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1.
Sleep Med Clin ; 14(3): 333-350, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31375202

RESUMO

Idiopathic hypersomnia (IH) is characterized by excessive daytime sleepiness despite normal or prolonged sleep. IH is distinguished from narcolepsy by the female predominance, severe morning inertia, continuous drowsiness (rather than sleep attacks), unrefreshing naps, absence of cataplexy, sleep onset in REM periods, and hypocretin deficiency. In IH, the multiple sleep latency test demonstrates low sensitivity, specificity, and reproducibility, compared with prolonged sleep monitoring. In some IH cases, an endogenous hypnotic peptide stimulating GABA receptors during wakefulness is suspected, which are improved by anti-GABA drugs. The benefits of modafinil, sodium oxybate, mazindol, and pitolisant were found in mostly retrospective studies.


Assuntos
Moduladores GABAérgicos/uso terapêutico , Hipersonia Idiopática/tratamento farmacológico , Promotores da Vigília/uso terapêutico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Claritromicina/uso terapêutico , Flumazenil/uso terapêutico , Humanos , Hipersonia Idiopática/metabolismo , Hipersonia Idiopática/fisiopatologia , Mazindol/uso terapêutico , Modafinila/uso terapêutico , Orexinas/metabolismo , Piperidinas/uso terapêutico , Polissonografia , Medicina de Precisão , Sono , Oxibato de Sódio/uso terapêutico , Vigília
2.
CNS Drugs ; 32(3): 289-301, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29557078

RESUMO

BACKGROUND: Mazindol is under investigation for the treatment of attention-deficit/hyperactivity disorder (ADHD) because of its alertness-enhancing properties. A novel controlled-release (CR) formulation of mazindol was developed to allow once-daily dosing. OBJECTIVE: The aim of this study was to evaluate the efficacy of mazindol CR in adults with ADHD. DESIGN: We conducted a randomized, double-blind, placebo-controlled 6-week trial. METHODS: Subjects diagnosed with ADHD using the Mini-International Neuropsychiatric Structured Interview (MINI) and with an ADHD Rating Scale, Diagnostic and Statistical Manual of Mental Disorders 5th Edition (ADHD-RS-DSM5) score ≥ 28 were randomized to receive placebo or 1-3 mg/day of mazindol for 6 weeks. The primary endpoint was the reduction from baseline in the ADHD-RS-DSM5 score on Day 42. Secondary endpoints were response rates defined by change in ADHD-RS-DSM5 (≥ 30 or ≥ 50% reduction) and dichotomized Clinical Global Impression-Improvement (CGI-I) score (1 or 2). An exploratory endpoint of functional impairment, as measured by the Target Impairment Scale, examined individualized deficits in specific settings. Safety, tolerability, and pharmacokinetics were assessed. RESULTS: Eighty-five participants were randomized (n = 43 active, 42 placebo); 75 completed. Weekly ADHD-RS-DSM5 measurements after mazindol differed from placebo beginning at Day 7, with a least squares mean difference (active-placebo) of - 13.2 at Day 42 and an effect size of 1.09. For the 30% or more reduction in ADHD-RS-DSM5 (minimal response), a significant difference (active-placebo) was seen starting at Day 7 and continuing to Day 42. For the CGI-I (1 or 2) and for the 50% or more reduction in ADHD-RS-DSM5 (measures of excellent response), the differences began at Day 14 and continued to Day 42. Functional impairment was significantly different in the proportion achieving at least a 50% reduction in target impairment score (42.9% mazindol vs 11.9% placebo) by Day 42. Dry mouth, nausea, fatigue, heart rate (HR) increased, decreased appetite, and constipation were more prevalent for mazindol versus placebo. Overall, mazindol CR had minimal effects on blood pressure and small effects on HR. CONCLUSION: Mazindol CR was efficacious in the treatment of adults with ADHD, with a large effect size, and was well tolerated, supporting the progression to phase III. (Clinicaltrials.gov Registration No. NCT02808104).


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Preparações de Ação Retardada/administração & dosagem , Mazindol/uso terapêutico , Adolescente , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Resultado do Tratamento , Adulto Jovem
3.
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
4.
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
5.
Sleep Med ; 34: 168-169, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28522087

RESUMO

Mazindol is an imidazo-isoindole derivative, a tricyclic compound and a non-amphetamine central nervous system stimulant that blocks dopamine and norepinephrine reuptake. Mazindol was withdrawn from the US and European markets in 1999 for reasons unrelated to its efficacy or safety around a time when other anorexic drugs were found to be associated with the development of pulmonary arterial hypertension (PAH). Despite the use of mazindol for decades, reports of PAH due to mazindol intake have been extremely rare. Recent interest on mazindol has emerged for the treatment of narcolepsy and attention-deficit/hyperactivity disorder. Therefore, an updated understanding of the potential benefits and risks of mazindol in these patient populations is warranted.


Assuntos
Estimulantes do Sistema Nervoso Central/efeitos adversos , Hipertensão Pulmonar/epidemiologia , Mazindol/efeitos adversos , Estimulantes do Sistema Nervoso Central/uso terapêutico , Humanos , Mazindol/uso terapêutico , Fatores de Risco
6.
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
7.
Neuropsychopharmacology ; 42(4): 974-982, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27402414

RESUMO

Inconsistent evidence implicates disruptions of striatal dopaminergic indices in suicide and major depression. To determine whether there are alterations in the striatal dopamine system in suicide, we conducted a quantitative autoradiographic survey of dopamine transporter (DAT; [3H]mazindol), D1 receptor ([3H]SCH23390), and D2 receptor ([3H]sulpiride) binding in the dorsal striatum postmortem from matched suicides and controls. Axis I and axis II psychiatric diagnosis, recent treatment history, and early life adversity (ELA) were determined by psychological autopsy. Mean DAT, D2, and D1 receptor binding did not differ in suicide. However, there was a positive correlation between D1 and D2 receptor binding in the dorsal striatum of control subjects (R2=0.31, p<0.05) that was not present in suicides (R2=0.00, p=0.97). In suicides and controls with reported ELA, there was no correlation between striatal DAT and D1 receptor binding (R2=0.07, p=0.33), although DAT and D1 receptor binding was positively correlated in subjects with no report of ELA (R2=0.32, p<0.05). After controlling for age, there were no significant ELA-related mean differences. Binding of D1 receptors and DAT throughout the striatum correlated negatively with age (D1 receptor: R2=0.12, p<0.05; DAT: R2=0.36, p<0.001). There appears to be an imbalance in dopaminergic receptor and transporter expression related to suicide that differs from that associated with ELA or age.


Assuntos
Dopaminérgicos/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Transtornos Mentais/metabolismo , Neostriado/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Suicídio , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autorradiografia , Benzazepinas/metabolismo , Feminino , Humanos , Masculino , Mazindol/metabolismo , Pessoa de Meia-Idade , Ligação Proteica , Sulpirida/metabolismo , Adulto Jovem
8.
Psychopharmacology (Berl) ; 234(3): 323-328, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27766370

RESUMO

RATIONALE: The beneficial effects of psychostimulant drugs in the treatment of psychiatric disorders occur because they increase the extracellular dopamine concentration by inhibiting re-uptake of extracellular dopamine at dopamine transporters. However, the psychological effects at low dopamine transporter occupancy have not been well demonstrated. OBJECTIVES: The purpose of the study was to evaluate the psychological effects, dopamine transporter occupancy, and dopamine release induced by a single oral administration of a clinical dose of mazindol. METHODS: Ten healthy male volunteers were orally administered a placebo and a clinical dose of mazindol (1.5 mg) on separate days. The psychological effects of mazindol were assessed using a visual analogue scale to detect alterations in the state of consciousness. The amount of blockade of dopamine transporters was assessed using positron emission tomography with [18F]FE-PE2I and extracellular dopamine release was measured as the amount of change in [11C]raclopride binding. RESULTS: Following administration of a clinical dose of mazindol, the dopamine transporters were blocked by 24-25 %, and the binding potential of [11C]raclopride was reduced by 2.8-4.6 %. The differences of a score measuring derealisation and depersonalization associated with a positive basic mood were significantly correlated with the change in the [11C]raclopride binding in the limbic striatum. CONCLUSIONS: A subtle alteration in the state of consciousness was detected with a correlation to the changes in the [11C]raclopride binding, which implies that a subtle alteration in extracellular dopamine concentration in the limbic striatum by a small amount of dopamine transporter occupancy can affect the state of consciousness. TRIAL REGISTRATION HTTPS://UPLOAD.UMIN.AC.JP/CGI-OPEN-BIN/CTR_E/CTR_VIEW.CGI?RECPTNO=R000009703 : UMIN000008232.


Assuntos
Encéfalo/metabolismo , Estado de Consciência/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Mazindol/farmacologia , Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono , Corpo Estriado/metabolismo , Despersonalização/induzido quimicamente , Dopamina/metabolismo , Antagonistas de Dopamina , Humanos , Masculino , Tomografia por Emissão de Pósitrons , Racloprida , Adulto Jovem
9.
Neurosci Lett ; 633: 141-145, 2016 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-27658895

RESUMO

In this study, we evaluated the preventive effect of mazindol on the development of obesity and sought to elucidate the drug's effects on the reward system. In mice, body weight gain and hyperphagia induced by high-fat diet (HFD) were decreased by 38.6% and 13.9%, respectively, by subcutaneous infusion of mazindol (1.5mg/kg/day) for 28days. A single intraperitoneal administration of mazindol (1.5mg/kg) significantly reduced lipid preference, as assessed using the two-bottle preference paradigm (vehicle, 89.98±1.66%; mazindol, 75.65±5.47%; p<0.05). In addition, the conditioned place preference (CPP) test demonstrated that mazindol (1.5mg/kg) significantly decreased CPP score for HFD as compared with vehicle (vehicle, 330.44±58.61s; mazindol, 144.72±43.02s; p<0.05). Moreover, at the dose required for these effects, mazindol did not elicit abuse potential or induce psychostimulant-like behavior. These results confirm that mazindol prevents diet-induced obesity without addictive behavior and demonstrate that its action is mediated at least in part via the reward system, advancing our understanding of mazindol in clinical practice.


Assuntos
Fármacos Antiobesidade/farmacologia , Mazindol/farmacologia , Recompensa , Animais , Condicionamento Psicológico/efeitos dos fármacos , Gorduras na Dieta/administração & dosagem , Tolerância a Medicamentos , Preferências Alimentares/efeitos dos fármacos , Infusões Subcutâneas , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos
10.
Eur J Clin Pharmacol ; 72(8): 945-51, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27066959

RESUMO

PURPOSE: There are no pharmacokinetics studies in oral fluid reported in the literature, as well as there are no data on correlation of drug levels in plasma, urine, and oral fluid in order to propose alternative matrices to monitor the use of mazindol by drivers. The present work aimed to study, preliminarily, mazindol's pharmacokinetics in plasma and oral fluid, as well as investigate the correlation of drug levels in urine, plasma, and oral fluid. METHOD: Blood, urine, and oral fluid samples from seven healthy male volunteers were collected at 0, 1, 2, 4, 5, 6, 8, 10, and 24 h after administration of tablets of 2 mg mazindol and analyzed by a previously validated method by LC-MS with liquid-liquid extraction. Levels of the drug found were higher in plasma when compared with oral fluid and higher in urine in relation to plasma. The study of the mazindol's pharmacokinetics showed that the most suitable model to describe the variation of the concentration over time is the compartment open model with absorption and elimination following the first-order kinetics, and confirming literature data, drug is metabolized, being the major metabolite detected, but not quantified. CONCLUSION: It was not found a good correlation between the concentrations of mazindol in urine and plasma, but between plasma and oral fluid, there was a good correlation, suggesting this as an alternative matrix to plasma. However, studies involving more subjects are needed.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacocinética , Mazindol/farmacocinética , Administração Oral , Adulto , Estimulantes do Sistema Nervoso Central/sangue , Estimulantes do Sistema Nervoso Central/urina , Voluntários Saudáveis , Humanos , Masculino , Mazindol/sangue , Mazindol/urina , Modelos Biológicos , Saliva/química , Adulto Jovem
11.
Artigo em Inglês | MEDLINE | ID: mdl-26718151

RESUMO

INTRODUCTION: Even after removal of some stimulants, like fenproporex, amfepramone and mazindol, from Brazilian market, the use of these substances is still high, especially by drivers. Mazindol is the second most used anorectic agent in the world acting as an indirect sympathomimetic agonist, having stimulatory action on central nervous system. Plasma is a good matrix to monitor since it reflects the psychomotor effects of these drugs, but unlike urine has an invasive collection; drug levels and detection time are quite low. METHOD: The method involved a liquid-liquid extraction of the samples and a LC-MS analysis was fully validated. Method was used to analyze samples of urine and plasma collected from health volunteers in a period of 24h. Metabolite of mazindol was synthesized using alkaline conditions. RESULTS: After validation the method proved to be adequate to analyze samples collected from health volunteers. Method was linear in the concentration range of 0.1-10ng/mL (r=0.9982) for plasma and 5-50ng/mL (r=0.9973) for urine. DISCUSSION: Analysis of the samples showed that mazindol can be detected after 1h of administration and that concentration levels in urine were always higher than in plasma. Mazindol metabolite was detected only in urine.


Assuntos
Cromatografia Líquida/métodos , Mazindol/sangue , Mazindol/urina , Espectrometria de Massas por Ionização por Electrospray/métodos , Estimulantes do Sistema Nervoso Central/sangue , Estimulantes do Sistema Nervoso Central/urina , Humanos , Extração Líquido-Líquido/métodos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
12.
s.l; ANMAT; 2016. ilus.
Não convencional em Espanhol | BRISA/RedTESA | ID: biblio-877137

RESUMO

ANTECEDENTES Y CONTEXTO: El mazindol es un estimulante central imidazólico, de efecto similar a las anfetaminas, utilizado fundamentalmente como anorexígeno y también para el tratamiento de otras patologías. Produce excitabilidad, irritabilidad y aumenta el riesgo cardiovascular; también genera rápida tolerancia, dependencia y un alto potencial de abuso. En la actualidad el uso de mazindol es controvertido y ha sido retirado del mercado en la mayoría de los países. OBJETIVO: Evaluar la seguridad y la eficacia del mazindol en la práctica clínica. MÉTODO: Revisión sistemática de la bibliografía obtenida en las bases de datos de estudios publicados desde 1975 a 2016, sin restricción de lenguaje y que evaluaran la eficacia y/o seguridad de mazindol en seres humanos. RESULTADOS: Cumplieron las condiciones de inclusión 20 estudios de un total de 338 encontrados: cuatro revisiones sistemáticas, un metaanálisis, siete ICCAs, tres guías de práctica clínica, dos series de casos, una revisión narrativa, un estudio observacional de corte transversal y un estudio descriptivo. Los estudios incluidos carecen de potencia suficiente para evaluar la eficacia y seguridad del mazindol para los puntos finales evaluados con excepción del tratamiento de la narcolepsia o narcolepsia/cataplexia. En síntesis: -Obesidad Refractaria: Los estudios presentan un limitado número de pacientes y del tiempo de seguimiento. Son de baja calidad metodológica y reportan severos eventos adversos; -Diabéticos con sobrepeso: hay fuerte evidencia para desaconsejar su uso; -Sindrome de Prader Willi: no demostró eficacia; -Distrofia muscular de Aran-Duchenne: no demostró eficacia a los nueve meses de seguimiento; -Narcolepsia y Narcolepsia/Cataplexia: es efectivo, redujo a la mitad o menos la frecuencia de la parálisis del sueño, constituyendo una segunda opción terapéutica luego del modafilino, metilfenidato, oxibato sódica; -Prevención de la recaída en el consumo de cocaína: no hay evidencia de eficacia; -Efectos adversos: los más frecuentes se circunscriben a los sistemas cardiovascular, gastrointestinal y nervioso. Son moderados a severos. El 84% de las notificaciones al Sistema Nacional de Farmacovigilancia están vinculadas a preparaciones magistrales con mazindol. CONCLUSIONES: Las evidencias disponibles, en términos de eficacia, efectividad y riesgo/beneficio, no justifican el uso del mazindol en el tratamiento de la obesidad y de las demás condiciones analizadas a lo largo de esta revisión, excepto para su empleo en el tratamiento de la narcolepsia o narcolepsia/cataplexia como droga de segunda línea cuando los pacientes no responden a modafinilo, metilfenidato u oxibato sódico.(AU)


Assuntos
Humanos , Anfetaminas/efeitos adversos , Depressores do Apetite/efeitos adversos , Mazindol/efeitos adversos , Argentina , Análise Custo-Benefício , Avaliação da Tecnologia Biomédica
13.
Drug Des Devel Ther ; 8: 2321-32, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25525331

RESUMO

OBJECTIVE: Mazindol has been proposed as a potential treatment of children with attention deficit/hyperactivity disorder (ADHD). The purpose of this pilot study was to assess its pharmacokinetics, short-term efficacy, and safety. SUBJECTS AND METHODS: A total of 24 children (aged 9-12 years) with ADHD (according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, text-revision criteria) received a daily dose of 1 mg for 7 days and were followed for 3 additional weeks. Pharmacokinetic samples were collected after the first administration. ADHD symptoms were assessed using the ADHD Rating Scale (RS)-IV, Conners' Parent Rating Scale - Revised: Long (CPRS-R:L) at screening, baseline, and the end of the study. The Clinical Global Impression - Severity (CGI-S) scale was assessed at baseline, and the CGI - Improvement (CGI-I) scale was assessed at subsequent visits. RESULTS: Twenty-one subjects (aged 10±1 years) were analyzed. Pharmacokinetic data were described by a one-compartment model with first-order absorption, elimination, and lag time. The typical apparent clearance and apparent volume of distribution were 27.9 L/h and 234 L, and increased with fat-free mass and age, respectively. The mean change in score in ADHD RS-IV after 1 week of mazindol was -24.1 (P<0.0001), greater than a 90% improvement from baseline. Reduction of CPRS-R:L and CGI-S scores were -52.1 (P<0.0001) and -2.5 (P<0.01), respectively. Adverse events were mild to moderate, decreased appetite and upper abdominal pain being the most common. CONCLUSION: This preliminary study shows that mazindol might be an effective, well-tolerated, and long-acting (more than 8 hours) agent for the treatment of ADHD in children.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Mazindol/uso terapêutico , Adolescente , Criança , Esquema de Medicação , Feminino , Humanos , Masculino , Mazindol/administração & dosagem , Mazindol/efeitos adversos , Mazindol/farmacocinética , Projetos Piloto , Segurança
14.
Acta Neuropsychiatr ; 26(3): 146-54, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25142190

RESUMO

OBJECTIVES: Mazindol is a sympathomimetic amine, widely used as an anorectic agent in the treatment of obesity. This drug causes psychostimulant effects because of its pharmacological profile similar to amphetamine, acting like a monoamine reuptake inhibitor. However, the mechanisms underlying the action of mazindol are still not clearly understood. METHODS: Swiss mice received a single acute administration of mazindol (0.25, 1.25 and 2.5 mg/kg, ip) or saline. After 2 h, the animals were killed by decapitation; the brain was removed and used for the evaluation of activities of mitochondrial respiratory chain complexes, Krebs cycle enzymes and creatine kinase. RESULTS: Acute administration of mazindol decreased complex I activity only in the hippocampus. Complex IV activity was increased in the cerebellum (2.5 mg/kg) and cerebral cortex (0.25 mg/kg). Citrate synthase activity was increased in the cerebellum (1.25 mg/kg) and cerebral cortex (1.25 mg/kg), and creatine kinase activity was increased in the cerebellum (1.25 mg/kg). CONCLUSION: We suggest that the inhibition of complex I in the hippocampus only and activation of complex IV, citrate synthase and creatine kinase occurs because of a stimulus effect of mazindol in the central nervous system, which causes a direct impairment on energy metabolism.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Metabolismo Energético/efeitos dos fármacos , Mazindol/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/uso terapêutico , Masculino , Mazindol/administração & dosagem , Mazindol/uso terapêutico , Camundongos , Obesidade/tratamento farmacológico , Obesidade/metabolismo
15.
Behav Brain Res ; 270: 206-12, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-24859175

RESUMO

Recent research has shown that pharmacological enhancement of dopaminergic function increases an optimism bias in humans. The present study investigated whether acute dopaminergic system stimulation through the administration of two dopamine-mimetic drugs, cocaine and mazindol, have similar effects in rats. To accomplish this goal, after initial behavioural training, two groups of rats received single injections of either cocaine or mazindol and were subsequently tested with the ambiguous-cue interpretation (ACI) paradigm. Both drugs were administered in three doses using the fully randomised Latin square designs. Cocaine (1, 2 and 5mg/kg) had no significant effect on the interpretation of the ambiguous cue. Mazindol at all three doses (0.5, 1 and 2mg/kg) significantly biased animals towards negative interpretation of the ambiguous cue. The results are discussed in relation to pharmacological and behaviourally evoked actions of tested compounds.


Assuntos
Cocaína/farmacologia , Cognição/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Julgamento/efeitos dos fármacos , Mazindol/farmacologia , Animais , Cocaína/administração & dosagem , Sinais (Psicologia) , Inibidores da Captação de Dopamina/administração & dosagem , Relação Dose-Resposta a Droga , Masculino , Mazindol/administração & dosagem , Testes Neuropsicológicos , Ratos , Ratos Sprague-Dawley
16.
Biomed Chromatogr ; 28(8): 1064-9, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24458547

RESUMO

Brazil is one of the countries most affected by abuse of stimulant medications by professional drivers, especially fenproporex, amfepramone and mazindol. Even though their sale is banned, they can be found in illegal markets, such as those located on the country's borders. The use of oral fluid to monitor drug levels has many advantages over plasma and urine because it is noninvasive, easier to collect and more difficult to adulterate. The aim of this study was to develop and validate a sensitive and specific method to quantify mazindol in human oral fluid by liquid chromatography-mass spectrometry (LC-MS). The LC system consisted of an LC-MS system operated in selected ion monitoring mode. The mobile phase was composed of water at pH 4.0, acetonitrile and methanol (60:15:25 v/v/v) at a flow rate of 1.0 mL/min and propranolol was used as internal standard. Total running time was 10 min. The lower limit of quantification was 0.2 ng/mL and the method exhibited good linearity within the 0.2-20 ng/mL range (r = 0.9987). A rapid, specific, sensitive, linear, precise and accurate method was developed for determination of mazindol in human oral fluid according to European Medicines Agency guidelines, and is suitable for monitoring mazindol levels in oral fluid of professional drivers.


Assuntos
Estimulantes do Sistema Nervoso Central/análise , Cromatografia Líquida de Alta Pressão/métodos , Mazindol/análise , Saliva/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Condução de Veículo , Brasil , Estimulantes do Sistema Nervoso Central/química , Estabilidade de Medicamentos , Humanos , Modelos Lineares , Masculino , Mazindol/química , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
17.
Psychopharmacology (Berl) ; 231(11): 2321-5, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24398821

RESUMO

RATIONALE: Mazindol, an appetite suppressant, inhibits the reuptake of dopamine in the synaptic cleft. It has been considered that mazindol might enhance dopamine transmission in the human brain. However, there has been no study that investigated the extracellular dopamine concentration in vivo. OBJECTIVE: Using positron emission tomography (PET), we aimed to measure the effect of mazindol on the extracellular dopamine concentration and to evaluate how mazindol affects the dopamine system in the healthy human brain. METHODS: Eleven healthy individuals (six males, five females, age 30.9 ± 4.9 years) were enrolled in this study. Each participant was scanned with [(11)C]raclopride on 1 day without any medicine as baseline condition, and on another day with mazindol as drug condition. In the drug condition, participants took mazindol 0.5 mg (N = 5) or 1.5 mg (N = 6) 2 h before the PET scan. Plasma concentrations of mazindol were measured before the injection of [(11)C]raclopride, and urine concentrations of mazindol were measured after the scan. RESULTS: After taking mazindol, the calculated decrease in binding potential (ΔBP) in the striatum was 1.74 % for 0.5 mg and 8.14 for 1.5 mg, and the correlation with the blood concentration of mazindol was significant (P = 0.0016, R (2) = 0.69). ΔBP was not significantly correlated with the urine concentration of mazindol (P = 0.84, R (2) = 0.005). CONCLUSIONS: Mazindol increased the extracellular concentration of dopamine in the human brain, and its effect was dose dependent. A single administration of mazindol, even at usual dosage, elevated dopamine concentration similarly to other addictive drugs, suggesting that the risk of dependence may increase with the mazindol dose.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Dopamina/metabolismo , Espaço Extracelular/metabolismo , Mazindol/farmacologia , Adulto , Depressores do Apetite/análise , Depressores do Apetite/farmacologia , Análise Química do Sangue , Radioisótopos de Carbono , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Inibidores da Captação de Dopamina/sangue , Inibidores da Captação de Dopamina/urina , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Mazindol/sangue , Tomografia por Emissão de Pósitrons , Racloprida , Adulto Jovem
18.
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
19.
Mol Pharmacol ; 85(2): 208-17, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24214825

RESUMO

Mazindol has been explored as a possible agent in cocaine addiction pharmacotherapy. The tetracyclic compound inhibits both the dopamine transporter and the serotonin transporter, and simple chemical modifications considerably alter target selectivity. Mazindol, therefore, is an attractive scaffold for both understanding the molecular determinants of serotonin/dopamine transporter selectivity and for the development of novel drug abuse treatments. Using molecular modeling and pharmacologic profiling of rationally chosen serotonin and dopamine transporter mutants with respect to a series of mazindol analogs has allowed us to determine the orientation of mazindol within the central binding site. We find that mazindol binds in the central substrate binding site, and that the transporter selectivity can be modulated through mutations of a few residues in the binding pocket. Mazindol is most likely to bind as the R-enantiomer. Tyrosines 95 and 175 in the human serotonin transporter and the corresponding phenylalanines 75 and 155 in the human dopamine transporter are the primary determinants of mazindol selectivity. Manipulating the interaction of substituents on the 7-position with the human serotonin transporter Tyr175 versus dopamine transporter Phe155 is found to be a strong tool in tuning the selectivity of mazindol analogs and may be used in future drug design of cocaine abuse pharmacotherapies.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Mazindol/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Sítios de Ligação , Células Cultivadas , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Humanos , Mazindol/química , Mazindol/uso terapêutico , Modelos Moleculares , Relação Estrutura-Atividade
20.
Nature ; 503(7474): 141-5, 2013 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-24121440

RESUMO

The biogenic amine transporters (BATs) regulate endogenous neurotransmitter concentrations and are targets for a broad range of therapeutic agents including selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). Because eukaryotic BATs are recalcitrant to crystallographic analysis, our understanding of the mechanism of these inhibitors and antidepressants is limited. LeuT is a bacterial homologue of BATs and has proven to be a valuable paradigm for understanding relationships between their structure and function. However, because only approximately 25% of the amino acid sequence of LeuT is in common with that of BATs, and as LeuT is a promiscuous amino acid transporter, it does not recapitulate the pharmacological properties of BATs. Indeed, SSRIs and TCAs bind in the extracellular vestibule of LeuT and act as non-competitive inhibitors of transport. By contrast, multiple studies demonstrate that both TCAs and SSRIs are competitive inhibitors for eukaryotic BATs and bind to the primary binding pocket. Here we engineered LeuT to harbour human BAT-like pharmacology by mutating key residues around the primary binding pocket. The final LeuBAT mutant binds the SSRI sertraline with a binding constant of 18 nM and displays high-affinity binding to a range of SSRIs, SNRIs and a TCA. We determined 12 crystal structures of LeuBAT in complex with four classes of antidepressants. The chemically diverse inhibitors have a remarkably similar mode of binding in which they straddle transmembrane helix (TM) 3, wedge between TM3/TM8 and TM1/TM6, and lock the transporter in a sodium- and chloride-bound outward-facing open conformation. Together, these studies define common and simple principles for the action of SSRIs, SNRIs and TCAs on BATs.


Assuntos
Antidepressivos de Segunda Geração/farmacologia , Antidepressivos Tricíclicos/farmacologia , Aminas Biogênicas/metabolismo , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores , Proteínas Recombinantes de Fusão/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Antidepressivos de Segunda Geração/metabolismo , Antidepressivos Tricíclicos/metabolismo , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Ligação Competitiva/efeitos dos fármacos , Cloretos/metabolismo , Cristalografia por Raios X , Humanos , Mazindol/metabolismo , Mazindol/farmacologia , Modelos Moleculares , Mutação , Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/química , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/metabolismo , Conformação Proteica/efeitos dos fármacos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Reprodutibilidade dos Testes , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Inibidores de Captação de Serotonina/metabolismo , Sertralina/metabolismo , Sertralina/farmacologia , Sódio/metabolismo , Relação Estrutura-Atividade
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