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1.
Cochrane Database Syst Rev ; 3: CD012650, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33765343

RESUMO

BACKGROUND: Clinicians primarily recommend weight loss for obese women seeking pregnancy. The effectiveness of interventions aimed at weight loss in obese women with subfertility is unclear. OBJECTIVES: To assess the effectiveness and safety of pharmacological and non-pharmacological strategies compared with each other, placebo, or no treatment for achieving weight loss in obese women with subfertility. SEARCH METHODS: We searched the CGF Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, and AMED from inception to 18 August 2020. We also checked reference lists and contacted experts in the field for additional relevant papers. SELECTION CRITERIA: We included published and unpublished randomised controlled trials in which weight loss was the main goal of the intervention. Our primary effectiveness outcomes were live birth or ongoing pregnancy and primary safety outcomes were miscarriage and adverse events. Secondary outcomes included clinical pregnancy, weight change, quality of life, and mental health outcome. DATA COLLECTION AND ANALYSIS: Review authors followed standard Cochrane methodology. MAIN RESULTS: This review includes 10 trials. Evidence was of very low to low quality: the main limitations were due to lack of studies and poor reporting of study methods. The main reasons for downgrading evidence were lack of details by which to judge risk of bias (randomisation and allocation concealment), lack of blinding, and imprecision. Non-pharmacological intervention versus no intervention or placebo Evidence is insufficient to determine whether a diet or lifestyle intervention compared to no intervention affects live birth (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.65 to 1.11; 918 women, 3 studies; I² = 78%; low-quality evidence). This suggests that if the chance of live birth following no intervention is assumed to be 43%, the chance following diet or lifestyle changes would be 33% to 46%. We are uncertain if lifestyle change compared with no intervention affects miscarriage rate (OR 1.54, 95% CI 0.99 to 2.39; 917 women, 3 studies; I² = 0%; very low-quality evidence). Evidence is insufficient to determine whether lifestyle change compared with no intervention affects clinical pregnancy (OR 1.06, 95% CI 0.81 to 1.40; 917 women, 3 studies; I² = 73%; low-quality evidence). Lifestyle intervention resulted in a decrease in body mass index (BMI), but data were not pooled due to heterogeneity in effect (mean difference (MD) -3.70, 95% CI -4.10 to -3.30; 305 women, 1 study; low-quality evidence; and MD -1.80, 95% CI -2.67 to -0.93; 43 women, 1 study; very low-quality evidence). Non-pharmacological versus non-pharmacological intervention We are uncertain whether intensive weight loss interventions compared to standard care nutrition counselling affects live birth (OR 11.00, 95% CI 0.43 to 284; 11 women, 1 study; very low-quality evidence), clinical pregnancy (OR 11.00, 95% CI 0.43 to 284; 11 women, 1 study; very low-quality evidence), BMI (MD -3.00, 95% CI -5.37 to -0.63; 11 women, 1 study; very low-quality evidence), weight change (MD -9.00, 95% CI -15.50 to -2.50; 11 women, 1 study; very low-quality evidence), quality of life (MD 0.06, 95% CI -0.03 to 0.15; 11 women, 1 study; very low-quality evidence), or mental health (MD -7.00, 95% CI -13.92 to -0.08; 11 women, 1 study; very low-quality evidence). No study reported on adverse events . Pharmacological versus pharmacological intervention For metformin plus liraglutide compared to metformin we are uncertain of an effect on the adverse events nausea (OR 7.22, 95% CI 0.72 to 72.7; 28 women, 1 study; very low-quality evidence), diarrhoea (OR 0.31, 95% CI 0.01 to 8.3; 28 women, 1 study; very low-quality evidence), and headache (OR 5.80, 95% CI 0.25 to 133; 28 women, 1 study; very low-quality evidence). We are uncertain if a combination of metformin plus liraglutide vs metformin affects BMI (MD 2.1, 95% CI -0.42 to 2.62; 28 women, 1 study; very low-quality evidence) and total body fat (MD -0.50, 95% CI -4.65 to 3.65; 28 women, 1 study; very low-quality evidence). For metformin, clomiphene, and L-carnitine versus metformin, clomiphene, and placebo, we are uncertain of an effect on miscarriage (OR 3.58, 95% CI 0.73 to 17.55; 274 women, 1 study; very low-quality evidence), clinical pregnancy (OR 5.56, 95% CI 2.57 to 12.02; 274 women, 1 study; very low-quality evidence) or BMI (MD -0.3, 95% CI 1.17 to 0.57, 274 women, 1 study, very low-quality evidence). We are uncertain if dexfenfluramine versus placebo affects weight loss in kilograms (MD -0.10, 95% CI -2.77 to 2.57; 21 women, 1 study; very low-quality evidence). No study reported on live birth, quality of life, or mental health outcomes. Pharmacological intervention versus no intervention or placebo We are uncertain if metformin compared with placebo affects live birth (OR 1.57, 95% CI 0.44 to 5.57; 65 women, 1 study; very low-quality evidence). This suggests that if the chance of live birth following placebo is assumed to be 15%, the chance following metformin would be 7% to 50%. We are uncertain if metformin compared with placebo affects gastrointestinal adverse events (OR 0.91, 95% CI 0.32 to 2.57; 65 women, 1 study; very low-quality evidence) or miscarriage (OR 0.50, 95% CI 0.04 to 5.80; 65 women, 1 study; very low-quality evidence) or clinical pregnancy (OR 2.67, 95% CI 0.90 to 7.93; 96 women, 2 studies; I² = 48%; very low-quality evidence). We are also uncertain if diet combined with metformin versus diet and placebo affects BMI (MD -0.30, 95% CI -2.16 to 1.56; 143 women, 1 study; very low-quality evidence) or waist-to-hip ratio (WHR) (MD 2.00, 95% CI -2.21 to 6.21; 143 women, 1 study; very low-quality evidence). Pharmacological versus non-pharmacological intervention No study undertook this comparison. AUTHORS' CONCLUSIONS: Evidence is insufficient to support the use of pharmacological and non-pharmacological strategies for obese women with subfertility. No data are available for the comparison of pharmacological versus non-pharmacological strategies. We are uncertain whether pharmacological or non-pharmacological strategies effect live birth, ongoing pregnancy, adverse events, clinical pregnancy, quality of life, or mental heath outcomes. However, for obese women with subfertility, a lifestyle intervention may reduce BMI. Future studies should compare a combination of pharmacological and lifestyle interventions for obese women with subfertility.


Assuntos
Infertilidade Feminina/terapia , Nascido Vivo/epidemiologia , Obesidade/terapia , Perda de Peso , Aborto Espontâneo/epidemiologia , Depressores do Apetite/uso terapêutico , Viés , Carnitina/uso terapêutico , Clomifeno/uso terapêutico , Dexfenfluramina/uso terapêutico , Quimioterapia Combinada/métodos , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Infertilidade Feminina/dietoterapia , Estilo de Vida , Liraglutida/efeitos adversos , Liraglutida/uso terapêutico , Saúde Mental , Metformina/efeitos adversos , Metformina/uso terapêutico , Obesidade/dietoterapia , Gravidez , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
2.
Int J Mol Sci ; 21(11)2020 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-32503311

RESUMO

Several clinical reports indicate that the use of amphetaminic anorectic drugs or ergot derivatives could cause valvular heart disease (VHD). We sought to investigate whether valvular lesions develop in response to long-term oral administration of these drugs and to identify drug-targeted biological processes that may lead to VHD. Treatment of New Zealand White rabbits with pergolide, dexfenfluramine, or high-dose serotonin for 16 weeks induced valvular alterations characterized by extracellular matrix remodeling. Transcriptome profiling of tricuspid valves using RNA sequencing revealed distinct patterns of differentially expressed genes (DEGs) that clustered according to the different treatments. Genes that were affected by the three treatments were functionally enriched for reduced cell metabolism processes. The two drugs yielded more changes in gene expression than serotonin and shared most of the DEGs. These DEGs were mostly enriched for decreased biosynthetic processes, increased cell-matrix interaction, and cell response to growth factors, including TGF-ß, which was associated with p38 MAPK activation. Treatment with pergolide specifically affected genes involved in homeostasis, which was corroborated by the activation of the master regulator of cell energy homeostasis, AMPK-α, as well as decreased levels of metabolism-related miR-107. Thus, both pergolide and dexfenfluramine may cause VHD through valve metabolic reprogramming and matrix remodeling.


Assuntos
Dexfenfluramina/efeitos adversos , Matriz Extracelular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Doenças das Valvas Cardíacas/induzido quimicamente , Pergolida/efeitos adversos , Valva Tricúspide/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Administração Oral , Animais , Proliferação de Células , Análise por Conglomerados , Ativação Enzimática , Feminino , Doenças das Valvas Cardíacas/metabolismo , Doenças das Valvas Cardíacas/patologia , Homeostase , MicroRNAs/genética , Coelhos , Análise de Sequência de RNA , Serotonina/efeitos adversos , Transcriptoma , Fator de Crescimento Transformador beta/metabolismo , Valva Tricúspide/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
5.
Exp Clin Psychopharmacol ; 26(4): 335-340, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29792471

RESUMO

The anorexigenic effects of intramuscular d-amphetamine HCl (0.06-0.50 mg/kg) and dexfenfluramine HCl (0.25-2.0 mg/kg) were determined in experimentally naïve baboons. A group of 8 adult male baboons was tested prior to a group of 7 adult female baboons. A 120-min session occurred at 9:00 a.m. during which baboons could respond for food pellets. Drug was given 30 min prior to the 9:00 a.m. morning session. Beginning at 11:00 a.m., baboons had a 6-hr multiple-meal session during which they could have up to 4 food pellet meals. Food was not available overnight, but food was available for 90 min upon awakening such that drug effects were evaluated in non-food-deprived animals. Under baseline conditions baboons earned between 30 and 70 pellets during the morning session and another 175-225 pellets during the remainder of the day. Amphetamine and dexfenfluramine produced dose-dependent decreases in food pellet intake during both the morning food session and the later multiple-meal session. Whereas there were minimal sex differences in the effects of dexfenfluramine, many of the amphetamine doses produced greater decreases in pellet intake in males than females. These results are discordant with much of the rodent literature on abuse-related drug effects that generally reports greater effects of amphetamine in females than males. Additional work is needed to replicate the current findings in nonhuman primates. (PsycINFO Database Record


Assuntos
Anfetamina/farmacologia , Depressores do Apetite/farmacologia , Dexfenfluramina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Caracteres Sexuais , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Relação Dose-Resposta a Droga , Ingestão de Alimentos/fisiologia , Feminino , Masculino , Papio , Agonistas do Receptor de Serotonina/farmacologia
6.
Curr Med Res Opin ; 33(10): 1773-1781, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28704161

RESUMO

OBJECTIVE: Dravet syndrome (DS) is a rare, treatment-resistant epilepsy syndrome for which current treatment regimens are often ineffective. Fenfluramine is currently in development for treatment of DS, based on reports in the 1980s and 1990s of its anti-epileptic activity in pediatric patients with intractable epilepsy. However, fenfluramine was withdrawn from global markets in 1997 following reports of its association with pulmonary hypertension and heart valve disease in adult patients treated for obesity. This review was conducted to assess cardiac safety of fenfluramine when used at lower doses for treatment of DS. METHODS: Pubmed was searched for clinical studies of fenfluramine in obese adults who reported incidence of heart valve disease. These data were reviewed against published results from Belgian patients with DS who have been treated with low-dose fenfluramine for up to 28 years. RESULTS: Nine controlled studies of fenfluramine and related compounds (dexfenfluramine and/or phentermine) which assessed incidence and severity of cardiac valve disease in 3,268 treated patients and 2,017 control subjects have been reported. Mild or greater aortic valve regurgitation was found in 9.6% of treated patients compared with 3.9% of control subjects, and moderate or greater mitral valve regurgitation was found in 3.1% of treated patients and 2.5% of control subjects. Nineteen DS patients have been treated for up to 28 years with 10-20 mg/day fenfluramine, with no clinical signs or symptoms of cardiac valve disease or pulmonary hypertension. Slight and clinically unimportant changes in valve structure have been seen on echocardiography in five patients at some time during the observation period. CONCLUSIONS: A different benefit-risk relationship appears to be emerging when fenfluramine is used at low doses for extended periods in young patients with DS. Continued cardiac assessments during ongoing Phase 3 clinical trials will provide additional safety information for this potential new and effective treatment.


Assuntos
Depressores do Apetite/administração & dosagem , Epilepsias Mioclônicas/tratamento farmacológico , Fenfluramina/administração & dosagem , Adulto , Depressores do Apetite/efeitos adversos , Dexfenfluramina/administração & dosagem , Dexfenfluramina/efeitos adversos , Fenfluramina/efeitos adversos , Doenças das Valvas Cardíacas/epidemiologia , Humanos , Hipertensão Pulmonar/epidemiologia , Incidência , Obesidade/tratamento farmacológico , Fentermina/administração & dosagem , Fentermina/efeitos adversos
7.
J Invest Dermatol ; 137(6): 1208-1210, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28532757

RESUMO

The NOX (nicotinamide adenine dinucleotide phosphate oxidase) family includes seven unique members that are involved in a multitude of physiological functions, including extensive interaction with UVR and the skin. NOX1 is uniquely present and activated by UVB radiation with biphasic expression of the enzyme immediately and then after a several-hour delay. Specific inhibition of both early and late NOX1 activation leads to evidence of decreased photocarcinogenesis in in vitro keratinocytes and in well-characterized mouse models in which antitumor efficacy has been shown; inhibiting only late NOX activation does not exhibit such effects. These results suggest a crucial function of early NOX activation in transducing a signal for cellular protection after UVB carcinogenesis provocation. We term this an intrinsic cellular ROS priming function for quenching DNA damage and promoting survival. Evolutionally, this type of priming function may be essential for addressing various types of stimuli from adverse environments.


Assuntos
Carcinogênese/metabolismo , NADPH Oxidases/metabolismo , Estresse Oxidativo/fisiologia , Neoplasias Cutâneas/fisiopatologia , Raios Ultravioleta/efeitos adversos , Animais , Carcinogênese/patologia , Dexfenfluramina , Humanos , Camundongos , Oxirredução , Espécies Reativas de Oxigênio , Sensibilidade e Especificidade , Neoplasias Cutâneas/metabolismo
8.
Arch Cardiovasc Dis ; 108(3): 172-80, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25754908

RESUMO

BACKGROUND: Fenfluramine and its derivatives have been associated with significant risk of developing valvular heart disease but its exact prevalence and severity are still debated. AIM: To evaluate the clinical and echocardiographic characteristics of patients hospitalized in a cardiology centre and who had past exposure to these drugs. METHODS: Between July 2011 and February 2012, patients admitted to the hospitalization and intensive care units at the University Centre of Montpellier, France were questioned about past exposure to fenfluramine or its derivatives. In patients who reported exposure, a questionnaire assessing prescribing patterns and medical history was proposed and echocardiography performed. All of the usual echocardiographic variables were analysed. We applied criteria from a French multicentre registry for diagnosis of drug-induced valvulopathy: leaflets and subvalvular apparatus thickening and retraction, leaflets loss of coaptation, no calcification, and no stenosis. RESULTS: Ninety-five patients exposed to these drugs were included. The majority were female (n=62, 65.3%), 53.2% (n=50) had diabetes and 90.5% (n=86) were exposed to benfluorex. Mean treatment duration was 52.3months (95% confidence interval [CI] 39.0-65.6). Valvular regurgitations were observed in 64.0% of patients (n=57) while 19.8% (n=17) had pulmonary hypertension. Highly probable fenfluramine-induced regurgitations were present in 18.6% (n=16) of patients, possibly fenfluramine-induced regurgitations in 38.2% (n=34) of patients, and unlikely fenfluramine-induced regurgitations in 25.8% (n=23) of patients. Highly probable fenfluramine-induced regurgitations were mild to moderate in severity in all except three patients. CONCLUSION: Considering the frequency of probable or possible fenfluramine-induced regurgitations and in the absence of definite knowledge about the evolution of drug-induced valvular disease, systematic questioning about fenfluramine use may be advisable in hospitalized cardiac patients.


Assuntos
Depressores do Apetite/efeitos adversos , Fenfluramina/análogos & derivados , Fenfluramina/efeitos adversos , Cardiopatias/induzido quimicamente , Cardiopatias/diagnóstico , Idoso , Dexfenfluramina/efeitos adversos , Feminino , Cardiopatias/diagnóstico por imagem , Humanos , Masculino , Estudos Prospectivos , Ultrassonografia
9.
Psychopharmacology (Berl) ; 232(11): 1973-82, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25524140

RESUMO

RATIONALE: Synergistic or supra-additive interactions between the anorectics (dex)fenfluramine and phentermine have been reported previously in the rat and in the clinic. Studies with 5-HT2C antagonists and 5-HT2C knockouts have demonstrated dexfenfluramine hypophagia in the rodent to be mediated by actions at the 5-HT2C receptor. Given the recent FDA approval of the selective 5-HT2C agonist lorcaserin (BELVIQ®) for weight management, we investigated the interaction between phentermine and 5-HT2C agonists on food intake. OBJECTIVES: This study aims to confirm dexfenfluramine-phentermine (dex-phen) synergy in a rat food intake assay, to extend these findings to other 5-HT2C agonists, and to determine whether pharmacokinetic interactions could explain synergistic findings with particular drug combinations. METHODS: Isobolographic analyses were performed in which phentermine was paired with either dexfenfluramine, the 5-HT2C agonist AR630, or the 5-HT2C agonist lorcaserin, and inhibition of food intake measured in the rat. Subsequent studies assessed these same phentermine-drug pair combinations spanning both the full effect range and a range of fixed ratio drug combinations. Satellite groups received single doses of each drug either alone or in combination with phentermine, and free brain concentrations were measured. RESULTS: Dex-phen synergy was confirmed in the rat and extended to the 5-HT2C agonist AR630. In contrast, although some synergistic interactions between lorcaserin and phentermine were observed, these combinations were largely additive. Synergistic interactions between phentermine and dexfenfluramine or AR630 were accompanied by combination-induced increases in brain levels of phentermine. CONCLUSIONS: Dex-phen synergy in the rat is caused by a pharmacokinetic interaction, resulting in increased central concentrations of phentermine.


Assuntos
Depressores do Apetite/farmacologia , Dexfenfluramina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Fenfluramina/farmacologia , Fentermina/farmacologia , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Animais , Depressores do Apetite/farmacocinética , Dexfenfluramina/farmacocinética , Sinergismo Farmacológico , Fenfluramina/farmacocinética , Masculino , Fentermina/farmacocinética , Ratos , Ratos Sprague-Dawley , Agonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia
10.
Artigo em Inglês | MEDLINE | ID: mdl-23752124

RESUMO

Mammalian studies have shown a link between serotonin (5-HT) and neuropeptide Y (NPY) in the acute regulation of feeding and energy homeostasis. Taking into account that the actions of 5-HT and NPY on food intake in fish are similar to those observed in mammals, the objective of this study was to characterize a possible short-term interaction between hypothalamic 5-HT and NPY, by examining whether 5-HT regulates NPY gene expression, to help clarify the mechanism underlying the observed anorexigenic action of central 5-HT in the rainbow trout. We used qRT-PCR to determine the levels of NPY mRNA in the hypothalamus-preoptic area (HPA) of rainbow trout after intraperitoneal (i.p.) injection of a single dose of dexfenfluramine (dFF, 3mgkg(-1); 24h-fasted and fed fish) or intracerebroventricular (i.c.v.) administration of 5-HT (100µgkg(-1); 24h-fasted fish). Significant suppression of food intake was observed after administration of 5-HT and dFF. No significant changes in NPY gene expression were obtained 150min after administration of 5-HT or dFF. However, administration of the 5HT1B receptor agonist anpirtoline did not have any significant effect on food intake in rainbow trout. The results suggest that in fish, unlike in mammals, neither the NPY neurons of the HPA nor the 5-HT1B receptor subtype participate in the neural circuitry involved in the inhibition of food intake induced by central serotoninergic activation.


Assuntos
Hipotálamo/metabolismo , Neuropeptídeo Y/genética , Oncorhynchus mykiss/genética , Serotonina/farmacologia , Animais , Dexfenfluramina/administração & dosagem , Dexfenfluramina/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Injeções Intraperitoneais , Neuropeptídeo Y/metabolismo , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Piridinas/administração & dosagem , Piridinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Serotonina/administração & dosagem
11.
Cardiovasc Res ; 99(1): 24-34, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23519266

RESUMO

AIMS: Pulmonary arterial hypertension (PAH) occurs more frequently in women than men. Oestrogen and the oestrogen-metabolising enzyme cytochrome P450 1B1 (CYP1B1) play a role in the development of PAH. Anorectic drugs such as dexfenfluramine (Dfen) have been associated with the development of PAH. Dfen mediates PAH via a serotonergic mechanism and we have shown serotonin to up-regulate expression of CYP1B1 in human pulmonary artery smooth muscle cells (PASMCs). Thus here we assess the role of CYP1B1 in the development of Dfen-induced PAH. METHODS AND RESULTS: Dfen (5 mg kg(-1) day(-1) PO for 28 days) increased right ventricular pressure and pulmonary vascular remodelling in female mice only. Mice dosed with Dfen showed increased whole lung expression of CYP1B1 and Dfen-induced PAH was ablated in CYP1B1(-/-) mice. In line with this, Dfen up-regulated expression of CYP1B1 in PASMCs from PAH patients (PAH-PASMCs) and Dfen-mediated proliferation of PAH-PASMCs was ablated by pharmacological inhibition of CYP1B1. Dfen increased expression of tryptophan hydroxylase 1 (Tph1; the rate-limiting enzyme in the synthesis of serotonin) in PAH-PASMCs and both Dfen-induced proliferation and Dfen-induced up-regulation of CYP1B1 were ablated by inhibition of Tph1. 17ß-Oestradiol increased expression of both Tph1 and CYP1B1 in PAH-PASMCs, and Dfen and 17ß-oestradiol had synergistic effects on proliferation of PAH-PASMCs. Finally, ovariectomy protected against Dfen-induced PAH in female mice. CONCLUSION: CYP1B1 is critical in the development of Dfen-induced PAH in mice in vivo and proliferation of PAH-PASMCs in vitro. CYP1B1 may provide a novel therapeutic target for PAH.


Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Dexfenfluramina , Hipertensão Pulmonar/enzimologia , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Animais , Pressão Arterial , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Hidrocarboneto de Aril Hidroxilases/deficiência , Hidrocarboneto de Aril Hidroxilases/genética , Proliferação de Células , Células Cultivadas , Citocromo P-450 CYP1B1 , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Estradiol/farmacologia , Hipertensão Pulmonar Primária Familiar , Feminino , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Norfenfluramina/toxicidade , Ovariectomia , Artéria Pulmonar/enzimologia , Artéria Pulmonar/fisiopatologia , Serotonina/metabolismo , Fatores Sexuais , Triptofano Hidroxilase/metabolismo , Função Ventricular Direita , Pressão Ventricular
12.
Orv Hetil ; 153(10): 363-73, 2012 Mar 11.
Artigo em Húngaro | MEDLINE | ID: mdl-22370224

RESUMO

Currently, obesity presents one of the biggest health problems. Management strategies for weight reduction in obese individuals include changes in life style such as exercise and diet, behavioral therapy, and pharmacological treatment, and in certain cases surgical intervention. Diet and exercise are best for both prevention and treatment, but both require much discipline and are difficult to maintain. Drug treatment of obesity offer a possible adjunct, but it may only have modest results, limited by side effects; furthermore, the weight lowering effects last only as long as the drug is being taken and, unfortunately, as soon as the administration is stopped, the weight is regained. These strategies should be used in a combination for higher efficacy. Drugs used to induce weight loss have various effects: they increase satiety, reduce the absorption of nutrients or make metabolism faster; but their effect is usually moderate. In the past, several drugs were used in the pharmacological therapy of weight reduction including thyroid hormone, dinitrophenol, amphetamines and their analogues, e.g. fenfluramine, At present, only orlistat is available in the long term treatment (≥ 24 weeks) of obesity as sibutramine and rimonabant were withdrawn form the market. Several new anti-obesity drugs are being tested at present, and liraglutide, a GLP-1 analogue (incretin mimetic), is the most promising one.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Obesidade/tratamento farmacológico , Amidas/uso terapêutico , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/efeitos adversos , Fármacos Antiobesidade/farmacologia , Anticonvulsivantes/uso terapêutico , Antidepressivos/uso terapêutico , Metabolismo Basal/efeitos dos fármacos , Benzazepinas/uso terapêutico , Benzoxazinas/uso terapêutico , Índice de Massa Corporal , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Fator Neurotrófico Ciliar/uso terapêutico , Ensaios Clínicos como Assunto , Terapia Combinada , Ciclobutanos/uso terapêutico , Dexfenfluramina/uso terapêutico , Ácidos Graxos/uso terapêutico , Feminino , Fenfluramina/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Absorção Intestinal/efeitos dos fármacos , Lactonas/uso terapêutico , Leptina/uso terapêutico , Estilo de Vida , Liraglutida , Masculino , Norepinefrina/análogos & derivados , Obesidade/prevenção & controle , Obesidade/terapia , Obesidade Mórbida/tratamento farmacológico , Orlistate , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Rimonabanto , Saciação/efeitos dos fármacos , Serotonina/análogos & derivados , Proteínas de Transporte de Sódio-Glucose/antagonistas & inibidores , Sacarose/análogos & derivados , Sacarose/uso terapêutico , Hormônios Tireóideos/uso terapêutico
13.
Mol Cell Endocrinol ; 350(1): 136-44, 2012 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-22209745

RESUMO

Serotonin and insulin are key regulators of homeostatic mechanisms in the hypothalamus. However, in type 2 diabetes, the hypothalamic responsiveness to serotonin is not clearly established. We used a diabetic model, the Goto Kakizaki (GK) rats, to explore insulin receptor expression, insulin and serotonin efficiency in the hypothalamus and liver by means of Akt phosphorylation. Insulin or dexfenfluramine (stimulator of serotonin) treatment induced Akt phosphorylation in Wistar rats but not in GK rats that exhibit down-regulated insulin receptor. Studies in a neuroblastoma cell line showed that serotonin-induced Akt phosphorylation is PI3-kinase dependent. Finally, in response to food intake, hypothalamic serotonin release was reduced in GK rats, indicating impaired responsiveness of this neurotransmitter. In conclusion, hypothalamic serotonin as insulin efficiency is impaired in diabetic GK rats. The insulin-serotonin cross-talk and impairment observed is one potential key modification in the brain during the onset of diabetes.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Insulina/sangue , Receptor Cross-Talk , Serotonina/sangue , Animais , Glicemia , Linhagem Celular Tumoral , Dexfenfluramina/farmacologia , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Ingestão de Alimentos , Humanos , Hipotálamo/enzimologia , Hipotálamo/metabolismo , Insulina/farmacologia , Insulina/fisiologia , Leptina/sangue , Fígado/enzimologia , Fígado/metabolismo , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Período Pós-Prandial , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Receptor de Insulina/metabolismo , Serotonina/farmacologia , Serotonina/fisiologia , Agonistas do Receptor de Serotonina/farmacologia
14.
Neuroimage ; 59(4): 3922-32, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21996132

RESUMO

Although alterations of serotonin (5-HT) system functioning have been proposed for a variety of psychiatric disorders, a direct method quantitatively assessing 5-HT release capacity in the living human brain is still lacking. Therefore, we evaluated a novel method to assess 5-HT release capacity in vivo using dexfenfluramine challenge and [(18)F]altanserin positron emission tomography (PET). Thirteen healthy male subjects received placebo and single oral doses of 40 mg (n = 6) or 60 mg (n = 7) of the potent 5-HT releaser dexfenfluramine separated by an interval of 14 days. Three further subjects received placebo on both days. Two hours after placebo/drug administration, 250 MBq of the 5-HT(2A) receptor selective PET-radiotracer [(18)F]altanserin was administered intravenously as a 30s bolus. Dynamic PET data were subsequently acquired over 90 min. Moreover, arterial blood samples were drawn for measurement of total activity and metabolite correction of the input function. Dexfenfluramine as well as cortisol and prolactin plasma concentration-time profiles was quantitatively determined. Tracer distribution volumes for five volumes-of-interest (prefrontal and occipital cortex, insula, thalamus, caudatum) were calculated by the Logan plot and a 2-tissue compartment model. Dexfenfluramine dose-dependently decreased the total distribution volume of [(18)F]altanserin in cortical regions independent of the PET modeling approach. Cortisol and prolactin plasma concentrations were dose-dependently increased by dexfenfluramine. The decrease in cortical [(18)F]altanserin receptor binding under dexfenfluramine was correlated with the increase of plasma prolactin. These data suggest that the combination of a dexfenfluramine-induced 5-HT release and subsequent assessment of 5-HT(2A) receptor availability with [(18)F]altanserin PET is suitable to measure cortical 5-HT release capacity in the human brain.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Dexfenfluramina , Radioisótopos de Flúor , Ketanserina/análogos & derivados , Tomografia por Emissão de Pósitrons , Agonistas do Receptor de Serotonina , Serotonina/metabolismo , Adulto , Método Duplo-Cego , Humanos , Masculino , Tomografia por Emissão de Pósitrons/métodos , Adulto Jovem
15.
Chest ; 140(4): 1066-1068, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21972386

RESUMO

We report a case of pulmonary arterial hypertension (PAH) occurring in a patient with Cowden syndrome with a mutation in the phosphatase and tensin (PTEN) tumor suppressor gene, in the context of exposure to the appetite suppressant dexfenfluramine. Anorexigen exposure is known to be a risk factor for PAH. However, the role of PTEN in cell function and the development of pulmonary vascular remodeling and histopathologic signs of PAH in mice with a Pten depletion in smooth muscle cells suggest that the association of PAH and Cowden syndrome may be relevant. In this case report, we hypothesize that PTEN mutations may be a predisposing factor for the development of PAH, with anorexigen exposure as a potential trigger.


Assuntos
Depressores do Apetite/efeitos adversos , Síndrome do Hamartoma Múltiplo/epidemiologia , Síndrome do Hamartoma Múltiplo/genética , Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/genética , Comorbidade , Dexfenfluramina/efeitos adversos , Hipertensão Pulmonar Primária Familiar , Feminino , Humanos , Pessoa de Meia-Idade , Mutação/genética , PTEN Fosfo-Hidrolase/genética , Linhagem , Fatores de Risco
17.
PDA J Pharm Sci Technol ; 65(2): 91, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21502069
18.
Physiol Behav ; 103(5): 493-500, 2011 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-21510964

RESUMO

We examined the effects of periodic access to a palatable, high sugar content food (candy) in 8 male baboons on the anorectic response to d-amphetamine, which increases dopamine, and dexfenfluramine, which increases serotonin. During candy access, up to 200 candies containing 75% of energy as sugar were available during the morning on Mondays, Wednesdays and Fridays; food pellets (19% of energy as sugar) were available in the afternoon and throughout the remaining days of the week. During candy access, baboons consumed a mean of 177 pieces of candy containing 696 kcal (2.91 MJ) in the morning compared to 44 food pellets and 150 kcal (0.63 MJ) in the morning on non-candy days. Food pellet intake was lower during candy access. Complete dose-response functions for the effects of the drugs on food pellet intake on days that candy was not available were determined before, during, and after the period of access to candy. Dexfenfluramine and amphetamine produced dose-dependent decreases in food pellet intake and increases in latency to eat food pellets before, during, and after candy access. During access to candy, the dose-response function for dexfenfluramine was shifted to the right indicating the development of tolerance, while that for amphetamine was shifted to the left indicating sensitization. Only the dose-response function for dexfenfluramine returned to baseline after candy access suggesting that the difference was specific to concurrent palatable food consumption. We hypothesize that tolerance to the effects of dexfenfluramine reflects a decrease in the satiating effect of serotonin release due to repeatedly eating large amounts of palatable food.


Assuntos
Anfetamina/farmacologia , Anorexia/dietoterapia , Dexfenfluramina/farmacologia , Sacarose na Dieta/uso terapêutico , Anfetamina/antagonistas & inibidores , Animais , Anorexia/induzido quimicamente , Dexfenfluramina/antagonistas & inibidores , Sacarose na Dieta/farmacologia , Modelos Animais de Doenças , Inibidores da Captação de Dopamina/antagonistas & inibidores , Inibidores da Captação de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Tolerância a Medicamentos , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Masculino , Papio , Agonistas do Receptor de Serotonina/farmacologia
19.
Curr Opin Biotechnol ; 22(3): 371-7, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21353525

RESUMO

The production of biofuels and biochemicals is highly electron intensive. To divert fermentative and respiratory pathways to the product of interest, additional electrons (i.e. reducing power) are often needed. Meanwhile, the past decade has seen the breakthrough of sustainable electricity sources such as solar and wind. Microbial electrosynthesis (MES) is at the nexus of both, as it uses electrical energy as source of reducing power for microorganisms. This review addresses the key opportunities and challenges for MES. While exciting as a concept, MES needs to overcome many biological, electrochemical, logistical and economic challenges. Particularly the latter is critical, as on a 'per electron basis' MES does not yet appear to deliver a substantial benefit relative to existing approaches.


Assuntos
Eletricidade , Fenômenos Microbiológicos , Biocombustíveis/economia , Vias Biossintéticas , Carbono/metabolismo , Análise Custo-Benefício , Dexfenfluramina , Elétrons , Fermentação , Glucose/metabolismo
20.
Neuropsychopharmacology ; 36(2): 423-33, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20927048

RESUMO

The now-banned anorectic molecule, dexfenfluramine, promotes serotonin release through a serotonin transporter-dependent mechanism, and it has been widely prescribed for the treatment of obesity. Previous studies have identified that 5-HT(2B) receptors have important roles in dexfenfluramine side effects, that is, pulmonary hypertension, plasma serotonin level regulation, and valvulopathy. We thus investigated a putative contribution of 5-HT(2B) receptors in dexfenfluramine-dependent feeding behavior in mice. Interestingly, the hypophagic response to dexfenfluramine (3-10 mg/kg) observed in wild-type mice (1-4 h) was eliminated in mice lacking 5-HT(2B) receptors (5-HT(2B)(-/-)). These findings were further validated by the lack of hypophagic response to dexfenfluramine in wild-type mice treated with RS127445, a highly selective and potent antagonist (pKi=8.22 ± 0.24). Using microdialysis, we observed that in 5-HT(2B)(-/-) awake mice, the dexfenfluramine-induced hypothalamic peak of serotonin release (1 h) was strongly reduced (fourfold) compared with wild type. Moreover, using hypothalamic synaptosomes, we established the serotonergic neuron autonomous properties of this effect: a strong serotonin release was observed upon dexfenfluramine stimulation of synaptosome preparation from wild type but not from mice lacking active 5-HT(2B) receptors. These findings strongly suggest that activation of presynaptic 5-HT(2B) receptors is a limiting step in the serotonin transporter dependent-releasing effect of dexfenfluramine, whereas other serotonin receptors act downstream with respect to feeding behavior.


Assuntos
Depressores do Apetite/farmacologia , Regulação do Apetite/efeitos dos fármacos , Dexfenfluramina/farmacologia , Obesidade/tratamento farmacológico , Receptor 5-HT2B de Serotonina/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Animais , Depressores do Apetite/uso terapêutico , Regulação do Apetite/fisiologia , Dexfenfluramina/uso terapêutico , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Receptor 5-HT2B de Serotonina/deficiência , Receptor 5-HT2B de Serotonina/genética , Serotonina/metabolismo , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo
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