piperidines and Feeding-and-Eating-Disorders

The promotility agents currently available to treat gastroparesis and feed intolerance in the critically ill are limited by adverse effects. The aim of this study was to assess the pharmacodynamic effects and pharmacokinetics of single doses of the novel gastric promotility agent motilin agonist camicinal (GSK962040) in critically ill feed-intolerant patients.. A prospective, randomized, double-blind, parallel-group, placebo-controlled, study was performed in mechanically ventilated feed-intolerant patients [median age 55 (19-84), 73 % male, APACHE II score 18 (5-37) with a gastric residual volume ≥200 mL]. Gastric emptying and glucose absorption were measured both pre- and post-treatment after intragastric administration of 50 mg (n = 15) camicinal and placebo (n = 8) using the (13)C-octanoic acid breath test (BTt1/2), acetaminophen concentrations, and 3-O-methyl glucose concentrations respectively.. Following 50 mg enteral camicinal, there was a trend to accelerated gastric emptying [adjusted geometric means: pre-treatment BTt1/2 117 minutes vs. post- treatment 76 minutes; 95 % confidence intervals (CI; 0.39, 1.08) and increased glucose absorption (AUC240min pre-treatment: 28.63 mmol.min/L vs. post-treatment: 71.63 mmol.min/L; 95 % CI (1.68, 3.72)]. When two patients who did not have detectable plasma concentrations of camicinal were excluded from analysis, camicinal accelerated gastric emptying (adjusted geometric means: pre-treatment BTt1/2 121 minutes vs. post-treatment 65 minutes 95 % CI (0.32, 0.91) and increased glucose absorption (AUC240min pre-treatment: 33.04 mmol.min/L vs. post-treatment: 74.59 mmol.min/L; 95 % CI (1.478, 3.449). In those patients receiving placebo gastric emptying was similar pre- and post-treatment.. When absorbed, a single enteral dose of camicinal (50 mg) accelerates gastric emptying and increases glucose absorption in feed-intolerant critically ill patients.. The study protocol was registered with the US NIH clinicaltrials.gov on 23 December 2009 (Identifier NCT01039805 ).

Topics: Adult; Aged; Aged, 80 and over; Critical Illness; Double-Blind Method; Enteral Nutrition; Feeding and Eating Disorders; Female; Gastric Absorption; Gastric Emptying; Gastrointestinal Motility; Glucose; Humans; Intensive Care Units; Male; Middle Aged; Piperazines; Piperidines; Placebos; Prospective Studies; South Australia

Topics: Appetite; Benzocycloheptenes; Body Weight; Clinical Trials as Topic; Drug Evaluation; Feeding and Eating Disorders; Growth; Humans; Piperidines; Thiophenes

Topics: Adolescent; Adult; Body Weight; Clinical Trials as Topic; Cycloheptanes; Feeding and Eating Disorders; Female; Headache; Humans; Male; Methysergide; Middle Aged; Migraine Disorders; Piperidines; Thiophenes; Time Factors

Topics: Adolescent; Appetite; Benzocycloheptenes; Body Weight; Child; Child, Preschool; Clinical Trials as Topic; Feeding and Eating Disorders; Humans; Infant; Piperidines; Serotonin Antagonists; Thiophenes

The prevalence of eating disorders and obesity in western societies is epidemic and increasing in severity. Preclinical research has focused on the development of animal models that can mimic the maladaptive patterns of food intake observed in certain forms of eating disorders and obesity. This study was aimed at characterizing a recently established model of palatable diet alternation in female rats. For this purpose, females rats were fed either continuously with a regular chow diet (Chow/Chow) or intermittently with a regular chow diet for 2 days and a palatable, high-sucrose diet for 1 day (Chow/Palatable). Following diet cycling, rats were administered rimonabant (0, 0.3, 1, 3 mg/kg intraperitoneally) during access to either palatable diet or chow diet and were assessed for food intake and body weight. Finally, rats were pretreated with rimonabant (0, 3 mg/kg, intraperitoneally) and tested in the elevated plus maze during withdrawal from the palatable diet. Female rats with alternating access to palatable food cycled their intake, overeating during access to the palatable diet and undereating upon returning to the regular chow diet. Rimonabant treatment resulted in increased chow hypophagia and anxiety-like behavior in Chow/Palatable rats. No effect of drug treatment was observed on the compulsive eating of palatable food in the diet-cycled rats. The results of this study suggest that withdrawal from alternating access to the palatable diet makes individuals vulnerable to the anxiogenic effects of rimonabant and provides etiological factors potentially responsible for the emergence of severe psychiatric side-effects following rimonabant treatment in obese patients.

Topics: Animals; Anxiety; Behavior, Animal; Cannabinoid Receptor Antagonists; Dietary Sucrose; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Feeding and Eating Disorders; Female; Maze Learning; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant

Central CB1 cannabinoid receptors regulate anxiety-like and appetitive consummatory behaviors. Pharmacological antagonism/inverse-agonism of CB1 receptors increases anxiety and decreases appetitive behaviors; however, neither well-defined dose nor context dependence of these effects has been simultaneously assessed in one behavioral assay.. We sought to determine the context and dose dependence of the effects of CB1 receptor blockade on anxiety-like and consummatory behaviors in a model that allowed for simultaneous detection of anxiety-like and consummatory-related behaviors.. We determined the effects of the CB1 receptor antagonist/inverse-agonist, rimonabant, in the novelty-induced hypophagia (NIH) assay in juvenile male ICR mice.. Rimonabant dose-dependently decreased consumption of a palatable reward solution completely independent of contextual novelty. Grooming and scratching behavior was also increased by rimonabant in a context-independent manner. In contrast, rimonabant increased feeding latency, a measure of anxiety-like behaviors, only in a novel, mildly anxiogenic context. The effects of rimonabant were specific since no effects of rimonabant on despair-like behavior were observed in the tail suspension assay. Blockade of CB2 receptors had no effect on novelty-induced increases in feeding latency or palatable food consumption.. Our findings indicate that CB1 receptor blockade decreases the hedonic value of palatable food irrespective of environmental novelty, whereas the anxiogenic-like effects are highly context-dependent. Blockade of CB2 receptors does not regulate either anxiety-like or consummatory behaviors in the NIH assay. These findings suggest that rimonabant modulates distinct and dissociable neural processes regulating anxiety and consummatory behavior to sculpt complex and context-dependent behavioral repertories.

Topics: Animals; Anxiety; Cannabinoid Receptor Antagonists; Consummatory Behavior; Dose-Response Relationship, Drug; Feeding and Eating Disorders; Hindlimb Suspension; Male; Mice; Mice, Inbred ICR; Motor Activity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Stress, Psychological

The ability of the endocannabinoid (EC) system to control appetite, food intake and energy balance has recently received great attention, particularly in the light of the different modes of action underlying these functions. The EC system modulates rewarding properties of food by acting at specific mesolimbic areas in the brain. In the hypothalamus, cannabinoid type 1 receptors (CB1) and ECs are integrated components of the networks controlling appetite and food intake. Interestingly, the EC system has recently been shown to control several metabolic functions by acting on peripheral tissues, such as adipocytes, hepatocytes, the skeletal muscles and the endocrine pancreas. The relevance of the system is further strengthened by the notion that visceral obesity seems to be a condition in which an overactivation of the EC system occurs; therefore, drugs interfering with this overactivation by blocking CB1 receptors are considered valuable candidates for the treatment of obesity and related cardiometabolic risk factors.

Topics: Amides; Animals; Cannabinoid Receptor Modulators; Clinical Trials as Topic; Eating; Energy Metabolism; Feeding and Eating Disorders; Humans; Islets of Langerhans; Liver; Muscle, Skeletal; Obesity; Piperidines; Pyrazoles; Pyridines; Receptor, Cannabinoid, CB1; Rimonabant

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

To study the functional contributions of the 5-HT4 receptor subtype of serotonin (5-HT), we have generated knockout mice lacking the 5-HT4 receptor gene. The male mutant mice exhibit a hyposensitivity to anorexic stress. Our recent data indicate that the pharmacological inactivation, using a systemic injection of the 5-HT4 receptor antagonist RS39604 (0.5 mg/kg), suppressed restraint stress-induced anorexia in wild-type female mice. In parallel, the same treatment reduced the 3,4-N-methylenedioxymethamphetamine (" ecstasy", 10 mg/kg)-induced anorexia in male wild-type mice. Our neurochemical analyses suggest that the mechanisms underlying feeding disorders in 5-HT4 receptor knockout mice are related to a lesser efficacy of 5-HT (hypothalamus, nucleus accumbens), leptin and the cocaine-amphetamine related transcript to reduce food intake following stress.

Topics: Animals; Anorexia; Appetite; Chromatography, High Pressure Liquid; Corticosterone; Feeding and Eating Disorders; Gene Expression Regulation; Leptin; Limbic System; Male; Mice; Mice, Knockout; N-Methyl-3,4-methylenedioxyamphetamine; Nerve Tissue Proteins; Piperidines; Propane; Receptors, Serotonin, 5-HT4; Restraint, Physical; Reverse Transcriptase Polymerase Chain Reaction; Serotonin; Serotonin 5-HT4 Receptor Antagonists; Serotonin Antagonists; Stress, Psychological

The anorectic effect of CM 57373 in dogs and in rats food-deprived or with experimentally induced hyperphagia (cafeteria-diet hyperphagia and insulin hyperphagia) was compared to the effect of serotoninergic anorectic drug dl-fenfluramine. CM 57373 and dl-fenfluramine administered orally caused a dose-related reduction of food consumption by food-deprived rats (ID50 = 7.4 mg/kg and 2.5 mg/kg respectively). The oral ID50 in dogs was 2.4 mg/kg for CM 57373 and 1.1 mg/kg for dl-fenfluramine. This animal species tolerated CM 57373 better than dl-fenfluramine. The latter induced mydriasis, dyskinesia and reduced spontaneous activity. The anorectic effects of CM 57373 and dl-fenfluramine in cafeteria-diet hyperphagic rats were comparable. Tolerance to the anorectic effect developed in rats treated with both CM 57373 and dl-fenfluramine although tolerance was initially less pronounced with CM 57373 than dl-fenfluramine. The brain serotonin levels of cafeteria-fed rats were unchanged by CM 57373 throughout treatment whereas dl-fenfluramine decreased the monoamine levels starting from the 8th day. Both drugs reduced 5-hydroxyindolacetic acid levels. CM 57373 (7.4 mg/kg p.o.) and dl-fenfluramine (2.5 mg/kg p.o.) markedly reduced the overeating caused by insulin injection. These results indicate that CM 57373 shows several characteristics of drugs that act via serotonin to depress food intake in various animal species.

Topics: Animals; Appetite Depressants; Body Weight; Diet; Dogs; Eating; Feeding and Eating Disorders; Female; Fenfluramine; Hydroxyindoleacetic Acid; Hyperphagia; Insulin; Male; Piperidines; Rats; Rats, Inbred Strains; Serotonin

The present study investigated the effect on the rat's eating behavior of the new selective 5HT2 antagonist ritanserin. The results obtained indicate that: single subcutaneous (SC) injection of ritanserin, at doses between 0.1 and 1 mg/kg b.wt., neither elicits food intake in sated rats, nor increases the intake induced by food deprivation; subchronic SC treatment (15 days) with 0.1 mg/kg does not increase food intake nor body weight gain; subchronic SC treatment with high doses, 1 or 10 mg/kg, produces small and transient increases in food intake without affecting body weight gain. When ritanserin was tested for its ability to block the anorectic effect of exogenous 5HT, it inhibited the effect of intraperitoneal (IP) 5HT, but proved to be completely inactive versus the effect of 5HT injected into the hypothalamic paraventricular nucleus, which is highly sensitive to this effect of 5HT. This last finding suggests that the anorectic action of central endogenous 5HT is also not blocked by ritanserin, thus proposing a reasonable explanation for the absence of orexigenic effect following its administration. Moreover, it suggests that in rats the hypothalamic receptors mediating the effect of 5HT on eating behavior are different from the 5HT2 of the frontal cortex which have been shown to be completely blocked by ritanserin under the experimental conditions employed in our study.

Topics: Animals; Anorexia; Brain; Drinking Behavior; Feeding and Eating Disorders; Feeding Behavior; Food Deprivation; Male; Piperidines; Rats; Rats, Inbred Strains; Ritanserin; Satiation; Serotonin; Serotonin Antagonists

4-(3-Indolyl-2-ethyl) piperidine (LM 5008), 2-(1-piperazinyl) quinoline (quipazine), and metachlorophenylpiperazine (mCPP) were studied for their ability to affect serotonergic mechanisms in vitro. Their relative potency in inhibiting serotonin (5-HT) uptake in vivo and reducing food intake in rats was also examined. mCPP was very potent in displacing 3H-5-HT bound to brain membranes (IC50, 6.2 X 10(-7) M), followed by quipazine, which showed an IC50 of 3.8 X 10(-6) M. LM 5008 was the least effective with an IC50 of 3.6 X 10(-5) M. mCPP and quipazine were less potent than d-fenfluramine in releasing 14C-5-HT from brain synaptosomes, while LM 5008 caused no significant effects at a concentration of 10(-5) M. Conversely, both in vitro and in vivo studies on 5-HT uptake showed that LM 5008 was the most potent compound in inhibiting 5-HT uptake and mCPP the least potent. Since a 50% reduction of food intake was not reached even with a dose of LM 5008 27-times higher than the ED50 for inhibiting 5-HT uptake in vivo, it is suggested that even marked inhibition of 5-HT uptake at central synapses is not sufficient per se to trigger serotonin-dependent anorexia in the rat. Increased release and/or direct stimulation of post-synaptic receptors may be necessary to obtain this effect. This could be of interest for developing new agents which can cause anorexia by interacting with brain serotonin.

Topics: Animals; Anorexia; Brain; Feeding and Eating Disorders; Feeding Behavior; Female; Fenfluramine; Humans; Piperazines; Piperidines; Quipazine; Rats; Serotonin; Serotonin Antagonists; Synaptosomes; Time Factors

Topics: Body Weight; Coronary Disease; Diuresis; Feeding and Eating Disorders; Humans; Maleates; Perhexiline; Piperidines; Vasodilator Agents

Topics: Aggression; Criminal Psychology; Feeding and Eating Disorders; Headache; Humans; Nitriles; Phenothiazines; Piperidines; Sleep Wake Disorders; Tranquilizing Agents

Topics: Biopsy; Body Temperature; Body Weight; Brain Diseases; Calcium; Child; Child, Preschool; Chlorides; Creatine; Dehydration; Diabetes Insipidus; Diagnosis, Differential; Diet; Diuresis; Feeding and Eating Disorders; Female; Humans; Hydrochlorothiazide; Hypothalamus; Infant; Kidney; Male; Mineralocorticoid Receptor Antagonists; Obesity; Osmolar Concentration; Osmosis; Piperidines; Potassium; Sodium; Urography; Vasopressins

Topics: Amitriptyline; Animals; Behavior, Animal; Body Weight; Central Nervous System; Central Nervous System Stimulants; Chlordiazepoxide; Chlorpromazine; Chlorprothixene; Eating; Feeding and Eating Disorders; Female; Haloperidol; Humans; Imipramine; Nutritional Physiological Phenomena; Oxazepam; Oxazoles; Pemoline; Phenobarbital; Piperidines; Promethazine; Psychopharmacology; Rats; Reserpine; Thiazines