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 Mazindol was withdrawn from the US and European markets in 1999 for reasons unrelated to its efficacy or safety around a time when other anorexic drugs were found to be associated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

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.

Therapeutic effects of mazindol on narcolepsy.

Mazindol, a new anorexiant, was administered at a daily dose of 0.5-4 mg to 10 narcoleptic subjects aged 21-63 years. All the patients suffered from sleep attacks and one or more of the REM-related symptoms. Eight patients received only mazindol, and two patients received mazindol simultaneously with clomipramine or flurazepam. Sleep attacks were reduced in nine patients, and cataplexy was also markedly reduced in four patients. Mild adverse reactions were reported in six patients: two patients complained of headache, four of nocturnal sleep disturbance, and two of reduced appetite. Most side effects disappeared spontaneously or after dose reduction, and none of the patients had to stop medication. The results suggest that mazindol is effective not only for sleep attacks but also for cataplexy. It is recommended as a treatment for mild cases of narcolepsy.

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.

Bethanechol chloride can reverse erectile and ejaculatory dysfunction induced by tricyclic antidepressants and mazindol: case report.

A 43-year-old man who experienced profound dose-related erectile and ejaculatory dysfunction without loss of libido on three separate antidepressants and on the anorectic agent mazindol is described. Bethanechol chloride 20 mg p.o., taken 1 to 2 hours prior to sexual activity, permitted satisfactory erection and ejaculation during sexual intercourse, while the patient continued to take protriptyline or mazindol. Bethanechol chloride may prove to be of use in treating sexual dysfunction associated with drugs or conditions which increase sympathetic tone.

A multi-centre trial of mazindol ('Teronac') in general practice in Ireland.

In a multi-centre trial of mazindol ('Teronac'), a new anorectic agent unrelated to amphetamine, 274 male and female patients were treated by 53 investigators in Eire. All patients were overweight according to the Metropolitan Life Assurance Company Tables, and 166 patients completed the treatment regime of one 2 mg. tablet daily and a 100 calorie diet for 12 weeks. The average weight loss was 18.8 lbs. (8.5 kg.); 85% of patients reported good appetite supression and good ability to adhere to their diet, and the attending physicians rated mazindol as being of considerable help in 92% of the patients. Mazindol was well tolerated, only 29 patients dropped out of the trial because of side-effects.

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 comparison of mazindol (Teronac) with diethylpropion in the treatment of exogenous obesity.

Fifty obese patients were entered into a 12-week parallel group study of mazindol with diethylpropion in a general practice group. Both drugs produced weight loss, but patients on mazindol lost 19.9 lbs in 12 weeks, while those on diethylpropion lost 11.6 lbs, a statistically significant difference (p less than 0.01). At each visit during the trial, patients had lost more weight with mazindol, but this was only significant statistically in the period 8-12 weeks (p less than 0.01). Patients developed tolerance to the effect of diethylpropion in the last period (8-12 weeks) but this was not evident in those patients taking mazindol. The number of side-effects was less in the mazindol group and mainly of an adrenergic, peripheral type, while those in the diethylpropion group are mainly of the central stimulant type.

Short-term and long-term clinical evaluation of a non-amphetaminic anorexiant (mazindol) in the treatment of obesity.

The effectiveness and tolerance of a non-amphetaminic anorexiant drug has been evaluated in a short-term and in a long-term clinical trial in simple obesity and in refractory obesity. In the short-term 'crossover' trial, a more evident effectiveness and tolerance result when the anorexiant is given in a late phase of treatment. The association of an anorexiant drug with the hypocaloric diet was seen to be effective in the treatment of so-called refractory obesity. In the evaluation of the long-term treatment it is seen that weight loss is greater and remains so farr longer periods in patients receiving anorexiant, as compared to controls. This is related to a better maintenance of a restricted calorie regimen. Mazindol did not affect the improvement of glucose tolerance and insulin secretion which follows the weight reduction.

[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.

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.