food consumption, cognitive function, and neurotransmitters in mice. Sabra mice were treated with vehicle, THC, or THC+CB1 antagonist (SR141716A). The mice were fed for 2.5 h a day for 9 or 50 days. In the 9-day schedule, THC-treated mice showed a 16% increase in food intake compared with controls (P<.001). This effect was reversed by the antagonist (P<.01). In the long-term schedule a 22% increase in intake (P<.05) was recorded. During the course of the 9- and 50-day experimental protocol, all mice lost about 20% and 10% of their original weight, respectively, to reach approximately the same weights, which were not significantly different between the different treatment groups. In addition, THC caused an increase in activity (P<.05). Cognitive function showed a tendency to improve (P<.06) in the THC-treated mice, which was reversed by the antagonist for Days 4 and 5 of the maze (P<.01, and P<.05, respectively). Significant decreases in dopamine and serotonin (5-HT) levels were found both in the hypothalamus (P<.01) and the hippocampus (P<.01, P<.05), respectively, while norepinephrine (NE) levels showed tendency to increase in both the hypothalamus and hippocampus. Delta(8)-THC increased food intake significantly more (P<.05) than did delta(9)-THC, while performance and activity were similar. Thus, delta(8)-THC (0.001 mg/kg) caused increased food consumption and tendency to improve cognitive function, without cannabimimetic side effects. Hence, a low dose of THC might be a potential therapeutic agent in the treatment of weight disorders.

Topics: Animals; Dronabinol; Eating; Female; Maze Learning; Mice; Neurotransmitter Agents; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Topics: Cannabinoid Receptor Antagonists; Coronary Artery Disease; Dose-Response Relationship, Drug; Humans; Lipids; Metabolic Syndrome; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Smoking Cessation; United States; Weight Loss

Topics: Bradykinin; Cannabinoid Receptor Antagonists; Cannabinoids; Clinical Trials, Phase III as Topic; Double-Blind Method; Humans; Metabolic Syndrome; Piperidines; Placebos; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Time Factors; Weight Loss

Kappa-opioid receptors (KOR) have been implicated in neuroprotection from ischemic neuronal injury, but less work has been performed with transient focal cerebral ischemia to determine the role of KOR during reperfusion. We tested the effects of a selective and specific KOR agonist, BRL 52537 hydrochloride [(+/-)-1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine], and the standard KOR antagonist, nor-binaltorphimine dihydrochloride [nor-BNI; 17,17'-(dicyclopropylmethyl)-6,6',7,7'-6,6'-imino-7,7'-binorphinan-3,4',14,14'-tetrol], on functional and histological outcome after transient focal ischemia in the rat. By use of the intraluminal filament technique, halothane-anesthetized adult male Wistar rats were subjected to 2 h of middle cerebral artery occlusion confirmed by laser Doppler flowmetry. In a blinded, randomized fashion, rats were treated with 1). saline (vehicle) 15 min before reperfusion followed by saline at reperfusion for 22 h, 2). saline 15 min before reperfusion followed by BRL 52537 (1 mg x kg(-1) x h(-1)) at reperfusion for 22 h, 3). saline 15 min before reperfusion followed by nor-BNI (1 mg x kg(-1) x h(-1)) at reperfusion for 22 h, or 4) nor-BNI (1 mg/kg) 15 min before reperfusion followed by BRL 52537 (1 mgx kg(-1)x h(-1)) and nor-BNI (1 mg x kg(-1) x h(-1)) at reperfusion for 22 h. Infarct volume (percentage of ipsilateral structure) analyzed at 4 days of reperfusion was significantly attenuated in saline/BRL 52537 rats (n = 8; cortex, 10.2% +/- 4.3%; caudoputamen [CP], 23.8% +/- 6.7%) (mean +/- SEM) compared with saline/saline treatment (n = 8; cortex, 28.6% +/- 4.9%; CP, 53.3% +/- 5.8%). Addition of the specific KOR antagonist nor-BNI to BRL 52537 completely prevented the neuroprotection (n = 7; cortex, 28.6% +/- 5.3%; CP, 40.9% +/- 6.2%) conferred by BRL 52537. BRL 52537 did not produce postischemic hypothermia. These data demonstrate that KORs may provide a therapeutic target during early reperfusion after ischemic stroke.. The neuroprotective effect of selective kappa-opioid agonists in transient focal ischemia is via a selective action at the kappa-opioid receptors.

Topics: Animals; Behavior, Animal; Cerebral Cortex; Cranial Nerves; Functional Laterality; Gait; Hemodynamics; Ischemic Attack, Transient; Laser-Doppler Flowmetry; Male; Middle Cerebral Artery; Muscle Tonus; Naltrexone; Neuroprotective Agents; Pain; Piperidines; Putamen; Pyrrolidines; Rats; Rats, Wistar; Receptors, Opioid, kappa; Weight Loss

Prandial glucose regulation has the potential for achieving good metabolic control with a low risk of hypoglycaemia and increased flexibility with regard to eating patterns. Comparative studies have suggested that the prandial glucose regulator repaglinide is at least equivalent to sulphonylureas in terms of efficacy, but incurs a lower risk of major hypoglycaemia. However, these trials employed fixed dosing and mealtime regimens, so repaglinide was not used as intended. This prospective investigation in a daily clinical setting aimed to assess the efficacy and tolerability profile of flexible prandial glucose regulation with repaglinide in Type 2 diabetes.. 5,985 patients with Type 2 diabetes in Germany were surveyed prospectively. These patients were assessed before and after a mean of 46 days treatment with repaglinide. At baseline, available data showed that 64% of patients had previously received therapy with conventional oral antidiabetic drugs, 22% were on diet alone, and 13% were naive to any treatment.. Overall, mean HbA1c decreased from 8.6 to 7.4%, fasting blood glucose from 183.9 to 134.2 mg/dl (10.2 to 7.4 mmol/l), blood glucose prior to main meals from 198.5 to 141.4 mg/dl (11 to 7.8 mmol/l), and blood glucose 2 hours after main meals from 219.3 mg/dl to 153.2 mg/dl (12.2 to 8.5 mmol/l). Subgroup analysis showed significant improvements in each of these parameters (P<0.0001) in therapy-naive patients, in patients switched from other oral antidiabetic drugs, and in patients receiving repaglinide as combination therapy. Body weight decreased slightly (1.2+/-2.7 kg). Only 49 hypoglycaemic episodes were reported, of which 38 cases were mild and no adverse sequelae to these events have been reported. Repaglinide also led to a liberating effect on lifestyle when patients were switched from other oral hypoglycaemic agents (OHAs), with 80% reporting a sense of relief at the prospect of being able to miss meals. The proportion of these patients reporting lifestyle restrictions as a result of fixed mealtimes declined from 36% to 7%. Before switching, 38% of the patients admitted to eating when not hungry for fear of hypoglycaemia, but only 10% continued this behaviour and patients took fewer supplementary snacks after switching to repaglinide.. Prandial glucose regulation with repaglinide improves metabolic control in patients with Type 2 diabetes without causing weight gain and with few hypoglycaemic episodes. This beneficial effect is seen in patients who are therapy-naive, have switched from alternative OHAs, or are in need of combination therapy. The prandial approach to treatment has a liberating effect with regard to eating behaviour that is welcomed by most patients switched from alternative therapies.

Topics: Attitude to Health; Blood Glucose; Carbamates; Cohort Studies; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Eating; Feeding Behavior; Female; Germany; Humans; Hypoglycemic Agents; Life Style; Male; Middle Aged; Piperidines; Professional Practice; Prospective Studies; Surveys and Questionnaires; Treatment Outcome; Weight Loss

Topics: Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Exercise; Humans; Hyperglycemia; Hypoglycemic Agents; Piperidines; Weight Loss

The present study investigated the effects of the NMDA receptor antagonists dizocilpine (MK-801) and ifenprodil on the appearance of diazepam withdrawal signs caused by discontinuation of long-term diazepam treatment using a drug-admixed food (DAF) method in Fischer 344 rats. The total withdrawal score was significantly decreased by after-withdrawal treatment with dizocilpine or ifenprodil. Dizocilpine, in particular, markedly suppressed the motor withdrawal signs and body weight loss, while ifenprodil suppressed the motor and emotional withdrawal signs. Furthermore, the decrease in the food intake during withdrawal (anorexia) was significantly reduced by dizocilpine, but not by ifenprodil. These behavioral results indicated that the activation of NMDA receptors during withdrawal may play an important role in the appearance of withdrawal signs (in particular motor withdrawal signs) caused by discontinuation of chronic diazepam treatment, and that inhibitory agents for NMDA receptors may be effective in alleviation of the appearance of benzodiazepine withdrawal signs.

Topics: Administration, Oral; Animals; Anorexia; Anti-Anxiety Agents; Behavior, Animal; Diazepam; Dizocilpine Maleate; Eating; Emotions; Excitatory Amino Acid Antagonists; Male; Motor Activity; Piperidines; Rats; Rats, Inbred F344; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome; Time Factors; Weight Loss

The effect of the cannabinoid CB1 receptor antagonist, SR 141716, on food intake and body weight was assessed in adult, non-obese Wistar rats. The daily administration of SR 141716 (2.5 and 10 mg/kg; i.p.) reduced dose-dependently both food intake and body weight. Tolerance to the anorectic effect developed within 5 days; in contrast, body weight in SR 141716-treated rats remained markedly below that of vehicle-treated rats throughout the entire treatment period (14 days). The results suggest that brain cannabinoid receptors are involved in the regulation of appetite and body weight.

Topics: Animals; Appetite; Appetite Depressants; Cannabinoids; Drinking; Drug Tolerance; Eating; Kinetics; Male; Piperidines; Pyrazoles; Rats; Rats, Wistar; Rimonabant; Weight Loss

The long-term effects of portacaval anastomosis (PCA) on histamine H3 receptors in rat brain were studied by in vitro and in vivo methods. The overflow of histamine from the anterior hypothalamus and from cortex after long-term PCA was determined by in vivo microdialysis. The binding properties of [3H]-R-alpha-methylhistamine in membranes from cortex, cerebellum, and rest of brain (ROB) were examined with saturation binding experiments. The regional distribution of [3H]-R-alpha-methylhistamine binding sites in the brain of sham- and PCA-operated rats was assessed also with autoradiography. The tissue levels of histamine were significantly elevated in cortex and ROB of PCA-operated rats. In addition, the spontaneous and K+-evoked overflow of histamine from anterior hypothalamus, and the thioperamide-induced overflow from both anterior hypothalamus and cortex were increased after chronic PCA. In spite of the significantly elevated tissue concentrations and the moderate increase in histamine release, the binding properties of [3HI-R-alpha-methylhistamine to cortical membranes were not significantly changed. However, the autoradiography study did reveal a decrease in [3H]-R-alpha-methylhistamine binding density, particularly in striatum and cortex, where H3 receptors are located mainly at non-histaminergic neurons. In conclusion, we suggest that there is a region-selective increase in the histaminergic activity in chronic PCA, which leads to the down-regulation of somadendritic and pre-synaptic H3 receptors located at non-histaminergic neurons. At the same time, the autoreceptor mediated control of histamine neuronal activity via pre-synaptic H3 receptors located at histaminergic neurons is preserved after long-term PCA.

Topics: Animals; Autoradiography; Body Weight; Brain; Cerebral Cortex; Histamine Antagonists; Histamine Release; Hypothalamus; Liver; Male; Microdialysis; Piperidines; Portacaval Shunt, Surgical; Radioligand Assay; Rats; Rats, Wistar; Receptors, Histamine H3; Weight Loss