OBJECTIVE: Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal (GI) disorders characterized by pain and impaired bowel movements. Currently available drugs show limited efficacy. Cannabinoid 1 receptor (CB1) inverse agonists (CB1-RAN) cause diarrhea and may be candidates for the treatment of constipation-predominant IBS (IBS-C). We evaluated the effects of CB1-RAN in clinical trials for their potential use in IBS-C.
METHODS: Database search identified all clinical trials published up to May 2018 that reported rimonabant and taranabant treatment for at least one month and detailed the GI adverse events (AEs). Categorical outcomes (subgroups of AEs) were analyzed using the odds ratio (OR).
RESULTS: Eighteen trials met the inclusion criteria. Rimonabant 20 mg produced significantly more overall AEs (OR=1.35, CI: 1.19-1.52, p<0.0001), psychiatric events (OR=1.79, CI: 1.46-2.21, p<0.001) and GI AEs (OR=2.05, CI: 1.65-2.55, p<0.001) compared to placebo. Taranabant at doses ranging from 0.5 to 8 mg produced significantly more overall AEs (OR=1.36, CI: 1.13-1.64, p<0.002), psychiatric AEs (1.82, CI: 1.54-2.16, p<0.001) and GI AEs (OR=1.75, CI: 1.29-2.37, p<0.001) compared to placebo.
CONCLUSIONS: The approach to target CB1 in the gut for the treatment of IBS-C or chronic constipation seems a promising therapeutic option. Prospective clinical trials on the possible targeting of CB1 and the endocannabinoid system are warranted.

BACKGROUND: Obesity is a rapidly expanding worldwide health problem. Various targets are investigated presently for the treatment of obesity, but there remains an unmet need for an effective drug therapy with acceptable efficacy levels and reduced side effects. Targeting peripherally located cannabinoid 1 (CB1) receptors is an attractive strategy as these receptors play a vital role in energy homeostasis.
METHODS: CB1 receptor antagonists constitute one of the most important categories of compounds of interest for the control of obesity. In this review, the authors focus on recent advances (since 2007) in diverse chemical classes of patented compounds belonging to the category of CB1 receptor antagonists.
CONCLUSIONS: Safer CB1 receptor antagonists for the treatment of obesity can be discovered by developing such compounds that act peripherally. Increasing the polar service area, decreasing the lipophilicity and designing of neutral antagonists and allosteric inhibitors are some interesting strategies that could offer promising results.

Several lines of experimental and clinical evidence point to a close relationship between cannabis, the endogenous cannabinoid system, and schizophrenia. A variety of animal and human studies found a dysregulation of endocannabinoid signalling in psychosis. Elevated anandamide levels in schizophrenia patients that are negatively correlated with psychotic symptomatology indicate a protective role, whereas 2-arachidonoylglycerol appears to counteract psychosis-related cognitive impairments. Thus, pharmacological manipulation of the endogenous cannabinoid system might be associated with potential antipsychotic properties. In the present systematic review, both preclinical studies using different animal models of psychosis as well as clinical trials investigating the antipsychotic effects of both cannabidiol and rimonabant are presented together with the possible underlying mechanisms of action. The results predominantly confirm the hypothesis of an antipsychotic activity of both cannabinoids. In comparison, cannabidiol appears to be superior to rimonabant with a pharmacological profile similar to atypical antipsychotic drugs.

BACKGROUND: Obesity [defined as a body mass index (BMI) ≥ 30 kg/m(2)] represents a considerable public health problem and is associated with a significant range of comorbidities and an increased mortality risk. The primary aim of the management of obesity is to achieve weight reduction in the interests of health. For obese patients who cannot achieve or maintain a healthy weight by non-pharmacological means, drug therapy is recommended in combination with non-pharmacological interventions such as dietary modifications and exercise.
OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of three pharmacological interventions in obese patients.
METHODS: Clinical effectiveness data used in the meta-analysis were sourced from articles identified in a systematic review of the literature. Data used to inform transitions to obesity-related comorbidities were derived from the General Practice Research Database (GPRD). The results of the meta-analysis and GPRD analyses informed the economic model supplemented by data from the Health Survey for England and other UK-specific data sourced from the literature.
METHODS: A systematic literature review was conducted of the clinical effectiveness and cost-effectiveness of orlistat, sibutramine and rimonabant within their licensed indications for the treatment of obese patients. Electronic bibliographic databases including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases and Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched in January 2009, and the reference lists of relevant articles were checked. Studies were included if they compared orlistat, sibutramine or rimonabant with lifestyle and/or exercise advice (standard care), placebo or metformin.
RESULTS: Overall, 94 studies involving 24,808 individuals were included in the clinical meta-analysis. Eighty-three trials included data on weight change, 41 included data on BMI change and 45 and 36 studies reported on 5% and 10% body weight loss, respectively. Overall, the results show that the active drug interventions are all effective at reducing weight and BMI compared with placebo. In the case of sibutramine, the higher dose (15 mg) resulted in a greater reduction than the lower dose (10 mg). Generally, the data quality of the trials included was low with poor reporting of standard errors and standard deviations. Results from the BMI risk models derived from the GPRD showed consistent increases in risk with increasing BMI. Adjustments for key confounders, such as age, sex and smoking status, were found to be statistically significant at the 5% level, in all risk models. Applying linear models to estimate BMI trajectories, for the diabetic cohort, an average increase in BMI of 0.040 per year for both men and women was observed. The non-diabetic cohort model showed an increase in BMI of 0.175 per year for women and 0.145 per year for men. The results of the cost-effectiveness analyses suggest that sibutramine 15 mg dominates the other three active interventions and the net benefit analyses show that sibutramine 15 mg is the most cost-effective alternative for thresholds > £2000 per quality-adjusted life-year (QALY). However, both sibutramine and rimonabant have been withdrawn because of safety concerns relating to potential treatment-induced fatal adverse events. If the proportion of patients who experienced a fatal adverse event was > 1.8% (1.5%, 1.0%) for sibutramine 15 mg (sibutramine 10 mg, rimonabant) the treatment would not be considered cost-effective when using a threshold of £20,000 per QALY.
CONCLUSIONS: The clinical review did not include all possible lifestyle comparators, with the inclusion limited to only those trials included one of the active drug interventions. We also excluded all studies not reported in English. Although the clinical review included data from 94 studies, the quality of data was generally low, particularly in terms of the reporting of standard deviation. There was also inconsistency between the results of the mixed-treatment comparison (MTC) and the pair-wise analyses.
CONCLUSIONS: The MTC of anti-obesity treatments shows that all the active treatments are effective at reducing weight and BMI. The economic results show that, compared with placebo, the treatments are all cost-effective when using a threshold of £20,000 per QALY, and, within the limitations of the data available, sibutramine 15 mg dominates the other three interventions. This work has highlighted many areas of methodological research that could be explored, including assessing inconsistencies within a network to determine differences between the results of pair-wise and MTC analyses; the use of meta-regression methods to look for effect modifiers; exploring the effect of local publication bias; and the use of joint models to analyse the repeated measures of BMI and the time-to-event processes simultaneously.
BACKGROUND: The National Institute for Health Research Health Technology Assessment programme.

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.

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.

OBJECTIVE: To carry out a systematic review of the effectiveness of relapse prevention interventions (RPIs) among abstinent smokers who had completed an initial course of treatment or who had abstained unassisted, pooling only outcome data from similar follow-up time points.
METHODS: We used the same search strategy as was used in Cochrane reviews of RPIs to identify randomized trials of behavioural and pharmacological studies of smoking RPIs published up to July 2008. Abstinence from smoking was defined as either continuous abstinence or point prevalence abstinence, measured at three follow-up time points: short term (1-3 months post randomization), medium term (6-9 months) and long term (12-18 months). Abstinence among pregnant/postpartum women was also measured at delivery or the last follow-up prior to delivery. Random effect meta-analysis was used to estimate pooled odds ratios (OR) with 95% confidence intervals (CI).
RESULTS: Thirty-six studies randomizing abstainers were included. Self-help materials appeared to be effective in preventing relapse at long-term follow up in initially unaided quitters (pooled OR 1.52; 95% CI 1.15 to 2.01, I2 = 0%, NNT = 11, 3 studies). Other behavioural interventions for relapse prevention appeared effective in the short term only. There were positive results for the use of pharmacotherapies for relapse prevention. Bupropion was effective at long-term follow-up (pooled OR 1.49; 95% CI 1.10 to 2.01; I2 = 0%; NNT = 11; 4 studies). Nicotine replacement therapy (NRT) was effective at medium-term (pooled OR 1.56; 95% CI 1.16 to 2.11; I2 = 37%; NNT = 14; 4 trials) and long-term follow-ups (pooled OR 1.33; 95% CI 1.08 to 1.63; I2 = 0%; NNT = 20; 4 trials). Single trials of extended treatment of Varenicline and rimonabant were also found to be effective at short-term and medium-term follow-ups.
CONCLUSIONS: Self-help materials appear to prevent relapse in initially unaided quitters. Use of NRT, bupropion and varenicline appears to be effective in preventing relapse following an initial period of abstinence or an acute treatment episode. There is currently no good evidence that behavioural support prevents relapse after initial unaided abstinence or following an acute treatment period.

BACKGROUND: The cannabinoid-1 receptor blockers have been proposed in the management of obesity and obesity-related liver diseases (fatty liver as NAFLD or NASH). Due to increasing number of patients to be potentially treated and the need to assess the advantage of this treatment in terms of risk/benefit, we analyze the side events reported during the treatment with rimonabant by a systematic review and meta-analysis of all randomized controlled studies.
METHODS: All published randomized controlled trials using rimonabant versus placebo in adult subjects were retrieved. Relative risks (RR) with 95% confidence interval for relevant adverse events and number needed to harm was calculated.
RESULTS: Nine trials (n = 9635) were considered. Rimonabant 20 mg was associated with an increased risk of adverse event (RR 1.35; 95%CI 1.17-1.56), increased discontinuation rate (RR 1.79; 95%CI 1.35-2.38), psychiatric (RR 2.35; 95%CI 1.66-3.34), and nervous system adverse events (RR 2.35; 95%CI 1.49-3.70). The number needed to harm for psychiatric adverse events is 30.
CONCLUSIONS: Rimonabant is associated with an increased risk of adverse events. Despite of an increasing interest for its use on fatty liver, the security profile and efficacy it is needs to be carefully assessed before its recommendation. At present the use of rimonabant on fatty liver cannot be recommended.

Type 2 diabetes mellitus (T2DM) is a progressive disorder caused by a combination of insulin resistance and beta cell dysfunction. It is associated with an increased and premature risk of cardiovascular disease as well as specific microvascular complications such as retinopathy, nephropathy and neuropathy. In the last 5 years new glucose lowering drugs acting on novel pathways have been developed, licensed and launched, such as the glucagon-like peptide (GLP-1) agonists (exenatide) and dipeptidyl peptidase (DPP-IV) inhibitors such as sitagliptin and vildagliptin. This review looks at these new agents in terms of their mode of action, pharmacokinetics and use in clinical practice. This review also includes new agents in the area of weight loss that may have a positive effect for glucose management-for example, rimonabant.

OBJECTIVE: To review economic evaluations of weight loss drugs and compare reported incremental cost-effectiveness ratios (ICERs).
METHODS: A literature search was conducted for cost-effectiveness (CEAs) and cost-utility analyses (CUAs) of sibutramine, orlistat and rimonabant.
RESULTS: Fourteen unique articles were identified (11 CUAs and 3 CEAs; 9 orlistat, 4 sibutramine and 1 rimonabant). All used diet and exercise as comparator, whereas none included indirect costs. Time horizons varied from treatment period only (1-4 years) to 80 years (median 7.5 years). Longer studies modeled effects on diabetes, micro- and macrovascular complications, coronary heart disease and death. Of the CUAs, the median ICER was 16,000 euro(2007)/QALY (quality-adjusted life-year; range 10,000-88,000), with the worst cost-effectiveness when recommended stop rules for non-responding patients were not applied. All studies but three were funded by the manufacturing company, and the median ICER was considerably higher for independent than for sponsored analyses (62,000 euro vs 15,000 euro/QALY). However, two of the three independent CUAs did not use recommended stop rules, as compared with one of eight manufacturer-sponsored analyses. The results were most sensitive to assumptions regarding weight loss sustainability and utility per kilogram lost. Side effects and dropout because of reasons other than lack of efficacy were generally not incorporated.
CONCLUSIONS: Published economic evaluations indicate that orlistat, sibutramine and rimonabant are within the range of what is generally regarded as cost-effective. Uncertainty remains about weight loss sustainability, utility gain associated with weight loss and extrapolations from transient weight loss to long-term health benefits. Modeling of head-to-head comparisons and attrition is needed, as are analyses conducted independently of manufacturing companies.