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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human volunteer subjects of normal weight received oral doses of (+)amphetamine (10 mg) or (+/-)fenfluramine (30 mg and 60 mg) together with a placebo control according to a within-subjects design. The effects of these treatments were monitored by measuring food intake in a test meal, subjective ratings of hunger motivation and the micro-structure of eating behaviour abstracted from videotaped recordings of the test meal. Various measures of the rate of feeding were computed from these recordings. Amphetamine and fenfluramine (60 mg) showed generally similar effects on food intake and on the subjective experience of hunger, but displayed differing actions on the fine structure of eating. Amphetamine increased latency to initiation of eating and increased the rate of food ingestion, whilst fenfluramine slowed the local rate of eating and eliminated the characteristic decline in the rate of feeding across the course of a meal. These findings display certain resemblance to the results of animal experiments involving similar pharmacological manipulations and emphasise the importance of measuring rate of feeding in animal and human studies. The results of this study suggest that the micro-analysis of feeding behaviour not only provides a tool for understanding systems involved in the modulation of food consumption but also reveals information which may be helpful for the use of drugs in the treatment of obesity.
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PMID:Effect of anorexic drugs on food intake and the micro-structure of eating in human subjects. 11 58

This minireview deals with the possible roles of monoamines in feeding and feeding disorders. The introduction sketches the results of earlier studies with local drug injections and selective neurotoxins which provided pharmacological evidence that monoamines can influence food intake and body weight. A table summarizing this evidence is used to list monoamine changes that could underlie anorexia or hyperphagia. It is apparent that abnormalities in the monoamines, along with their cotransmitters, could cause many forms of feeding disorder. It is proposed as a working hypothesis that several varieties of hyperphagia leading to obesity have a common element. This common factor is a change in excitability of a lateral hypothalamic reinforcement system as manifested in self-stimulation at a stimulation-bound feeding site. Understanding this feeding reward-aversion system helps us understand hyperphagia and anorexia. The neurochemistry of reward and aversion involves the monoamines. This paper focuses on dopamine and serotonin. The data support the hypothesis that dopamine systems projecting to the nucleus accumbens and other forebrain areas from the mid-brain ventral tegmental area (VTA) are important for approach and positive reinforcement in ingestive behavior and self-stimulation. Serotonin is hypothesized to facilitate satiety and inhibition of feeding reward in the hypothalamus. The next section abstracts our recent experiments that measured pharmacological and physiological release of the monoamines in the hypothalamus and nucleus accumbens during ingestive behavior and self-stimulation. In vivo microdialysis in freely moving rats suggested the following: (1) Norepinephrine was released in the paraventricular nucleus during the active, feeding period of the circadian cycle. (2) The serotonin metabolite 5-HIAA also increased in the PVN at the same time if there was food to eat. (3) Amphetamine infused into the lateral hypothalamus (LH) by reverse dialysis increased synaptic dopamine, norepinephrine, and serotonin. (4) The anorectic drug d-fenfluramine increased synaptic serotonin in the LH and also increased the dopamine metabolite DOPAC, suggesting that serotonin and dopamine in the LH might contribute to fenfluramine-induced satiety. Local d-fenfluramine injection into the LH or local infusion by reverse dialysis again increased serotonin and decreased 5-HIAA and interfered with local dopamine metabolism as reflected in decreased DOPAC and HVA. (5) Tryptophan, a serotonin precursor, given systemically at an anorectic dose, increased extracellular serotonin in the LH, but this effect was only detectable in food-deprived rats. This was seemingly pH independent (between 5.8 and 8). The passage other cations through CFo is strictly suppressed (even at pH 8 and with 300 mM NaCl in the medium).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Microdialysis studies of brain norepinephrine, serotonin, and dopamine release during ingestive behavior. Theoretical and clinical implications. 269 87

Twelve rats were tested in an animal model for self-administration of dl-, d-, and l-fenfluramine. Amphetamine and saline were used as reference substances. In addition to being tested on the reference substances amphetamine and saline, each rat was only tested on one drug and dose. Analyses of variance were performed to assert that high rates of self-administration were maintained on amphetamine whereas saline gave low rates of responding. The results showed that all three forms of fenfluramine (dl-fenfluramine 0.1, 0.5, 2.0 mg/kg; d-fenfluramine 0.05, 0.1, 0.25, 1.0 mg/kg; l-fenfluramine 0.1, 0.5, 1.0, 2.0 mg/kg) differed significantly from amphetamine, but not from saline. As d-fenfluramine is both more effective in reducing food intake, and has less sedative action than dl-fenfluramine, it may be an improvement in the pharmacotherapy of obesity.
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PMID:Lack of self-administration of different fenfluramine isomers in rats. 275 May 66

1 The sympathetic noradrenergic activation of brown adipose tissue and the biochemical mechanisms involved in diet-induced thermogenesis were studied in rats. 2 A close correlation was found between brown adipose tissue Na+, K+-adenosinetriphosphatase (Na+, K+-ATPase) activity in vitro and in vivo measurements of resting oxygen consumption (VO2). The effects of noradrenaline on in vitro NA+, K+-ATPase activity in brown adipose tissue and in vivo VO2 could be mimicked by a variety of agents. These included beta-adrenoceptor agonists and agents known to induce the release of noradrenaline or inhibit the noradrenaline uptake process. The pharmacological evidence suggests that dopaminergic mechanisms may also be involved in the control of thermogenesis. 3 Amphetamine did not increase VO2 in rats without causing associated increases in locomotor activity. Ciclazindol at doses of 3-30 mg/kg intraperitoneally increased VO2 but did not appear to increase locomotor activity or evoke any other signs of CNS stimulation including lengthening of time to sleep onset or stereotypy. Separation of metabolic and CNS effects occurred only at the lowest dose of mazindol used (0.3 mg/kg i.p.). These results are probably a reflection of (a) the relative abilities of these drugs to inhibit brain and brown adipose noradrenaline uptake processes and (b) the relatively high accumulation of ciclazindol in brown adipose. 4 Of the drugs tested, only ciclazindol was a more potent inhibitor of the noradrenaline uptake system in brown adipose tissue (BAT) than in brain. Kinetic analysis also revealed that the actions of ciclazindol on the NA uptake system and Na+, K+-ATPase in BAT differed from those of mazindol. 5 These findings suggest that ciclazindol may produce an energy wasting effect in rodents without causing overt CNS stimulation; the implications of these findings in terms of human obesity are discussed.
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PMID:Sympathetic mechanisms in diet-induced thermogenesis: modification by ciclazindol and anorectic drugs. 627 18

In a double-blind, placebo-controlled evaluation in obese adults given comparable dietary and exercise recommendations, controlled-release diethylpropion hydrochloride promoted significantly more weight loss than matching placebo. The mean reduction in 12 weeks was 15.9 lb (average 1.32 lb/week) for 12 patients taking diethylpropion hydrochloride, 10.0 lb (0.84 lb/week) for 13 taking placebo, and 12.2 lb for 13 taking drug for two four-week periods separated by four weeks of placebo (1.38 lb/week on active drug and 0.30 lb/week on placebo). Amphetamine-like side effects were virtually absent. Diethylpropion hydrochloride is an effective adjunct to caloric restriction in therapy of obesity.
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PMID:Controlled-release diethylpropion hydrochloride used in a program for weight reduction. 747 Nov 28

Long-term administration of sulpiride induces hyperphagia and obesity in female rats. After sulpiride withdrawal, a significant hypophagia has been observed. The hyperphagia could be related to the blockade and the hypophagia to supersensitivity of dopamine D2 receptors, in particular those D2 receptors located in the perifornical hypothalamus. If this were the case, an enhancement of anorexia induced by amphetamine and dopamine should be observed after interruption of long-term sulpiride treatment. Two doses of systemic sulpiride (20 or 200 mg/kg) and one dose of intrahypothalamic sulpiride (15 micrograms) were tested. Amphetamine was administered by systemic or intrahypothalamic infusion. Dopamine was administered in the hypothalamus. After withdrawal of systemic administration of sulpiride (200 mg/kg), an enhancement of anorexia induced by systemic amphetamine was observed. However, the anorexia induced by intrahypothalamic injections of amphetamine or dopamine was not affected by the interruption of the sulpiride treatment. These results suggest that the hypophagia following chronic sulpiride treatment is not due to supersensitivity of D2 dopamine receptors in the lateral hypothalamus. Moreover, the change in the response to amphetamine might be related to supersensitivity of extrahypothalamic D2 receptors.
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PMID:Enhancement of amphetamine anorexia after chronic administration of sulpiride in rats. 851 71

Autopsy reports at the Forensic Science Centre, Adelaide, South Australia, were reviewed for the 8 years from January 1991 to December 1998 for cases with unusual features in which deaths had been attributed to exposure to high environmental temperatures. Amphetamine-related hyperpyrexial deaths, anesthetic deaths caused by malignant hyperpyrexia, deaths of elderly incapacitated individuals during heat waves, and deaths of children trapped in the back of cars were excluded from the study. In 9 cases, where heat-related deaths had occurred (age range 21 to 77 years; M:F = 8:1). Predisposing factors included lack of familiarity with Australian environmental conditions, excessive clothing, prolonged sun exposure, acute alcohol intoxication, obesity, benztropine and trifluoperazine medication, and underlying dementia, alcoholic liver disease, and possibly epilepsy.
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PMID:An analysis of factors contributing to a series of deaths caused by exposure to high environmental temperatures. 1139 59

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for amphetamines to cause adverse effects on reproduction and development in humans. Amphetamines evaluated were D- and D,L-amphetamine and methamphetamine. Amphetamine is approved by the U.S. Food and Drug Administration for the treatment of attention deficit hyperactivity disorder (ADHD) in persons over 3 years of age and narcolepsy; methamphetamine is approved for the treatment of ADHD in persons 6 years of age and older and for short-term treatment of obesity. Amphetamines were selected for evaluation because of 1) widespread usage in children, 2) availability of developmental studies in children and experimental animals, and 3) public concern about the effect of this stimulant on child development. The results of this evaluation on amphetamines are published in an NTP-CERHR monograph which includes: 1) the NTP Brief, 2) the Expert Panel Report on the Reproductive and Developmental Toxicity of Methylphenidate, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to methylphenidate on human development and reproduction. First, there is some concern for developmental effects, specifically for potential neurobehavioral alterations, from prenatal amphetamine exposure in humans both in therapeutic and non-therapeutic settings. After prenatal exposure to therapeutic doses of amphetamine, rat pups demonstrated neurobehavioral alterations. Data from human and animal studies were judged insufficient for an evaluation of the effect of amphetamine exposure on growth and other related developmental effects. Second, there is concern for methamphetamine-induced adverse developmental effects, specifically on growth and neurobehavioral development, in therapeutic and non-therapeutic settings. This conclusion is based on evidence from studies in experimental animals that prenatal and postnatal exposures to methamphetamine produce neurobehavioral alterations, small litter size, and low birth weight. Results from studies in humans suggest that methamphetamine may cause low birth weight and shortened gestation, but study confounders such as possible multiple drug usage prevent a definite conclusion. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available in electronic PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).
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PMID:NTP-CERHR monograph on the potential human reproductive and developmental effects of amphetamines. 1613 31

Amphetamine is a psychostimulant commonly used to treat several disorders, including attention deficit, narcolepsy, and obesity. Plasmalemmal and vesicular monoamine transporters, such as the neuronal dopamine transporter and the vesicular monoamine transporter-2, are two of its principal targets. This review focuses on new insights, obtained from both in vivo and in vitro studies, into the molecular mechanisms whereby amphetamine, and the closely related compounds methamphetamine and methylenedioxymethamphetamine, cause monoamine, and particularly dopamine, release. These mechanisms include amphetamine-induced exchange diffusion, reverse transport, and channel-like transport phenomena as well as the weak base properties of amphetamine. Additionally, amphetamine analogs may affect monoamine transporters through phosphorylation, transporter trafficking, and the production of reactive oxygen and nitrogen species. All of these mechanisms have potential implications for both amphetamine- and methamphetamine-induced neurotoxicity, as well as dopaminergic neurodegenerative diseases.
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PMID:New insights into the mechanism of action of amphetamines. 1720 1

Obesity has reached epidemic proportions across the developed world. Even though there have been numerous scientific advances in terms of the understanding of the regulation of energy homeostasis, few novel anti-obesity drugs have emerged. Furthermore, those that are available have limited efficacy in producing and maintaining a weight loss beyond 10%. This is partly attributable to the complex neuronal circuitry at play within the central nervous system and periphery, which acts to regulate food intake and energy expenditure. This article will focus on a selection of the many products (peptides, neurotransmitters and others) such as endocannabinoids, Neuropeptide Y, Orexins, Melanin-Concentrating Hormone, Melanocortins, Cocaine and Amphetamine Regulated Transcript and Serotonin, expressed within the brain, that have been shown to influence energy balance. The true relevance of many of these to the regulation of human energy balance remains uncertain, but some novel anti-obesity drugs aimed at these targets are likely to emerge in the next few years.
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PMID:The hypothalamus and obesity. 1822 Dec 12


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