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1.
Drug Dev Res ; 79(5): 225-233, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30188585

RESUMO

Preclinical Research & Development Current drugs for obesity treatment have limited efficacy and considerable adverse effects. Combination of drugs with complementary mechanisms of action at lower doses may produce a greater efficacy with a better safety profile. This study was designed to assess the anorectic effect and safety of a diethylpropion + topiramate mixture in rats. The anorectic effect of drugs was measured using a sweetened milk consumption model, and the corresponding interaction was determined by isobolographic analysis, interaction index and confidence intervals. Additionally, blood pressure was measured using a sphygmomanometer in the rat tail. Diethylpropion and topiramate alone or in combination increased the anorectic effect in a dose-dependent fashion in either nondeprived or 12 hr food-deprived rats. All theoretical ED30 values of diethylpropion + topiramate combinations at 1:1, 1:3, and 3:1 dose ratios were significantly higher than experimental ED30 values. In addition, interaction indices and confidence intervals confirmed the potentiation between both drugs. Theoretical ED30 of diethylpropion + topiramate combination did not affect the blood pressure. Data suggests that low doses of the diethylpropion + topiramate combination can potentiate the anorectic effect of individual drugs with a better safety profile, which deserves further investigation in clinical trials.


Assuntos
Depressores do Apetite/administração & dosagem , Dietilpropiona/administração & dosagem , Topiramato/administração & dosagem , Animais , Depressores do Apetite/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Dietilpropiona/efeitos adversos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Humanos , Masculino , Leite , Ratos Wistar , Topiramato/efeitos adversos
2.
Clinics (Sao Paulo) ; 72(5): 317-324, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28591345

RESUMO

The aim of this study was to evaluate efficacy and safety of amfepramone, fenproporex and mazindol as a monotherapy for the treatment of obese or overweight patients. A systematic review of primary studies was conducted, followed by a direct meta-analysis (random effect) and mixed treatment comparison. Medline and other databases were searched. Heterogeneity was explored through I2 associated with a p-value. Of 739 identified publications, 25 were included in the meta-analysis. The global evaluation of Cochrane resulted in 19 studies with a high level of bias and six with unclear risk. Due to the lack of information in primary studies, direct meta-analyses were conducted only for amfepramone and mazindol. Compared to placebo, amfepramone resulted in higher weight loss in the short-term (<180 days; mean difference (MD) -1.281 kg; p<0.05; I2: 0.0%; p=0.379) and long-term (≥180 days; MD -6.518 kg; p<0.05; I2: 0.0%; p=0.719). Only studies with long-term follow up reported efficacy in terms of abdominal circumference and 5-10% weight reduction. These results corroborated the finding that the efficacy of amfepramone is greater than that of placebo. Treatment with mazindol showed greater short-term weight loss than that with placebo (MD -1.721 kg; p<0.05; I2: 0.9%; p=0.388). However, metabolic outcomes were poorly described, preventing a meta-analysis. A mixed treatment comparison corroborated the direct meta-analysis. Considering the high level of risk of bias and the absence of important published outcomes for anti-obesity therapy assessments, this study found that the evaluated drugs showed poor evidence of efficacy in the treatment of overweight and obese patients. Robust safety data were not identified to suggest changes in their regulatory status.


Assuntos
Depressores do Apetite/uso terapêutico , Dietilpropiona/uso terapêutico , Mazindol/uso terapêutico , Obesidade/tratamento farmacológico , Sobrepeso/tratamento farmacológico , Depressores do Apetite/metabolismo , Dietilpropiona/metabolismo , Humanos , Mazindol/metabolismo , Obesidade/metabolismo , Sobrepeso/metabolismo , Viés de Publicação , Reprodutibilidade dos Testes , Fatores de Risco , Resultado do Tratamento , Perda de Peso/efeitos dos fármacos
3.
Rev Assoc Med Bras (1992) ; 63(3): 203-206, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28489121

RESUMO

Antiobesity pharmacotherapy remains the main point of disagreement among both scientists and regulators. This is probably due to small sample sizes, high levels of heterogeneity, and low methodological quality. For many years, Brazil was one of the largest consumers of appetite suppressants worldwide, with evidence of irrational use of this drug class. Therefore, the country was the scene of a debate that divided the Brazilian Health Surveillance Agency (Anvisa - Agência Nacional de Vigilância Sanitária) and medical societies over the maintenance record of diethylpropion, mazindol and fenproporex. In this context, this commentary presents new arguments to contribute to the discussion, as well as recommendations for future studies.


Assuntos
Depressores do Apetite/uso terapêutico , Dietilpropiona/uso terapêutico , Mazindol/uso terapêutico , Obesidade/tratamento farmacológico , Anfetaminas/uso terapêutico , Brasil , Ciclobutanos/uso terapêutico , Aprovação de Drogas , Humanos , Medição de Risco/tendências , Resultado do Tratamento
4.
Clinics ; 72(5): 317-324, May 2017. tab, graf
Artigo em Inglês | LILACS | ID: biblio-840075

RESUMO

The aim of this study was to evaluate efficacy and safety of amfepramone, fenproporex and mazindol as a monotherapy for the treatment of obese or overweight patients. A systematic review of primary studies was conducted, followed by a direct meta-analysis (random effect) and mixed treatment comparison. Medline and other databases were searched. Heterogeneity was explored through I2 associated with a p-value. Of 739 identified publications, 25 were included in the meta-analysis. The global evaluation of Cochrane resulted in 19 studies with a high level of bias and six with unclear risk. Due to the lack of information in primary studies, direct meta-analyses were conducted only for amfepramone and mazindol. Compared to placebo, amfepramone resulted in higher weight loss in the short-term (<180 days; mean difference (MD) -1.281 kg; p<0.05; I2: 0.0%; p=0.379) and long-term (≥180 days; MD -6.518 kg; p<0.05; I2: 0.0%; p=0.719). Only studies with long-term follow up reported efficacy in terms of abdominal circumference and 5-10% weight reduction. These results corroborated the finding that the efficacy of amfepramone is greater than that of placebo. Treatment with mazindol showed greater short-term weight loss than that with placebo (MD -1.721 kg; p<0.05; I2: 0.9%; p=0.388). However, metabolic outcomes were poorly described, preventing a meta-analysis. A mixed treatment comparison corroborated the direct meta-analysis. Considering the high level of risk of bias and the absence of important published outcomes for anti-obesity therapy assessments, this study found that the evaluated drugs showed poor evidence of efficacy in the treatment of overweight and obese patients. Robust safety data were not identified to suggest changes in their regulatory status.


Assuntos
Humanos , Depressores do Apetite/uso terapêutico , Dietilpropiona/uso terapêutico , Mazindol/uso terapêutico , Obesidade/tratamento farmacológico , Sobrepeso/tratamento farmacológico , Depressores do Apetite/metabolismo , Dietilpropiona/metabolismo , Mazindol/metabolismo , Obesidade/metabolismo , Sobrepeso/metabolismo , Viés de Publicação , Reprodutibilidade dos Testes , Fatores de Risco , Resultado do Tratamento , Perda de Peso/efeitos dos fármacos
5.
Eur Respir J ; 47(6): 1727-36, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26989105

RESUMO

Treatment for pulmonary arterial hypertension (PAH) has been underpinned by single-agent therapy to which concomitant drugs are added sequentially when pre-defined treatment goals are not met.This retrospective analysis of real-world clinical data in 97 patients with newly diagnosed PAH (86% in New York Heart Association functional class III-IV) explored initial dual oral combination treatment with bosentan plus sildenafil (n=61), bosentan plus tadalafil (n=17), ambrisentan plus tadalafil (n=11) or ambrisentan plus sildenafil (n=8).All regimens were associated with significant improvements in functional class, exercise capacity, dyspnoea and haemodynamic indices after 4 months of therapy. Over a median follow-up period of 30 months, 75 (82%) patients were still alive, 53 (71%) of whom received only dual oral combination therapy. Overall survival rates were 97%, 94% and 83% at 1, 2 and 3 years, respectively, and 96%, 94% and 84%, respectively, for the patients with idiopathic PAH, heritable PAH and anorexigen-induced PAH. Expected survival rates calculated from the French equation for the latter were 86%, 75% and 66% at 1, 2 and 3 years, respectively.Initial combination of oral PAH-targeted medications may offer clinical benefits, especially in PAH patients with severe haemodynamic impairment.


Assuntos
Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Hipertensão Pulmonar Primária Familiar/fisiopatologia , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/fisiopatologia , Adulto , Idoso , Anti-Hipertensivos/administração & dosagem , Bosentana , Dietilpropiona , Quimioterapia Combinada , Feminino , Seguimentos , Hemodinâmica , Humanos , Hipertensão Pulmonar/genética , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Fenilpropionatos/administração & dosagem , Piridazinas/administração & dosagem , Estudos Retrospectivos , Índice de Gravidade de Doença , Citrato de Sildenafila/administração & dosagem , Sulfonamidas/administração & dosagem , Tadalafila/administração & dosagem , Fatores de Tempo , Resultado do Tratamento
6.
Appetite ; 100: 152-61, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-26867698

RESUMO

Obesity is a public health problem caused by excessive consumption of high caloric diets and/or lack of physical activity. Although treatments for obesity include low caloric diets and exercise programs, these activities frequently are supplemented with appetite suppressants. For the short-term treatment of weight loss, diethylpropion (DEP) is a commonly used appetite suppressant. However, little is known with regard to how to improve its weight loss efficacy. We therefore evaluated, in rats, two administration protocols where the animals received daily injections of DEP. First, when these nocturnal animals were normally active (at night) and when they were normally inactive (daytime), and second, with or without high fat dietary restriction (HFDR). We observed that DEP induced a greater weight-loss administered when the animals were in their active phase than in their inactive phase. Moreover, DEP's administration during the inactive phase (and to a lesser degree in the active phase) promotes the consumption of food during normal sleeping time. In addition, we found that DEP-induced weight loss under ad libitum access to a HF diet, but its efficacy significantly improved under conditions of HFDR. In summary, the efficacy of DEP, and presumably other like appetite suppressants, is enhanced by carefully controlling the time it is administered and under dietary restriction of HF diets.


Assuntos
Depressores do Apetite/uso terapêutico , Regulação do Apetite/efeitos dos fármacos , Dieta com Restrição de Gorduras , Dieta Redutora , Dietilpropiona/uso terapêutico , Sobrepeso/tratamento farmacológico , Perda de Peso/efeitos dos fármacos , Animais , Depressores do Apetite/administração & dosagem , Depressores do Apetite/efeitos adversos , Depressores do Apetite/farmacocinética , Biotransformação , Ritmo Circadiano/efeitos dos fármacos , Terapia Combinada/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Dietilpropiona/administração & dosagem , Dietilpropiona/efeitos adversos , Dietilpropiona/análogos & derivados , Dietilpropiona/sangue , Dietilpropiona/farmacocinética , Esquema de Medicação , Ingestão de Energia/efeitos dos fármacos , Meia-Vida , Injeções Intraperitoneais , Masculino , Sobrepeso/sangue , Sobrepeso/dietoterapia , Sobrepeso/etiologia , Fenilpropanolamina/análogos & derivados , Fenilpropanolamina/sangue , Ratos Sprague-Dawley
7.
Int J Clin Pharmacol Ther ; 53(7): 541-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26073353

RESUMO

Amfepramone, also known as diethylpropion, is an anorectic drug used for the short-term treatment of obesity; however, its efficacy and safety during periods greater than 3 months has been scarcely studied. To evaluate the 6-month efficacy and safety of amfepramone treatment in obese adult Mexican patients resistant to diet and exercise, a double-blinded, randomized, and placebo-controlled clinical trial study was designed on 156 volunteers with a body mass index (BMI) greater than 30 kg/m2 and less than 45 kg/m2. Patients were randomized to receive a 75 mg tablet of amfepramone or placebo daily for 6 months. Primary outcome was the absolute body weight loss, whereas secondary outcomes were the percentage of patients who achieved at least 5% or 10% weight loss, as well as the improvement of anthropometric and metabolic parameters. Amfepramone treatment produced a superior efficacy to decrease body weight than placebo at 3 months (-4.9±0.25 kg vs. -0.7±0.32 kg) and 6 months (-7.7±0.52 kg vs. -1.1±0.7 kg). In addition, 64 and 34 patients achieved at least 5% or 10% weight loss, respectively, with amfepramone at 6 months, compared with 8 and 0 patients on placebo. Amfepramone also significantly improved BMI and waist circumference, but it only showed a favorable tendency in the waist-hip index (WHI), glucose, total cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL), triglycerides, heart rate, systolic blood pressure, and diastolic blood pressure at 3 and 6 months. Amfepramone produced only mild adverse events, and they were presented in a greater number than placebo only at 3 months, dry mouth being the the main adverse event. Data suggest that amfepramone is effective and well tolerated in obese Mexican patients during a 6-month regimen.


Assuntos
Depressores do Apetite/uso terapêutico , Dietilpropiona/uso terapêutico , Obesidade/tratamento farmacológico , Perda de Peso/efeitos dos fármacos , Adulto , Depressores do Apetite/efeitos adversos , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Índice de Massa Corporal , Dietilpropiona/efeitos adversos , Método Duplo-Cego , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Lipídeos/sangue , Masculino , México/epidemiologia , Obesidade/sangue , Obesidade/diagnóstico , Obesidade/epidemiologia , Obesidade/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Circunferência da Cintura , Relação Cintura-Quadril
8.
Braz. j. med. biol. res ; 48(6): 537-544, 06/2015. graf
Artigo em Inglês | LILACS | ID: lil-748218

RESUMO

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.


Assuntos
Animais , Masculino , Acetilcolina/farmacologia , Aorta Torácica/efeitos dos fármacos , Depressores do Apetite/farmacologia , Dietilpropiona/farmacologia , Vasodilatadores/farmacologia , Aorta Torácica/metabolismo , Canais de Cálcio/efeitos dos fármacos , Canais de Cálcio/metabolismo , Endotélio Vascular/efeitos dos fármacos , NG-Nitroarginina Metil Éster/metabolismo , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Fenilefrina/farmacologia , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/metabolismo , Ratos Wistar , Tetraetilamônio/metabolismo , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos
9.
J Neurophysiol ; 114(1): 585-607, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25972577

RESUMO

Obesity is a worldwide health problem that has reached epidemic proportions. To ameliorate this problem, one approach is the use of appetite suppressants. These compounds are frequently amphetamine congeners such as diethylpropion (DEP), phentermine (PHEN), and bupropion (BUP), whose effects are mediated through serotonin, norepinephrine, and dopaminergic pathways. The nucleus accumbens (NAc) shell receives dopaminergic inputs and is involved in feeding and motor activity. However, little is known about how appetite suppressants modulate its activity. Therefore, we characterized behavioral and neuronal NAc shell responses to short-term treatments of DEP, PHEN, and BUP. These compounds caused a transient decrease in weight and food intake while increasing locomotion, stereotypy, and insomnia. They evoked a large inhibitory imbalance in NAc shell spiking activity that correlated with the onset of locomotion and stereotypy. Analysis of the local field potentials (LFPs) showed that all three drugs modulated beta, theta, and delta oscillations. These oscillations do not reflect an aversive-malaise brain state, as ascertained from taste aversion experiments, but tracked both the initial decrease in weight and food intake and the subsequent tolerance to these drugs. Importantly, the appetite suppressant-induced weight loss and locomotion were markedly reduced by intragastric (and intra-NAc shell) infusions of dopamine antagonists SCH-23390 (D1 receptor) or raclopride (D2 receptor). Furthermore, both antagonists attenuated appetite suppressant-induced LFP oscillations and partially restored the imbalance in NAc shell activity. These data reveal that appetite suppressant-induced behavioral and neuronal activity recorded in the NAc shell depend, to various extents, on dopaminergic activation and thus point to an important role for D1/D2-like receptors (in the NAc shell) in the mechanism of action for these anorexic compounds.


Assuntos
Depressores do Apetite/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Receptores de Dopamina D1/antagonistas & inibidores , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Depressores do Apetite/efeitos adversos , Benzazepinas/farmacologia , Bupropiona/efeitos adversos , Bupropiona/farmacologia , Dietilpropiona/efeitos adversos , Dietilpropiona/farmacologia , Interações Medicamentosas , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Núcleo Accumbens/fisiologia , Fentermina/efeitos adversos , Fentermina/farmacologia , Racloprida/farmacologia , Distribuição Aleatória , Ratos Sprague-Dawley , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Comportamento Estereotipado/efeitos dos fármacos , Comportamento Estereotipado/fisiologia , Perda de Peso/efeitos dos fármacos , Perda de Peso/fisiologia
10.
Braz J Med Biol Res ; 48(6): 537-44, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25831200

RESUMO

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.


Assuntos
Acetilcolina/farmacologia , Aorta Torácica/efeitos dos fármacos , Depressores do Apetite/farmacologia , Dietilpropiona/farmacologia , Vasodilatadores/farmacologia , Animais , Aorta Torácica/metabolismo , Canais de Cálcio/efeitos dos fármacos , Canais de Cálcio/metabolismo , Endotélio Vascular/efeitos dos fármacos , Masculino , NG-Nitroarginina Metil Éster/metabolismo , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Fenilefrina/farmacologia , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/metabolismo , Ratos Wistar , Tetraetilamônio/metabolismo , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos
11.
Org Lett ; 17(3): 406-9, 2015 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-25633934

RESUMO

A metal-free one-pot strategy has been developed for the first time to synthesize pharmaceutically important α-amino ketones from readily available benzylic secondary alcohols and amines using N-bromosuccinimide. This new reaction proceeds via three consecutive steps involving oxidation of alcohols, α-bromination of ketones, and nucleophilic substitution of α-bromo ketones to give α-amino ketones. Importantly, this novel one-pot greener reaction avoids direct usage of toxic and corrosive bromine. This methodology has been employed efficiently to synthesize pharmaceutically important amfepramone and pyrovalerone in a single step.


Assuntos
Álcoois/química , Bromosuccinimida/química , Cetonas/síntese química , Aminas/química , Catálise , Dietilpropiona/síntese química , Dietilpropiona/química , Halogenação , Cetonas/química , Estrutura Molecular , Oxirredução , Pirrolidinas/síntese química , Pirrolidinas/química , Estereoisomerismo
12.
Hum Exp Toxicol ; 34(3): 300-7, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25005806

RESUMO

Diethylpropion has been available in the market for treating obesity for over 50 years. Refined studies are lacking to fully elucidate its action spectrum. The aim of our study was to evaluate possible toxic effects of anorectic diethylpropion in Chinese hamster ovary (CHO) cells. Comet assay (detects breaks in the DNA strand), micronucleus test (detects clastogenic/aneugenic damage), and cell survival test (detects cytotoxic damage) were used to evaluate the toxic effects. In comet assay, we found that the damage scores with diethylpropion treatments at the concentrations of 20 and 40 µg/mL were more significant ( p < 0.05) than that of the negative control. When assessing the possible aneugenic and/or clastogenic damage caused by the drug in CHO cells, we found no difference ( p > 0.05) in the values of micronucleated cells when comparing different diethylpropion treatments and the negative control. Regarding the cell viability, for all the diethylpropion concentrations tested, higher values ( p < 0.05) of apoptosis were found compared with those of the negative control. In relation to the number of necrotic cells, no difference ( p > 0.05) was noted between the means of the three concentrations of diethylpropion evaluated and the negative control. In the experimental conditions, we conclude that diethylpropion has weak genotoxic and cytotoxic activities.


Assuntos
Depressores do Apetite/toxicidade , Citotoxinas/toxicidade , Dietilpropiona/toxicidade , Mutagênicos/toxicidade , Animais , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Cricetinae , Cricetulus , Dano ao DNA , Testes para Micronúcleos
13.
J Anal Toxicol ; 38(7): 432-7, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25038769

RESUMO

Brazil is considered one of the countries with the highest number of amphetamine-type stimulant (ATS) users worldwide, mainly diethylpropion (DIE) and fenproporex (FEN). The use of ATS is mostly linked to diverted prescription stimulants and this misuse is widely associated with (ab)use by drivers. A validated method was developed for the simultaneous analysis of amphetamine (AMP), DIE and FEN in plasma samples employing direct immersion-solid-phase microextraction, and gas chromatographic/mass spectrometric analysis. Trichloroacetic acid 10% was used for plasma deproteinization. In situ derivatization with propylchloroformate was employed. The linear range of the method covered from 5.0 to 100 ng/mL. The detection limits were 1.0 (AMP), 1.5 (DIE) and 2.0 ng/mL (FEN). The accuracy assessment of the control samples was within 85.58-108.33% of the target plasma concentrations. Recoveries ranged from 46.35 to 84.46% and precision was <15% of the value of relative standard deviation. This method is appropriate for screening and confirmation in plasma forensic toxicology analyses of these basic drugs.


Assuntos
Anfetaminas/sangue , Estimulantes do Sistema Nervoso Central/sangue , Dietilpropiona/sangue , Detecção do Abuso de Substâncias/métodos , Adulto , Anfetamina/sangue , Brasil , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Limite de Detecção , Masculino , Reprodutibilidade dos Testes , Microextração em Fase Sólida
14.
Artigo em Inglês | MEDLINE | ID: mdl-24795175

RESUMO

Mephedrone, an erstwhile "legal high", and some non-abused cathinones (ethcathinone, diethylpropion and bupropion) were tested for stimulant effects in vitro, through assessing their abilities to increase basal and electrically evoked dopamine efflux in rat accumbens brain slices, and compared with cocaine and amphetamine. We also tested mephedrone against cocaine in a dopamine transporter binding study. Dopamine efflux was electrically evoked and recorded using voltammetry in the rat accumbens core. We constructed concentration response curves for these cathinones for effects on basal dopamine levels; peak efflux after local electrical stimulation and the time-constant of the dopamine decay phase, an index of dopamine reuptake. We also examined competition between mephedrone or cocaine and [(125)I]RTI121 at the dopamine transporter. Mephedrone was less potent than cocaine at displacing [(125)I]RTI121. Mephedrone and amphetamine increased basal levels of dopamine in the absence of electrical stimulation. Cocaine, bupropion, diethylpropion and ethcathinone all increased the peak dopamine efflux after electrical stimulation and slowed dopamine reuptake. Cocaine was more potent than bupropion and ethcathinone, while diethylpropion was least potent. Notably, cocaine had the fastest onset of action. These data suggest that, with respect to dopamine efflux, mephedrone is more similar to amphetamine than cocaine. These findings also show that cocaine was more potent than bupropion and ethcathinone while diethylpropion was least potent. Mephedrone's binding to the dopamine transporter is consistent with stimulant effects but its potency was lower than that of cocaine. These findings confirm and further characterize stimulant properties of mephedrone and other cathinones in adolescent rat brain.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Dopamina/metabolismo , Metanfetamina/análogos & derivados , Núcleo Accumbens/efeitos dos fármacos , Anfetamina/farmacologia , Anfetaminas/farmacologia , Animais , Bupropiona/farmacologia , Cocaína/análogos & derivados , Cocaína/farmacologia , Dietilpropiona/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Relação Dose-Resposta a Droga , Estimulação Elétrica , Radioisótopos do Iodo , Masculino , Metanfetamina/farmacologia , Microeletrodos , Núcleo Accumbens/fisiologia , Propiofenonas/farmacologia , Ensaio Radioligante , Ratos Wistar , Técnicas de Cultura de Tecidos
15.
Int J Obes (Lond) ; 38(8): 1097-103, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24287940

RESUMO

CONTEXT: No long-term studies have compared centrally acting drugs for treating obesity. OBJECTIVE: To compare the efficacy and safety of diethylpropion (DEP), fenproporex (FEN), mazindol (MZD), fluoxetine (FXT) and sibutramine (SIB) in promoting weight loss. DESIGN AND SETTING: A prospective, randomized, placebo (PCB)-controlled study conducted at a single academic institution. PATIENTS: A total of 174 obese premenopausal women. INTERVENTION: Participants randomly received DEP 75 mg (n=28), FEN 25 mg (n=29), MZD 2 mg (n=29), SIB 15 mg (n=30), FXT 20 mg (n=29) or PCB (n=29) daily over 52 weeks. Diet and physical activity were encouraged. MAIN OUTCOME MEASURES: The primary endpoints were changes in body weight and the proportion of women who achieved at least 5% weight loss by week 52 in the intent-to-treat population. Other measurements included anthropometry, safety, metabolic and cardiovascular parameters. RESULTS: Weight loss was greater than PCB (-3.1±4.3 kg) with DEP (-10.0±6.4 kg; P<0.001), SIB (-9.5±5.9 kg; P<0.001), FEN (-7.8±6.9 kg; P<0.01) and MZD (-7.4±4.9 kg; P<0.01) but not with FXT (-2.5±4.1 kg). Ten (33.3%) women lost⩾5% of their initial weight with PCB, compared with 20 (71.4%; P<0.001) with DEP, 20 (69%; P<0.02) with FEN, 21 (72.4%; P<0.01) with MZD, 22 (73.3%; P<0.001) with SIB and 10 (35.5%) with FXT. Each medically treated group experienced more adverse events compared with PCB (P<0.001). Compared with PCB, constipation was more prevalent with DEP, SIB and MZD (P<0.01); anxiety was more prevalent with DEP (P=0.01); and irritability occurred more frequently with DEP and FEN (P=0.02). Significant improvements in the depression and anxiety scores, binge-eating episodes and quality of life correlated with weight loss. CONCLUSION: The centrally acting drugs DEP, FEN, MZD and SIB were more effective than PCB in promoting weight loss in obese premenopausal women, with a satisfactory benefit-risk profile.


Assuntos
Anfetaminas/uso terapêutico , Fármacos Antiobesidade/uso terapêutico , Ciclobutanos/uso terapêutico , Dietilpropiona/uso terapêutico , Fluoxetina/uso terapêutico , Mazindol/uso terapêutico , Obesidade/tratamento farmacológico , Perda de Peso/efeitos dos fármacos , Adulto , Índice de Massa Corporal , Brasil , Dieta Redutora , Feminino , Seguimentos , Humanos , Obesidade/prevenção & controle , Estudos Prospectivos , Inquéritos e Questionários , Resultado do Tratamento
16.
J Toxicol Environ Health A ; 76(19): 1121-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24274153

RESUMO

The abusive use of amfepramone in Brazilian population has grown in recent years. Few studies have been conducted on amphetamine with respect to DNA damage, and there have been no apparent investigations examining the influence of amfepramone on humans. The aim of this study was to determine the possible mutagenic actions of amfepramone on humans using the micronucleus (MN) assay with buccal cells and the effects of supplementation with vitamin C as a potential protective agent. The study included 108 females with 52 as control and 56 taking amfepramone at 120 mg/d for at least the whole previous month. All women were intentionally selected to be nonsmokers and nondrinkers. After 30 d of amfepramone women were given amfepramone plus vitamin C use at 1000 mg/d for another month. Results showed a marked increase in the number of MN in amfepramone users in both basal and differentiated cells, indicating a mutagenic action. After vitamin C supplementation, a significant decrease in the frequency of MN and apoptosis was observed. Evidence indicates that the main mechanism of action of amfepramone in inducing DNA damage occurs through formation of reactive oxygen species (ROS), intercalation and topoisomerase binding, attributed to the presence of an N-dialkyl group. In addition, data demonstrated that vitamin C effectively inhibited amfepramone-induced DNA damage.


Assuntos
Ácido Ascórbico/farmacologia , Suplementos Nutricionais , Dietilpropiona/toxicidade , Testes para Micronúcleos/métodos , Mutagênicos/toxicidade , Brasil , Dano ao DNA/efeitos dos fármacos , Feminino , Humanos , Mucosa Bucal/citologia , Mucosa Bucal/efeitos dos fármacos
17.
J Am Chem Soc ; 135(43): 16074-7, 2013 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-24107144

RESUMO

The direct α-amination of ketones, esters, and aldehydes has been accomplished via copper catalysis. In the presence of catalytic copper(II) bromide, a diverse range of carbonyl and amine substrates undergo fragment coupling to produce synthetically useful α-amino-substituted motifs. The transformation is proposed to proceed via a catalytically generated α-bromo carbonyl species; nucleophilic displacement of the bromide by the amine then delivers the α-amino carbonyl adduct while the catalyst is reconstituted. The practical value of this transformation is highlighted through one-step syntheses of two high-profile pharmaceutical agents, Plavix and amfepramone.


Assuntos
Aminas/química , Ticlopidina/análogos & derivados , Aldeídos/química , Brometos/química , Catálise , Clopidogrel , Cobre/química , Dietilpropiona/síntese química , Ésteres/química , Ticlopidina/síntese química
18.
Einstein (Sao Paulo) ; 11(1): 47-52, 2013.
Artigo em Inglês, Português | MEDLINE | ID: mdl-23579743

RESUMO

OBJECTIVE: To investigate the prevalence of appetite suppressant use among health sciences students in Southern Brazil. METHODS: Undergraduate students (n=300) from seven health science undergraduate courses of the Universidade de Caxias do Sul completed a questionnaire about the use of substances to suppress appetite. RESULTS: A significant percentage (15%; n=45) of research participants used appetite suppressants at least once in their lives. The most commonly used substances were sympathomimetic stimulant drugs (5%), including amfepramone (3.3%) and fenproporex (1.7%). The lifetime use of appetite suppressants was more prevalent among Nursing (26.7%) and Nutrition (24.4%%) students. There was no reported use of appetite suppressants among medical students. The use of appetite suppressants was significantly more prevalent among women. The majority of those who used these substances did so under medical recommendation. Most of users took appetite suppressants for more than 3 months. CONCLUSION: Lifetime use of appetite suppressants was substantial, being sympathomimetic stimulant drugs the most commonly used agents. Students enrolled in Nursing and Nutrition courses presented a significantly higher prevalence of lifetime use of appetite suppressants.


Assuntos
Depressores do Apetite/administração & dosagem , Estudantes de Ciências da Saúde/estatística & dados numéricos , Adolescente , Adulto , Anfetaminas/administração & dosagem , Brasil , Dietilpropiona/administração & dosagem , Feminino , Humanos , Masculino , Obesidade/tratamento farmacológico , Automedicação , Inquéritos e Questionários , Simpatomiméticos/administração & dosagem , Fatores de Tempo , Adulto Jovem
19.
Pharmacol Biochem Behav ; 107: 11-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23537731

RESUMO

The exposure to adverse events early in life may affect brain development. Omega-3 polyunsaturated fatty acid (n-3 PUFA) deficiency has been linked to the development of mood and anxiety disorders. The aim of this study was to examine the interaction between variations in the early environment (handling or maternal separation) and the chronic exposure to a nutritional n-3 PUFA deficiency on locomotor activity, sucrose preference, forced swimming test and on serum and hippocampal brain-derived neurotrophic factor (BDNF) levels. Rats were randomized into Non-handled (NH), Neonatal Handled (H) and Maternal Separated (MS) groups. Pups were removed from their dams (incubator at 32°C on postnatal days (PND) 1-10) during 10 min/day (H) or 3h/day (MS). On PND 35, males were subdivided into diets adequate or deficient in n-3 PUFA for 15 weeks. H and MS gained weight differently, and animals receiving the n-3 PUFA deficient diet gained less weight. MS displayed a higher food consumption and higher consumption of sucrose solution during the second hour of exposure to the sucrose preference test. No differences were observed in the swimming test. H group had increased locomotion and showed a higher response to amfepramone. No significant effect was observed on serum BDNF levels. BDNF protein levels were decreased in animals receiving the n-3 PUFA deficient diet. We observed that early life environment and a mild n-3 PUFA deficiency are able to affect several behavioral aspects (food and sucrose consumption and locomotor response), and lead to a differential hippocampal BDNF metabolism in adult life.


Assuntos
Ácidos Graxos Ômega-3/farmacologia , Privação Materna , Estresse Psicológico/metabolismo , Animais , Animais Recém-Nascidos , Peso Corporal , Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dieta com Restrição de Gorduras/efeitos adversos , Dietilpropiona/farmacologia , Ácidos Graxos Ômega-3/metabolismo , Feminino , Preferências Alimentares , Manobra Psicológica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Resposta de Imobilidade Tônica , Masculino , Atividade Motora/efeitos dos fármacos , Gravidez , Ratos , Estresse Psicológico/sangue , Estresse Psicológico/dietoterapia , Estresse Psicológico/psicologia
20.
Acta amaz ; 42(2): 215-220, June 2012. ilus, tab
Artigo em Inglês | LILACS | ID: lil-616882

RESUMO

OBJECTIVES: The International Narcotics Control Board released its 2005 annual report, highlighting the Brazil population as one of the largest consumers of anorectics. In Brazil, the National Health Surveillance Agency issued the resolution RDC 58/2007 in order to control the prescription and sale of such drugs. In Belém, the biggest city in the Brazilian Amazon region, this resolution came into force in 2008, leading to inspections of drugstores and magistral pharmacies. The aim of this work was to evaluate the consumption of psychotropic anorectic drugs and the impact of RDC 58/2007 on the prescription and dispensing of anorectics in drugstores and magistral pharmacies in Belém. METHODOLOGY: A retrospective quantitative and descriptive study was conducted of records from the Municipal Department of Health Surveillance of Belém, for 2005 to 2008. The differences in findings were regarded significant when p < 0.05. RESULTS: A total of 1,641 balance sheets of drugstores and magistral pharmacies were analyzed. Amfepramone was the most dispensed medication, followed by fenproporex and mazindol. The highest consumption of anorectics occurred in magistral pharmacies. In 2008, there was a significant reduction in dispensing of anorectics, in drugstores as well as in magistral pharmacies. CONCLUSIONS: This study showed that there was a decrease in the dispensing of anorectics after RDC 58/2007 came into force, and that the magistral pharmacies dispensed more of these drugs. This resolution is a remarkable tool in health control, where it is of great benefit to public health and contributes substantially to the rational use of medicines in Brazil.


OBJETIVOS: O International Narcotics Control Board publicou em 2005 sua pesquisa anual que demonstrou que a população brasileira são um dos maiores consumidores de anorexígenos. No Brasil, a Agência Nacional de Vigilância Sanitária publicou a resolução RDC 58/2007 com o objetivo de controlar a prescrição e comercialização deste tipo de medicamento. Em Belém, a maior cidade da Amazônia brasileira, esta resolução entrou em vigor em 2008, levando à inspeções em drogarias e farmácias. Este trabalho propõe avaliar o consumo de psicotrópicos anorexígenos e o impacto da RDC 58/2007 na prescrição e dispensação de anorexígenos nas drogarias e farmácias magistrais de Belém. METODOLOGIA: foi realizado um estudo retrospectivo, quantitativo e descritivo, com dados coletados do Departamento de Vigilância Sanitária de Belém, de 2005 a 2008. Os dados foram considerados quando p < 0,05. RESULTADOS: Um total de 1.641 balanços foram analisados oriundos de drogarias e farmácias magistrais. Anfepramona foi o medicamento mais dispensado, seguido do femproporex e manzidol. O maior consumo de anorexígenos ocorreu nas farmácias magistrais. Em 2008, houve uma redução significativa na dispensação de anorexígenos, tanto em drogarias quanto em farmácias magistrais. CONCLUSÕES: Este estudo demonstrou que houve uma diminuição na dispensação de anorexígenos após a entrada em vigor da RDC 58/2007, e as farmácias magistrais foram responsáveis por um elevado número na dispensação destes medicamentos. Esta resolução é um marco divisor no controle sanitário, para enorme benefício da saúde pública, contribuindo substancialmente para o uso racional de medicamentos no Brasil.


Assuntos
Depressores do Apetite , Vigilância Sanitária , Dietilpropiona , Mazindol
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