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1 Ciclazindol, like mazindol, produced a significant concentration-dependent increase in glucose-uptake into human skeletal muscle in both the presence and absence of insulin. 2 Methysergide, which inhibits the action of fenfluramine on glucose-uptake into skeletal muscle, did not influence the effect of mazindol.
Mazindol is chemically unrelated to the phenethylamines and has not shown the side-effects or abuse potential of the amphetamine anorectics. To further define its potential for causing weight loss, a six-week double-blind placebo controlled study was undertaken in four centres. A common protocol was used except in one centre, behavioural modification also was employed, whereas in the other centres, no additional measures were used to cause weight loss. Two hundred and forty-five obese patients were assigned randomly to two mazindol groups and one placebo group in each centre. Ninety-eight and forty patients receiving mazindol and placebo respectively completed the protocol. The conclusions were: (a) no significant clinical or laboratory abnormalities occurred from mazindol therapy, (b) the placebo therapy patients did not lose weight without behavioural modification, (c) the placebo therapy group had a higher drop-out rate compared to the mazindol therapy group attributable to the patients' dissatisfaction with failure to lose weight, (d) mazindol therapy without behavioural modification and behavioural modification alone both resulted in a statistically significant mean weight loss of 1 pound/patient/week and (e) mazindol plus behavioural modification resulted in a greater mean weight loss of 1/2 pound/patient/week than with behavioural modification alone. Hence, mazindol is of value in the initial therapy of obesity.
The effects of mazindol, amphetamine and fenfluramine on uptake and release of 3H-DA by synaptosomes were studied in different systems. In in vitro incubations of 3H-DA with synaptosomes isolated from the caudate nucleus of the rat, mazindol inhibited the uptake of the radioactivity more potently than did amphetamine. When the synaptosomes were isolated from the caudate nuclei of rats treated in vivo with either mazindol or amphetamine, the uptake of 3H-DA during in vitro incuation was lower with synaptosomes of amphetamine-treated rats than with those of mazindol-treated rats. When synaptosomes of untreated rats were prelabelled with 3H-DA and incubated in the presence of amphetamine or of mazindol, amphetamine caused a greater release of radioactivity than did mazindol. Fenfluramine was without activity in all these systems. In spite of the quantitative differences, both amphetamine and mazindol appear to have similar effects on uptake and release of dopamine, and this may account for their analogous pharmacological profile.
Mazindol was devoid of effect both on rat brain steady state levels of 5-HT, 5-HIAA and tryptophan and on the rate of synthesis of 5-HT in the rat brain. Mazindol had no effect on rat brain 5-HT uptake in vivo as determined by the effect of drug pretreatment on the ability of p-chloroamphetamine to lower central 5-HT levels. A large dose of mazindol caused a slight transient decrease in rat brain levels of NA and DA. Blockade of rat brain catecholamine uptake was quantified by studying drug effects on the ability of intraventricularly administered 6-hydroxydopamine to lower brain NA and DA content. Mazindol was an extremely potent inhibitor of rat brain NA uptake in vivo, being 4-5 times more potent than desipramine. Mazindol also blocked rat brain DA uptake. Doses of mazindol needed to release alpha-methyl-m-tyramine from the rat striatum were appreciably greater than the corresponding doses of d-amphetamine. The neurochemical profile of mazindol bears a much closer resemblance to that of d-amphetamine than to that of fenfluramine.
The effect of an imidazo-isoindole derivative (mazindol) upon motor and feeding activity and two different avoidance behaviours have been compared with those of d-amphetamine in rats. It was found that both drugs depress feeding activity in a dose-related manner and increase the motor activity of the animals. However, the ratio of the lowest motility-increasing dose and the lowest appetite suppressant dose is 0.5 for d-amphetamine and 2 for mazindol. Mazindol, like d-amphetamine, caused a stereotyped behaviour in rats when given in very high doses, but the range between the anorexic and the stereotyped behaviour dose is much higher for mazindol than for d-amphetamine. The shuttle-box avoidance behaviour suppressed by tetrabenazine is completely restored by d-amphetamine and partially by mazindol. Lever-pressing avoidance suppressed by tetrabenazine is restored by d-amphetamine while mazindol at the doses used is ineffective. It is concluded that mazindol could be an anorexic agent better suited than d-amphetamine for clinical use.
Mazindol, 5-hydroxy-5-(4'-chlorophenyl)-i, 3-dihydro-5H-imidazo-(2, 1-a) isoindole, has demonstrated anorexic activity and other pharmacological responses which suggest alterations in brain norepinephrine metabolism. Studies of the effects of mazindol on neuronal uptake and/or release of norepinephrine showed that mazindol, when given before cerebral intraventricular injection of 3-H-norepinephrine by a mechanism that increases 3-H-normetanephrine synthesis via catechol-O-methyl-transferase and provided no significant effect on deamination of the catecholamine. Studies designed to measure norepinephrine release showed that mazindol (in contrast to d-amphetamine) did not cause release of 3-H-norepinephrine from neuronal stores. Furthermore, mazindol did not inhibit norepinephrine synthesis, whereas d-amphetamine did. The effect of d-amphetamine on norepinephrine release and synthesis may be more important than effects on uptake of this catecholamine. In contrast, mazindol appears to produce its primary effect on norepinephrine metabolism by inhibition of neuronal uptake mechanism.
Mazindol, a drug with tricyclic structure unrelated to amphetamine and other anorectic drugs, has been used as an anorectic agent in a double blind clinical trial at a dose of 2 mg/day for 12 week (mazindol v. s. placebo), associated with a 1000 calorie diet on 46 obese diabetic patients. Thirty seven patients completed the trial with no significant difference between the two groups in the drop-out population; mazindol was well tolerated. In the mazindol-treated group the mean weight loss was 13.5 kg (22.3%) which was significantly greater (p less than 0.001) than in the placebo treated group where the mean weight loss was 4.2 kg (9.8%). Comparing the two groups after the 12 week trial, decrease in fasting blood glucose, serum insulin and triglycerides was not significant. In the mazindol-treated group a significant decrease of serum cholesterol, triglycerides and of the mean area under the curve of insulinemia during the OGTT has been observed. In the placebo treated group only serum triglycerides decreased significantly. The variations of plasma insulin and serum cholesterol were found to be correlated to the magnitude of weight loss. In conclusion mazindol is an effective drug for weight loss on the whole well tolerated but without specific properties on metabolism.
Mazindol and fenfluramine inhibited in vitro the uptake of 5-HT into rat forebrain synaptosomes, whether the synpatosomes were incubated in vitro with the drugs or obtained from animals pretreated in vitro. Chlorimipramine was also effective in this latter preparation. Dose-response relationships and time course of this effect for the various drugs were determined. Fenfluramine also caused release of 5-HT from preloaded synaptosomes in in vitro incubations. Mazindol did not. Brain 5-HT levels were measured after acute and chronic administration of mazindol, fenfluramine and chlorimipramine. Mazindol had no effect, fenfluramine was active in reducing brain 5-HT concentrations acutely and chlorimipramine only after chronic administration. Therefore, it seems that even a long lasting inhibition of the uptake, such as that induced by mazindol, is not sufficient, per se, to cause depletion of brain 5-HT.
Mazindol, a new anorexigenic agent which possesses a different chemical structure from phenylethylamine derivatives such as amphetamine, causes anorexia along with increases in locomotor activity and body temperature. Mazindol also induces stereotyped behaviour and, if injected into rats with unilateral nigro-striatal lesions, causes turning towards the lesioned side. Mazindol-induced anorexia is antagonized by pretreatment with alpha-methyl-p-tyrosine or pimozide. Pimozide pretreatment prevents the rotation induced by Mazindol in rats with unilateral nigro-striatal lesions. The involvement of dopamine in the mechanism whereby Mazindol elicits anorexia and turning behaviour is discussed.
Amobarbital, diazepam, prochlorperazine and thioridazine were tested alone and in combination with d-amphetamine or mazindol on food consumption and spontaneous motor activity in rats. Of the four depressants tested (1) only amobarbital enhanced the anorexic effects of d-amphetamine and (2) amobarbital, diazepam and prochlorperazine enhanced the hypermotility induced by d-amphetamine. None of the depressants altered the anorexic effect of mazindol but amobarbital and diazepam decreased and prochlorperazine increased the hypermotility induced by mazindol. These differential effects of the CNS depressants suggest that d-amphetamine and mazindol might have different mechanisms of anorexiant or stimulatory action. The data also suggest that, to achieve anorexia with diminished CNS stimulation, combinations of d-amphetamine and any of the tested CNS depressants seem to be precluded. In fact, this desired clinical objective might be achieved with combinations of mazindol and either amobarbital or diazepam.
The interaction of mazindol and d-amphetamine with brain monoamines was studied in rats. At each dose used, both compounds markedly counteracted the decrease of brain noradrenaline induced by 6-hydroxydopamine while only at high doses they did significantly reduce the effect of 6-hydroxydopamine on brain dopamine. Unlike d-amphetamine, mazindol significantly counteracted the decrease of brain serotonin induced by fenfluramine. The anorectic effect of mazindol and of d-amphetamine was markedly reduced by an electrolytic lesion at the level of the ventral noradrenergic bundle but not by an electrolytic lesion of the nucleus raphe medianus. An intrastriatal injection of 6-hydroxydopamine significantly reduced the effect of mazindol but not that of d-amphetamine. The results indicate that both compounds may block noradrenaline uptake in the brain while their effect on dopamine uptake is less evident. Ulike d-amphetamine, mazindol appears to inhibit serotonin uptake also. In addition, the integrity of the noradrenergic neurons in the brain appears to be an important condition for these drugs to exert their anorectic effect.
The effects of the anorexic and stimulant agents mazindol and dita on 3H-biogenic amine uptake and release were determined. Mazindol and dita were very potent inhibitors of 3H-norepinephrine uptake into rat brain occipital cortex slices with ED50 values (point of 50% inhibition of uptake) of 1.5 X 10(-9) M and 3.2 X 10(-9) M, respectively. Mazindol (ED50 of 2.8 X 10(-7) M) and dita (ED50 value of 8.5 X 10(-7) M) were also potent inhibitors of 3H-dopamine uptake into rat neostriatal slices and of 3H-serotonin uptake into whole brain slices (ED50 values of 5.5 X 10(-7) M and 5.1 X 10(-7) M for mazindol and dita respectively). Both compounds proved however to be extremely weak releasing agents for the 3H-biogenic amines in the respective brain areas. The effects of mazindol and dita on uptake may help to explain some of their pharmacological properties.
The effects of mazindol, a non-phenethylamine anorexic, were determined in pigeons key pecking under a multiple fixed-ratio 30 response, fixed-interval 5 min schedule of food presentation. The low average rates of responding under the fixed-interval schedule were greatly increased (from 0.7 response/sec to 2 responses/sec) at doses from 0.1 to 10 mg/kg. The higher rates of responding under the fixed-ratio schedule were only decreased by increasing doses of mazindol. Throughout the fixed interval, mazindol tended to produce a constant rate of responding completely disrupting the normal, positively accelerated pattern of responding. These rate-increasing effects of mazindol were much greater than those of phenethylamines tested under similar conditions. The large increases in rates of responding under the fixed-interval component were discussed in terms of the known biochemical effects of mazindol.
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.
Thirty-eight obese patients, resistant to conventional diet therapy, agreed to consume a 1.09 MJ (260 kcal)/day semi-synthetic diet consisting of 25 g egg albumin, 40 g oligosaccharides, vitamins and minerals, and were seen weekly as outpatients for eight weeks. At the beginning, the semi-synthetic diet was given with either the anorectic drug, mazindol (2 mg/day) or a placebo for four weeks and then changed over for the remaining four weeks; the study being conducted on a double-blind basis. The final treatment was a 4.2 MJ (1000 KCAL) conventional diet for a further four weeks without drug or placebo. Twenty-five patients completed the first eight weeks and 21 patients the final four weeks of the trial. The total mean weight losses were as follows: week 4, 9.3 kg; week 8, 13.7 kg; week 12, 12.2 kg. There was no significant difference in weight loss between mazindol treatment and placebo but the former group reported feeling less hungry. The chief side-effects observed were dizziness, nausea, dry mouth, insomnia and depression which were more frequent with mazindol. Six patients had to stop mazindol because of side-effects, but were able to continue the diet alone. It is concluded that a semi-synthetic diet containing 1.09 MJ (260 kcal) daily can be successfully employed in the treatment of obese outpatients, and is a practical therapeutic alternative to admission to hospital. There is no clinical advantage to be gained by the additional use of the anorectic drug, mazindol.
1 Anorexia in rats following injections of mazindol (0.1-8 mg/kg i.p.) could be antagonized by pretreatment with a dopamine receptor blocker (primozide) but not by pretreatment with an alpha-adrenoceptor blocker (phenoxybenzamine), a beta-adrenoceptor blocker ((-)-propranolol), or a 5-hydroxytryptamine receptor blocker (methergoline). 2 In rats with a unilateral lesion in the substantia nigra made by stereotaxic injection of 6-hydroxydopamine, mazindol caused a dose-dependent turning towards the lesioned side, indicating an indirect mechanism of action. This effect could be antagonized by pretreatment with a dopamine receptor blocker. 3 In rats pretreated with reserpine and alpha-methyl-p-tyrosine, mazindol did not have any motor stimulant action. 4 In vitro studies with synaptosomes prepared from rat brain, indicated that mazindol blocks uptake and causes release of dopamine. 5 It is concluded that the anorectic action of mazindol is mediated by a dopaminergic mechanism.
Mazindol, an anorexic drug, caused a large increase in brain 3, 4-dihydroxyphenylacetic acid (DOPAC) concentration in spiperone-pretreated rats. The increase was dose-related over a 1--10 mg/kg dose range of mazindol and was maximum within 1 hour after maxzindol injection into rats pretreated 1 hour previously with spiperone. In spiperone-pretreated rats, mazindol accelerated the disappearance of dopamine after the inhibition of dopamine synthesis by alpha-methyltyrosine. Mazindol apparently resembles amfonelic acid, methylphenidate, and cocaine in facilitating the impulse-mediated release of dopamine.
Mazindol induced a dose-related inhibition of the uptake of labelled 5-hydroxytryptamine (5-HT) by guinea pig blood platelets. It was more potent than d-fenfluramine. Mazindol and d-fenfluramine decreased 5-hydroxy-indoleacetic acid formation in intact platelets but not in sonicated ones. The inhibitory effects of both drugs appeared to the competitive in nature and were markedly reduced in platelets suspended in plasma instead of in Tyrode solution. Mazindol neither decreased the stored endogenous 5-HT nor caused efflux of the labelled amine from preloaded platelets, whereas d-fenfluramine induced a significant release of the amine. It is concluded that mazindol, like d-fenfluramine, competes with 5-HT for the same transport mechanisms at the cytoplasmic membrane level but this effect is not accompanied, as is the case with d-fenfluramine, by a concomitant release of the amine.