Efficacy and safety of the metformin-mazindol anorectic combination in rat.

The current study investigates the anorectic interaction and safety of the mazindol-metformin combination in rats. Isobologram and interaction index were used to determine anorectic interaction between mazindol and metformin in the sweetened milk model. The safety profile of the mazindol-metformin combination was determined by measuring anxiety, blood pressure, hematic biometry and blood chemistry. An acute dose of mazindol and metformin administered per os, individually or as a mixture, has reduced the milk consumption in rats in a dose-dependent manner. Theoretical effective dose 40 (ED40t) did not differ from the experimental effective dose 40 (ED40e) obtained with the mazindol-metformin mixture in the anorexia experiments, by Student's t-test. In addition, the interaction index confirmed the additive anorectic effect between both drugs. A single oral dose of ED40e mazindol-metformin mixture induced anxiolysis in the elevated plus-maze test. Moreover, oral administration of mazindol-metformin combination for 3 months significantly decreased glycemia, but not blood pressure nor other parameters of hematic biometry and blood chemistry. Results suggest that mazindol-metformin combination exerts an additive anorectic effect, as well as anxiolytic and hypoglycemic properties. Mazindol-metformin combination might be useful in obese patients with anxiety disorders or diabetes risk factors.

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.

Effects of acute administration of mazindol on brain energy metabolism in adult mice.

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.

The effects of cocaine and mazindol on the cognitive judgement bias of rats in the ambiguous-cue interpretation paradigm.

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.

Systemic mazindol reduces food intake in rats via suppression of meal size and meal number.

The aim of the present study was to determine the impact of the appetite suppressant mazindol on meal pattern in rats. Meal patterns were monitored in adult male rats after mazindol dosing during the first three hours of the dark cycle using automated feeding chambers (BioDAQ). Mazindol (0, 0.25, 1.25 and 2.5 mg/kg, IP) produced a dose-dependent hypophagia and hypodipsia. Meal size and meal number were significantly suppressed by mazindol. The meal pattern findings indicate that mazindol inhibits eating in the rat via a suppression of both meal size and meal number.

Effect of mazindol on body weight and insulin sensitivity in severely obese patients after a very-low-calorie diet therapy.

The present investigations were performed in order to clarify the effects of mazindol on body weight and insulin sensitivity in patients with morbid obesity who had already been treated with a very-low-calorie diet containing 480 kcal food (VLCD) with various amino acids. We attempted to study whether a further decrease in body weight would be achieved by the administration of mazindol, because it is difficult to obtain sufficient and continuous reduction of body weight after VLCD therapy. Thirteen female severely obese subjects were 51.0 +/- 13.9 years old (25-73 years old), with a mean height of 154.7 +/- 5.6 cm (146.0-160.5 cm), mean weight of 84.5 +/- 9.4 kg (69-98 kg) and a mean body mass index (BMI) of 35.3 +/- 3.6 kg/m2 (29.2-41.0 kg/m2). Their mean body weight decreased to 76.7 +/- 2.2 kg (net decrease: 6.3 +/- 0.9 kg) after VLCD therapy for 2-4 weeks. Then they were treated by the administration of mazindol with diet restriction (1000-1200 kal/day). Mazindol administration resulted in a further weight reduction of 2.9 +/- 0.5 kg after 4 weeks, 4.9 +/- 0.5 kg after 8 weeks and 6.9 +/- 0.9 kg after 12 weeks. Their blood pressure was not changed after mazindol treatment. The responses of blood glucose and insulin levels in a 75 g oral glucose tolerance test (OGTT) were not significantly different before and after mazindol administration. The blood glucose area calculated from the data obtained during OGTT for 120 min did not significantly differ before and after mazindol administration, while the insulin area significantly decreased after mazindol treatment (from 98.0 +/- 12.1 before administration to 70.1 +/- 7.8). The mean M value reflecting insulin sensitivity in the whole body determined by euglycemic glucose clamping was increased significantly after mazindol treatment (from 4.92 +/- 0.30 mg/kg/min to 6.36 +/- 0.43 mg/kg/min). The results demonstrated that mazindol administration with diet restriction further reduced body weight in the morbidly obese subjects after treatment with VLCD, with an increase in the M value and a decrease in insulin release. The results suggest that mazindol is useful for reducing body weight as well as improving insulin sensitivity.

[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 for relapse prevention to cocaine abuse in methadone-maintained patients.

We conducted a double-blind, randomized clinical trial of mazindol (n = 37) for the prevention of relapse to cocaine abuse in methadone-maintained patients who were in the "action" stage of change, i.e., had a history of cocaine dependence but who had been abstinent for at least 2 weeks prior to entry into the study. Eight-one percent of subjects completed the 12-week course of treatment. Overall, cocaine use during the study was comparatively low-17% of the urine screens submitted were positive for cocaine metabolite. Differences between the mazindol and placebo groups of rates of relapse, number of days to relapse, and cocaine use did not reach statistical significance, but were in the direction of a treatment effect. Results suggest that stage of abstinence initiation may be a potentially useful category to employ as an independent variable in future pharmacotherapy trials for the treatment of cocaine addiction in this patient population.

Mazindol: anorectic and behavioral effects in female rats.

The anorectic and behavioral effects of mazindol (2.5, 5 and 10 mg/kg) were determined. The experiments comprized acute and chronic administration to female rats, and the effects were compared with those produced by 2.5 mg/kg of methamphetamine. The following evaluation parameters were considered: food intake, body weight, motor activity, and stereotyped behavior. Acute administration of the three doses of mazindol, as well as of the methamphetamine dose, decreased food intake. Administered chronically to female rats, mazindol (5 and 10 mg/kg) and methamphetamine induced loss of body weight during the first fifteen days. However, weight was subsequently regained by the animals, indicating development of tolerance. Mazindol (10 mg/kg) and methamphetamine produced an increase in motor activity. This increase was, however, not observed after chronic treatment, suggesting development of tolerance. Additionally, mazindol induced noticeable dose-dependent effects, involving stereotyped behavior (sniffing, continuous licking, false bites), similar to those produced by methamphetamine. Verticalization, however, was only observed after administration of 2.5 and 5 mg/kg of mazindol, and was absent after administration of the higher dose of mazindol as well as of methamphetamine. Finally, it should be stressed that features of stereotyped behavior induced by both drugs, such as licking, false bites, sniffing and verticalization, were very similar.

Sex difference in sensitization to the locomotor effects of mazindol in rats.

Male and female rats were treated daily for 7 days with mazindol (5, 10, and 20 mg/kg), an anorectic drug, and tested in the open field. Mazindol developed sensitization to its locomotor stimulatory effect in both sexes on day 7 with a nondose-dependent pattern of response. However, the locomotor activity appeared to be sex dependent, female rats being more sensitive. Following a challenge dose of mazindol (10 and 20 mg/kg) on day 10, a marked enhancement of locomotion was seen in female rats. These findings indicate that repeated administration of mazindol produces sex-dependent sensitization to its effect on locomotor behavior.

Effects of cocaine alone and in combination with mazindol in human cocaine abusers.

Mazindol is a catecholamine reuptake inhibitor that blocks binding of cocaine at the dopamine reuptake site. This study was conducted to determine whether the acute administration of mazindol modulates the pharmacological effects of intravenous cocaine in humans. In a crossover study, twelve acute drug conditions were tested in randomized order under double-blind, double-dummy conditions in eight cocaine abusers. Cocaine (0, 12.5, 25 and 50 mg, i.v.) was administered in combination with mazindol (0, 1 and 2 mg given orally 2 hr before the cocaine injection). Physiological and subject- and observer-rated responses were measured. Cocaine and mazindol alone both significantly increased heart rate and blood pressure. Cocaine increased ratings on stimulant-like subjective effect measures, including desire for cocaine; mazindol had mild, stimulant-like subjective effects. There were significant interactions between the effects of cocaine and mazindol on heart rate and blood pressure, with combinations producing significantly large and more sustained increases compared with cocaine alone. There was no evidence that mazindol substantially altered the magnitude or profile of the subjective effects of cocaine, including cocaine-induced craving for cocaine. These results do not support the utility of acute administration of mazindol in the treatment of cocaine abusers through a mechanism of modulation of cocaine's subjective effects. Furthermore, mazindol treatment may increase the cardiovascular risks of cocaine.

Differing neurotoxic potencies of methamphetamine, mazindol, and cocaine in mesencephalic cultures.

The potent reinforcing effects of methamphetamine and cocaine are thought to be mediated by their interactions with CNS dopamine neurons. Both stimulants share the ability to block dopamine uptake potently, and methamphetamine can release cytoplasmic dopamine as well. There is also abundant evidence demonstrating the neurotoxic effects of methamphetamine. There are, however, limited studies that attempt to discern the neurotoxic mechanisms of these agents. The purpose of the present study was to characterize and compare the chronic in vitro effects of methamphetamine, cocaine, and the dopamine uptake blocker, mazindol, on cultured fetal mesencephalic dopamine neurons. Our studies examined biochemical mechanisms to evaluate the contribution of reuptake blockade versus release of dopamine. Using a dispersed cell preparation of fetal mesencephalon, cultures were treated for 5 days with the three uptake blockers. Dopamine function was assessed by measuring high-affinity [3H]dopamine uptake and by examining cultures for the presence of tyrosine hydroxylase-immunopositive neurons. Nonspecific neurotoxicity was assessed by staining for neuron-specific enolase and measuring lactate dehydrogenase activity. The results indicate that repeated administration of high concentrations of methamphetamine (10(-4) and 10(-3) M) caused a generalized neurotoxicity whereas the effects of 10(-5) M methamphetamine appeared to be specific to dopamine cells. Likewise, treatment of the cultures with mazindol (10(-6) M) resulted in reduced dopamine uptake while not significantly affecting neuron-specific enolase or tyrosine hydroxylase immunostaining. On the other hand, repeated exposure to cocaine (10(-5) and 10(-4) M) did not alter dopaminergic function in these cultures. The different mechanisms of action of these stimulants may explain the differences in neurotoxic potency of these compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

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

Nocturnal rhythm of growth hormone in Duchenne patients: effect of different doses of mazindol and/or cyproheptadine.

Human growth hormone (hGH) inhibition may be beneficial for Duchenne muscular dystrophy (DMD) patients and slow the rate of progression of the disease. The purpose of the present investigation was 1) to assess, before any therapeutic trial, the natural growth hormone (GH) rhythm during physiological sleep in DMD patients and in normal control boys of comparable age; 2) to evaluate the effect of different doses of two potential GH inhibitors on nocturnal GH secretion in DMD patients receiving mazindol (1-4 mg), cyproheptadine (4-8 mg), or both drugs. The results from the present investigation showed 1) wide variability in nocturnal GH secretion before medication; 2) no correlation between nocturnal GH concentration and height, age, bone age, L-dopa provocative test, or Tanner staging; and 3) no consistent effect on GH release after mazindol, cyproheptadine therapy, or combined therapy.

[Value of mazindol in Gélineau's disease. Apropos of 10 cases]. / Intérêt du mazindol dans la maladie de gélineau. A propos de 10 observations.

Ten narcoleptic patients were treated daily with Mazindol 2-6 mg for 42.2 months (31-63 months). The response was excellent on narcoleptic attacks in 6 and on cataplexy in 7 cases. However, the nocturnal sleep disturbance persisted unchanged. The improvement was poor in 1 case and inexistant in 1 subject. Minor side effects (dry mouth) occurred in 3 cases, and urinary retention obliged to stop the medication in 2 cases.

[Changes in meal patterns and endogenous chemical determinants related to food intake following intra-ventricle III infusion of mazindol].

To clarify suppressive effects of mazindol on food intake in rats, changes in body weight, meal patterns as well as 24-hr food intake, and endogenous chemical substances were investigated following the intra-ventricle III infusion of 0.03 mumole mazindol. Experiments were carried out under the condition of a 12: 12 light-dark cycle (light: 0800-2000 hr). Mazindol decreased food intake as well as body weight after a 12 hr starvation. Reduced food consumption was observed during 12 hr following the injection. Weight reduction, however, lasted over all 3-tested days. When food was available ad. lib., mazindol decreased meal size during the 4 hr after injection and prolonged postprandial intermeal interval during the 4 hr period starting 2 hr after the injection. The infusion of mazindol also produced relative hyperglycemia and decreased free fatty acids, which was not accompanied with hyperinsulinemia. These findings, together with other reports, indicates that mazindol, unlike amphetamine and fenfluramine, possesses inhibitory actions on the hypothalamic feeding center.

[Pharmacological action of mazindol on behaviors and metabolism].

To elucidate the mechanism of the action of mazindol, an anorectic drug, mazindol effects on behaviors of rats such as feeding, drinking and activities were examined. Mazindol (40 mg/100 g of diet) addition to the diet elicited the transient decrease in food and water intakes, and increases in Animex and running wheel activities compared to those behaviors seen before the mazindol addition. The mazindol addition essentially did not affect the circadian rhythms of the above behaviors. Continuous infusion of mazindol (1-10 ng/h) into the brain reduced the total food intake and increased the light period food intake. The strongest effect of mazindol on food intake was observed when it was infused into a site of median eminence which was 2 mm posterior to the suprachiasmatic nucleus of the hypothalamus. This fact suggests that the site of the anorectic action of mazindol might be located in this area. Since food efficiency (= body weight increase per day/food intake per day) reduced during the period of mazindol addition to the diet in the above experiment, metabolic alterations due to mazindol were examined in rats. The results suggest that mazindol administration enhances degradations of proteins and amino acids and increases gluconeogenesis in the liver.

[Mazindol effects on the salivary and gastric acid secretory mechanisms].

The effects of mazindol on the salivary secretion of dogs was investigated. Mazindol (2 mg/kg, i.v.) decreased the volume and pressure of salivary secretion induced by either chemical (carpronium) stimulation or electrical nerve stimulation. It also reduced spontaneous salivary secretion. Secretion velocity in the mazindol treated group was significantly less than in the physiological saline administered control group at 4 to 6 min after injection. Saline and mazindol produced no significance differences in Na+, Cl- or K+ concentrations in the saliva or serum. Thus mazindol inhibition of salivary secretion was not caused by ion transport. The existence of some other inhibitory mechanism is suggested. The effects of mazindol on the peripheral and central control of gastric acid secretion was also investigated in rats. Gastric acid secretion induced by direct application of cholinergic agents on oxyntic cells was not affected by mazindol. Gastric acid secretion induced by insulin and/or 2-DG, on the other hand, was markedly inhibited by intra-hypothalamic injection or systemic (i.v.) injections of mazindol. Electro-osmotic mazindol mimicked the effects of glucose in the lateral (inhibition) and ventromedial (excitation) hypothalamus. The results suggest that the inhibitory effects of mazindol on salivary secretion may be through the hypothalamic feeding control centers. Mazindol also directly affected gastric acid secretory neurons in the lateral hypothalamus. It might thus be expected to be effective in the treatment of obesity.