piperidines and Weight-Gain

A prior systematic review on the efficacy of halofuginone (HFG) treatment to prevent or treat cryptosporidiosis in bovine calves was inconclusive. We undertook an updated synthesis and meta-analyses on key outcomes for the treatment of calves with HFG. Evaluated outcomes were oocyst shedding, diarrhoea, mortality and weight gain. Experiments had to describe results for same age animals in contemporary arms. Most doses were 100-150 mcg kg-1 day-1. Results were subgrouped by study design, experiments with the lowest risk of bias and lack of industry funding. Eighteen articles were found that described 25 experiments. Most evidence came from randomized controlled trials in Europe. Significantly lower incidence of oocyst shedding, diarrhoea burden and mortality was reported when treatment started before calves were 5 days old. Most studies reported on outcomes for animals up to at least 28 days old. Publication bias was possible in all outcomes and seemed especially likely for diarrhoea outcomes. Beneficial results when HFG treatment was initiated in calves older than 5 days were also found. Prophylactic treatment to prevent cryptosporidiosis is effective in preventing multiple negative outcomes and is beneficial to calf health and will result in a reduction of environmental contamination by Cryptosporidium oocysts.

Topics: Animals; Cattle; Cattle Diseases; Coccidiostats; Cryptosporidiosis; Cryptosporidium parvum; Diarrhea; Feces; Oocysts; Piperidines; Quinazolinones; Weight Gain

Schizophrenia has a prevalence of approximately 1% in the general population, with 15.2 per 100,000 persons affected. Iloperidone is a second-generation antipsychotic drug approved for the treatment of schizophrenia in adults. It acts primarily by D2/5HT2a receptor antagonism, with greater affinity for the 5HT2a receptor than for the D2 receptor.. This article discusses iloperidone and aims to provide useful information for clinicians to determine which circumstances would best suit the use of iloperidone to treat schizophrenic patients. In this review, the authors briefly discuss schizophrenia and its treatment, before they discuss properties of iloperidone, its indications, approval process, and adverse effects. Finally, the authors review the specific strengths and weaknesses of the medication.. Iloperidone would be an attractive option in patients who are particularly prone to EPS, or who are showing prominent negative symptoms, as well as cognitive deficits. Its availability only in an oral formulation makes it a better option for patients with good medication adherence, and though it could be useful in patients prone to weight gain or hepatic dysfunction on other second generation antipsychotics, it should be used with caution in patients prone to side effects related to alpha adrenergic blockade.

Topics: Antipsychotic Agents; Humans; Isoxazoles; Piperidines; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Schizophrenia; Weight Gain

The present study aimed to evaluate cardiometabolic risks [weight gain, blood lipid levels (total cholesterol and triglycerides), blood glucose levels, hemoglobin A1c (HbA1c) levels, and corrected QT interval (QTc) prolongation] associated with the use of blonanserin and perospirone versus other antipsychotics in the management of patients with schizophrenia.. We conducted a systematic review and meta-analysis of patient data from randomized controlled trials comparing blonanserin or perospirone with other antipsychotics.. In total, 4 blonanserin studies (n = 1080) were identified [vs. risperidone (2 studies, n = 508); vs. haloperidol (2 studies, n = 572)]. Blonanserin produced less weight gain compared with risperidone (weighted mean difference = -0.86, 95% confidence intervals = -1.36 to -0.36, p = 0.0008; 2 studies, 480 patients). However, no significant differences were observed in blood lipid, glucose, and HbA1c levels or QTc prolongation between blonanserin and risperidone or haloperidol. For perospirone studies, 5 studies [562 adult patients with schizophrenia randomized to perospirone (n = 256), olanzapine (n = 20), quetiapine (n = 28), risperidone (n = 53), aripiprazole (n = 49), haloperidol (n = 75), or mosapramine (n = 81)] were identified. Perospirone did not differ from other antipsychotics with regard to weight gain and total cholesterol levels.. Our results suggest that blonanserin is associated with a lower of weight gain compared with other antipsychotics. Because the number of studies was small, additional controlled clinical trials with larger number of patients are indicated.

Topics: Adult; Antipsychotic Agents; Blood Glucose; Double-Blind Method; Glycated Hemoglobin; Heart; Humans; Isoindoles; Piperazines; Piperidines; Randomized Controlled Trials as Topic; Risk; Schizophrenia; Thiazoles; Weight Gain

Dipeptidyl peptidase-4 (DPP-4) inhibitors offer new options for the management of type 2 diabetes. Direct comparisons with active glucose-lowering comparators in drug-naive patients have demonstrated that DPP-4 inhibitors exert slightly less pronounced HbA(1c) reduction than metformin (with the advantage of better gastrointestinal tolerability) and similar glucose-lowering effects as with a thiazolidinedione (TZD; with the advantage of no weight gain). In metformin-treated patients, gliptins were associated with similar HbA(1c) reductions compared with a sulphonylurea (SU; with the advantage of no weight gain, considerably fewer hypoglycaemic episodes and no need for titration) and a TZD (with the advantage of no weight gain and better overall tolerability). DPP-4 inhibitors also exert clinically relevant glucose-lowering effects compared with a placebo in patients treated with SU or TZD (of potential interest when metformin is either not tolerated or contraindicated), and as oral triple therapy with a good tolerability profile when added to a metformin-SU or pioglitazone-SU combination. Several clinical trials also showed a consistent reduction in HbA(1c) when DPP-4 inhibitors were added to basal insulin therapy, with no increased risk of hypoglycaemia. Because of the complex pathophysiology of type 2 diabetes and the complementary actions of glucose-lowering agents, initial combination of a DPP-4 inhibitor with either metformin or a glitazone may be applied in drug-naive patients, resulting in greater efficacy and similar safety compared with either drug as monotherapy. However, DPP-4 inhibitors were less effective than GLP-1 receptor agonists for reducing HbA(1c) and body weight, but offer the advantage of being easier to use (oral instead of injected administration) and lower in cost. Only one head-to-head trial demonstrated the non-inferiority of saxagliptin vs sitagliptin. Clearly, more trials of direct comparisons between different incretin-based therapies are needed. Because of their pharmacokinetic characteristics, pharmacodynamic properties (glucose-dependent glucose-lowering effect) and good overall tolerability profile, DPP-4 inhibitors may have a key role to play in patients with renal impairment and in the elderly. The role of DPP-4 inhibitors in the therapeutic armamentarium of type 2 diabetes is rapidly evolving as their potential strengths and weaknesses become better defined mainly through controlled clinical trials.

Topics: Adamantane; Clinical Trials as Topic; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Nitriles; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Triazoles; Uracil; Vildagliptin; Weight Gain

Most people who stop smoking gain weight. There are some interventions that have been designed to reduce weight gain when stopping smoking. Some smoking cessation interventions may also limit weight gain although their effect on weight has not been reviewed.. To systematically review the effect of: (1) Interventions targeting post-cessation weight gain on weight change and smoking cessation.(2) Interventions designed to aid smoking cessation that may also plausibly affect weight on post-cessation weight change.. Part 1 - We searched the Cochrane Tobacco Addiction Group's Specialized Register and CENTRAL in September 2011.Part 2 - In addition we searched the included studies in the following "parent" Cochrane reviews: nicotine replacement therapy (NRT), antidepressants, nicotine receptor partial agonists, cannabinoid type 1 receptor antagonists and exercise interventions for smoking cessation published in Issue 9, 2011 of the Cochrane Library.. Part 1 - We included trials of interventions that were targeted at post-cessation weight gain and had measured weight at any follow up point and/or smoking cessation six or more months after quit day.Part 2 - We included trials that had been included in the selected parent Cochrane reviews if they had reported weight gain at any time point.. We extracted data on baseline characteristics of the study population, intervention, outcome and study quality. Change in weight was expressed as difference in weight change from baseline to follow up between trial arms and was reported in abstinent smokers only. Abstinence from smoking was expressed as a risk ratio (RR). We used the most rigorous definition of abstinence available in each trial. Where appropriate, we performed meta-analysis using the inverse variance method for weight and Mantel-Haenszel method for smoking using a fixed-effect model.. Part 1: Some pharmacological interventions tested for limiting post cessation weight gain (PCWG) resulted in a significant reduction in WG at the end of treatment (dexfenfluramine (Mean difference (MD) -2.50 kg, 95% confidence interval (CI) -2.98 to -2.02, 1 study), phenylpropanolamine (MD -0.50 kg, 95% CI -0.80 to -0.20, N=3), naltrexone (MD -0.78 kg, 95% CI -1.52 to -0.05, N=2). There was no evidence that treatment reduced weight at 6 or 12 months (m). No pharmacological intervention significantly affected smoking cessation rates.Weight management education only was associated with no reduction in PCWG at end of treatment (6 or 12m). However these interventions significantly reduced abstinence at 12m (Risk ratio (RR) 0.66, 95% CI 0.48 to 0.90, N=2). Personalised weight management support reduced PCWG at 12m (MD -2.58 kg, 95% CI -5.11 to -0.05, N=2) and was not associated with a significant reduction of abstinence at 12m (RR 0.74, 95% CI 0.39 to 1.43, N=2). A very low calorie diet (VLCD) significantly reduced PCWG at end of treatment (MD -3.70 kg, 95% CI -4.82 to -2.58, N=1), but not significantly so at 12m (MD -1.30 kg, 95% CI -3.49 to 0.89, N=1). The VLCD increased chances of abstinence at 12m (RR 1.73, 95% CI 1.10 to 2.73, N=1). There was no evidence that cognitive behavioural therapy to allay concern about weight gain (CBT) reduced PCWG, but there was some evidence of increased PCWG at 6m (MD 0.74, 95% CI 0.24 to 1.24). It was associated with improved abstinence at 6m (RR 1.83, 95% CI 1.07 to 3.13, N=2) but not at 12m (RR 1.25, 95% CI 0.83 to 1.86, N=2). However, there was significant statistical heterogeneity.Part 2: We found no evidence that exercise interventions significantly reduced PCWG at end of treatment (MD -0.25 kg, 95% CI -0.78 to 0.29, N=4) however a significant reduction was found at 12m (MD -2.07 kg, 95% CI -3.78 to -0.36, N=3).Both bupropion and fluoxetine limited PCWG at the end of treatment (bupropion MD -1.12 kg, 95% CI -1.47 to -0.77, N=7) (fluoxetine MD -0.99 kg, 95% CI -1.36 to -0.61, N=2). There was no evidence that the effect persisted at 6m (bupropion MD -0.58 kg, 95% CI -2.16 to 1.00, N=4), (fluoxetine MD -0.01 kg, 95% CI -1.11 to 1.10, N=2) or 12m (bupropion MD -0.38 kg, 95% CI -2.00 to 1.24, N=4). There were no data on WG at 12m for fluoxetine.Overall, treatment with NRT attenuated PCWG at the end of treatment (MD -0.69 kg, 95% CI -0.88 to -0.51, N=19), with no strong evidence that the effect differed for the different form. Although some pharmacotherapies tested to limit PCWG show evidence of short-term success, other problems with them and the lack of data on long-term efficacy limits their use. Weight management education only, is not effective and may reduce abstinence. Personalised weight management support may be effective and not reduce abstinence, but there are too few data to be sure. One study showed a VLCD increased abstinence but did not prevent WG in the longer term. CBT to accept WG did not limit PCWG and may not promote abstinence in the long term. Exercise interventions significantly reduced weight in the long term, but not the short term. More studies are needed to clarify whether this is an effect of treatment or a chance finding. Bupropion, fluoxetine, NRT and varenicline reduce PCWG while using the medication. Although this effect was not maintained one year after stopping smoking, the evidence is insufficient to exclude a modest long-term effect. The data are not sufficient to make strong clinical recommendations for effective programmes to prevent weight gain after cessation.

Topics: Antidepressive Agents; Benzazepines; Exercise; Female; Humans; Male; Nicotine; Nicotinic Agonists; Piperidines; Pyrazoles; Quinoxalines; Randomized Controlled Trials as Topic; Smoking Cessation; Weight Gain

The introduction of second-generation antipsychotics (SGAs) over the past 2 decades generated considerable optimism that better antipsychotic treatments for schizophrenia and bipolar disorder were possible. SGAs offer several tolerability benefits over first-generation antipsychotics (FGAs), particularly with respect to extrapyramidal symptoms. However, SGAs can induce serious metabolic dysregulations, especially in drug-naive, first-episode, and child and adolescent populations, with olanzapine and clozapine having the highest propensity to cause these abnormalities. In this context, newer SGAs were developed to further improve the adverse effect burden of available agents. However, until now, the metabolic risk profile of the newly approved SGAs - asenapine, iloperidone, lurasidone and paliperidone (paliperidone extended release and paliperidone palmitate) - has not been compared.. The objective of this systematic review and exploratory meta-analysis was to assess the effects of asenapine, iloperidone, lurasidone and paliperidone on body weight and other metabolic parameters (cholesterol, triglycerides and glucose), as this information is relevant to guide clinical decision making.. A systematic literature search (1966-March 2012), using the Cochrane Central Register of Controlled Trials and MEDLINE, CINAHL and EMBASE databases, was conducted for randomized, placebo-controlled and head-to-head clinical trials of asenapine, iloperidone, lurasidone and paliperidone. Published and unpublished data on changes in body weight and glucose and lipid metabolism parameters were extracted. For placebo-controlled, short-term (≤12 weeks) and longer-term (>12 weeks) trials with available data on ≥7% weight increase compared with pre-treatment weight, or mean weight change with standard deviation, a formal meta-analysis was performed, estimating the pooled effect size (represented as relative risk [RR], numbers-needed-to-harm [NNH] and weighted mean difference [WMD]). An exploratory meta-analysis was also performed for the other metabolic variables (cholesterol, triglycerides and glucose). Data from active- and placebo-controlled studies were used for a pooled comparison of simple mean changes in weight, cholesterol, triglyceride and glucose levels.. Fifty-six trials (n = 21 691) in schizophrenia (N = 49, n = 19 299) or bipolar disorder (N = 7, n = 2392) were identified (asenapine: N = 9, iloperidone: N = 11, lurasidone: N = 8, paliperidone: N = 28). Most of the trials (64.3%) were of ≤12 weeks' duration. In the short-term trials, compared with placebo, a ≥7% weight increase was statistically significantly (p < 0.05) most prevalent for asenapine (5 trials, n = 1360, RR = 4.09, 95% confidence interval [CI] 2.25, 7.43, NNH = 17), followed by iloperidone (4 trials, n = 1931, RR = 3.13, 95% CI 2.08, 4.70, NNH = 11) and paliperidone (12 trials, n = 4087, RR = 2.17, 95% CI 1.64, 2.86, NNH = 20). The effect of lurasidone on body weight (6 trials, n = 1793, RR = 1.42, 95% CI 0.87, 2.29) was not statistically significant. Short-term weight gain was statistically significantly (p < 0.001) greater than placebo with iloperidone (1 trial, n = 300, +2.50 kg, 95% CI 1.92, 3.08), paliperidone (15 trials, n = 3552, +1.24 kg, 95% CI 0.91, 1.57), asenapine (3 trials, n = 751, +1.16 kg, 95% CI 0.83, 1.49), as well as with lurasidone (5 trials, n = 999, +0.49 kg, 95% CI 0.17, 0.81, p < 0.01). Sufficient meta-analysable, longer-term, weight change data were only available for asenapine and paliperidone, showing statistically significantly (p < 0.001) greater weight gain versus placebo for both drugs (asenapine, 3 trials, n = 311, +1.30 kg, 95% CI 0.62, 1.98; paliperidone, 6 trials, n = 1174, +0.50 kg, 95% CI 0.22, 0.78). Although statistically significant, in general, no clinically meaningful differences were observed between the four newly approved SGAs and placebo regarding the mean change from baseline to endpoint in cholesterol levels in short-term trials, with the exception of iloperidone for total cholesterol (1 trial, n = 300, +11.60 mg/dL, 95% CI 4.98, 18.22, p ≤ 0.001), high-density cholesterol (1 trial, n = 300, +3.6 mg/dL, 95% CI 1.58, 5.62, p < 0.001) and low-density cholesterol (1 trial, n = 300, +10.30 mg/dL, 95% CI 4.94, 15.66, p < 0.001) and with the exception of lurasidone for high-density cholesterol (5 trials, n = 1004, +1.50 mg/dL, 95% CI 0.56, 2.44, p < 0.01). Asenapine increased total cholesterol statistically significantly (p < 0.05) during longer-term treatment (1 trial, n = 194, +6.53 mg/dL, 95% CI 1.17, 11.89). Regarding triglycerides, only short-term (3 trials, n = 1152, +1.78 mg/dL, 95% CI 0.40, 3.17, p < 0.01) and longer-term treatment with paliperidone (4 trials, n = 791, -0.20 mg/dL, 95% CI -. While preliminary data suggest the lowest weight gain potential with lurasidone and potentially relevant short-term metabolic effects for asenapine and iloperidone, data are still too sparse to comprehensively evaluate the metabolic safety of the newly approved SGAs. Therefore, there is a clear need for further controlled studies to evaluate whether these agents are less problematic regarding treatment-emergent weight gain and metabolic disturbances than other currently available antipsychotics.

Topics: Antipsychotic Agents; Bipolar Disorder; Blood Glucose; Dibenzocycloheptenes; Heterocyclic Compounds, 4 or More Rings; Humans; Isoindoles; Isoxazoles; Lipid Metabolism; Lurasidone Hydrochloride; Paliperidone Palmitate; Piperidines; Pyrimidines; Randomized Controlled Trials as Topic; Schizophrenia; Thiazoles; Weight Gain

Iloperidone is a new second-generation (atypical) antipsychotic medication approved for the treatment of schizophrenia in adults. The target dose of 6 mg bid can be achieved in 4 days, with titration recommended to minimize postural hypotension. The maximum recommended dose is 12 mg bid. The tolerability profile of iloperidone is noteworthy in terms of modest weight gain, no medically important changes in lipid and glucose levels, little in the way of prolactin elevation, and absence of extrapyramidal side effects, including akathisia. However, iloperidone can prolong the QTc interval on electrocardiogram. Iloperidone may be best suited for patients who are sensitive to akathisia or who are unable to tolerate the sedation and weight gain that can occur more frequently with other antipsychotics.

Topics: Antipsychotic Agents; Electrocardiography; Heart Rate; Humans; Isoxazoles; Long QT Syndrome; Piperidines; Schizophrenia; Treatment Outcome; Weight Gain

Most people who stop smoking gain weight, on average about 7 kg in the long term. There are some interventions that have been specifically designed to tackle smoking cessation whilst also limiting weight gain. Many smoking cessation pharmacotherapies and other interventions may also limit weight gain.. This review is divided into two parts. (1) Interventions designed specifically to aid smoking cessation and limit post-cessation weight gain (2) Interventions designed to aid smoking cessation that may also plausibly have an effect on weight. Part 1: We searched the Cochrane Tobacco Addiction Group's Specialized Register which includes trials indexed in MEDLINE, EMBASE, SciSearch and PsycINFO, and other reviews and conference abstracts. Part 2: We searched the included studies of Cochrane smoking cessation reviews of nicotine replacement therapy, antidepressants, nicotine receptor partial agonists, cannabinoid type 1 receptor antagonists (rimonabant), and exercise interventions, published in Issue 4, 2008 of The Cochrane Library.. Part 1: We included trials of interventions designed specifically to address both smoking cessation and post-cessation weight gain that had measured weight at any follow-up point and/or smoking six months or more after quitting.Part 2: We included trials from the selected Cochrane reviews that could plausibly modify post-cessation weight gain if they had reported weight gain by trial arm at end of treatment or later.. We extracted data in duplicate on smoking and weight for part 1 trials, and on weight only for part 2. Abstinence from smoking is expressed as a risk ratio (RR), using the most rigorous definition of abstinence available in each trial, and biochemically validated rates if available. The outcome is expressed as the difference in weight change between trial arms from baseline. Where appropriate, we performed meta-analysis using the Mantel-Haenszel method for smoking and inverse variance for weight using a fixed-effect model.. We found evidence that pharmacological interventions aimed at reducing post-cessation weight gain resulted in a significant reduction in weight gain at the end of treatment (dexfenfluramine (-2.50kg [-2.98kg to -2.02kg], fluoxetine (-0.80kg [-1.27kg to -0.33kg], phenylpropanolamine (PPA) (-0.50kg [-0.80kg to -0.20kg], naltrexone (-0.76kg [-1.51kg to -0.01kg])). No evidence of maintenance of the treatment effect was found at six or 12 months.Among the behavioural interventions, only weight control advice was associated with no reduction in weight gain and with a possible reduction in abstinence. Individualized programmes were associated with reduced weight gain at end of treatment and at 12 months (-2.58kg [-5.11kg to -0.05kg]), and with no effect on abstinence (RR 0.74 [0.39 to 1.43]). Very low calorie diets (-1.30kg (-3.49kg to 0.89kg] at 12 months) and cognitive behavioural therapy (CBT) (-5.20kg (-9.28kg to -1.12kg] at 12 months) were both associated with improved abstinence and reduced weight gain at end of treatment and at long-term follow up.Both bupropion (300mg/day) and fluoxetine (30mg and 60mg/day combined) were found to limit post-cessation weight gain at the end of treatment (-0.76kg [-1.17kg to -0.35kg] I(2)=48%) and -1.30kg [-1.91kg to -0.69kg]) respectively. There was no evidence that the weight reducing effect of bupropion was dose-dependent. The effect of bupropion at one year was smaller and confidence intervals included no effect (-0.38kg [-2.001kg to 1.24kg]).We found no evidence that exercise interventions significantly reduced post-cessation weight gain at end of treatment but evidence for an effect at 12 months (-2.07kg [-3.78kg, -0.36kg]).Treatment with NRT resulted in attenuation of post-cessation weight gain (-0.45kg [-0.70kg, -0.20kg]) at the end of treatment, with no evidence that the effect differed for different forms of NRT. The estimated weight gain reduction was similar at 12 months (-0.42kg [-0.92kg, 0.08kg]) but the confidence intervals included no effect.There were no relevant data on the effect of rimonabant on weight gain.We found no evidence that varenicline significantly reduced post-cessation weight gain at end of treatment and no follow-up data are currently available. One study randomizing successful quitters to 12 more weeks of active treatment showed weight to be reduced by 0.71kg (-1.04kg to -0.38kg). In three studies, participants taking bupropion gained significantly less weight at the end of treatment than. Behavioural interventions of general advice only are not effective and may reduce abstinence. Individualized interventions, very low calorie diets, and CBT may be effective and not reduce abstinence. Exercise interventions are not associated with reduced weight gain at end of treatment, but may be associated with worthwhile reductions in weight gain in the long term, Bupropion, fluoxetine, nicotine replacement therapy, and probably varenicline all reduced weight gain while being used. Although this effect was not maintained one year after quitting for bupropion, fluoxetine, and nicotine replacement, the evidence is insufficient to exclude a modest long-term effect. The data are not sufficient to make strong clinical recommendations for effective programmes.

Topics: Antidepressive Agents; Benzazepines; Exercise; Female; Humans; Male; Nicotine; Nicotinic Agonists; Piperidines; Pyrazoles; Quinoxalines; Rimonabant; Smoking Cessation; Varenicline; Weight Gain

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

Iloperidone, a mixed D2/5-HT2 antagonist, is currently in clinical development for the treatment of schizophrenia. This article assesses the short-term safety of iloperidone using a pooled analysis of 3 phase 2, short-term acute schizophrenia studies conducted between 1998 and 2002 (N = 1943). Patients exposed to 3 dose ranges of iloperidone, another antipsychotic, or placebo were compared on rates of serious adverse events (SAEs), adverse events (AEs), extrapyramidal symptoms, akathisia, prolactin, weight and metabolic parameters, QTc, and other standard safety parameters. The most common treatment-related AEs observed with iloperidone were dizziness, headache, dry mouth, nausea, and insomnia. Discontinuation due to AEs was 4.8% for iloperidone, 7.6% for haloperidol, 6.2% for risperidone, and 4.8% for placebo. Iloperidone groups showed better overall performance on the Extrapyramidal Symptom Rating Scale and Barnes Akathisia Scale than risperidone or haloperidol groups. Patients taking iloperidone experienced a mild weight increase (range, 1.5-2.1 kg) similar to that of risperidone (1.5 kg), whereas those on haloperidol and placebo showed mean weight loss (-0.1 kg and -0.3 kg, respectively). QTc interval significantly increased across all iloperidone groups (least squares mean change from baseline to end point, 2.9-9.1 msec) and for haloperidol (5.0 msec). No significant QTc changes occurred in the risperidone or placebo groups. Iloperidone was associated with no change from baseline in total cholesterol, mild elevation in serum glucose, and slight decrease in triglycerides. Prolactin levels decreased with iloperidone and increased significantly with risperidone and haloperidol. These short-term trials suggest that iloperidone has a reassuring safety profile in many of the areas that are of potential concern, including relatively low dropout rates because of AEs, low extrapyramidal symptoms, akathisia, and prolactin elevation, and a modest short-term effect on weight gain.

Topics: Adolescent; Adult; Aged; Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Double-Blind Method; Female; Humans; Isoxazoles; Long QT Syndrome; Male; Middle Aged; Patient Dropouts; Piperidines; Prospective Studies; Psychotic Disorders; Randomized Controlled Trials as Topic; Schizophrenia; Weight Gain

Type 2 diabetes is characterized by decreases in insulin secretion and insulin sensitivity. Several classes of oral antidiabetic medications are currently approved for the treatment of type 2 diabetes. A stepwise treatment approach from monotherapy to combination therapy is traditionally used; however, the frequency of treatment failure with monotherapy has resulted in a move towards earlier treatment with combination therapies that target the two principal defects in glycaemic control. One such combination regimen is repaglinide (a prandial glucose regulator that increases insulin release) plus metformin (an insulin sensitizer that inhibits hepatic glucose output, increases peripheral glucose uptake and utilization and minimizes weight gain). Findings from several clinical trials have shown that combination therapy with repaglinide plus metformin is well tolerated and results in greater reductions of haemoglobin A(1c) and fasting plasma glucose values compared with either monotherapy. Repaglinide may also provide a more suitable alternative to combination therapy with sulphonylureas and metformin because of its reduced propensity for hypoglycaemia. The combination regimen of repaglinide plus metformin should therefore be considered as a valuable option in the management of patients with type 2 diabetes when monotherapy is no longer adequate.

Topics: Administration, Oral; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin; Metformin; Piperidines; Treatment Outcome; Weight Gain

The endocannabinoid system modulates synaptic neurotransmission centrally and peripherally and is involved in the brain pathways concerned with addiction, central regulation of body weight and adipose tissue function. The system is overactivated in animal models of obesity and nicotine use. This review discusses the role of rimonabant, a cannabinoid receptor 1 blocker, which has undergone Phase III clinical testing, in the treatment of obesity and tobacco dependence.. Results of Phase III clinical trials have shown that rimonabant has promising efficacy in the treatment of obesity, dyslipidaemia and diabetes associated with obesity, in preventing weight gain following smoking cessation, and possibly in smoking cessation. No critical problems with the tolerance and safety of the compound have appeared in studies to date.. Rimonabant may prove to be a useful aid in the treatment of the most widespread cardiometabolic risk factors.

Topics: Cannabinoid Receptor Antagonists; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Humans; Hyperlipidemias; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Smoking Cessation; Tobacco Use Disorder; Treatment Outcome; Weight Gain

The complications of diabetes mellitus, arising from inadequate glycemic control, have serious consequences for society as well as individuals. It is now urged that tight glycemic control be the goal for all patients, regardless of type of diabetes. Unfortunately, hypoglycemia can be a consequence of this aggressive approach. Treatment with a combination of agents and improved therapies are needed to maintain glycemic balance in patients. A better understanding of the pathophysiology of diabetes has yielded many treatment options based on various mechanisms of action. The sulfonyluereas, repaglinide, metformin, acarbose and the thiazolidinediones are effective in decreasing fasting plasma glucose levels, but their limitations may include adverse effects, such as weight gain and hypoglycemia, and an inability to modify some of the important comorbidities of diabetes. Therapies aimed at treating mealtime hyperglycemia are gaining attention. One promising investigational agent in this category is nateglinide. Early data suggest that its rapid onset and short duration of action result in increased early mealtime insulin release, reduced mealtime glucose excursions, and improved glycemic control.

Topics: Acarbose; Administration, Oral; Blood Glucose; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Combinations; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Metformin; Nateglinide; Phenylalanine; Piperidines; Randomized Controlled Trials as Topic; Thiazolidinediones; United States; Weight Gain

Ghrelin is a hormone that induces orexigenic effects in mammals. However, in avian species, there is scant and conflictive results on the effect of ghrelin on feed intake (FI). Therefore, we evaluated the effect of a ghrelin receptor agonist (capromorelin) on FI, ADG, water intake (WI), animal behavior and concentrations of ghrelin, glucose, growth hormone (GH) and insulin in broiler chickens. One-day-old male broilers were reared as recommended by the industry. At 4 wk of age (experimental day 0; D0), birds were blocked by weight and randomly assigned to 3 treatments in 2 identical trials. Control birds received a vehicle control solution containing 0 mg/kgBW/d of capromorelin. Birds in treatments 2 and 3 received capromorelin at target doses of 6 or 12 mg/kgBW/d of capromorelin (n = 27). FI and WI were measured 3 times a day at 0700 h (Period 1; P1), 1200 h (P2) and 1700 h (P3), while BW was recorded daily. Blood samples were collected on D-1 and D5. Bird behavior (pecking, sitting and standing) was evaluated for 9 h on D2. Data were analyzed using a randomized complete block design with repeated measures over time. Orthogonal polynomial contrasts were used to determine linear and quadratic effects of increasing levels of capromorelin. Polynomial contrasts showed that capromorelin doses linearly increased FI (P = 0.002) and ADG (P = 0.019). There were no treatment, day or treatment x d interactions on glucose, ghrelin and GH concentrations. However, there was a treatment x d interaction (P = 0.041) on insulin concentrations. Concentrations of insulin were higher on D5 for the 0 and 12 mg/kgBW/d treatments as compared with D-1. Polynomial contrasts showed that capromorelin doses linearly increased number of pecks/h (P = 0.018). Per hour FI and WI was higher during P1 (i.e., 0700-1200) as compared to P2 and P3 (P < 0.001). Our observations suggest that capromorelin linearly increases feed intake; thus, the same effect of that reported in mammalian species.

Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Body Weight; Chickens; Diet; Eating; Male; Piperidines; Pyrazoles; Receptors, Ghrelin; Weight Gain

This Japanese, multicenter, randomized, double-blind trial, evaluating the efficacy and safety of blonanserin compared with haloperidol in patients with schizophrenia, was previously published by Murasaki in the Japanese language. In this article, we present the results of the trial based on full analysis dataset instead of per protocol dataset formerly reported and discuss the findings in light of the latest knowledge of pharmacological treatment for schizophrenia.. A total of 265 patients were randomized to receive blonanserin (8 to 24 mg/d) or haloperidol (4 to 12 mg/d) twice daily for 8 weeks. Efficacy assessments included the Clinical Global Impressions-Improvement (CGI-I) and the Positive and Negative Syndrome Scale (PANSS).. Blonanserin was not inferior to haloperidol with a margin of 10% with respect to the improvement rate on CGI-I at end of study (60.5% vs 50.0%, P < 0.001). The decrease in the PANSS total score did not differ between the drugs (-10.3 vs -7.1). For the PANSS negative symptom score, the decrease was significantly greater with blonanserin than with haloperidol (P = 0.006). Blonanserin was well tolerated. The incidence of adverse events was similar for the two drugs. Extrapyramidal adverse events, sedation, hypotension, and prolactin increase were rarer with blonanserin than with haloperidol. No clinically important weight gain was observed.. Blonanserin is as effective as haloperidol for the treatment of schizophrenia. Blonanserin is more effective for negative symptoms with a lower risk of extrapyramidal symptoms compared with haloperidol.

Topics: Adult; Antipsychotic Agents; Double-Blind Method; Drug Tolerance; Female; Haloperidol; Humans; Male; Middle Aged; Piperazines; Piperidines; Schizophrenia; Weight Gain

Second generation antipsychotics are prescribed for an increasing number of psychiatric conditions, despite variable associations with weight gain, dyslipidemia, and impaired glucose tolerance. The mechanism(s) of the apparent causal relationships between these medications and metabolic effects have been inadequately defined and are potentially confounded by genetic risk of mental illness, attendant lifestyle, and concomitant medications. Therefore, we conducted a study in which 24 healthy volunteers were randomized to olanzapine (highly weight-gain liability), iloperidone (less weight-gain liability), or placebo treatment for 28 days under double-blind conditions. We hypothesized that antipsychotics induce weight gain primarily through increased caloric intake, which causes secondary dyslipidemia and insulin resistance. Subjects were phenotyped pre- and post-treatment for body weight, adiposity by dual energy X-ray absorptiometry, energy expenditure by indirect calorimetry, food intake, oral glucose tolerance, plasma lipids, glucose, insulin, and other hormones. We found significantly increased food intake and body weight but no change in energy expenditure in olanzapine-treated subjects, with associated trends towards lipid abnormalities and insulin resistance the extent of which were presumably limited by the duration of treatment. Iloperidone treatment led to modest non-significant and placebo no weightgain, lipid increases and alterations in insulin metabolism. We conclude that second generation antipsychotic drugs, as represented by olanzapine, produce their weight and metabolic effects, predominantly, by increasing food intake which leads to weight gain that in turn induces metabolic consequences, but also through other direct effects on lipid and glucose metabolism independant of food intake and weight gain.

Topics: Adolescent; Adult; Antipsychotic Agents; Blood Glucose; Body Weight; Double-Blind Method; Dyslipidemias; Eating; Energy Metabolism; Female; Glucose Tolerance Test; Healthy Volunteers; Humans; Insulin; Insulin Resistance; Isoxazoles; Lipids; Male; Obesity; Olanzapine; Piperidines; Weight Gain; Young Adult

This was a post hoc analysis of a 2-year, double-blind study of 2639 patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin monotherapy, which assessed achievement of a composite endpoint of sustained glycated haemoglobin (HbA1c) reduction (≤7.0% at week 104 or ≥0.5% decrease from baseline) with no weight gain and no hypoglycaemic events with alogliptin 12.5 and 25 mg daily or glipizide (≤20 mg daily), each added to metformin. With an HbA1c target of ≤7.0%, 24.2 and 26.9% of patients treated with alogliptin 12.5 and 25 mg, respectively, achieved the composite endpoint versus 10.7% of patients treated with glipizide (both p < 0.001). With a criterion of ≥0.5% decrease in HbA1c, the composite endpoint was reached in 22.5, 25.2 and 10.4% of patients treated with alogliptin 12.5 mg, alogliptin 25 mg and glipizide, respectively. Odds ratios for achieving the composite endpoint favoured alogliptin in the primary analysis set and in all subgroups of patients. Patients with T2DM failing metformin monotherapy were more likely to achieve sustained glycaemic control with no hypoglycaemia or weight gain at 2 years with alogliptin than with glipizide.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Endpoint Determination; Female; Glipizide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines; Treatment Outcome; Uracil; Weight Gain; Young Adult

This randomized, double-blind study compared the efficacy and safety of blonanserin and risperidone to treat Chinese schizophrenia patients aged ≥18 and < 65 years. Patients with Positive and Negative Syndrome Scale (PANSS) total scores ≥70 and ≤ 120 were randomized to receive blonanserin or risperidone using a gradual dose-titration method (blonanserin tablets: 8-24 mg/day; risperidone tablets: 2-6 mg/day), twice daily. Treatment populations consisted of 128 blonanserin-treated patients and 133 risperidone-treated patients. Intention-to-treat analysis was performed using the last observation carried forward method. Reductions of PANSS total scores by blonanserin and risperidone treatment were -30.59 and -33.56, respectively. Risperidone treatment was associated with elevated levels of serum prolactin (67.16% risperidone versus 52.31% blonanserin) and cardiac-related abnormalities (22.39% risperidone versus 12.31% blonanserin), and blonanserin patients were more prone to extrapyramidal side effects (48.46% blonanserin versus 29.10% risperidone). In conclusion, blonanserin was as effective as risperidone for the treatment of Chinese patients with schizophrenia. The overall safety profiles of these drugs are comparable, although blonanserin was associated with a higher incidence of EPS and risperidone was associated with a higher incidence of prolactin elevation and weight gain. Thus, blonanserin is useful for the treatment of Chinese schizophrenia patients.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Asian People; China; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Piperazines; Piperidines; Prolactin; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Weight Gain; Young Adult

To evaluate the efficacy and safety of alogliptin added to insulin in Japanese patients with type 2 diabetes mellitus (T2DM) who are poorly controlled with insulin and diet or exercise.. This was a randomized, double-blind, 12-week comparative trial of alogliptin and insulin versus placebo and insulin in 179 patients with T2DM followed by a 40-week, open-label phase in 169 patients on alogliptin and insulin.. Change in glycated hemoglobin (HbA1c) from baseline to the end of double-blind phase (week 12).. The change in HbA1c (least squares means) from baseline to week 12 was -0.96% for the alogliptin and insulin group and -0.29% for the placebo and insulin group. The point estimate (95% confidence interval) intergroup difference was -0.66% ([-0.824%, -0.503%]). In the alogliptin and insulin group, HbA1c started to decrease from week 2 onward and peaked by week 12. The proportions of patients who achieved HbA1c < 8.0, < 7.0 and < 6.0% at week 12 were significantly higher in alogliptin and insulin group (73.0, 23.3 and 1.1%) than in placebo and insulin group (25.0, 5.7 and 0%). Incidences of adverse effects were comparable between groups, with no relevant increases in hypoglycemia or weight gain seen.. Alogliptin 25 mg/day was effective and well tolerated when added to insulin in Japanese patients with inadequately controlled T2DM.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Japan; Male; Middle Aged; Piperidines; Placebo Effect; Uracil; Weight Gain

To prospectively evaluate the efficacy and safety of alogliptin versus glipizide in elderly patients with type 2 diabetes mellitus (T2DM) over 1 year of treatment.. This was a randomized, double-blind, active-controlled study of elderly T2DM patients (aged 65-90 years) with mild hyperglycaemia on diet/exercise therapy alone [glycosylated haemoglobin (HbA1c) 6.5-9.0%] or plus oral antidiabetic monotherapy (HbA1c 6.5-8.0%). Patients were randomized to once-daily alogliptin 25 mg or glipizide 5 mg titrated to 10 mg, if needed. Hypoglycaemic episodes were systematically captured under predefined criteria.. In the primary analysis, HbA1c mean changes from a baseline of 7.5% were -0.14% with alogliptin (n = 222) and -0.09% with glipizide (n = 219) at the end of the study, demonstrating non-inferiority of alogliptin to glipizide [least squares (LS) mean difference = -0.05%; one-sided 97.5% confidence interval (CI): -∞, 0.13%]. More clinically relevant HbA1c reductions occurred among patients who completed the study: -0.42 and -0.33% with alogliptin and glipizide, with non-inferiority again confirmed (LS mean difference = -0.09%; one-sided 97.5% CI: -∞, 0.07%). Overall, alogliptin was safe and well tolerated, with notably fewer hypoglycaemic episodes than glipizide [5.4% (31 episodes) vs. 26.0% (232 episodes), respectively]; three patients experienced severe hypoglycaemia, all with glipizide. Alogliptin also resulted in favourable weight changes versus glipizide (-0.62 vs. 0.60 kg at week 52; p < 0.001).. Alogliptin monotherapy maintained glycaemic control comparable to that of glipizide in elderly patients with T2DM over 1 year of treatment, with substantially lower risk of hypoglycaemia and without weight gain.

Topics: Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dizziness; Double-Blind Method; Female; Glipizide; Glycated Hemoglobin; Headache; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Piperidines; Prospective Studies; Treatment Outcome; Triglycerides; Uracil; Weight Gain

Acarbose was administered at 300 mg/day to patients with type 2 diabetes mellitus (T2DM) who had been taking 25 mg/day of alogliptin, and levels of blood glucose were analyzed by continuous glucose monitoring (CGM) for 3 days. The mean blood glucose level with acarbose (136.4 ± 30.7 mg/dL) did not differ significantly from that without acarbose (141.7 ± 28.3 mg/dL). However, in the condition of the combination therapy, there were significant decreases in the standard deviation of the mean blood glucose levels for the 24-hour period (27.6 ± 9.1 vs. 16.2 ± 6.9 mg/dL, p<0.001) and mean amplitude of glycemic excursions (MAGE) (65.8 ± 26.1 vs. 38.8 ± 19.2 mg/dL, p=0.010). In addition, a meal tolerance test was conducted to monitor changes in insulin secretion and active GLP-1 and total GIP values. Ten subjects (5 males, 5 females) of 54.9 ± 6.9 years with BMI 25.9 ± 5.2 kg/m² and HbAlc 9.2 ± 1.2% were enrolled. In the meal tolerance test, active GLP-1 values before and after acarbose administration were 17.0 ± 5.8 and 24.1 ± 9.3 pmol·hr/mL (p=0.054), respectively, showing an increasing tendency, and total GIP(AUC0-180) values were 685.9 ± 209.7 and 404.4 ± 173.7 pmol·hr/mL, respectively, showing a significant decrease (p=0.010). The results indicate that the combined administration of both inhibitors is effective not only in decreasing blood glucose fluctuations and preventing postprandial insulin secretion. The beneficial effects may also protect the endocrine pancreas and inhibit body weight gain.

Topics: Acarbose; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Enzyme Inhibitors; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Overweight; Piperidines; Uracil; Weight Gain

A hyperactive endocannabinoid signalling system may contribute to addictions. We tested the efficacy and safety of surinabant, a novel selective CB₁ cannabinoid receptor antagonist, for smoking cessation. In a randomized, double-blind, placebo-controlled, parallel-group clinical trial, participants were assigned to brief counselling and one of three doses of surinabant, 2.5 mg/day (n = 199), 5 mg/day (n = 204), or 10 mg/day (n = 205) or placebo (n = 202) orally for 8 weeks with 6 weeks of non-drug follow-up. For weeks 5 through 8, the 4-week continuous abstinence rates were 25.2% for placebo vs. 22.6%, 22.1% and 21.5% for 2.5 mg/day, 5 mg/day and 10 mg/day doses of surinabant (p for trend, 0.4). The gain in body weight from baseline was reduced with surinabant 2.5 mg/day, 5 mg/day and 10 mg/day (0.75 kg [SE, 0.13], 0.53 kg [SE, 0.13], and 0.24 kg [SE, 0.13], respectively, versus 1.19 kg [SE, 0.13] for placebo; p for trend, < 0.001). The most common adverse events for participants receiving active drug with a greater incidence than placebo were headache, nausea, insomnia, anxiety, nasopharyngitis, diarrhoea and hyperhidrosis. Surinabant did not improve smoking cessation rates compared with placebo, but had a small effect on reducing post-cessation weight gain.

Topics: Adolescent; Adult; Aged; Dose-Response Relationship, Drug; Double-Blind Method; Europe; Female; Follow-Up Studies; Humans; Intention to Treat Analysis; Male; Middle Aged; Patient Dropouts; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Secondary Prevention; Smoking Cessation; Smoking Prevention; Weight Gain; Young Adult

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA that produces the farnesylated aberrant lamin A protein, progerin. This multisystem disorder causes failure to thrive and accelerated atherosclerosis leading to early death. Farnesyltransferase inhibitors have ameliorated disease phenotypes in preclinical studies. Twenty-five patients with HGPS received the farnesyltransferase inhibitor lonafarnib for a minimum of 2 y. Primary outcome success was predefined as a 50% increase over pretherapy in estimated annual rate of weight gain, or change from pretherapy weight loss to statistically significant on-study weight gain. Nine patients experienced a ≥50% increase, six experienced a ≥50% decrease, and 10 remained stable with respect to rate of weight gain. Secondary outcomes included decreases in arterial pulse wave velocity and carotid artery echodensity and increases in skeletal rigidity and sensorineural hearing within patient subgroups. All patients improved in one or more of these outcomes. Results from this clinical treatment trial for children with HGPS provide preliminary evidence that lonafarnib may improve vascular stiffness, bone structure, and audiological status.

Topics: Adolescent; Carotid Arteries; Child; Child, Preschool; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Inhibitors; Farnesyltranstransferase; Fatigue; Female; Humans; Male; Piperidines; Progeria; Pulse Wave Analysis; Pyridines; Treatment Outcome; Vomiting; Weight Gain

Weight gain is a common side effect of antipsychotics, contributing to poor treatment adherence, and previously linked to the -759C/T polymorphism near the serotonin receptor 2C gene. The effect of this polymorphism was analyzed in schizophrenia patients treated with iloperidone for up to 7 months. No association was detected with the modest weight changes observed in these patients.

Topics: Analysis of Variance; Antipsychotic Agents; Female; Follow-Up Studies; Gene Frequency; Genotype; Humans; Isoxazoles; Male; Piperazines; Piperidines; Polymorphism, Genetic; Receptor, Serotonin, 5-HT2C; Schizophrenia; Thiazoles; Weight Gain

The objective of this study was to evaluate the efficacy and tolerability of blonanserin for the treatment of Korean patients with schizophrenia using a double-blind risperidone-compared design.. Patients aged 18 to 65 years with schizophrenia were randomly assigned to blonanserin or risperidone treatment for 8 weeks. The efficacy was assessed using the mean change in Positive and Negative Syndrome Scale score total scores from baseline to week 8. Safety assessments included monitoring of vital signs, a physical examination, laboratory tests, and adverse events.. Of 206 randomly enrolled patients, 103 receiving blonanserin and 103 receiving risperidone were included in the analysis. In this study, noninferiority between blonanserin and risperidone was demonstrated. The mean change in the Positive and Negative Syndrome Scale total score at the final evaluation time point was -23.48 +/- 19.73 for the blonanserin group and -25.40 +/- 18.38 for the risperidone group. Adverse events, which occurred less frequently in the blonanserin than in the risperidone group, included dysarthria (P = 0.0288), dizziness (P = 0.0139), increased alanine aminotransferase and aspartate aminotransferase (P = 0.0095 and P = 0.0032, respectively), and increased level blood prolactin (P = 0.0012). On the other hand, the adverse events that occurred more frequently in the blonanserin than in the risperidone group was hand tremor (P = 0.0006).. Blonanserin was effective in the treatment of Korean patients with schizophrenia compared with risperidone and was more tolerable with a better safety profile, particularly with respect to prolactin elevation. These findings suggest that blonanserin is useful in the treatment of schizophrenia.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hyperprolactinemia; Male; Middle Aged; Piperazines; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Weight Gain; Young Adult

Because smoking cessation rates might be improved by combining drugs and by reducing post-cessation weight gain, we tested the smoking cessation efficacy, safety and effect on body weight of adding the nicotine patch to rimonabant, a cannabanoid type-1 receptor antagonist that reduces body weight.. Randomized double-blind placebo-controlled trial.. Fifteen US research centers.. A total of 755 smokers (> OR = 15 cigarettes/day). Intervention Rimonabant (20 mg daily) was given open-label for 9 weeks. The 735 participants completing week 1 were randomized at day 8 (target quit day) to add a nicotine patch (n = 369) or placebo patch (n = 366) for 10 weeks (21 mg daily for 8 weeks plus a 2-week taper). Participants received weekly smoking counseling and were followed for 24 weeks.. Biochemically validated 4-week continuous abstinence at end-of-treatment (weeks 6-9; primary end-point); 7-day point prevalence abstinence at weeks 9 and 24; sustained abstinence (weeks 6-24); change in body weight; and adverse events.. Rimonabant plus nicotine patch was superior to rimonabant plus placebo in validated continuous abstinence at weeks 6-9 (39.0% versus 21.3%; odds ratio 2.36, 95% confidence interval: 1.71-2.37; P < 0.01) and in all other efficacy measures. Mean end-of-treatment weight gain among quitters did not differ between groups (0.04 kg for combination versus 0.49 kg for rimonabant only, P = 0.15) and was similar in weight-concerned smokers. Serious adverse event rates did not differ between groups. Depression- and anxiety-related adverse events occurred in 32 (4.2%) and 44 (5.8%) subjects, respectively; eight (1.1%) and nine (1.2%) subjects stopped the drug due to depression and anxiety, respectively.. Adding a nicotine patch to rimonabant was well tolerated and increased smoking cessation rates over rimonabant alone. There was little post-cessation weight gain in either group, even among weight-concerned smokers, during drug treatment.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Aged, 80 and over; Counseling; Double-Blind Method; Female; Humans; Male; Middle Aged; Nicotine; Nicotinic Agonists; Odds Ratio; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Smoking; Smoking Cessation; Smoking Prevention; Treatment Outcome; Weight Gain; Young Adult

Combinations of insulin and oral antidiabetic drugs (OAD) are often prescribed instead of insulin alone. In this study, the effects of insulin glargine (IG) in combination with repaglinide or acarbose on glycemic parameters were investigated. Obese Type 2 diabetic patients with fasting blood glucose (FBG) levels >or= 7.7 mmol/l [corrected] and hemoglobin glycated (A1C) >or=9% under maximal OAD combination therapy were enrolled. Previous therapies were discontinued, and patients were randomized into 2 groups. The combinations of IG and repaglinide were administered to group 1, and of IG and acarbose to group 2 for 13 weeks. Twenty patients in group 1 and 18 patients in group 2 completed the study. A1C levels were significantly decreased from 10.9+/-1.4% to 7.7+/-1.1% in group 1 and 11.0+/-1.4% to 8.1+/-1.4% in group 2. FBG levels were significantly decreased from 11.9+/-2.7 to 7.1+/-2.3 mmol/l in group 1 and 11.1+/-2.5 to 6.8+/-1.4 mmol/l in group 2. Post-prandial glucose levels were significantly decreased from 15.3+/-3.8 to 10.3+/-3.0 mmol/l in group 1 and 14.0+/-3.1 to 8.9+/-2.2 mmol/l in group 2. Intergroup comparisons indicated no significant differences. More weight gain was detected in group 1, compared to the baseline. Symptomatic hypoglycemia incidence was similar in both groups. Severe hypoglycemic attacks were seen in two patients in group 1. Flatulence incidence was higher in acarbose group. Conclusively, repaglinide and acarbose were equally effective when combined with IG for obese Type 2 diabetic patients controlled inadequately with OAD alone. Furthermore, acarbose seems to have advantages over repaglinide concerning weight gain and severe hypoglycemic attacks.

Topics: Acarbose; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Obesity; Piperidines; Weight Gain

To assess the efficacy and safety of alogliptin added to insulin in patients with type 2 diabetes inadequately controlled with insulin alone or combined with metformin.. In this 26-week, double-blind, placebo-controlled study, 390 patients were randomized to receive alogliptin 12.5 mg (n = 131), alogliptin 25 mg (n = 129) or placebo (n = 130) once daily, as add-on to stable insulin therapy with or without metformin. The primary endpoint was change in haemoglobin A(1C) (HbA(1C)) at week 26.. At week 26, mean HbA(1C) changes from the mean baseline value of 9.3% were significantly greater for alogliptin 12.5 mg (-0.63 +/- 0.08%) and alogliptin 25 mg (-0.71 +/- 0.08%) than placebo (-0.13 +/- 0.08%; p < 0.001). Significantly greater proportions of patients receiving alogliptin 12.5 or 25 mg than placebo had HbA(1C) decreases of > or =0.5, > or =1.0 and > or =1.5%. Insulin doses remained unchanged, and there were no differences in the proportions of patients experiencing hypoglycaemia among placebo (24%), alogliptin 12.5 mg (27%) and alogliptin 25 mg (27%). Mean weight increases from baseline at week 26 were similar for placebo (0.6 +/- 0.2 kg), alogliptin 12.5 mg (0.7 +/- 0.2 kg) and alogliptin 25 mg (0.6 +/- 0.2 kg). Incidences of overall adverse events, and of gastrointestinal, dermatological and infection-related events, were similar among groups.. Adding alogliptin to previous insulin therapy (with or without metformin) significantly improved glycaemic control in patients with type 2 diabetes inadequately controlled on insulin, without causing weight gain or increasing the incidence of hypoglycaemia. Further studies are warranted to explore the role of alogliptin added to optimized basal insulin regimens.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Piperidines; Treatment Outcome; Uracil; Weight Gain; Young Adult

To study the effect of insulin treatment in combination with metformin or an insulin secretagogue, repaglinide, on glycaemic regulation in non-obese patients with type 2 diabetes.. Randomised, double blind, double dummy, parallel trial.. Secondary care in Denmark between 2003 and 2006.. Non-obese patients (BMI

Topics: Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Aspart; Male; Metformin; Middle Aged; Patient Compliance; Piperidines; Treatment Outcome; Weight Gain

To evaluate the efficacy and safety of the association of repaglinide, metformin and bedtime NPH insulin compared to two classic regimens: metformin plus NPH and two doses of NPH in patients with poorly controlled type 2 diabetes despite two or more oral antidiabetic drugs (OADs).. Random, parallel and open study of 24 weeks with 37 patients randomized into three therapeutic groups: group A (n=12) (repaglinide/metformin/NPH), group B (n=12) (metformin/NPH) and group C (n=13) (NPH/NPH). The insulin was adjusted in the visits to obtain a basal blood glucose <110 mg/dl. The endpoint criteria included HbA1c, blood glucose profile, hypoglycemias and body weight.. At the end of the study, group A presented HbA1c (mean+/-standard deviation) 7.2+/-0.7%, which was significantly less than B (8.8+/-0.1%) and C (8.4+/-1.2%). In terms of absolute reduction, there were only differences (p=0.01) between group A (-2.4+/-1.1%) and B (-0.7+/-1.2%). Group A presented lower postprandial blood glucose values (p<0.01). Nor were there any significant differences in weight gain and incidence of hypoglycemia.. The combination of repaglinide, metformin and bedtime NPH is safe and effective and it provides better postprandial blood glucose control. The association of metformin and a dose of NPH does not obtain suitable control in patients with a long evolution who have already received two or more OADs.

Topics: Aged; Blood Glucose; Blood Pressure; Body Mass Index; Carbamates; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Insulin, Isophane; Male; Metformin; Middle Aged; Piperidines; Prospective Studies; Safety; Weight Gain

To compare combination use of repaglinide, metformin and bedtime Neutral Protamine Hagedorn (NPH) insulin with conventional approaches of insulin initiation in patients with Type 2 diabetes (T2DM).. Eighty-two patients with T2DM with suboptimal glycaemic control on oral glucose-lowering agents were randomized to one of three treatment regimens for 4 months. Group 1 received metformin and twice daily biphasic 30/70 human insulin mixture (n = 27), group 2 metformin and bedtime NPH insulin (n = 26) and group 3 metformin, bedtime NPH insulin and mealtime repaglinide (n = 25).. Seventy-five patients completed the study. Baseline and end-point mean HbA1c levels fell from 9.0 +/- 1.1 to 7.9 +/- 1.1% in group 1, 10.0 +/- 2.2 to 9.2 +/- 1.4% group 2 and 10.0 +/- 1.7 to 8.1 +/- 1.5% in group 3, respectively. All groups showed improvements in HbA1c. There was no significant difference between groups in the proportions of patients experiencing hypoglycaemia (29.6, 25.0 and 16.7%, respectively; P = 0.55) or in mean weight gain (2.9, 0.7 and 2.2 kg, respectively; P = 0.06). By 4 months, insulin doses were 0.63 +/- 0.32 IU/kg in group 1, 0.58 +/- 0.21 IU/kg in group 2 and 0.37 +/- 0.22 IU/kg in group 3 (group 3 vs. groups 1 and 2: P < 0.002).. The approach using repaglinide, metformin and NPH insulin improved glycaemic control with a similar safety profile to conventional insulin initiation in T2DM and produced final glycaemic control similar to metformin and a twice daily biphasic insulin mixture.

Topics: Adult; Aged; Aged, 80 and over; Carbamates; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Isophane; Male; Metformin; Middle Aged; Piperidines; Treatment Outcome; Weight Gain

This 24-week, randomized, multicentre, open-label, parallel-group clinical trial compared efficacy and safety of repaglinide monotherapy, rosiglitazone monotherapy, and combination therapy (repaglinide plus rosiglitazone) in Type 2 diabetes after unsatisfactory response to sulphonylurea or metformin monotherapy.. Enrolled patients (n = 252) were adults having Type 2 diabetes for at least 1 year, with HbA(1c) values > 7.0% after previous monotherapy (sulphonylurea or metformin, >/= 50% maximal dose). Prior therapy was withdrawn for 2 weeks, followed by randomization to repaglinide, rosiglitazone, or repaglinide/rosiglitazone. Study treatments were initiated with a 12-week dose optimization period (doses optimized according to labelling), followed by a 12-week maintenance period. Efficacy endpoints were changes in HbA(1c) values (primary) or fasting plasma glucose values (secondary).. Baseline HbA(1c) values were comparable (9.3% for repaglinide, 9.0% for rosiglitazone, 9.1% for combination). Mean changes in HbA(1c) values at the end of treatment were greater for repaglinide/rosiglitazone therapy (-1.43%) than for repaglinide (-0.17%) or rosiglitazone (-0.56%) monotherapy. Reductions of fasting plasma glucose values were also greater for combination therapy (-5.2 mmol/l, -94 mg/dl) than for repaglinide monotherapy (-3.0 mmol/l, -54 mg/dl) or rosiglitazone monotherapy (-3.7 mmol/l, -67 mg/dl). Minor hypoglycaemic events occurred in 9% of combination therapy patients, vs. 6% for repaglinide and 2% for rosiglitazone. Individual weight gains for combination therapy were correlated to HbA(1c) response.. The combination therapy regimen was well tolerated. In patients previously showing unsatisfactory response to oral monotherapy, glycaemic reductions were greater for the repaglinide/rosiglitazone combination regimen than for use of either repaglinide or rosiglitazone alone.

Topics: Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Rosiglitazone; Thiazolidinediones; Treatment Outcome; Weight Gain

This open-label randomized controlled clinical trial compared the effect on glycaemic control and weight gain of repaglinide vs. gliclazide combined with bedtime NPH insulin in patients with Type 2 diabetes inadequately controlled with oral hypoglycaemic therapy [HbA1c>7.0% (DCCT aligned assay, normal range 4.6-6.2%)].. Eighty subjects with Type 2 diabetes were randomized to 13 weeks' open-label treatment with repaglinide 4 mg t.i.d. or gliclazide 160 mg b.i.d. in combination with bedtime NPH insulin (initial dose 0.5 units/kg). The fasting blood glucose (FBG) target was < or =6.0 mmol/l.. Baseline characteristics were similar for age, sex, weight, BMI, FBG and HbA1c. Glycaemic control improved similarly in both groups-insulin/gliclazide by (mean) 1.0%, from 9.2 to 8.2% (P=0.001) and by 0.9%, from 9.4 to 8.5% in the insulin/repaglinide group (P=0.005) (P=0.83 between groups). Weight gain averaged (mean +/- sem) 4.1 +/- 0.5 and 3.4 +/- 0.4 kg in the insulin/gliclazide and insulin/repaglinide groups, respectively (P<0.0001 for both groups from baseline) (P=0.29 between groups). The mean number of hypoglycaemic episodes experienced per patient was 2.95 +/- 0.82 (insulin/gliclazide) and 2.3 +/- 0.52 (insulin/repaglinide) (P=0.81 between groups). Both treatments were associated with significant improvements in Diabetes Treatment Satisfaction [Diabetes Treatment Satisfaction Questionnaire-potential range 0 (min) to 36 (max)]; in the insulin/gliclazide group, by 4.9 +/- 1.1 points to 33.3 +/- 0.6 (P<0.0001) and by 3.0 +/- 0.9 points to 34.6 +/- 0.4 (P=0.0006) in the insulin/repaglinide group (P=0.29 between groups).. Over 13 weeks, both repaglinide and gliclazide, when combined with bedtime NPH insulin produce similar significant improvements in glycaemic control (-1%) and similar weight gain.

Topics: Administration, Oral; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Gliclazide; Hemoglobin A; Humans; Hypoglycemic Agents; Insulin, Isophane; Male; Metformin; Middle Aged; Patient Satisfaction; Piperidines; Surveys and Questionnaires; Weight Gain

To determine the efficacy of cisapride, 10 mg three times daily, in improving gastric emptying, reducing distress during meals, and facilitating weight gain in anorexia nervosa, we conducted an 8-week, randomized, double-blind, placebo-controlled trial on 29 inpatients. Measures included scintigraphic gastric emptying studies at 0, 2, 4, and 8 weeks; subjective distress during meals measured by visual analogue scales; self-rating of degree of global improvement in symptoms associated with eating at end of study; and weight measured weekly. Gastric emptying improved significantly but equally in both groups over the study period. Yet subjective measures were better in the cisapride group; they rated themselves as more hungry (p = .02) and more improved on the global measure of change in symptoms (p = .02). Even so, the cisapride group did not gain more weight. The correlation between gastric emptying and weight gain was modest (r = .30; p = .11), and between gastric emptying and the subjective measures, virtually absent.

Topics: Adolescent; Adult; Anorexia Nervosa; Cisapride; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Gastric Emptying; Humans; Pain Measurement; Piperidines; Serotonin Antagonists; Treatment Outcome; Weight Gain

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

A series of benzoisoxazoleylpiperidine derivatives were synthesized by using the multi-target strategies and their potent affinities for dopamine (DA), serotonin (5-HT) and human histamine H

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Cognition; Dopamine; Drug Design; Humans; Hyperprolactinemia; Mice; Models, Animal; Movement; Piperidines; Protein Binding; Receptors, Histamine H3; Risperidone; Serotonin; Structure-Activity Relationship; Weight Gain

Topics: Adenine; Aged; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Weight Gain

A high-fat diet (HFD) causes obesity-associated morbidities involved in macroautophagy and chaperone-mediated autophagy (CMA). AMPK, the mediator of macroautophage, has been reported to be inactivated in HFD-caused renal injury. However, PAX2, the mediator for CMA, has not been reported in HFD-caused renal injury. Here we report that HFD-caused renal injury involved the inactivation of Pax2 and Ampk, and the activation of soluble epoxide hydrolase (sEH), in a murine model. Specifically, mice fed on an HFD for 2, 4, and 8 wk showed time-dependent renal injury, the significant decrease in renal Pax2 and Ampk at both mRNA and protein levels, and a significant increase in renal sEH at mRNA, protein, and molecular levels. Also, administration of an sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea, significantly attenuated the HFD-caused renal injury, decreased renal sEH consistently at mRNA and protein levels, modified the renal levels of sEH-mediated epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs) as expected, and increased renal Pax2 and Ampk at mRNA and/or protein levels. Furthermore, palmitic acid (PA) treatment caused significant increase in

Topics: Adenylate Kinase; Animals; Cytochrome P-450 Enzyme System; Diet, High-Fat; Disease Models, Animal; Eicosanoids; Enzyme Inhibitors; Epoxide Hydrolases; Hypertrophy; Kidney; Mesangial Cells; Mice; Palmitic Acid; PAX2 Transcription Factor; Phenylurea Compounds; Piperidines; Solubility; Time Factors; Weight Gain

Piperine (E,E-) is a naturally occurring pungent and spicy constituent of black pepperand is also used as an added flavoring ingredient to foods and beverages. Piperine has been determined safe under conditions of intended use as a flavoring substance by regulatory and scientific expert bodies. While concurring with the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and Flavor and Extract Manufacturers Association (FEMA) Expert Panel on the safety of piperine, the European Food Safety Authority (EFSA) requested additional toxicological data. The results of a 90-day GLPcompliant dietary study, conducted in Sprague-Dawley rats at target doses of 0, 5, 15, or 50 mg/kg bw/day, to respond to this request are presented herein. No adverse effects were found attributable to ingestion of piperine. Statistically significant changes in food consumption, body weight gain, and plasma cholesterol levels were not considered adverse as discussed in this paper. Therefore, the oral no-observed-adverse-effect level (NOAEL) was determined to be the highest dose tested of 50 mg/kg bw/day. EFSA derived a lower NOAEL of 5 mg/kg bw/day based on increased plasma cholesterol levels which still affords an adequate margin of safety of over 48,000 and concluded that piperine is not of safety concern.

Topics: Alkaloids; Animals; Benzodioxoles; Cholesterol; Dietary Exposure; Dose-Response Relationship, Drug; Feeding Behavior; Female; Male; No-Observed-Adverse-Effect Level; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Weight Gain

Tofacitinib is the first Janus Kinase (JAK) inhibitor to treat moderately to severely active RA. In this study, we investigated whether the effect of tofacitinib have any effects on body composition in mice and female patients with RA. Female C57BL/6 mice fed with a high-fat diet were treated with 30 mg/kg/day tofacitinib or vehicle for 70 days. Following treatment, trunk muscle, subcutaneous fat, and visceral fats were measured using X-ray computed tomography CT scan. Glucose tolerance and insulin sensitivity were assessed. In female RA patients treated with biological disease modified anti-rheumatic-drugs (biological DMARDs) or tofacitinib (n=4 per group), we also evaluated the body composition after 3 months from the start of treatment initiation using bioelectrical impedance analysis. Treatment with tofacitinib did not affect the body weight, and body composition in C57BL/6 mice. It also did not affect glucose, and insulin tolerance in mice. In patients with RA, treatment with biological DMARDs did not affect the body composition whereas the muscle mass was unchanged after receiving tofacitinib and the fat mass was significantly increased. J. Med. Invest. 65:166-170, August, 2018.

Topics: Adiposity; Adult; Aged; Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Body Composition; Diet, High-Fat; Female; Glucose; Humans; Janus Kinase Inhibitors; Lipolysis; Mice; Mice, Inbred C57BL; Middle Aged; Piperidines; Pyrimidines; Pyrroles; Weight Gain

Previous studies reported that the co-injection of leptin and cannabinoid CB1 receptor antagonists reduces food intake and body weight in rats, and this effect is more profound than that induced by these compounds individually. Additionally, serotonin mediates the effects of numerous anorectic drugs. To investigate whether serotonin interacts with leptin and endocannabinoids to affect food intake and body weight, we administered 5-hydroxytryptamine(HT)1B and 5-hydroxytryptamine(HT)2C serotonin receptor antagonists (3 mg/kg GR 127935 and 0.5 mg/kg SB 242084, respectively) to male Wistar rats treated simultaneously with leptin (100 μg/kg) and the CB1 receptor inverse agonist AM 251 (1 mg/kg) for 3 days. In accordance with previous findings, the co-injection of leptin and AM 251, but not the individual injection of each drug, resulted in a significant decrease in food intake and body weight gain. Blockade of the 5-HT1B and 5-HT2C receptors completely abolished the leptin- and AM 251-induced anorectic and body-weight-reducing effects. These results suggest that serotonin mediates the leptin- and AM 251-dependent regulation of feeding behavior in rats via the 5-HT1B and 5-HT2C receptors.

Topics: Aminopyridines; Animals; Cannabinoid Receptor Agonists; Drug Synergism; Eating; Indoles; Leptin; Male; Oxadiazoles; Piperazines; Piperidines; Pyrazoles; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Antagonists; Weight Gain

In type 2 diabetes mellitus (T2DM) patients, the gradual loss of pancreatic β-cell function is a characteristic feature of disease progression that is associated with sustained hyperglycemia. Recently, G protein-coupled receptor 119 (GPR119) has been identified as a promising anti-diabetic therapeutic target. It is predominantly expressed in pancreatic β-cells, directly promotes glucose stimulated insulin secretion and indirectly increases glucagon-like peptide 1 (GLP-1) levels reducing appetite and food intake. Activation of GPR119 leads to insulin release in β-cells by increasing intracellular cAMP. Here, we identified a novel structural class of small-molecule GPR119 agonists, HD0471042, consisting of substituted a 3-isopropyl-1,2,4-oxadiazol-piperidine derivative with promising potential for the treatment of T2DM. The GPR119 agonist, HD0471042 increased intracellular cAMP levels in stably human GPR119 expressing CHO cell lines and HIT-T15 cell lines, hamster β-cell line expressing endogenously GPR119. HD0471042, significantly elevated insulin release in INS-1 cells of rat pancreatic β-cell line. In in vivo experiments, a single dose of HD0471042 improved glucose tolerance. Insulin and GLP-1 level were increased in a dose-dependent manner. Treatment with HD0471042 for 6 weeks in diet induced obesity mice and for 4 weeks in ob/ob and db/db mice improved glycemic control and also reduced weight gain in a dose-dependent manner. These data demonstrate that the novel GPR119 agonist, HD0471042, not only effectively controlled glucose levels, but also had an anti-obesity effect, a feature observed with GLP-1. We therefore suggest that HD0471042 represents a new type of anti-diabetes agent with anti-obesity potential for the effective treatment of type 2 diabetes.

Topics: Animals; Anti-Obesity Agents; Blood Glucose; CHO Cells; Cricetulus; Cyclic AMP; Diabetes Mellitus, Type 2; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Male; Mice, Inbred C57BL; Obesity; Oxadiazoles; Piperidines; Rats; Receptors, G-Protein-Coupled; Structure-Activity Relationship; Time Factors; Transfection; Weight Gain

The molecular mechanisms involved in the development of obesity and related complications remain unclear. Here, we report that obese mice and human subjects have increased activity of neutrophil elastase (NE) and decreased serum levels of the NE inhibitor α1-antitrypsin (A1AT, SerpinA1). NE null (Ela2(-/-)) mice and A1AT transgenic mice were resistant to high-fat diet (HFD)-induced body weight gain, insulin resistance, inflammation, and fatty liver. NE inhibitor GW311616A reversed insulin resistance and body weight gain in HFD-fed mice. Ela2(-/-) mice also augmented circulating high molecular weight (HMW) adiponectin levels, phosphorylation of AMP-activated protein kinase (AMPK), and fatty acid oxidation (FAO) in the liver and brown adipose tissue (BAT) and uncoupling protein (UCP1) levels in the BAT. These data suggest that the A1AT-NE system regulates AMPK signaling, FAO, and energy expenditure. The imbalance between A1AT and NE contributes to the development of obesity and related inflammation, insulin resistance, and liver steatosis.

Topics: Adiponectin; Adipose Tissue, Brown; alpha 1-Antitrypsin; AMP-Activated Protein Kinase Kinases; Animals; Diet, High-Fat; Energy Metabolism; Fatty Acids; Fatty Liver; Hep G2 Cells; Humans; Inflammation; Insulin Resistance; Ion Channels; Leptin; Leukocyte Elastase; Liver; Metabolome; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Mice, Transgenic; Mitochondrial Proteins; Obesity; Oxidation-Reduction; Phosphorylation; Piperidines; Protein Kinases; Uncoupling Protein 1; Weight Gain

Recent research suggests that cannabinoid receptor CB1 antagonists can affect appetite and body weight gain, although their influence on other parameters related to metabolic syndrome is not well documented. The present study was designed to assess the effects of chronic treatment with the CB1 receptor inverse agonist AM 251 (3 mg/kg for 3 weeks) in obese and lean Zucker rats on parameters related to metabolic syndrome.. Four groups of rats were used: lean Zucker rats, untreated obese Zucker rats, AM 251-treated obese Zucker rats and a pair-fed obese Zucker rat experimental group which received the same amount of food as that consumed by the animals treated with AM251. Food intake, body weight gain, energy expenditure, plasma biochemical parameters, leptin, insulin and hepatic status markers were analysed.. Daily injection of AM 251 in obese Zucker rats produced a marked and sustained decrease in daily food intake and body weight and a considerable increase in energy expenditure in comparison with untreated obese Zucker rats. AM 251 administration to obese rats significantly reduced plasma levels of glucose, leptin, AST, ALT, Gamma GT, total bilirubin and LDL cholesterol whereas HDL cholesterol plasma levels increased. The results also showed a decrease in liver/weight body ratio and total fat content in the liver. The main effects of AM251 (3 mg/kg) found in this study were not observed in pair-fed obese animals, highlighting the additional beneficial effects of treatment with AM 251. The results obtained in obese rats can be interpreted as a decrease in leptin and insulin resistance, thereby improving glucose and lipid metabolism, alleviating the steatosis present in the metabolic syndrome and thus favourably modifying plasma levels of hepatic biomarkers.. Our results indicate that the cannabinoid CB1 inverse agonist AM 251 represents a promising therapeutic strategy for the treatment of obesity and metabolic syndrome.

Topics: Animals; Biomarkers; Cannabinoid Receptor Antagonists; Eating; Energy Metabolism; Fatty Liver; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Male; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rats; Rats, Zucker; Receptor, Cannabinoid, CB1; Weight Gain

The cannabinoid 1 receptor antagonist rimonabant (SR141716) alters rewarding properties and intake of food and drugs. Additionally, striatal dopamine D2 receptor (DRD2) availability has been implicated in reward function. This study shows that chronic treatment of rats with rimonabant (1.0 and 3.0 mg/kg/day) dose-dependently increased DRD2 availability in the dorsal striatum (14 and 23%) compared with vehicle. High-dose rimonabant also increased DRD2 availability in the ventral striatum (12%) and reduced weight gain. Thus, up-regulation of striatal DRD2 by chronic rimonabant administration may be an underlying mechanism of action and confirms the interactions of the endocannabinoid and dopaminergic systems.

Topics: Animals; Basal Ganglia; Cannabinoid Receptor Antagonists; Dose-Response Relationship, Drug; Male; Piperidines; Pyrazoles; Random Allocation; Rats; Receptors, Dopamine D2; Reward; Rimonabant; Up-Regulation; Weight Gain

Diet-induced obesity produces changes in endocannabinoid signaling (ECS), influencing the regulation of energy homeostasis. Recently, we demonstrated that, in high-fat-diet-fed rats, blockade of CB1 receptor by AM251 not only reduced body weight but also increased adult neurogenesis in the hippocampus, suggesting an influence of diet on hippocampal cannabinoid function. To further explore the role of hippocampal ECS in high-fat-diet-induced obesity, we investigated whether the immunohistochemical expression of the enzymes that produce (diacylglycerol lipase alpha and N-acyl phosphatidylethanolamine phospholipase D) and degrade (monoacylglycerol lipase and fatty acid amino hydrolase) endocannabinoids may be altered in the hippocampus of AM251 (3 mg/kg)-treated rats fed three different diets: standard diet (normal chow), high-carbohydrate diet (70% carbohydrate) and high-fat diet (60% fat). Results indicated that AM251 reduced caloric intake and body weight gain, and induced a modulation of the expression of ECS-related proteins in the hippocampus of animals exposed to hypercaloric diets. These effects were differentially restricted to either the 2-arachinodoyl glycerol or anandamide signaling pathways, in a diet-dependent manner. AM251-treated rats fed the high-carbohydrate diet showed a reduction of the diacylglycerol lipase alpha : monoacylglycerol lipase ratio, whereas AM251-treated rats fed the high-fat diet showed a decrease of the N-acyl phosphatidylethanolamine phospholipase D : fatty acid amino hydrolase ratio. These results are consistent with the reduced levels of hippocampal endocannabinoids found after food restriction. Regarding the CB1 expression, AM251 induced specific changes focused in the CA1 stratum pyramidale of high-fat-diet-fed rats. These findings indicated that the cannabinoid antagonist AM251 modulates ECS-related proteins in the rat hippocampus in a diet-specific manner. Overall, these results suggest that the hippocampal ECS participates in the physiological adaptations to different caloric diets.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Diet, High-Fat; Dietary Carbohydrates; Dietary Fats; Endocannabinoids; Hippocampus; Lipoprotein Lipase; Male; Monoacylglycerol Lipases; Obesity; Phospholipase D; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Weight Gain

Obesity is a global problem with often strong neurobiological underpinnings. The cannabinoid 1 receptor (CB1R) was put forward as a promising drug target for antiobesity medication. However, the first marketed CB1R antagonist/inverse agonist rimonabant was discontinued, as its use was occasionally associated with negative affect and suicidality. In artificial cell systems, CB1Rs can become constitutively active in the absence of ligands. Here, we show that such constitutive CB1R activity also regulates GABAergic and glutamatergic neurotransmission in the ventral tegmental area and basolateral amygdala, regions which regulate motivation and emotions. We show that CB1R inverse agonists like rimonabant suppress the constitutive CB1R activity in such regions, and cause anxiety and reduced motivation for reward. The neutral CB1R antagonist NESS0327 does not suppress constitutive activity and lacks these negative effects. Importantly, however, both rimonabant and NESS0327 equally reduce weight gain and food intake. Together, these findings suggest that neutral CB1R antagonists can treat obesity efficiently and more safely than inverse agonists.

Topics: Amygdala; Animals; Anxiety; Dopaminergic Neurons; Eating; GABAergic Neurons; Humans; Male; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Ventral Tegmental Area; Weight Gain

Casopitant is a potent and selective NK-1 receptor antagonist that has shown clinical efficacy in the prevention of chemotherapy-induced and postoperative-induced nausea and vomiting.. In an embryo-fetal development study, pregnant mice were given vehicle (sterile water) or doses of 30, 100, or 300 mg/kg/day casopitant on Gestation Day (GD) 6 to 15. Fetuses were evaluated for external, visceral, and skeletal abnormalities on GD 18. In a follow-on study to investigate casopitant-induced hormonal changes during the developmental period for palate formation, pregnant mice were given vehicle (sterile water) or 300 mg/kg/day casopitant once daily on GD 6 to 13. Blood was collected on GD 13 at various time-points for measurement of plasma adrenocorticotropic hormone and corticosterone (CRT) concentrations.. There was no evidence of developmental toxicity in mice at 30 or 100 mg/kg/day but 9% of fetuses at 300 mg/kg/day had cleft palate. Mice are sensitive to glucocorticoid-induced cleft palates, and NK-1 antagonists are known to modulate the hypothalamic-pituitary-adrenal axis leading to increases in corticosterone. On GD 13, mean plasma adrenocorticotropic hormone levels at 300 mg/kg/day were elevated by approximately twofold from vehicle-treated levels at 1 hr post-dose and mean plasma CRT levels were elevated by 3, 5, and 10-fold at 0.5, 1, and 2 hr post-dose, respectively.. The increased level of CRT was in the range previously shown in the literature to cause cleft palates in mice and was likely the underlying mechanism behind casopitant-induced cleft palate in mice.

Topics: Adrenocorticotropic Hormone; Animals; Cesarean Section; Cleft Palate; Corticosterone; Feeding Behavior; Female; Fetal Development; Mice; Neurokinin-1 Receptor Antagonists; Piperazines; Piperidines; Pregnancy; Receptors, Neurokinin-1; Weight Gain

Weight gain and dysfunction of glucose and lipid metabolism are well-known side effects of atypical antipsychotic drugs (AAPD). Here, we address the question whether a heat-shock protein (HSP) co-inducer, insulin sensitizer drug candidate, BGP-15, can prevent AAPD-induced glucose, lipid, and weight changes. We also examined how an AAPD alters HSP expression and whether BGP-15 alters that expression. Four different experiments are reported on the AAPD BGP-15 interventions in a human trial of healthy men, a rodent animal model, and an in vitro adipocyte cell culture system. Olanzapine caused rapid insulin resistance in healthy volunteers and was associated with decreased level of HSP72 in peripheral mononuclear blood cells. Both changes were restored by the administration of BGP-15. In Wistar rats, weight gain and insulin resistance induced by clozapine were abolished by BGP-15. In 3T3L1 adipocytes, clozapine increased intracellular fat accumulation, and BGP-15 inhibited this process. Taken together, our results indicate that BGP-15 inhibits multiple metabolic side effects of atypical antipsychotics, and this effect is likely to be related to its HSP co-inducing ability.

Topics: Adipocytes; Animals; Antipsychotic Agents; Cells, Cultured; Female; HSP72 Heat-Shock Proteins; Humans; Hypoglycemic Agents; Male; Oximes; Piperidines; Rats; Rats, Wistar; Up-Regulation; Weight Gain

1. The aim of the present study was to determine whether the addition of a subeffective dose of rimonabant (1 mg/kg) to orlistat would be beneficial in the treatment of diet-induced obesity in rats compared with orlistat monotherapy. 2. Male rats were divided into five groups: (i) rats fed a low-fat diet for 4 months; (ii) rats fed a high-fat diet (HFD) for 4 months and treated daily with vehicle (0.2% Tween-80 solution); (iii) orlistat (10 mg/kg per day)-treated HFD-fed rats; (iv) rimonabant (1 mg/kg per day)-treated HFD-fed rats; and (v) HFD-fed rats treated with a combination of orlistat plus rimonabant. Fasting blood glucose, serum insulin, leptin and adiponectin levels were measured. Liver and adiposity indices were calculated and liver and adipose tissues were processed for histological examination. 3. Over the 4 months of the study, vehicle-treated HFD-fed rats exhibited increased cumulative food intake, bodyweight and liver and adiposity indices. Moreover, vehicle-treated HFD-fed rats exhibited a deterioration in liver function and an abnormal lipid profile. Insulin resistance and serum leptin were increased in this group, whereas serum adiponectin levels were decreased. Orlistat monotherapy or combination therapy with orlistat plus rimonabant improved all these parameters. 4. The addition of the low subeffective dose of rimonabant to orlistat therapy ameliorated HFD-induced obesity to a much greater extent than orlistat monotherapy. This combination showed better weight control and metabolic profile compared with orlistat alone. Therefore, the results of the present study encourage reassessment of the use of a low dose of rimonabant to potentiate the effect of orlistat in the clinical management of obesity if proper clinical safety data are available.

Topics: Adiposity; Animals; Anti-Obesity Agents; Body Weight; Diet, High-Fat; Dose-Response Relationship, Drug; Drug Therapy, Combination; Lactones; Male; Obesity; Orlistat; Piperidines; Pyrazoles; Rats; Rats, Wistar; Rimonabant; Weight Gain

Atypical antipsychotic drugs (AAPD) are widely used to treat severe psychiatric disorders, have well documented metabolic side effects such as disturbances in glucose metabolism, insulin resistance and weight gain. It has been shown that BGP-15, a hydroxylamine derivative with insulin sensitizing activity can prevent AAPD provoked fat accumulation in adipocyte cultures, and insulin resistance in animal experiments and in healthy volunteers. The aim of this study was to compare the preventive effect of BGP-15 with conventional oral antidiabetics on metabolic side effects of AAPDs. We found that BGP-15 that does not belong to either conventional insulin sensitizers or oral antidiabetics, is able to counteract insulin resistance and weight gain provoked by antipsychotic agents in rats while rosiglitazone and metformin were not effective in the applied doses. Our results confirm that BGP-15 is a promising new drug candidate to control the metabolic side effects of atypical antipsychotics. Data indicate that this rat model is suitable to analyze the metabolic side effects of AAPDs and the protective mechanism of BGP-15.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Drug Interactions; Female; Glucose Clamp Technique; Insulin Resistance; Oximes; Piperidines; Protective Agents; Rats; Rats, Wistar; Weight Gain

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

The ECS (endocannabinoid system) plays an important role in the onset of obesity and metabolic disorders, implicating central and peripheral mechanisms predominantly via CB1 (cannabinoid type 1) receptors. CB1 receptor antagonist/inverse agonist treatment improves cardiometabolic risk factors and insulin resistance. However, the relative contribution of peripheral organs to the net beneficial metabolic effects remains unclear. In the present study, we have identified the presence of the endocannabinoid signalling machinery in skeletal muscle and also investigated the impact of an HFD (high-fat diet) on lipid-metabolism-related genes and endocannabinoid-related proteins. Finally, we tested whether administration of the CB1 inverse agonist AM251 restored the alterations induced by the HFD. Rats were fed on either an STD (standard/low-fat diet) or an HFD for 10 weeks and then treated with AM251 (3 mg/kg of body weight per day) for 14 days. The accumulated caloric intake was progressively higher in rats fed on the HFD than the STD, resulting in a divergence in body weight gain. AM251 treatment reduced accumulated food/caloric intake and body weight gain, being more marked in rats fed on the HFD. CB2 (cannabinoid type 2) receptor and PPARα (peroxisome-proliferator-activated receptor α) gene expression was decreased in HFD-fed rats, whereas MAGL (monoglyceride lipase) gene expression was up-regulated. These data suggest an altered endocannabinoid signalling as a result of the HFD. AM251 treatment reduced CB2 receptor, PPARγ and AdipoR1 (adiponectin receptor 1) gene expression in STD-fed rats, but only partially normalized the CB2 receptor in HFD-fed rats. Protein levels corroborated gene expression results, but also showed a decrease in DAGL (diacylglycerol) β and DAGLα after AM251 treatment in STD- and HFD-fed rats respectively. In conclusion, the results of the present study indicate a diet-sensitive ECS in skeletal muscle, suggesting that blockade of CB1 receptors could work towards restoration of the metabolic adaption imposed by diet.

Topics: Animals; Cannabinoids; Dietary Fats; Energy Intake; Gene Expression Regulation; Lipid Metabolism; Muscle, Skeletal; Piperidines; PPAR gamma; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Adiponectin; Weight Gain

The fruits of Piper retrofractum Vahl. have been used for their anti-flatulent, expectorant, antitussive, antifungal, and appetizing properties in traditional medicine, and they are reported to possess gastroprotective and cholesterol-lowering properties. However, their anti-obesity activity remains unexplored. The present study was conducted to isolate the anti-obesity constituents from P. retrofractum Vahl. and evaluate their effects in high-fat diet (HFD)-induced obese mice. Piperidine alkaloids from P. retrofractum Vahl. (PRPAs), including piperine, pipernonaline, and dehydropipernonaline, were isolated as the anti-obesity constituents through a peroxisome proliferator-activated receptor δ (PPARδ) transactivation assay. The molecular mechanism was investigated in 3T3-L1 adipocytes and L6 myocytes. PRPA treatment activated AMP-activated protein kinase (AMPK) signaling and PPARδ protein and also regulated the expression of lipid metabolism-related proteins. In the animal model, oral PRPA administration (50, 100, or 300mg/kg/day for 8weeks) significantly reduced HFD-induced body weight gain without altering the amount of food intake. Fat pad mass was reduced in the PRPA treatment groups, as evidenced by reduced adipocyte size. In addition, elevated serum levels of total cholesterol, low-density lipoprotein cholesterol, total lipid, leptin, and lipase were suppressed by PRPA treatment. PRPA also protected against the development of nonalcoholic fatty liver by decreasing hepatic triglyceride accumulation. Consistent with the in vitro results, PRPA activated AMPK signaling and altered the expression of lipid metabolism-related proteins in liver and skeletal muscle. Taken together, these findings demonstrate that PRPAs attenuate HFD-induced obesity by activating AMPK and PPARδ, and regulate lipid metabolism, suggesting their potential anti-obesity effects.

Topics: 3T3 Cells; Adiposity; Alkaloids; AMP-Activated Protein Kinases; Animals; Anti-Obesity Agents; Chlorocebus aethiops; COS Cells; Diet; Dietary Fats; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Obesity; Piper; Piperidines; PPAR delta; Rats; Weight Gain

We sought to determine the effect of dipeptidyl peptidase IV (DPP-IV) inhibition on streptozotocin diabetes-induced vascular and neural dysfunction. After 4 weeks of untreated diabetes, rats were treated for 12 weeks with Alogliptin (DPP-IV inhibitor). Diabetes caused a slowing of motor and sensory nerve conduction velocity, thermal hypoalgesia, reduction in intraepidermal nerve fiber density in the hindpaw, and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineurial arterioles. Treatment significantly improved motor nerve conduction velocity and thermal response latency. Sensory nerve conduction velocity was marginally improved with treatment of diabetic rats, and treatment did not improve the decrease in intraepidermal nerve fiber density. Vascular relaxation by epineurial arterioles to calcitonin gene-related peptide but not acetylcholine was significantly improved with treatment. These studies suggest that some but not all vascular and neural complications associated with type 1 diabetes can be improved with the inhibition of DPP-IV activity.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Neuropathies; Dipeptidyl-Peptidase IV Inhibitors; Hypoglycemic Agents; Male; Motor Neurons; Neural Conduction; Oxidative Stress; Pain Measurement; Pain Threshold; Piperidines; Rats; Rats, Sprague-Dawley; Sensory Receptor Cells; Time Factors; Uracil; Vasodilation; Weight Gain

In view of its potential advantages, drug polytherapy is currently attracting significant interest in the field of obesity research. In this context, concurrent manipulation of serotonergic and cannabinoid pathways in rodents has been found to reduce food and fluid intake in both an additive or synergistic manner. To further assess the value of this polytherapeutic approach, the current study examined the acute effects of low-dose combinations of the cannabinoid CB1 receptor antagonist/inverse agonist rimonabant (0.5 mg/kg) and the dual serotonin- and noradrenaline-reuptake inhibitor sibutramine (0.125 and 0.25 mg/kg) in male rats. Ethological analysis was used to generate comprehensive behavioural profiles, including the behavioural satiety sequence (BSS). Findings confirmed that, although neither drug given alone significantly altered food intake, feeding behaviour or weight gain, rimonabant per se tended to reduce consumption and time spent feeding while significantly increasing scratching and grooming responses. However, none of these effects of the CB1 receptor antagonist/inverse agonist was significantly altered by the presence of either dose of sibutramine. In striking contrast to recent reports of acute low-dose interactions (enhanced appetite suppression and reduced side-effects) between rimonabant and naloxone, present results would not appear to support the clinical potential of rimonabant/sibutramine polytherapy for obesity.

Topics: Animals; Appetite; Cyclobutanes; Drug Administration Schedule; Drug Therapy, Combination; Male; Piperidines; Pyrazoles; Rats; Reaction Time; Rimonabant; Satiety Response; Weight Gain

Low-dose combinations of naloxone and rimonabant produce additive effects on food intake and feeding behaviour, yet abolish the scratching syndrome typically induced by rimonabant per se. To assess the generality of these findings, we have examined the acute effects of low-dose combinations of naloxone (0.1 mg/kg) and the rimonabant derivative AM 251 (0.5 and 1.0 mg/kg) on food intake, feeding behaviour and weight gain in non-deprived male rats. Although ineffective when given alone, combined treatment with naloxone and 0.5 mg/kg AM 251 significantly and selectively suppressed mash intake and time spent feeding. By itself, 1.0 mg/kg AM 251 failed to alter any measure of feeding behaviour but did reduce food consumption and induce scratching behaviour. Co-administration of naloxone with 1.0 mg/kg AM 251 not only significantly suppressed both food intake and feeding behaviour but also simultaneously attenuated AM 251-induced scratching. This profile mirrors earlier findings with naloxone/rimonabant and is consistent with the reported diversity of opioid-cannabinoid system interactions at a more molecular level. Although further studies are required (e.g. 'neutral' CB1 receptor antagonists), current data constitute further proof of concept regarding the anorectic efficacy, selectivity and added value of low-dose polytherapy with opioid and CB1 receptor antagonists.

Topics: Animals; Drug Interactions; Eating; Feeding Behavior; Grooming; Male; Motor Activity; Naloxone; Narcotic Antagonists; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Weight Gain

Topics: Animals; Atherosclerosis; Cannabinoids; Clinical Trials as Topic; Heart Diseases; Humans; Metabolic Diseases; Mice; Mice, Knockout; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, LDL; Rimonabant; Weight Gain

Obesity is a severe health problem in the modernized world and understanding the central nervous mechanisms underlying food-seeking behaviour and reward are at the forefront of medical research. Cannabinoid receptors have proven an efficient target to suppress hunger and weight gain by their pharmacological inactivation.. A standard fasted protocol and a novel long-term home-cage observation system with free-feeding animals were used to assess the feeding behaviour of mice treated with the CB1 antagonist AM251. Similarly, the effects of the phytocannabinoid Delta9-tetrahydrocannabivarin (Delta9-THCV), which behaves like a CB1 antagonist, were also determined in free-feeding animals.. AM251 suppressed food intake and weight gain in fasted and non-fasted animals. The suppression of food intake by AM251 (10 mg.kg-1) endured for a period of 6-8 h when administered acutely, and was continuous when injected for four consecutive days. Pure Delta9-THCV also induced hypophagia and weight reduction at doses as low as 3 mg.kg-1. No rebound was observed on the following day with all drug groups returning to normal activity and feeding regimes. However, a Delta9-THCV-rich cannabis-extract failed to suppress food intake and weight gain, possibly due to residual Delta9-tetrahydrocannabinol (Delta9-THC) in the extract. This Delta9-THC effect was overcome by the co-administration of cannabidiol.. The data strongly suggest (i) the long-term home-cage observation system is a sensitive and obesity-relevant tool, and (ii) the phytocannabinoid Delta9-THCV is a novel compound with hypophagic properties and a potential treatment for obesity

Topics: Animals; Appetite Depressants; Cannabinoid Receptor Antagonists; Dronabinol; Eating; Fasting; Feeding Behavior; Male; Mice; Mice, Inbred C57BL; Piperidines; Pyrazoles; Solvents; Weight Gain

The cannabinoid CB1 selective antagonist SR141716A (Rimonabant) has been shown to decrease body weight in laboratory animals and humans. Furthermore, SR141716A can elicit scratching behavior in rodents, a behavior that has been hypothesized to contribute to SR141716A-induced decrease in food intake. Although childhood obesity is a rising health issue, it is unknown whether SR141716A is equipotent at modulating food intake and other CB1-mediated behaviors in younger subjects.. To determine whether CB1 receptor blockade is equipotent at modulating food and water intake, body weight, and scratching behavior, the effect of a range of SR141716A doses on these behaviors in food-restricted postnatal day (P) 18, 28, and 60 male rats was investigated. Brain concentrations of SR141716A were determined in each age group.. SR141716A dose- and age-dependently suppressed food and water intake and body weight gain and elicited head scratching, with the most potent effects observed in P18 and P28 rats. Brain concentrations of SR141716A were significantly elevated in P18 rats relative to P28 and P60 rats. SR141716A-elicited head scratching was attenuated by the 5-HT(2A/2C) antagonist ketanserin.. SR141716A is more potent at modulating food intake and head scratching in very young animals; these differences can be attributed to an increase in brain penetration of SR141716A for P18 but not for P28 and P60 rats. In addition, SR141716-elicited head scratching is modulated by 5HT receptor antagonism and is not a contributing factor to SR141716A's anorectic effects.

Topics: Age Factors; Animals; Brain; Dose-Response Relationship, Drug; Drinking; Eating; Feeding Behavior; Ketanserin; Male; Piperidines; Pruritus; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Serotonin Antagonists; Weight Gain

Endocannabinoids (EC) are involved in regulating energy homeostasis, particularly in promoting hyperphagia and the consumption of a palatable diet. We have previously shown that rats given a high-fat (HF) diet display a transient hyperphagia that is normalized by a process partially dependent on leptin. We now propose that the induction of this hyperphagia is mediated, at least partially, by the EC signaling system. Obesity, including diet-induced and age-related, is associated with dysregulation of the EC system, and obese rodent models are hypersensitive to a cannabinoid-1 (CB1) receptor antagonist. This suggests that aged rats will be more responsive to the anorectic effects of a CB1 receptor antagonist. To test this, we examined the responsiveness to CB1 receptor antagonist, AM251, in young and aged rats during two experimental paradigms. First, we administered AM251 simultaneously with the introduction of an HF diet. Second, AM251 treatment began after the establishment of diet-induced obesity. Responses were measured by changes in body weight and composition, calorie intake, serum leptin, and biochemical indicators. The results demonstrated three key findings. 1) CB1 receptor activity contributes to the hyperphagia seen with the introduction of an HF diet. 2) Increased AM251 sensitivity and efficacy is increased with age and HF feeding, with the greatest responsiveness observed in HF-fed, aged rats. 3) AM251 sensitivity is elevated to a greater extent with HF diet than with established obesity. Thus, both age and an HF diet are associated with enhanced anorectic responses to AM251, but the underlying mechanism of these responses remains speculative.

Topics: Age Factors; Animals; Appetite Depressants; Body Composition; Dietary Fats; Energy Intake; Hyperphagia; Ion Channels; Leptin; Male; Mitochondrial Proteins; Obesity; Piperidines; Pyrazoles; Rats; Rats, Inbred F344; Receptor, Cannabinoid, CB1; STAT3 Transcription Factor; Uncoupling Protein 1; Weight Gain

The severity of obesity is often more determined by the distribution of fat depots rather than by body weight itself. Therefore, the effect of rimonabant on fat distribution pattern was investigated in female candy-fed Wistar rats.. Female Wistar rats were fed a high fat, high carbohydrate (candy-) diet for 12 weeks. During the last 6 weeks rats were treated with rimonabant. Food intake and body weight development were investigated, as well as effects on total body fat, especially visceral fat and ectopic lipid accumulation in skeletal muscle and liver, determined by in vivo magnetic resonance imaging/magnetic resonance spectroscopy.. Candy-diet increased body weight, which was predominantly due to the increased total fat mass with predominance of visceral fat accumulation. Treatment with rimonabant fully reversed the weight gain and fat deposition in the visceral cavity and skeletal muscle, in contrast to pair feeding. In spite of an only transient reduction of food intake, body weight reduction, as well as normalized body fat, reduced visceral fat and intramyocellular lipids were maintained over the treatment period.. We conclude that additional factors other than reduced caloric intake must be responsible for the improvements in these lipid parameters. The complete cluster of results is consistent with increased lipid oxidation caused by rimonabant.

Topics: Adiposity; Animals; Dietary Carbohydrates; Eating; Female; Intra-Abdominal Fat; Lipid Metabolism; Lipids; Magnetic Resonance Imaging; Muscle, Skeletal; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Weight Gain

We investigated the effect of rimonabant on inflammation and enhanced platelet reactivity in type 2 diabetic Zucker rats, an experimental model of impaired glucose tolerance and the metabolic syndrome.. Rimonabant (10 mg kg(-1) by gavage) was fed for 2 weeks to 3-month-old male obese Zucker rats as an impaired glucose tolerance model and for 10 weeks to 6-month-old male obese Zucker rats as a model of the metabolic syndrome. RANTES (Regulated upon Activation, Normal T cell Expressed, and Secreted) and MCP-1 (monocyte chemotactic protein-1) serum levels were determined by ELISA. Leukocyte populations were quantitatively assessed using a veterinary differential blood cell counter. Platelet activation was assessed by flow-cytometry, platelet aggregation, and adhesion of isolated platelets to immobilized fibrinogen.. RANTES and MCP-1 serum levels were increased in obese vs lean Zucker rats and significantly reduced by long-term treatment with rimonabant, which slowed weight gain in rats with the metabolic syndrome. Neutrophils and monocytes were significantly increased in young and old obese vs lean Zucker rats and lowered by rimonabant. Platelet-bound fibrinogen was significantly enhanced in obese vs lean Zucker rats of both age, and was reduced by rimonabant. Platelets from obese rats were more sensitive to thrombin-induced aggregation and adhesion to fibrinogen, which were both attenuated by rimonabant therapy.. We demonstrate positive modulation of circulating neutrophil and monocyte numbers, reduced platelet activation and lower RANTES and MCP-1 levels by rimonabant in Zucker rats. This may potentially contribute to a reduction of cardiovascular risk.

Topics: Animals; Anti-Inflammatory Agents; Chemokine CCL2; Chemokine CCL5; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Glucose Intolerance; Inflammation Mediators; Leukocyte Count; Leukocytes; Lipids; Male; Metabolic Syndrome; Piperidines; Platelet Activation; Platelet Adhesiveness; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Pyrazoles; Rats; Rats, Zucker; Receptor, Cannabinoid, CB1; Rimonabant; Time Factors; Weight Gain

A series of pyrrolopyridinones was designed and synthesized as constrained analogs of the pyrazole CB-1 antagonist rimonabant. Certain examples exhibited very potent hCB-1 receptor binding affinity and functional antagonism with Ki and Kb values below 10 nM, and with high selectivity for CB-1 over CB-2 (>100-fold). A representative analog was established to cause significant appetite suppression and reduction in body weight gain in industry-standard rat models used to develop new therapeutics for obesity.

Topics: Animals; Anti-Obesity Agents; Body Weight; Crystallography, X-Ray; Drug Design; Eating; Humans; Magnetic Resonance Spectroscopy; Male; Models, Molecular; Obesity; Piperidines; Pyrazoles; Pyridones; Pyrroles; Rats; Rats, Wistar; Rats, Zucker; Receptor, Cannabinoid, CB1; Rimonabant; Structure-Activity Relationship; Weight Gain

Antidepressant pharmacotherapy has dramatically improved the quality of life for many patients. However, prolonged use may induce weight gain, resulting in enhanced risk for treatment noncompliance. Cannabinoid CB(1) receptor antagonists decrease food intake and body weight, but may also affect mood. We investigated in female Sabra mice first, whether acute treatment with the cannabinoid receptor antagonist rimonabant (5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide, SR141716, 5 mg/kg) interfered with the tricyclic antidepressant desipramine (15 mg/kg) or the selective serotonin reuptake inhibitor fluoxetine (20 mg/kg) in the Porsolt forced swimming test. Second, whether chronic treatment (3 months) with desipramine (5 mg/kg) enhanced weight gain and whether cotreatment with rimonabant (2 mg/kg), prevented the excessive weight gain, while retaining antidepressant effectiveness. Motor activity and anxiety-like behavior were also investigated. The acute studies indicated that rimonabant did not influence 'antidepressant' activity of desipramine or fluoxetine. In the chronic studies, desipramine enhanced weight gain, despite the observation that the injection procedure reduced weight gain. The enhanced weight gain continued at least 35 days after treatment ended. Rimonabant reduced weight gain to which no tolerance developed and which persisted at least 30 days beyond treatment. Mice cotreated with rimonabant and desipramine had body weights closer to controls or to those receiving rimonabant alone than to those treated with desipramine alone. The antidepressant effects of desipramine were maintained throughout treatment; this was not altered by the chronic rimonabant treatment at any time, although rimonabant together with desipramine transiently enhanced anxiety-like behavior. These observations suggest that combined treatment with antidepressants and cannabinoid CB(1) receptor antagonist to prevent undesirable weight gain, should be further investigated.

Topics: Analysis of Variance; Animals; Antidepressive Agents; Anxiety; Behavior, Animal; Desipramine; Female; Fluoxetine; Maze Learning; Mice; Motor Activity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Swimming; Time Factors; Weight Gain

In this study, we investigated the antidepressant-like effect of piperine in mice exposed to chronic mild stress (CMS) procedure. Repeated administration of piperine for 14 days at the doses of 2.5, 5 and 10 mg/kg reversed the CMS-induced changes in sucrose consumption, plasma corticosterone level and open field activity. Furthermore, the decreased proliferation of hippocampal progenitor cells was ameliorated and the level of brain-derived neurotrophic factor (BDNF) in hippocampus of CMS stressed mice was up-regulated by piperine treatment in the same time course. In addition, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactic dehydrogenase (LDH) assays showed that piperine (6.25-25 microM) or fluoxetine (FLU, 1 microM) dose-dependently protected primary cultured hippocampal neurons from the lesion induced by 10 microM corticosterone (CORT). Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the messenger ribonucleic acid (mRNA) level of BDNF in cultured neurons. Treatment with piperine (6.25-25 microM) for 72 h reversed the CORT-induced reduction of BDNF mRNA expression in cultured hippocampal neurons. In summary, up-regulation of the progenitor cell proliferation of hippocampus and cytoprotective activity might be mechanisms involved in the antidepressant-like effect of piperine, which may be closely related to the elevation of hippocampal BDNF level.

Topics: Alkaloids; Animals; Antidepressive Agents; Benzodioxoles; Brain-Derived Neurotrophic Factor; Cell Proliferation; Cell Survival; Cells, Cultured; Chronic Disease; Corticosterone; Depression; Hippocampus; Immunohistochemistry; L-Lactate Dehydrogenase; Male; Mice; Neurons; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Stem Cells; Stress, Psychological; Tetrazolium Salts; Thiazoles; Weight Gain

Rimonabant (Acomplia, SR141716A), a cannabinoid CB1 receptor inverse agonist, has recently been approved for the treatment of obesity. There are, however, concerns regarding its side effect profile. Developing a CB1 antagonist with a different pharmacological mechanism may lead to a safer alternative. To this end we have screened a proprietary small molecule library and have discovered a novel class of allosteric antagonist at CB1 receptors. Herein, we have characterized an optimized prototypical molecule, PSNCBAM-1, and its hypophagic effects in vivo.. A CB1 yeast reporter assay was used as a primary screen. PSNCBAM-1 was additionally characterized in [35S]-GTPgammaS, cAMP and radioligand binding assays. An acute rat feeding model was used to evaluate its effects on food intake and body weight in vivo.. In CB1 receptor yeast reporter assays, PSNCBAM-1 blocked the effects induced by agonists such as CP55,940, WIN55212-2, anandamide (AEA) or 2-arachidonoyl glycerol (2-AG). The antagonist characteristics of PSNCBAM-1 were confirmed in [35S]-GTPgammaS binding and cAMP assays and was shown to be non-competitive by Schild analyses. PSNCBAM-1 did not affect CB2 receptors. In radioligand binding assays, PSNCBAM-1 increased the binding of [3H]CP55,940 despite its antagonist effects. In an acute rat feeding model, PSNCBAM-1 decreased food intake and body weight.. PSNCBAM-1 exerted its effects through selective allosteric modulation of the CB1 receptor. The acute effects on food intake and body weight induced in rats provide a first report of in vivo activity for an allosteric CB1 receptor antagonist.

Topics: Allosteric Regulation; Animals; Appetite Depressants; Cell Line; Cell Membrane; Cerebral Cortex; Cyclic AMP; Cyclohexanols; Dose-Response Relationship, Drug; Eating; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Male; Molecular Structure; Phenylurea Compounds; Piperidines; Pyrazoles; Pyridines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Saccharomyces cerevisiae; Silicone Elastomers; Sulfur Radioisotopes; Weight Gain

Although the CB1 receptor antagonist/inverse agonist rimonabant acutely suppresses food intake in rodents, the behavioural specificity of this effect remains unclear.. To profile the behavioural effects of rimonabant in a free-feeding context.. Videoanalysis was employed to characterise the effects of acute rimonabant (1.5 and 3.0 mg/kg, IP) on the behaviour of non-deprived male rats exposed to palatable mash. Data were also collected on post-treatment weight gain, and, as prolonged appetite suppression has been found after single dosing with compounds of this series, rats were reassessed (drug-free) for food intake 7 days after initial testing.. Both doses of rimonabant not only decreased mash consumption (44-55%) but also reduced 24-h weight gain. Although videoanalysis confirmed the inhibitory effects of rimonabant on feeding behaviour, it also revealed concurrent reductions in locomotion, rearing and sniffing as well as substantial (up to tenfold) and dose-dependent increases in grooming and scratching. Timecourse analyses further revealed that rimonabant dose-dependently induced frequent episodes of atypical scratching that waned over the test but which were succeeded by prolonged and behaviourally disruptive grooming. Finally, as groups did not differ in mash consumption on retest, any prolonged anorectic effect of acute rimonabant dissipates within 7 days of treatment.. The anorectic response to rimonabant in male rats would appear to be due largely to response competition. This parsimonious conclusion is supported by the less profound (although still significant) increases in scratching and grooming observed in rats treated with a sub-anorectic dose (0.5 mg/kg) of the compound.

Topics: Animals; Anorexia; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Eating; Feeding Behavior; Grooming; Habituation, Psychophysiologic; Injections, Intraperitoneal; Male; Piperidines; Pruritus; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Rest; Rimonabant; Satiety Response; Time Factors; Videotape Recording; Weight Gain

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

Cannabinoid (CB)1 receptor inverse agonists inhibit food intake in animals and humans but also potentiate emesis. It is not clear whether these effects result from inverse agonist properties or from the blockade of endogenous cannabinoid signaling. Here, we examine the effect of a neutral CB1 antagonist, AM4113, on food intake, weight gain, and emesis. Neutral antagonist and binding properties were confirmed in HEK-293 cells transfected with human CB1 or CB2 receptors. AM4113 had no effect on forskolin-stimulated cAMP production at concentrations up to 630 nM. The Ki value of AM4113 (0.80 +/- 0.44 nM) in competitive binding assays with the CB1/2 agonist [3H]CP55,940 was 100-fold more selective for CB1 over CB2 receptors. We determined that AM4113 antagonized CB1 receptors in brain by blocking hypothermia induced by CP55,940. AM4113 (0-20 mg/kg) significantly reduced food intake and weight gain in rat. Compared with AM251, higher doses of AM4113 were needed to produce similar effects on food intake and body weight. Unlike AM251 (5 mg/kg), a highly anorectic dose of AM4113 (10 mg/kg) did not significantly potentiate vomiting induced by the emetic morphine-6-glucoronide. We show that a centrally active neutral CB1 receptor antagonist shares the appetite suppressant and weight loss effects of inverse agonists. If these compounds display similar properties in humans, they could be developed into a new class of antiobesity agents.

Topics: Animals; Appetite; Appetite Stimulants; Dose-Response Relationship, Drug; Eating; Male; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Weight Gain

Acolbifene (ACOL) is a fourth-generation selective estrogen receptor modulator (SERM) that has strong and pure antiestrogenic properties toward estrogen-sensitive cancers, but improves energy and lipid metabolism in an estrogen-like fashion in rodent models. The aim of this study was to determine the potency of ACOL to reduce cholesterolemia in a dietary model of hypercholesterolemia and to establish its mechanisms of action. Intact and ovariectomized (OVX) female rats were treated for 3 weeks with ACOL, and serum cholesterol and liver determinants of cholesterol metabolism were assessed. Acolbifene prevented both diet- and ovariectomy-induced weight gain and completely prevented diet-induced hypercholesterolemia. Relative to a reference chow diet, the high-cholesterol diet decreased the high-density lipoprotein (HDL) cholesterol fraction, which remained unaffected by ACOL, indicating that in hypercholesterolemic conditions, ACOL modulated only the non-HDL fraction. No impact of ACOL on determinants of liver cholesterol synthesis was observed. In contrast, ACOL increased hepatic low-density lipoprotein receptor protein in both intact and OVX rats, which was negatively correlated with serum total and non-HDL cholesterol (r=-0.59, P<.0001), suggesting a contribution of receptor-mediated hepatic uptake of cholesterol-rich lipoproteins to the hypocholesterolemic effect of ACOL. These findings establish that ACOL retains its powerful cholesterol-lowering action in diet-induced hypercholesterolemia and suggest that the SERM acts in such conditions through favoring hepatic low-density lipoprotein receptor-mediated uptake of cholesterol transported by non-HDL lipoprotein fractions.

Topics: Animals; ATP-Binding Cassette Transporters; Blood Glucose; Cholesterol, Dietary; Female; Hydroxymethylglutaryl CoA Reductases; Hypercholesterolemia; Liver; Ovariectomy; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, LDL; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Selective Estrogen Receptor Modulators; Statistics, Nonparametric; Sterol Regulatory Element Binding Proteins; Weight Gain

Ninety, seven- to 10-day-old calves were allocated to three groups of 30 and treated daily for seven days with either 100 microg/kg halofuginone hydrobromide or 2.5 mg/kg decoquinate orally or left untreated as controls. The levels of diarrhoea and dehydration were monitored daily for 28 days from the first day of treatment (day 0) and samples of faeces were collected on days 0, 7, 14, 21 and 28, to quantify the excretion of Cryptosporidium parvum oocysts. The calves were weighed on days 3 and 28. The treatments had no effect on the levels of diarrhoea or dehydration, the proportions of diarrhoeic calves or the proportions of calves shedding oocysts. However, unlike decoquinate, halofuginone significantly reduced the excretion of oocysts on day 7 (P<0.0001), and decoquinate increased the average daily weight gain of the calves (P=0.049).

Topics: Animals; Cattle; Cattle Diseases; Coccidiostats; Cryptosporidiosis; Cryptosporidium parvum; Decoquinate; Dehydration; Diarrhea; Feces; Female; Male; Parasite Egg Count; Piperidines; Quinazolinones; Random Allocation; Treatment Outcome; Weight Gain

Topics: Adipose Tissue; Antihypertensive Agents; Appetite; Body Weight; C-Reactive Protein; Cannabinoid Receptor Modulators; Cardiovascular Diseases; Cholesterol, HDL; Diabetes Mellitus; Humans; Hypoglycemic Agents; Life Style; Metabolic Syndrome; Obesity; Physician Assistants; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Assessment; Risk Factors; Weight Gain

We have investigated the effect of 2-arachidonylglyceryl-ether (Noladin) on food consumption, weight, activity, and cognitive function in mice during diet restriction for 17 days and subsequent ad libitum feeding for 32 days. Female Sabra mice were given food for 2.5 h/day (equal to 60% diet restriction), received Noladin (0.001, 0.01, 0.1 mg/(kg day) intraperitonially (i.p.)) with or without the CB1 antagonist SR141716A (1 mg/kg i.p.) during days 3-17. Noladin (0.001 mg/kg) significantly increased food consumption without a change in body weight, probably due to increased activity and there was no change in cognitive function. A higher dose (0.1 mg/kg) did not affect food consumption, but increased activity and slightly decreased weight 32 days after termination of Noladin administration; however, cognitive deterioration was observed. At all doses tested, Noladin did not affect weight during the diet-restriction period, whereas the CB1 antagonist (with or without Noladin) caused a very significant decline in weight in this phase. Weight catch-up was observed 1 month after administration of Noladin was discontinued. Weight at day 32 after the termination of Noladin (0.1 mg/(kg day)) treatment was 5% less than control. Female C57BL/6 mice (same protocol, with 0.001 mg/(kg day) Noladin) gave similar results to 0.1 mg/kg in Sabra mice as regards weight. CB1 antagonist treatment caused very significant decline in both weight and food consumption; cognition and activity were unchanged. These results indicate that Noladin has a significant dose-dependent effect on food consumption, cognition and weight maintenance after weight loss. Low doses of Noladin may possibly allow an increase in food intake without a gain in weight after dieting. Thus, Noladin could be of potential clinical benefit in treating disorders of body weight. Noladin seems to signal food consumption and weight through CB1 receptors based on effects observed with the CB1 antagonist, while the cognition and activity are probably mediated by non-cannabinoid receptors.

Topics: Animals; Body Weight; Cannabinoid Receptor Modulators; Cognition; Cognition Disorders; Dose-Response Relationship, Drug; Eating; Endocannabinoids; Feeding and Eating Disorders; Female; Food Deprivation; Glycerides; Mice; Mice, Inbred C57BL; Motor Activity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Species Specificity; Weight Gain

(1) There are few clinical trials comparing combination therapy with a sulphonylurea and metformin after oral antidiabetic monotherapy fails to provide adequate glycaemic control. The UKPDS study suggested that this combination had a negative impact on mortality. (2) The assessment of insulin therapy in patients in whom oral antidiabetic therapy fails is based solely on surrogate endpoints: mainly HbA1c (glycated haemoglobin), bodyweight, and the frequency of hypoglycaemia. (3) In a comparative randomised trial involving patients whose glucose levels were no longer controlled by a sulphonylurea, the addition of metformin or a daily injection of insulin isophane (NPH) was similarly effective in reducing HbA1c levels. However, metformin caused less weight gain. (4) There are no randomised controlled trials comparing the addition of insulin versus a sulphonylurea when ongoing metformin monotherapy is inadequate. (5) Randomised comparative trials show that, when glycaemia is no longer controlled by a sulphonylurea plus metformin, adding a daily insulin injection is more effective in lowering HbA1c levels than the addition of acarbose and as effective as adding a glitazone. The adjunction of insulin appears to have a better risk-benefit balance than an oral three-drug regimen. (6) Several randomised controlled trials have shown that the addition of an oral antidiabetic to ongoing insulin therapy reduces HbA1c levels in patients with type 2 diabetes. The addition of metformin is also beneficial in terms of body weight changes. (7) Nine randomised controlled trials involving patients whose glycaemia was inadequately controlled by a sulphonylurea, alone or in combination with metformin, have compared the addition of a bedtime injection of insulin isophane versus replacement of the oral antidiabetics by several daily insulin injections. The two strategies had a similar impact on HbA1c (-1.5% to -2.5%), but patients experienced less weight gain when the oral antidiabetics were continued and a single insulin injection was added. (8) The few available comparative trials fail to show which oral treatment (a sulphonylurea, metformin, or a combination of the two) has the best risk-benefit balance when combined with a bedtime injection of insulin isophane. (9) Insulin isophane is the first-choice insulin for combination therapy with an oral antidiabetic. In comparative trials, when combined with an oral antidiabetic, insulin glargine was no more effective than insulin is

Topics: Acarbose; Administration, Oral; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections; Insulin; Metformin; Piperidines; Randomized Controlled Trials as Topic; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome; Weight Gain

Our objective was to determine the effects of SCH 57068 alone and with 17 beta-estradiol (E(2)) on bone, lipids and uteri in ovariectomized (OVX) rats. In OVX animals lumbar vertebral and femoral bone mineral density (BMD) were significantly higher after 12 weeks of treatment with SCH 57068 than in untreated OVX controls. Similarly BMD was superior in OVX + E(2) + SCH 57068 treated animals than in OVX + E(2) controls. SCH 57068 also significantly reduced the increase in bone turnover markers, serum pyridinoline and serum osteocalcin levels, induced by OVX, and increased mechanical bone strength. SCH 57068 also significantly reduced the rise in serum cholesterol and low-density lipoprotein cholesterol induced by OVX. SCH 57068 had no stimulatory effect on uterine epithelium when given alone in OVX rats. SCH 57068 (1 and 2.5 mg/kg) reduced uterine weight and blocked endometrial stimulation induced by E(2). In summary, SCH 57068 adds to the positive effects of E(2) on bone and lipid metabolism but blocks the stimulatory effects of E(2) on the uterus. Potentially, E(2) + SCH 57068 could be combined for the treatment and prevention of breast cancer or as a novel hormone replacement therapy.

Topics: Animals; Biomarkers; Biomechanical Phenomena; Bone Density; Cholesterol; Disease Models, Animal; Estrogen Antagonists; Estrogens; Female; Femur; Hypertrophy; Lumbar Vertebrae; Molecular Structure; Organ Size; Osteoporosis; Ovariectomy; Piperidines; Rats; Rats, Sprague-Dawley; Selective Estrogen Receptor Modulators; Uterus; Weight Gain

The selective CB(1) receptor antagonist, SR 141716, has been demonstrated to reduce food consumption in a range of animal species.. To assess the effect of chronic administration of SR 141716 on body weight and ingestive behaviour of lean and obese (fa/fa) Zucker rats.. Lean and obese Zucker rats were orally dosed with SR 141716 (3, 10, 30 mg/kg PO), sibutramine (5 mg/kg PO) or vehicle for one week. Pair-fed controls provided insight as to whether the effect of SR 141716 on body weight was attributable to drug-induced hypophagia. Subsequently, the effect of chronic oral administration of SR 141716 (1, 3, 10 mg/kg) was assessed for 28 days. At the end of this period, all animals were given vehicle for 14 days. The incidence of wet-dog shakes, yawning, scratching, and grooming behaviours, was assessed after acute administration and at weekly intervals thereafter for 4 weeks.. SR 141716 dose-dependently decreased food intake and body weight gain in both lean and obese animals. The inhibition of food intake and body weight gain was greater in obese Zuckers than in lean Zucker controls. Changes in the body weights of pair-fed controls closely paralleled those of their drug-treated counterparts. Chronic 28-day treatment led to a maintained reduction of body weight gain. Withdrawal of SR 141716 on day 28 resulted in rebound hyperphagia and a significant weight gain. On acute administration, SR 141716 dose-dependently induced motor behaviours that showed tolerance upon repeated administration.. These data indicate that chronic oral treatment with SR 141716 significantly reduces the food intake and body weight gain of obese and lean Zucker rats, an effect that is greater in obese animals and reversible upon drug withdrawal.

Topics: Animals; Appetite Depressants; Cannabinoids; Cyclobutanes; Dose-Response Relationship, Drug; Eating; Energy Metabolism; Male; Motor Activity; Piperidines; Pyrazoles; Rats; Rats, Zucker; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Time Factors; Weight Gain

EM-652 is a pure antiestrogen in human breast and uterine cancer cells that also reduces bone loss and plasma lipid levels in the rat. This study aimed to assess the ability of EM-652, alone or with dehydroepiandrosterone (DHEA), to prevent obesity and related metabolic abnormalities induced by an obesity-promoting diet and ovariectomy.. Female rats were fed a high-sucrose, high-fat (HSHF) diet, were left intact or ovariectomized (OVX), and were treated with EM-652, DHEA, or both for 20 days. Variables of energy balance and determinants of lipid metabolism and insulin sensitivity were assessed.. The HSHF diet (vs. chow) and OVX both increased energy intake and gain, as well as energetic efficiency. Both EM-652 and DHEA prevented diet- and OVX-induced energy gain mainly by decreasing fat deposition, without being additive. The modest EM-652-induced increase in liver triglycerides of intact rats was prevented by its combination with DHEA. EM-652, but not DHEA, decreased cholesterolemia. The HSHF diet and OVX reduced insulin sensitivity, an effect that was attenuated by EM-652 and abrogated by DHEA and EM-652+DHEA. Treatment with EM-652, DHEA, or their combination abolished the diet- and OVX-induced increase in adipose lipoprotein lipase activity that accompanied fat gain.. EM-652 is an effective agent to prevent diet- and OVX-induced obesity and its associated cardiovascular risk factors such as insulin resistance. The addition of DHEA prevents hepatic lipid accumulation and further ameliorates insulin sensitivity. The beneficial metabolic effects of such combined steroid therapy may, therefore, eventually prove to be clinically relevant.

Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Cholesterol; Dehydroepiandrosterone; Diet; Dietary Fats; Dietary Sucrose; Eating; Energy Intake; Energy Metabolism; Estrogen Antagonists; Female; Insulin Resistance; Lipoprotein Lipase; Liver; Obesity; Ovariectomy; Piperidines; Rats; Rats, Sprague-Dawley; Triglycerides; Weight Gain

The aim of this study was to analyze the optimal time-window for neuroprotection by a novel NMDA antagonist, Gacyclidine, after experimental spinal cord injury, in terms of its functional, histopathological and electrophysiological effects. This molecule has already demonstrated its capacity for reducing the extent of an ischemic lesion and is currently experimented in a clinical trial of spinal cord injury. In this study, the spinal cord of rats was damaged by a contusive method and the animals were treated by saline or 1 mg/kg of Gacyclidine i.v., 10, 30, 60 and 120 min after injury. The time-course of the motor score was evaluated on days 1, 7 and 18 after injury, and somatosensory evoked potentials were determined on day 20. The animals were then killed and the cross-sectional area of the spinal cord (at the epicenter of the injury, above and below the injury), was measured. Walking recovery was better (P<0.0125) in the group treated 10 min after injury than in the untreated injured animals after 18 days of injury. Motor performances were related to the preservation of a larger undamaged area of spinal cord at the level of the injury (P<0.0125). Somatosensory evoked potential amplitudes were also higher in this group. These results confirm that Gacyclidine attenuates spinal cord damage after an experimental spinal cord lesion. Recovery was better within the group treated 10 min after injury compared with the other groups, which certainly confirms that the acute time-course of glutamate release requires rapid pharmacological intervention to achieve good results.

Topics: Animals; Contusions; Cyclohexanes; Cyclohexenes; Electrophysiology; Evoked Potentials, Somatosensory; Excitatory Amino Acid Antagonists; Male; Motor Activity; N-Methylaspartate; Neuroprotective Agents; Piperidines; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Injuries; Time Factors; Weight Gain

We have shown previously that chronic intrahippocampal, intraperitoneal and subcutaneous administrations of non-peptide opioid receptor agonists induced depressor responses in the spontaneously hypertensive rat (SHR). However, it is not clear whether the hypotensive effect of systemic administration involves kappa receptors behind the blood-brain barrier. In this study, the relative roles of central vs peripheral kappa-opioid receptors in the hypotensive effect of kappa-agonists was examined in conscious SHRs following chronic subcutaneous administration of two selective kappa-agonists, BRL 52656 which freely penetrates the blood-brain barrier, and BRL 52974 which has only limited ability to do so. Initial studies determined the dose-response relationship for each of the two drugs given intraperitoneally twice a day, while monitoring systolic arterial pressure (SAP), mean arterial pressure (MAP) and heart rate (HR) measured by the tail-cuff method. Both drugs caused biphasic arterial pressure responses, with lower doses of BRL 52656 causing depressor effects and higher doses resulting in pressor effects. By contrast, lower doses of BRL 52974 caused pressor effects and higher doses depressor effects. The biphasic effects occurred with BRL 52656 from 0.01 to 3.0 mg kg(-1) and that for BRL 52974 from 0.1 to 30 mg kg(-1). In subsequent studies the drugs were infused chronically, subcutaneously via osmotic minipumps over a 14-day period, BRL 52656 at 0.2 or 0.5 mg kg(-1)/day and BRL 52974 at 0.2 mg kg(-1)/day. At lower doses, BRL 52656 decreased SAP, MAP and HR but at higher doses only bradycardia was observed. BRL 52974 given chronically subcutaneously over 14 days had no significant effects on arterial pressure and decreased heart rate only after seven days of treatment. Collectively, the results established that only the kappa-agonist, which gained access to the central nervous system, lowered arterial pressure and heart rate, whereas the compound with limited ability to cross the blood-brain barrier was ineffective at equivalent doses. The complex dose-response pattern found with both drugs suggests that kappa-agonists have central hypotensive and bradycardic actions at low doses but at higher doses a mixture of both central and peripheral actions leads to hypertension and tachycardia.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Blood-Brain Barrier; Dose-Response Relationship, Drug; Drinking; Heart Rate; Hypertension; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Piperidines; Pyridines; Pyrrolidines; Rats; Rats, Inbred SHR; Receptors, Opioid, kappa; Weight Gain

The beneficial effect of long-term hormone replacement therapy in terms of a decreased risk of cardiovascular disease is now generally accepted. Raloxifene, a selective estrogen receptor modulator, has demonstrated hypolipidemic properties while leaving the endometrium unstimulated.. For our study of the effects of raloxifene on atherosclerosis, 75 rabbits were ovariectomized and treated with either raloxifene, 17beta-estradiol, or placebo; 25 rabbits were sham operated and treated with placebo. After 45 weeks, the raloxifene group had two thirds of the aortic atherosclerosis, as evaluated by the cholesterol content of the proximal inner part of the aorta, found in the placebo group (placebo, 577+/-55.1 nmol/mg protein; raloxifene, 397+/-53.6 nmol/mg protein; P<.05); the estrogen group had one third of the aortic atherosclerosis in the placebo group (estrogen, 177+/-32.1 nmol/mg protein; P<.001). The sham-operated group (473+/-59.6 nmol/mg protein) was not significantly different from placebo. These effects were only partly explained by the changes in serum lipids and lipoproteins, and treatment with both estrogen and raloxifene independently predicted the response in aorta cholesterol. Because plasma levels of total raloxifene were low relative to clinical values in postmenopausal women, dose-response data for raloxifene are required.. Our findings indicate that raloxifene hydrochloride has a potentially important antiatherogenic effect, analogous to that observed with estrogen in this model.

Topics: Animals; Aorta, Thoracic; Arteriosclerosis; Cholesterol; Cholesterol, Dietary; Disease Models, Animal; Estrogen Antagonists; Female; Organ Size; Ovariectomy; Piperidines; Rabbits; Raloxifene Hydrochloride; Uterus; Weight Gain

This study was conducted to assess the effect of the coccidiostat halofuginone (Stenorol) on growth, feed consumption, and survival of Chukar partridge. Halofuginone was fed to three replicates (14 chicks per replicate) of chukar chicks from 2 to 7 d of age at levels of 0, 1.5, 3.0, 6.0 and 12 ppm. Mortality from 2 to 7 d was 0, 0, 0, 11, and 21 birds, respectively, by treatment. Seven-day body weight showed a significant linear decrease with increasing halofuginone level (P < 0.01). On the 7th d, replicates receiving 6.0 and 12.0 ppm halofuginone were transferred to unmedicated feed for the remainder of the test due to excessive mortality. The other groups were continued until 6 wk of age. At 6 wk, chicks fed 6 or 12 ppm halofuginone from 2 to 7 d and then unmedicated feed did not differ in body weight from those fed the unmedicated control diet. A significant difference in mortality was not observed among the other three treatment groups to 6 wk of age. A linear depression in 3-, 4-, 5-, and 6-wk body weight with increasing halofuginone level was observed within the first three treatment levels (P < 0.05). It was concluded that 1.5 ppm halofuginone depressed growth of young chukars and that 6 ppm resulted in increased mortality.

Topics: Animals; Coccidiostats; Dose-Response Relationship, Drug; Feeding Behavior; Growth; Piperidines; Poultry; Quinazolines; Quinazolinones; Weight Gain

The benzothiophene antiestrogen, raloxifene (LY156758), has selective estrogen pharmacological antagonist activity in rats. The PAIII rat prostatic adenocarcinoma model was used to evaluate the effects of this agent on the lymphatic and pulmonary metastasis and survival in tumor-bearing male Lobund-Wistar (LW) rats. Raloxifene was inactive against colony formation of PAIII cells in vitro. Similarly, following subcutaneous (s.c.) implantation of 10(6) PAIII cells in the tail, s.c. administration of raloxifene (2.0, 10.0, or 20.0 mg/kg/day) for 30 days failed to demonstrate cytoreductive activity against primary tumor growth in the tail. However, in these same animals, raloxifene administration produced significant (P < 0.05) inhibition of PAIII metastasis from the primary tumor in the tail to the gluteal and iliac lymph nodes (maximal responses = 89% and 81% from control values, respectively). PAIII metastasis to the lungs was significantly inhibited by raloxifene treatment. Numbers of pulmonary foci in PAIII-bearing rats were significantly (P < 0.05) reduced by raloxifene administration in a dose-related manner (maximal reduction = 97% from control values). In these animals, maximal regression of 20% for ventral prostate and 21% for seminal vesicle were also seen after raloxifene administration (P < 0.05 for both). Coadministration of E2B and raloxifene had no consistent antagonistic effect upon the antitumor responses produced by raloxifene. Raloxifene (40.0 mg/kg/day for 28 days) produced marked decreases in PAIII metastasis in the lymphatic and pulmonary components. Continued administration of the compound produced significant (P < 0.05) extension of survival of PAIII-bearing rats. Further studies are needed to define the maximal antitumor efficacy and the mechanism of action of raloxifene in urogenital solid tumor animal models. These data support the contention that raloxifene represents a class of active antimetastatic agents with potential efficacy in the treatment of hormone-insensitive human prostatic cancer.

Topics: Adenocarcinoma; Adrenal Glands; Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Estradiol; Estrogen Antagonists; Fluorouracil; Incidence; Lung Neoplasms; Lymphatic Metastasis; Male; Organ Size; Piperidines; Prostate; Prostatic Neoplasms; Raloxifene Hydrochloride; Random Allocation; Rats; Rats, Wistar; Survival Rate; Testis; Weight Gain

In a chronic toxicity study in the rat, bidisomide administered as a dietary admixture produced a dose-related lowering of reticulocytes and leucocytes. Plasma alanine aminotransferase activity was increased at 300 mg/kg and decreased at 900 mg/kg. The potential mechanisms of these effects were investigated by comparing the responses in groups of male Sprague-Dawley rats receiving a control diet, or 300 or 1200 mg/kg/day bidisomide. Subsets of these groups were co-treated subcutaneously with folinic acid or with a vitamin B1, B6, B12 complex. Subsets of control and 300 mg/kg groups were maintained on a 20-25% feed restriction regimen for 3 months, to mimic the depression in body weight gain observed in animals receiving 1200 mg/kg. Body weight gains were significantly reduced at 1200 mg/kg and in all feed-restricted animals. Plasma and liver alanine aminotransferase (ALT) and plasma aspartate aminotransferase (AST) levels were also reduced at this dose level. At 300 mg/kg, plasma transaminases, glutamate dehydrogenase (GLDH) and sorbitol dehydrogenase (SDH) activities were increased. These changes were prevented in animals receiving folinic acid supplementation. Plasma glucose, triglycerides, and unsaturated and total iron binding capacities were decreased, while plasma iron levels tended to increase, mainly at the high dose. Vitamin supplementation prevented a decrease in reticulocyte counts at 300 mg/kg. Bidisomide increased urinary formimino-glutamic acid (FIGLU) excretion but did not affect methylmalonic acid (MMA) or taurine excretion. The effect on FIGLU at 1200 mg/kg was prevented by folinic acid co-treatment. Absolute liver weight was lowered at both dose levels and in feed-restricted animals. However, the relative liver weights were unaffected. Thymidine kinase and thymidylate synthase activity of the bone marrow cells were not altered by the bidisomide treatment. Except for the increase in plasma transaminase, GLDH and SDH levels at 300 mg/kg, changes in clinical chemistry parameters are considered to result mainly from nutritional restrictions. Changes in hematologic parameters appear to be related to the combination of decreased feed consumption (leukocytes) and decreased availability or utilization of folates (reticulocytes). This alteration, however, did not affect DNA synthesis in bone marrow. The prevention by folinic acid, but not by feed restriction, of the elevation of liver enzymes at 300 mg/kg is an intriguing, yet unexplained finding

Topics: Alanine Transaminase; Analysis of Variance; Animals; Anti-Arrhythmia Agents; Antidotes; Aspartate Aminotransferases; Body Weight; Bone Marrow; Bone Marrow Cells; Deoxyuridine; Diet; DNA; Eating; Femur; Food Deprivation; Formiminoglutamic Acid; Gas Chromatography-Mass Spectrometry; In Vitro Techniques; Leucovorin; Male; Methylmalonic Acid; Piperidines; Rats; Rats, Sprague-Dawley; Taurine; Vitamin B Complex; Weight Gain

Absorption, distribution, metabolism and excretion of ebastine (4'-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone, LAS-90, CAS 90729-43-4), a new potent histamine H1-receptor antagonist, were studied with 14C-labeled compound in male rats during and after 21 consecutive daily oral administrations at a dose of 2 mg/kg/d. Plasma levels at 2 h after each administration were virtually constant in the range of 81-166 ng eq./ml for 21 days. The plasma levels at 24 h following each administration were lower than the reliable limit of radioactivity measurements during the course of the experiment. Plasma level reached the maximum (Cmax) of 109 ng eq./ml at 2 h after the 21st administration and decreased monophasically with a half-life (t1/2) of 2.5 h, which was similar to the results in the previous single dose study. [14C]Ebastine radioactivity was distributed to the liver, kidney, submaxillary gland, hypophysis, adrenal, lung and pancreas twice as high or more, and to others including brain similarly as or lower than in plasma, at 1 h after the last administration. At 168 h, radioactivity was detected at low levels in several tissues such as liver, kidney, submaxillary gland, etc. and not in other examined tissues. About 2-3% and more than 90% of the daily dose were excreted in urine and feces, respectively, within 24 h after each administration and radioactivity was virtually completely excreted within 120 h after the last administration. The analysis by thin-layer chromatography revealed that the composition of radioactive metabolites in plasma, urine and feces after repeated administration was similar to that in the single dose study.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Animals; Autoradiography; Behavior, Animal; Biotransformation; Butyrophenones; Chromatography, Thin Layer; Eating; Histamine H1 Antagonists; Intestinal Absorption; Male; Piperidines; Rats; Rats, Wistar; Tissue Distribution; Weight Gain

LY255582, administered subcutaneously, decreased food intake and body weight gain of fed obese Zucker rats during the entire 30-day period of treatment. No tolerance to these biologic effects of LY255582 could be demonstrated. d-Amphetamine and naltrexone, administered subcutaneously, and d,l-fenfluramine and salbutamol, administered orally, decreased food intake for no more than 6 to 12 days, in contrast to the long-lasting effects of LY255582. Salbutamol suppressed the appetite of obese rats for 3-4 days only. After an additional 12 days of treatment, weight gain decreased significantly accompanied by no appetite suppression. Thus, there is a difference in the duration of action of the opioid antagonist, LY255582, when compared to amphetamine, fenfluramine, naltrexone, and salbutamol, on food intake and body weight gain of obese rats.

Topics: Albuterol; Animals; Appetite Depressants; Cyclohexanes; Dextroamphetamine; Drug Tolerance; Eating; Endorphins; Female; Fenfluramine; Injections, Subcutaneous; Male; Naltrexone; Obesity; Piperidines; Rats; Rats, Zucker; Weight Gain

Eighteen of 91 seven- to nine-month-old Belgian white and blue double-muscled male fattening cattle developed typical signs of shipping fever. They were all injected intramuscularly once a day for three days with 5 mg/kg of enrofloxacin, and in addition nine selected at random were injected intramuscularly five times at 12 hour intervals with 0.1 mg/kg of metrenperone, a 5-hydroxytryptamine blocker, the other nine receiving a placebo. During the outbreak of shipping fever metrenperone showed effective antipyretic properties, and all the calves treated with it made a complete recovery. Moreover, during the 360 day fattening period following the outbreak, the cattle treated with metrenperone gained on average 45.4 kg more weight than the control cattle.

Topics: Animals; Anti-Infective Agents; Cattle; Disease Outbreaks; Drug Therapy, Combination; Enrofloxacin; Fluoroquinolones; Injections, Intramuscular; Male; Pasteurellosis, Pneumonic; Piperidines; Quinolones; Respiration; Respiratory Function Tests; Weight Gain

A higher frequency (25%) of gastrooesophageal reflux (GOR) has been previously reported in patients over 5 years old with cystic fibrosis compared with controls without cystic fibrosis. It was believed that GOR was caused by the complications of cystic fibrosis. We looked for GOR in all 26 children younger than 60 months who had cystic fibrosis diagnosed. They had a classical genetic profile and the usual scattered clinical manifestations for age. GOR was confirmed in 21 (81%): 20 by abnormal pH tracings and in one on a clinical basis. After at least one month of adjusted cystic fibrosis treatment, antireflux treatment (cisapride) was given to 16 patients and variables of GOR improved dramatically. Weight gain was significant and recurrent cough and wheeze disappeared. One year later half of the patients still suffered from GOR. GOR is a major problem in the early life of those with cystic fibrosis and is not the consequence of either respiratory or gastrointestinal complications as it improves with age whereas cystic fibrosis becomes worse with age.

Topics: Child, Preschool; Cisapride; Cough; Cystic Fibrosis; Female; Follow-Up Studies; Gastroesophageal Reflux; Humans; Hydrogen-Ion Concentration; Infant; Infant, Newborn; Male; Piperidines; Respiratory Sounds; Serotonin Antagonists; Weight Gain

In vivo and in vitro experiments were conducted in an effort to elucidate the mechanism of suppression by halofuginone of skin strength in broilers. In the in vivo study, halofuginone was included at concentrations of 0, 1.5, 3, and 6 mg/kg of diet, corresponding to 0, 50, 100, and 200%, respectively, of the amount recommended for use as a coccidiostat. Each dietary treatment was given to 260 female broiler day-old chickens. Skin tearing was evaluated at the processing plant. Skin collagen and Kjeldahl-nitrogen were determined chemically. At the age of 7 wk, BW and feed efficiency were affected only in birds consuming the diet containing the highest concentration of the drug. Skin tearing increased but skin collagen concentration decreased in a dose-dependent manner. Fibroblasts were obtained by collagenase digestion from chicken skin and cultured. The cultured cells were incubated with various concentrations of halofuginone, monensin, and nicarbazin, and [3H]proline incorporation was evaluated in collagenase-digestible (representing mostly collagen) and nondigestible proteins exported by the cells into the medium. Halofuginone, at a concentration as low as 10(-11) M, inhibited incorporation of [3H]proline into collagenase-digestible proteins, but did not affect incorporation of [3H]proline into collagenase-nondigestible proteins. Even at concentrations as high as 10(-9) M, neither monensin nor nicarbazin affected collagenase-digestible proteins. The in vitro results suggest that halofuginone specifically inhibits collagen synthesis by skin fibroblasts. Results of both in vivo and in vitro trials suggest that the increase of skin tearing during processing, induced by halofuginone, is caused by direct suppression of skin collagen synthesis.

Topics: Animals; Cells, Cultured; Chickens; Coccidiostats; Collagen; Dose-Response Relationship, Drug; Female; Fibroblasts; Monensin; Nicarbazin; Piperidines; Quinazolines; Quinazolinones; Random Allocation; Skin; Weight Gain

Efficacy of virginiamycin (22 mg/kg) in combination with no drug, amprolium, carbarsone, halofuginone, or monensin, was studied. Male and female turkeys were raised to market age in five experiments conducted from 1983 to 1987. Body weights and feed:gain responses to virginiamycin for males and females were positive and significant (P less than .05). Virginiamycin resulted in mean 5.2 and 6.3% body weight responses and 3.3 and 2.2% feed:gain responses for males at 19 or 20 wk of age and for females at 16 or 17 wk of age, respectively. Mortality rates were low in all studies, and were not influenced by virginiamycin. In a processing study, virginiamycin in combination with halofuginone did not affect shrinkage, yield, or market grade. Feed was utilized by males and females 3.9 and 3.0%, respectively, more efficiently than expected with dietary virginiamycin, compared with results predicted by a simulation modeling technique. Profitability was considerably greater with dietary virginiamycin using actual data than with simulated feed consumption data.

Topics: Amebicides; Amprolium; Animal Feed; Animals; Arsanilic Acid; Drug Interactions; Eating; Energy Metabolism; Female; Male; Monensin; Mortality; Piperidines; Quinazolines; Quinazolinones; Sex Characteristics; Turkeys; Virginiamycin; Weight Gain

Two trials were conducted to evaluate the effects of feeding various anticoccidial products to turkeys to 8 wk and then growing to market age (16 wk for hens and 20 wk for toms). Anticoccidials evaluated in the first trial included amprolium at 187.5 mg/kg for 0 to 4 wk and 125 mg/kg for 4 to 8 wk; butynorate at 375 mg/kg for 0 to 8 wk; monensin at both 60 (MON-60) and 100 mg/kg for 0 to 8 wk; zoalene at 187.5 mg/kg for 0 to 4 wk and 125 mg/kg for 4 to 8 wk; and halofuginone at 3 mg/kg for 0 to 8 wk. In the second trial, MON-60 was replaced by a combination of sulfadimethoxine (62.5 mg/kg) plus ormetoprim (37.5 mg/kg) for 0 to 8 wk. In each trial each treatment was fed to four pens of 16 hens and four pens of 12 toms. Several of the anticoccidials significantly influenced the weight of both hens and toms by producing lower weights at the end of the 8-wk feeding period than birds in other treatments. However, after removal of the anticoccidials, compensatory gains were observed in almost every instance. Significant effects of previous anticoccidial feeding were noted on body weight of hens at 16 wk but not on weights of toms at 20 wk.

Topics: Amprolium; Animal Feed; Animals; Coccidiostats; Dietary Fats; Dinitolmide; Eating; Female; Male; Monensin; Organotin Compounds; Piperidines; Pyrimidines; Quinazolines; Quinazolinones; Random Allocation; Sulfadimethoxine; Turkeys; Weight Gain

Two trials were conducted to compare the efficacy of currently approved anticoccidials for turkeys against challenge using a field isolate of mixed Eimeria species; E. adenoides, E. gallopavonis, and E. meleagrimitis. Poults in wire-floored cages were fed unmedicated diets from day-old to 3 wk of age. Diets were supplemented with either amprolium (AMP, 125 mg/kg), butynorate (BUT, 375 mg/kg), monensin (MON-60, 60 mg/kg; MON-100, 100 mg/kg), halofuginone (HAL; 3 mg/kg), zoalene (ZOA; 125 mg/kg), or sulfadimethoxine plus ormetoprim (SUL + ORM, 62.5 mg/kg and 37.5 mg/kg, respectively). After 2 days on the test diets, poults were individually weighed and inoculated with sporulated coccidial oocysts from the field isolate. Total fecal collections were obtained for Days 0 to 5 and 6 to 10 to estimate oocyst output. At 10 days postinoculation, the birds were individually weighed and killed to determine severity of intestinal lesions. The HAL and MON were most effective and AMP, ZOA, and SUL + ORM were least effective in maintaining weight and in reducing the severity of intestinal lesions. All the coccidiostats tested reduced oocyst passage, but poults fed HAL produced fewer oocysts. The results demonstrated differences in efficacy among anticoccidials with the more recently approved drugs providing the best protection against coccidiosis.

Topics: Amprolium; Animals; Coccidiosis; Coccidiostats; Dinitolmide; Feces; Intestines; Male; Monensin; Organotin Compounds; Piperidines; Poultry Diseases; Pyrimidines; Quinazolines; Quinazolinones; Sulfadimethoxine; Turkeys; Weight Gain

Meal-fed Zucker rats were used to determine the acute and chronic s.c. effect of certain trans-3,4-dimethyl-4-phenylpiperidines (opioid antagonists) on food consumption. In acute studies, the active compounds suppressed food intake significantly of lean and obese meal-fed Zucker rats. LY117413 was the most effective over the 4-hr period immediately after the s.c. administration of the drug. Long-term chronic s.c. administration to the meal-fed obese Zucker rat showed that LY88329 and LY117413 significantly reduced food consumption for as long as the drug was administered and resulted in a significant decrease in body weight gain when compared to nontreated control obese rats. There was no evidence for the development of tolerance to these effects of LY88329 and LY117413 in this genetically obese rat model.

Topics: Animals; Appetite Depressants; Eating; Narcotic Antagonists; Obesity; Piperidines; Rats; Rats, Zucker; Weight Gain