Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obesity has become an epidemic in the United States and in many other countries of the world. Obesity is a chronic disease, not a failure of willpower. Diet, exercise, and behavioral modification of lifestyle are rarely successful over the long term. Medications have been used sparingly, because of concerns about addiction and ineffectiveness, but used chronically, obesity drugs are effective. The two main categories of obesity drugs are centrally active adrenergic and serotonergic agents. These drugs reduce appetite, enhance satiety, and increase energy expenditure. Use of single agents produces modest weight loss and use of combinations increases loss, but few patients reach their goal weight. Co-morbidities associated with obesity resolve or are reduced in severity with weight loss. Adverse events of major concern are changes in brain biochemistry and primary pulmonary hypertension. Published guidelines for use of obesity medications recommend they be used only for medically significant obesity.
 ...
PMID:Use of drugs in the treatment of obesity. 924 Sep 33

The pharmacology, pharmacokinetics, efficacy, and adverse effects of dexfenfluramine hydrochloride are reviewed. Dexfenfluramine, the dextrorotatory isomer of fenfluramine, is indicated for use in the management of obesity in patients with a body mass index of > or = 30 kg/m2, or > or = 27 kg/m2 in the presence of other risk factors. Unlike fenfluramine, dexfenfluramine is a pure serotonin agonist. Dexfenfluramine may mimic the effect of carbohydrate intake. Systemic bioavailability is about 68%, and the drug is metabolized in the liver. In randomized, placebo-controlled trials, dexfenfluramine was effective in reducing weight in obese patients given the drug for three or six months. In trials lasting one year, the statistically significant weight loss occurred during months 4 to 6. Dexfenfluramine reduces blood pressure, percent glycosylated hemoglobin, and concentrations of blood glucose and blood lipids, but these benefits may be indirect. Dexfenfluramine may also be of some value in controlling eating habits in diabetic patients, preventing weight gain after smoking cessation, and treating bulimia, seasonal affective disorder, neuroleptic-induced obesity, and premenstrual syndrome. Dexfenfluramine's most frequent adverse effects are insomnia, diarrhea, and headache; it has also been associated with primary pulmonary hypertension. The drug should not be combined with other serotonergic agonists because of the risk of serotonin syndrome. The recommended dosage is 15 mg twice daily. Dexfenfluramine is effective in the treatment of obesity in selected patients. Because its efficacy is lost after six months of continuous treatment, it should be viewed primarily as an adjunct to diet and exercise.
 ...
PMID:Dexfenfluramine hydrochloride: an anorexigenic agent. 937 5

In an effort to combat obesity, several medications have been developed. The nonamphetamine anorectics, such as phentermine, fenfluramine, and dexfenfluramine, have been recommended as first-line drug therapy for the treatment of obesity once diet and exercise alone have failed. Numerous studies have shown that these agents can promote weight loss when combined with diet restriction and exercise. Although fenfluramine and dexfenfluramine lack the abuse potential of amphetamine and its congeners, these agents are associated with drug interactions and adverse effects. Concomitant administration of fenfluramine or dexfenfluramine with medications that enhance serotonin levels (e.g., antidepressants, monoamine oxidase inhibitors, and migraine medications) can precipitate serotonin syndrome. Sudden discontinuation of fenfluramine or dexfenfluramine after prolonged administration can precipitate withdrawal depressive symptoms. Primary pulmonary hypertension, a potentially fatal disorder, has been reported to occur approximately 30 times more frequently in patients receiving anorectic agents for more than 3 months compared to the general population. More recently, the association of these popular anorectics with valvular heart disease has caused increased concerns about their use. The risks of primary pulmonary hypertension, valvular heart disease, and the occurrence of convulsions, coma, and death in overdose appear to be equally likely with dexfenfluramine and fenfluramine. In addition, many patients who lose weight while taking these anorectics rapidly regain it after the medication has been discontinued.
 ...
PMID:A close look at fenfluramine and dexfenfluramine. 954 1

To estimate the number of patients with intractable respiratory diseases, we conducted a two-stage nationwide epidemiological survey in 1997. The first survey was performed at randomly sampled hospitals to identify the number of patients treated. The second survey sought detailed clinico-epidemiological data on the patients reported in the first survey. The response rates were 54% for the first survey and 62% for the second. Based on the survey findings, we derived the following nationwide estimates: 450 patients (95% confidence interval: 360-530) with chronic thromboembolic pulmonary hypertension; 230 (200-260) with primary pulmonary hypertension; 180 (150-210) with obesity-associated hypoventilation syndrome; 40 (30-50) with primary alveolar hypoventilation syndrome; 160 (140-180) with histiocytosis X; and 190 (150-230) with juvenile pulmonary emphysema.
 ...
PMID:[Estimated numbers of patients with intractable respiratory diseases]. 1006 52

This review evaluates the benefits and potential health risks of the currently used drugs that are approved for the pharmacological treatment of obesity. Analysis of several long term clinical trials indicates that all of these drugs are efficient in reducing excess bodyweight, and that the majority of them allow the maintenance of the reduced bodyweight for at least 1 year. However, the loss of bodyweight attributable to these drugs is in general rather modest, approaching only 0.2 kg per week during the first 6 months of treatment, and at least a partial regain of bodyweight occurs when these drugs are used for periods longer than 1 year. All of these drugs induce several adverse effects. Although most of these adverse effects are mild and transient, the prolonged use of adrenergic or serotonergic anorectic drugs, or their use as combination treatment, may induce serious and potentially life-threatening complications, such as primary pulmonary hypertension or valvular heart disease. The adrenergic appetite-suppressing drugs are not recommended for the treatment of obesity, since their safety has never been evaluated in long term clinical trials, and because of their stimulatory effects on the cardiovascular and nervous systems. The serotonergic drugs, such as fenfluramine and dexfenfluramine, have been the most widely used during the past decade; however, both these compounds have recently been withdrawn from the market, since their use was associated with serious cardiovascular complications. The safety of the prolonged therapeutic use of newer compounds such as sibutramine and orlistat has not yet been demonstrated. Therefore, none of the currently available anti-obesity medications meets the criteria of an 'ideal anti-obesity drug' and, if prescribed, these medications should be used with caution and only under careful medical supervision. Since obesity is recognised as a chronic health-threatening condition, and since classical behavioural therapeutic approaches lack long term efficacy, there is clearly a need for an efficient pharmacological treatment offering an acceptable safety profile. Such a treatment is not available at present. Development of new agents and a more careful assessment of the safety of currently available drugs are needed.
 ...
PMID:A risk-benefit assessment of anti-obesity drugs. 1008 70

Phentermine and fenfluramine are widely used in the treatment of obesity. Despite the fact that primary pulmonary hypertension and mitral valve insufficiency have been associated with fenfluramine use, many of these patients need medication to achieve weight loss. Small degrees of weight loss have been shown to significantly improve obesity-related medical conditions such as hypertension, hypercholesterolemia, and noninsulin-dependent diabetes mellitus. Current practice is to give phentermine and fenfluramine in the morning and afternoon. Doses for phentermine have ranged from 15 to 37.5 mg and for fenfluramine from 20 to 120 mg per day. We report five cases of severely obese women with medical complications who were treated with phentermine 8 mg twice per day (at 1:00 p.m. and 4:00 p.m.) and fenfluramine 20 mg per day (at 4:00 p.m.). Because many obese patients skip breakfast and eat more in the afternoon and evening, medication was dosed in order to cover these high-risk eating periods. Overall, these patients lost a mean of 22.4% of their initial weight (range 18.6% to 32.8%) over an average of 8.4 months (range 3.5 to 16 months). These cases suggest that short-term weight loss can be achieved with a low dose of fenfluramine when both medications are given in the afternoon to better target the eating patterns of obese subjects.
 ...
PMID:Lower dosages of phentermine-fenfluramine given in the afternoon: five cases with significant weight loss. 1020 59

The lungs are a delicate interface between the atmosphere and our bodies across which oxygen diffuses from the air we breathe to the blood which carries oxygen to the cells and mitochondria. In healthy lungs at sea level where there is a surfeit of oxygen, this process occurs easily, whereas, in lungs with disease it becomes a task which may not be fully successful and hypoxemia may ensue or worsen. At high altitude where the barometric pressure (Pb) and thus the supply of oxygen is lower, the job of getting oxygen to the blood, even in the healthy lung is more difficult, and in the diseased lung it may be impossible. This presentation will review the lungs' responses to high altitude, with emphasis on the abnormal. Both acute and chronic responses of patients with pre-existing lung disease will be reviewed. Pulmonary diseases encountered at high altitude in previously healthy people, such as high altitude pulmonary edema and chronic mountain sickness will be touched on only as they pertain to other patients. Pre-existing lung disease (with and without hypoxemia at sea level) such as obstructive lung diseases (asthma, COPD, emphysema), and restrictive lung diseases (sarcoid, asbestosis, interstitial pulmonary fibrosis) will be discussed in terms of gas exchange, lung mechanics, and treatment at high altitude. Disorders of ventilatory control; e.g., obesity-hypoventilation syndrome and sleep apnea, may present formidable problems, and guidelines for their treatment will be discussed. Infectious lung diseases; e.g., pneumonia, cystic fibrosis, and pulmonary vascular disorders such as chronic mountain sickness, primary pulmonary hypertension, and congenital absence of the pulmonary artery are important disorders that require special attention because of the accentuated hypoxic pulmonary vascular response encountered at high altitude. The purpose therefore, is to provide the medical practitioner with the insight into prevention, recognition, and treatment of pulmonary problems encountered specifically at high altitude, as well as guidance on how best to advise patients with lung disease who want to fly in airplanes and/or ascend to high altitude for work or pleasure.
 ...
PMID:Lung disease at high altitude. 1063 92

This review summarizes the neurochemical, therapeutic and adverse effects of serotonin (5-HT) releasing agents. The 5-HT releaser (plus minus)-fenfluramine is composed of two stereoisomers, (+)-fenfluramine and (minus sign)-fenfluramine, which are N-de-ethylated to yield the metabolites, (+)-norfenfluramine and (minus sign)-norfenfluramine. Fenfluramines and norfenfluramines are 5-HT transporter substrates and potent 5-HT releasers. Other 5-HT releasing agents include m-chlorophenylpiperazine (mCPP), a major metabolite of the antidepressant drug trazodone. Findings from in vitro and in vivo studies support the hypothesis that fenfluramines and mCPP release neuronal 5-HT via a non-exocytotic carrier-mediated exchange mechanism involving 5-HT transporters. (+)-Norfenfluramine is a potent 5-HT(2B) and 5-HT(2C) receptor agonist. The former activity may increase the risk of developing valvular heart disease (VHD), whereas the latter activity is implicated in the anorectic effect of systemic fenfluramine. Anorectic agents that increase the risk of developing primary pulmonary hypertension (PPH) share the common property of being 5-HT transporter substrates. However, these drugs vary considerably in their propensity to increase the risk of PPH. In this regard, neither trazodone nor mCPP is associated with PPH. Similarly, although some 5-HT substrates can deplete brain 5-HT (fenfluramine), others do not (mCPP). In addition to the established indication of obesity, 5-HT releasers may be helpful in treating psychiatric problems such as drug and alcohol dependence, depression and premenstrual syndrome. Viewed collectively, it seems possible to develop new medications that selectively release 5-HT without the adverse effects of PPH, VHD or neurotoxicity. Such agents may have utility in treating a variety of psychiatric disorders.
 ...
PMID:Serotonin releasing agents. Neurochemical, therapeutic and adverse effects. 1188 73

The fenfluramines saga began in 1963 and ended in 1997. Fenfluramines are anorexigenic agents recommended, in April 1996, for the long-term treatment of obesity in USA, before being suddenly withdrawn from the market in September 1997. Over 34 years, about 60 million people were exposed to these drugs worldwide, mainly in Europe. The aim of this critical review is not to attempt to rehabilitate these appetite suppressants but to launch a plea for a more rational and rigorous approach to what might be called objective medical knowledge. Idiopathic primary pulmonary hypertension and cardiac valve disorders which have been both associated with fenfluramines have in common many puzzling features. The metamorphosis of facts into artifacts is only a hypothesis, but seems conceivable from a scientific point of view. Medicine is not only an art, it is also a science, which, like the others, implies adhesion to certain fundamental rules, such as refutation or verification of all experimental results by rigorous and standardized methods, before considering them as established facts. Firstly, a single study, moreover a case-control study like the International Primary Pulmonary Hypertension Study, is not sufficient to establish a causal relationship between exposure to appetite-suppressants and idiopathic pulmonary hypertension, because of the numerous biases which characterize even the best analytical research. Secondly, Doppler-echocardiography cannot be considered as a laboratory test, because of the poor interoperator reproducibility observed in obese patients. The use of this technique in pharmaco-epidemiology implies standardized procedures concerning not only reading data, but also their acquisition, because of possible uncontrolled interactions between sonographers, patients and sophisticated machines. In the case of the fenfluramines saga, numerous methodological artifacts concerning acquisition, processing and interpretation of epidemiologic and echocardiographic data might have contributed to distortion of reality. Let us recall how Webster's dictionary defines artifact: "a spurious observation or result arising from preparatory or investigative procedures or any feature that is not naturally present but is a product of an extrinsic agent, method, or the like".
 ...
PMID:Fenfluramines, idiopathic pulmonary primary hypertension and cardiac valve disorders: facts and artifacts. 1196 83

A variety of drugs release serotonin (5-HT, 5-hydroxytryptamine) from neurons by acting as substrates for 5-HT transporter (SERT) proteins. This review summarizes the neurochemical, therapeutic, and adverse actions of substrate-type 5-HT-releasing agents. The appetite suppressant (+/-)-fenfluramine is composed of (+) and (-) isomers, which are N-de-ethylated in the liver to yield the metabolites (+)- and (-)-norfenfluramine. Fenfluramines and norfenfluramines are potent 5-HT releasers. (+/-)-3,4-Methylenedioxymethamphetamine ((+/-)-MDMA, "ecstasy") and m-chlorophenylpiperazine (mCPP) are substrate-type 5-HT releasers. Fenfluramines, (+/-)-MDMA, and mCPP release neuronal 5-HT by a common non-exocytotic diffusion-exchange mechanism involving SERTs. (+)-Norfenfluramine is a potent 5-HT(2B) and 5-HT(2C) receptor agonist. The former activity may increase the risk of valvular heart disease, whereas the latter activity is implicated in the anorexic effect of systemic fenfluramine. Appetite suppressants that increase the risk for developing primary pulmonary hypertension (PPH) are all SERT substrates, but these drugs vary considerably in their propensity to increase this risk. For example, fenfluramine and aminorex are clearly linked to the occurrence of PPH, whereas other anorectics are not. Similarly, some SERT substrates deplete brain tissue 5-HT in animals (e.g., fenfluramine), while others do not (e.g., mCPP). In addition to the established indication of obesity, 5-HT releasers may help treat psychiatric disorders, such as drug and alcohol dependence, depression, and premenstrual syndrome. Viewed collectively, we believe new medications can be developed that selectively release 5-HT without increasing the risk for adverse effects of valvular heart disease, PPH, and neurotoxicity. Such agents may be useful for treating a variety of psychiatric disorders.
 ...
PMID:Therapeutic and adverse actions of serotonin transporter substrates. 1216 29


1 2 Next >>