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

Obesity is a multifactorial, chronic disorder that has reached epidemic proportions in most industrialised countries and is threatening to become a global epidemic. Clinical management of obese patients is complex and serious doubts have arisen with regard to safety and efficacy of drug therapy. Following the withdrawal of fenfluramine and dexfenfluramine in 1997, interest has focused on novel anti-obesity drugs. Pharmacological approaches to the management of obesity can, in broad terms, use different distinct strategies: firstly, to reduce energy intake; secondly, to increase energy expenditure; and thirdly, to alter the partitioning of nutrients between fat and lean tissue. Sibutramine is a serotonin-noradrenaline (norepinephrine) reuptake inhibitor indicated for the management of obesity in conjunction with a reduced calorie diet. The pharmacological mechanisms by which sibutramine exerts its weight loss effect are likely due to a combination of reduced appetite, feelings of satiety and possibly the induction of thermogenesis. The efficacy of sibutramine for inducing initial weight loss and the subsequent maintenance of weight loss is well proven in short- and long-term clinical trials of up to 2 years' duration. Most individual placebo-controlled trials and pooled estimates found that the drug produced statistically significant greater weight loss than placebo at all observed endpoints (weighted mean difference for weight change at 8 weeks: -3.4 kg; mean difference range for weight change at 6 months: -4.0 to -9.1 kg; and at 1 year: -4.1 to -4.8 kg). The most frequent dosage regimen in these trials was 10-20 mg daily. Findings suggested a dose-effect relationship in terms of weight loss. Sibutramine was also associated with better weight maintenance relative to placebo (statistically significant difference). Results from mainly small trials showed that sibutramine produced more favourable outcomes in terms of loss of fat mass, reduction in body mass index and loss of > or = 5-10% of initial bodyweight. The most commonly reported adverse effects of sibutramine are headache, constipation and nausea. Certain adverse events associated with the nervous system, including dizziness, dry mouth and insomnia, are reported by > 5% of patients receiving sibutramine. Increases in blood pressure and heart rate were possible adverse effects that require regular monitoring especially in obese hypertensive patients. Neither left-sided cardiac valve disease nor primary pulmonary hypertension was associated with the use of sibutramine. The assessment of the benefit-risk profile of sibutramine remained positive, although the product must be kept under regular review.
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PMID:A benefit-risk assessment of sibutramine in the management of obesity. 1458 64

The anorexigen (+)-fenfluramine was used for treatment of obesity until the association of use with valvular heart disease and primary pulmonary hypertension. (+)-Fenfluramine has been found in Chinese and Korean slimming pills. The hepatic metabolite of (+)-fenfluramine, (+)-norfenfluramine, has affinity for 5-hydroxytryptamine (5-HT)(2A) and 5-HT(2B) receptors. We tested the hypothesis that (+)-norfenfluramine contracts arterial smooth muscle in a 5-HT receptor-dependent manner and acts as a pressor in the conscious rat. Isometric contraction experiments showed that (+)-norfenfluramine (10 nM, 100 microM) but not (+)-fenfluramine nor the isomer (-)-norfenfluramine caused concentration-dependent contraction in arteries [-log EC(50) (moles per liter), thoracic aorta = 5.77 +/- 0.09; renal artery = 6.29 +/- 0.02; mesenteric resistance artery = 5.70 +/- 0.06]. Contraction was dependent on the 5-HT(2A) receptor because ketanserin (10 nM) rightward shifted (+)-norfenfluramine response curves (aorta = 16-fold, renal artery = 26-fold, and resistance artery = >100-fold). Dependence on activation of 5-HT(2A) receptors and independence of (+)-norfenfluramine-induced contraction from stimulation of alpha-adrenergic receptors and the sympathetic nervous system was validated by demonstrating 1) unchanged contraction to (+)-norfenfluramine in arteries from chemically denervated rats; 2) a minimal effect of the alpha(1)-adrenergic receptor antagonist prazosin (100 nM) on contraction; and 3) antagonism by [6-methyl-l-(1-methylethy)ergoline-8beta-carboxylic acid 2-hydroxy-1 methylpropyl ester maleate] LY53857 [6-methyl-1-(1-methylethy)-ergoline-8beta-carboxylic acid 2-hydroxy-1 methylpropyl ester maleate], a 5-HT(2) receptor antagonist without alpha-receptor affinity. (+)-Norfenfluramine (10-300 microg/kg i.v.) caused a dose-dependent increase in mean arterial blood pressure in conscious rats, the maximum of which could be virtually abolished by ketanserin (3 mg/kg i.v.) but not prazosin (0.2 mg/kg i.v.). Our findings demonstrate for the first time that (+)-norfenfluramine is vasoactive and has the potential to increase blood pressure.
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PMID:The fenfluramine metabolite (+)-norfenfluramine is vasoactive. 1475 59

Some of the medications used for weight loss in the management of obesity have been associated with unacceptable morbidity and mortality. Safety concerns have led to the withdrawal of aminorex, followed by the fenfluramines in 1997, and phenylpropanolamine (norephedrine) in 2000. Aminorex was associated with an increased prevalence of primary pulmonary hypertension (PPH), fenfluramines with an increased prevalence of PPH and valvulopathy, and phenylpropanolamine with an increased risk of haemorrhagic stroke. Several studies have investigated the safety of the fenfluramines, yet the benefit-risk profile has not been conclusively quantified. This is due to several deficiencies in the published studies, including a lack of data on the baseline prevalences of comorbid conditions in obese subjects, and potential confounders and biases in the study designs. Although several studies and systematic reviews support an increased risk of PPH and valvulopathy in patients who have taken fenfluramines, without knowledge of the background prevalence it is not possible to determine if the exposure preceded the outcome. The population at higher risk of these adverse effects includes those taking higher doses or with a longer duration of exposure to fenfluramines and those with pre-existing cardiac disease or a genetic predisposition. Patients exposed to fenfluramines continue to be monitored, with some follow-up studies indicating no overall worsening in valvulopathy over time. There are limited efficacy and safety data for amfepramone (diethylpropion) and phentermine and their approval for the management of obesity is limited to short-term use. Orlistat and sibutramine are the only currently approved medications for long-term management of obesity. Although the benefit-risk profiles of sibutramine and orlistat appear positive, sibutramine continues to be monitored because of long-term safety concerns. The safety and efficacy of currently approved drug therapies have not been evaluated in children and elderly patient populations and there is limited information in adolescents, whilst the long-term safety of current and potential new drug therapies in adults will require several years of postmarketing surveillance to fully elucidate their adverse effect profiles.
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PMID:Safety of drug therapies used for weight loss and treatment of obesity. 1656 79

Erectile dysfunction (ED) is a highly prevalent disease associated with aging as well as with several risk factors including hypertension, heart disease, obesity, dyslipidemia, diabetes, hypogonadism, drugs-related, and pelvic surgery. Many of these factors are components of the metabolic syndrome, a multiplex risk factor for cardiovascular disease (CVD). ED shares common risk factors with CVD. Endothelial dysfunction seems to be the early underlying pathophysiology across both conditions. The efficacy, tolerability and cardiovascular safety of sildenafil has been evaluated in numerous large, randomized, doubleblind, placebo-controlled clinical studies in the broad population of men with ED including men with several co-morbid conditions. Sildenafil is effective in several specific patient populations including the difficult-to-treat subpopulations such as diabetes mellitus and after radical prostatectomy. It is associated with rapid onset of action--within 14 minutes for some men--and an extended duration of action for up to 12 hours. Sildenafil improves quality of life and satisfaction for treated men and is well tolerated with a favorable safety profile. New data suggest that sildenafil has beneficial effects in several chronic conditions. It has been approved for the treatment of idiopathic pulmonary hypertension. Numerous articles have suggested that it improves endothelial function and a possible role on premature ejaculation or treatment of lower urinary tract symptoms has been suggested.
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PMID:Sildenafil in the treatment of erectile dysfunction: an overview of the clinical evidence. 1804 17

Fenfluramine is prescribed either alone or in combination with phentermine as part of Fen-Phen, an anti-obesity medication. Fenfluramine was withdrawn from the US market in 1997 due to reports of heart valvular disease, pulmonary arterial hypertension, and cardiac fibrosis. Particularly, idiopathic pulmonary arterial hypertension (IPAH), previously referred to as primary pulmonary hypertension (PPH), was found to be associated with the use of Fen-Phen, fenfluramine, and fenfluramine derivatives. The underlying mechanism of fenfluramine-associated pulmonary hypertension is still largely unknown. We reasoned that investigating drug-induced gene dysregulation would enhance our understanding of the fenfluramine-associated pathogenic mechanism of IPAH. Whole-genome gene expression profiles in fenfluramine-treated human pulmonary artery smooth muscle (PASMC) and endothelial (PAEC) cells (isolated from normal subjects) were compared with baseline expression in untreated cells. Fenfluramine treatment caused dysregulation in a substantial number of genes involved in a variety of pathways and biological processes. In addition to several common pathways and biological processes such as "MAPK signaling pathway," "inflammation response," and "calcium signaling pathway" shared between both cell types, pathways and biological processes such as "blood circulation," "muscle system process," and "immune response" were enriched among the dysregulated genes in PASMC. Pathways and biological processes such as those related to cell cycle, however, were enriched among the dysregulated genes in PAEC, indicating that fenfluramine could affect unique pathways (or differentially) in different types of pulmonary artery cells. While awaiting validation in a larger cohort, these results strongly suggested that fenfluramine could induce significant dysregulation of genes in multiple biological processes and pathways critical for normal pulmonary vascular functions and structure. The transcriptional and posttranscriptional changes in these genes may, therefore, contribute to the pathogenesis of fenfluramine-associated IPAH.
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PMID:Fenfluramine-induced gene dysregulation in human pulmonary artery smooth muscle and endothelial cells. 2214 Jun 31

Amfepramone (diethylpropion) is an appetite-suppressant drug used for the treatment of overweight and obesity. It has been suggested that the systemic and central activity of amfepramone produces cardiovascular effects such as transient ischemic attacks and primary pulmonary hypertension. However, it is not known whether amfepramone produces immediate vascular effects when applied in vitro to rat aortic rings and, if so, what mechanisms may be involved. We analyzed the effect of amfepramone on phenylephrine-precontracted rat aortic rings with or without endothelium and the influence of inhibitors or blockers on this effect. Amfepramone produced a concentration-dependent vasorelaxation in phenylephrine-precontracted rat aortic rings that was not affected by the vehicle, atropine, 4-AP, glibenclamide, indomethacin, clotrimazole, or cycloheximide. The vasorelaxant effect of amfepramone was significantly attenuated by NG-nitro-L-arginine methyl ester (L-NAME) and tetraethylammonium (TEA), and was blocked by removal of the vascular endothelium. These results suggest that amfepramone had a direct vasorelaxant effect on phenylephrine-precontracted rat aortic rings, and that inhibition of endothelial nitric oxide synthase and the opening of Ca2+-activated K+ channels were involved in this effect.
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PMID:Mechanisms involved in the vasorelaxant effects produced by the acute application of amfepramone in vitro to rat aortic rings. 2583 Dec


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