Mazindol: a risk factor for pulmonary arterial hypertension?

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 Mazindol was withdrawn from the US and European markets in 1999 for reasons unrelated to its efficacy or safety around a time when other anorexic drugs were found to be associated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.

Eficacia y seguridad del mazindol / Efficacy and safety of mazindol

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)

Pilot Phase II study of mazindol in children with attention deficit/hyperactivity disorder.

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.

Mazindol in narcolepsy and idiopathic and symptomatic hypersomnia refractory to stimulants: a long-term chart review.

OBJECTIVE: Mazindol is a tricyclic, anorectic, non-amphetamine stimulant used in narcolepsy and obesity since 1970. This study aimed to evaluate the long-term benefit/risk ratio in drug-resistant hypersomniacs and cataplexy sufferers. METHODS: By retrospective analysis of the patients' files in the hospitals of Paris-Salpêtrière (n=91), Montpellier (n=40) and Lyon (n=8), the benefit (Epworth Sleepiness Score (ESS), cataplexy frequency, authorization renewal) and tolerance (side-effects, vital signs, electrocardiogram and cardiac echography) of mazindol were assessed. RESULTS: The 139 patients (45% men) aged 36±15years (range: 9-74) suffered narcolepsy (n=94, 66% with cataplexy), idiopathic (n=37) and symptomatic hypersomnia (n=8) refractory to modafinil, methylphenidate and sodium oxybate. Under mazindol (3.4±1.3mg/day, 1-6mg) for an average of 30months, the ESS decreased from 17.7±3.5 to 12.8±5.1, with an average fall of -4.6±4.7 (p<0.0001) and the frequency of cataplexy fell from 4.6±3.1 to 2±2.8 episodes per week. The cataplexy was eliminated in 14.5% of patients, improved in 27.5%, and unchanged in 29% (missing data in 29%). The treatment was maintained long term in 83 (60%) patients, and stopped because of a lack of efficacy (22%) and/or secondary effects (9%). There was no pulmonary hypertension in the 45 patients who underwent a cardiac echography. The most common adverse effects were dry mouth (13%), palpitations (10%, including one with ventricular hyperexcitability), anorexia (6%), nervousness (6%) and headaches (6%). CONCLUSION: Mazindol has a long-term, favorable benefit/risk ratio in 60% of drug-resistant hypersomniacs, including a clear benefit on cataplexy.

Delayed onset of pulmonary hypertension associated with an appetite suppressant, mazindol: a case report.

The use of the appetite suppressant agents aminorex and fenfluramine derivatives has been reported as a risk factor for the development of pulmonary hypertension. A 29-year-old female developed pulmonary hypertension suspected to be due to an amphetamine-like appetite suppressant agent, mazindol ((+/-)-5-(p-chlorophenyl)-2,5-dihydro-3H-imidazo [2,1-a] isoindol-5-ol). She was admitted to Sapporo Medical University Hospital with dyspnea due to severe pulmonary hypertension. Twelve months prior to admission, she had taken mazindol continuously for a period of 10 weeks. As yet, her pulmonary hypertension has not completely improved. This is the first reported case of mazindol-associated pulmonary hypertension, which developed after a long latent interval, and it suggests that mazindol is also a risk factor for the development of pulmonary hypertension, making long-term follow-up necessary for patients taking this anorectic agent.

Serial echocardiographic and clinical evaluation of valvular regurgitation before, during, and after treatment with fenfluramine or dexfenfluramine and mazindol or phentermine.

OBJECTIVE: The prevalence of cardiac valvular regurgitation demonstrated by echocardiography in patients who took appetite-suppressant medication for weight loss has been assessed at 5%-30%. We studied 86 patients who had echocardiograms before treatment with appetite suppressants to determine the incidence of new cases and to evaluate the clinical implication of the echocardiographic findings. RESEARCH METHODS AND PROCEDURES: We studied 69 men [Mean+/-Standard Deviation (S) age 49+/-8] and 17 women (mean+/-S age 50+/-7) who had 233 echocardiograms before, during, and after a weight-loss program that used predominantly fenfluramine (or dexfenfluramine) with mazindol (or phentermine). Mean drug exposure was 17 months. Blinded echocardiographic readings were performed to identify and grade aortic regurgitation (AR) or mitral regurgitation (MR). RESULTS: Seven of 86 patients (8%) had pre-existing regurgitation with five (6%) meeting our case definition. Thirteen (16.5%) of initially normal patients developed valvular regurgitation and were new cases. Of the new cases, 12 were grade I/IV AR and one was both grade II/III MR and II/IV AR. All 13 patients were asymptomatic, and only two aortic insufficiency murmurs could be auscultated. There was significantly greater risk for developing valvulopathy for those who took medications longer than 6 months (p = 0.03), and no new cases were observed in patients exposed for less than 8 months. No increased risk associated with age, presence of hypertension, or exposure to fenfluramine-phentermine combination was demonstrated. Although there was a higher incidence of new regurgitation in women (31% vs. 13% for men), this was not statistically significant (p = 0.093). DISCUSSION: Some patients who had normal echocardiograms at baseline developed cardiac valvular regurgitation after exposure to fenfluramine or dexfenfluramine with mazindol or phentermine. The development of valvulopathy was significantly correlated with duration of exposure. The clinical implications of echocardiographically demonstrated regurgitation are uncertain, since there were only two audible murmurs and no other clinically relevant signs or symptoms among the patients.

Semen-like urethral discharge during the use of mazindol.

Two case reports are described of male patients experiencing a semen-like urethral discharge during micturition, suspected to be induced by mazindol. Mazindol has an indirect sympathomimetic action and is known to cause urogenital side effects such as urinary retention and testicular pain. It is suggested that seminal discharge may be added to this list.

Formulaçöes para emagrecimento: usos e abusos / Use and abuse of drug therapy in obesity

Este trabalho discute a questäo das formulaçöes para emagrecimento. Foi efetuado um levantamento das receitas recebidas por uma farmacológicas presentes nas fórmulas prescritas, sendo ainda discutidos os efeitos tóxicos provocados por essas associaçöes de alto risco. O estudo mostrou que as formulaçöes estudadas continham, em média, cinco componentes. As associaçöes medicamentosas eram, muitas vezes, duvidosas e, em alguns casos, os fármacos estavam presentes em dosagens extremamente altas que poderiam implicar no aparecimento de efeitos tóxicos e/ou na näo manifestaçäo do efeito terapêutico desejado.

[Behavioral changes induced by repeated administration of mazindol, an anorexiant, in rats].

Behavioral changes in locomotor activity and stereotyped behaviors induced by daily administration (for 7 days) of mazindol (5 and 10 mg/kg, po) were compared with those induced by methamphetamine (10 mg/kg) in rats. On day 1, mazindol increased locomotor activity, which was enhanced by daily administrations. Stereotyped behaviors were also induced by mazindol, which became more marked following daily administrations. Methamphetamine markedly increased stereotyped behavior rather than locomotor activity on day 1, and the effects were not enhanced by daily administrations. The increased locomotor activity and stereotyped behaviors caused by mazindol and methamphetamine were markedly reduced by the dopamine receptor antagonist pimozide (0.1-0.4 mg/kg, ip) in a dose-dependent manner. These results suggest that repeated mazindol administration enhances locomotor-stimulant and stereotypy-producing effects, which are mediated by the central dopaminergic system.

Mazindol treatment for cocaine dependence.

This double-blind placebo-controlled treatment study tested the efficacy of mazindol in currently cocaine-dependent out-patients. Forty-three patients were randomized to mazindol (2 mg QD) vs. placebo treatment for 6 weeks. All patients received weekly group counseling. Patients improved with respect to objective (urine toxicology) and subjective (self-report of times used, dollars spent, craving, etc.) measures. There was no response difference between patients treated with mazindol and those who received placebo.

A prescriçäo por médicos brasileiros de fórmulas magistrais para emagrecer: uma duvidosa prática para a saúde dos pacientes / The prescription by Brazilian medicins of magistral formulas to reduce weight: a doubtful practice for the health of patients

Consultas pagas foram feitas a pesquisadores (simulando ser pacientes) que procuraram 71 médicos em Säo Paulo e 36 em Recife, visando obter uma receita para emagrecer. Em 90,5 por cento das consultas de Säo Paulo e em 58,7 por cento das de Recife aos "pacientes" foram receitadas fórmulas magistrais, sendo ainda que em 9,5 por cento das de Säo Paulo e 37,9 por cento das de Recife foram prescritos produtos comerciais acabados. Nas fórmulas magistrais de 4 a 6 drogas (53,9 por cento das receitas de Säo Paulo e 27,5 por cento em Recife) mas houve prescriçöes contendo até 17 componentes. Os agentes anorexígenos mais prescritos foram o fenproporex (58,7 por cento em Säo Paulo e 47,2 por cento em Recife) e a anfepramona ou dietilpropiona (46,0 por cento em Sä Paulo e 37,4 por cento em Recife) mas mazindol, d,1-fenifluramina e d-fenfluramina foram também receitados. Sem exceçäo as fórmulas magistrais continham também benzodiazepínicos, sendo o diazepam (28,6 por cento em Sä Paulo e 27,5 por cento em Recife) e o clordiazepóxido (25,4 por cento em Säo Paulo e 21,9 por cento em Recife) os preferidos pelos médicos prescritores de fórmulas magistrais. Agentes diuréticos, tiroidianos, com açäo sobre o aparelho gastrointestinal plantas e substâncias várias completavam a receita. Notou-se também que em 19,0 por cento das receitas de Säo Paulo e em 6,9 por cento das de Recife havia prescriçäo de duas substâncias anorexígenas e que as doses prescritas chegavam até cinco vezes a posologia recomendada internacionalmente. A maior parte dos médicos näo advertiu os pesquisadores sobre as possíveis reaçöes adversas produzidas pelas substâncias anorexígenas e benxodiazepínicas, inclusive o perigo de dependência. Conclui-se que a prática de receitar fórmulas magistrais e medicamentos acabados à base de drogas anorexígenas e benzodiazepínicas é antes um risco do que benefício para a saúde

Consumo de anorexígenos tipo-anfetamina (dietilpropiona, fenproporex, mazindol) e de fenfluramina no Brasil: Prejuízo ou benefício para a saúde / Consumption of amphetamine-like anorectic drugs (diethylpropion, fenproporex and mazindol) and of anorectic d.1-fenfluramine in Brazil: Harm or benefit to health

O consumo brasileiro das drogas anorexígenas tipo-anfetamina (dietilpropiona, fenproporex, mazindol e de d.1-fenfluramina), obtido através de dados oficiais do Ministério da Saúde, foi avaliado expessando-se resultados em doses diárias definidas por 1.000 habitantes por dia. Esta medida calcula o número de doses terapêuticas que säo utilizadas por dia para cada 1.000 habitantes, permitindo assim comparaçöes independentes da quantidade de princípio ativo e de suas preparaçöes comerciais; é por esta razäo recomendada pela Organizaçäo Mundial da Saúde (DDDs/1.000 habitantes/dia). Em 1988 o Brasil consumia essas drogas equivalentes a 4,59DDDs/1.000 habitantes/dia e no ano seguinte houve um aumento de 43,8//. Esses valores podem ser triplicados quando se leva em consideraçäo apenas a populaçäo que tem acesso a medicamento. Estes números revelam um elevado consumo de drogas tipo-anfetamina, em constraste com outros países onde o mesmo quase inexistente. Constatou-se que 68,6//do consumo em 1988 e 39,4//em 1989 processaram-se através de receitas magistrais aviadas em farmácias de manipulaçäo, sendo o restante consumido através de produtos acabados manufaturados pelas industrias farmacêuticas. A d.l-fenfluramina foi a droga menos utilizadas nos dois anos e o mazindol e o fenproporex foram as mais utilizadas, respectivamente, em 1988 e 1989. Discute-se as razöes do uso exagerado destas drogas, as possíveis reaçöes adversas que podem resultar do mesmo e a ausência de providência das autoridades de saúde do país em controlar adequadamente a situaçäo

Clinical and basic aspects of an anorexiant, mazindol, as an antiobesity agent in Japan.

The Japanese Mazindol study group investigated the action of an anorexiant, mazindol, and found that it reduced food intake by directly suppressing neurons in the lateral hypothalamus, inhibited gastric acid secretion, increased motor activity, decreased glucose absorption, and inhibited insulin secretion. It thus appears that the main effect of mazindol is to decrease food intake through suppressing feeding centers in the hypothalamus. A multicenter open study of mazindol in Japan revealed that loss of body weight and relative body weight in 14 wk were 4.6 kg and 9.2%, respectively, with suppression of appetite in the majority of obese patients. A multicenter double-blind study demonstrated that mazindol was superior to the placebo in the treatment of simple obesity. We also suggest that mazindol is effective in the maintenance of reduced body weight after obesity therapy and in the treatment of obesity-related diseases such as diabetes, hypertension, or hyperlipidemia.

Randomized, double-blind trial of mazindol in Duchenne dystrophy.

There is evidence that growth hormone may be related to the progression of weakness in Duchenne dystrophy. We conducted a 12-month controlled trial of mazindol, a putative growth hormone secretion inhibitor, in 83 boys with Duchenne dystrophy. Muscle strength, contractures, functional ability and pulmonary function were tested at baseline, and 6 and 12 months after treatment with mazindol (3 mg/d) or placebo. The study was designed to have a power of greater than 0.90 to detect a slowing to 25% of the expected rate of progression of weakness at P less than 0.05. Mazindol did not benefit strength at any point in the study. Side effects attributable to mazindol included decreased appetite (36%), dry mouth (10%), behavioral change (22%), and gastrointestinal symptoms (18%); mazindol dosage was reduced in 43% of patients. The effect of mazindol on GH secretion was estimated indirectly by comparing the postabsorptive IGF-I levels obtained following 3, 6, 9, and 12 months in the mazindol treated to those in the placebo groups. Although mazindol-treated patients gained less weight and height than placebo-treated patients, no significant effect on IGF-I levels was observed. Mazindol doses not slow the progression of weakness in Duchenne dystrophy.

Effect of mazindol on growth hormone levels in patients with Duchenne muscular dystrophy.

Human growth hormone (HGH) inhibition may be beneficial in Duchenne muscular dystrophy (DMD) and slow down the rate of progression of the disease. The purposes of the present investigation were: 1) to assess, through pharmacological stimuli (L-dopa test), the HGH response in untreated DMD patients, and 2) to evaluate the inhibitory effect of mazindol on HGH levels as a potential treatment for DMD. In 55 DMD patients, HGH levels were measured through the L-dopa test, and 40 received mazindol. After 1 year, there was wide variability in the individual response to mazindol. An apparent diminution in the mean HGH level was observed in the whole group of patients; this was statistically significant after 3 and 6 months but not after 9 and 12 months of treatment. The results suggest that this drug is not effective for arresting growth or inhibiting HGH secretion for a prolonged period of time.