SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
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.
In the search for mechanisms supporting the weight-reducing effect of mazindol, we examined the influence of the drug on metabolism and gastric evacuation in two groups of 10 women each. In the first group the effect of mazindol on thermogenesis was assessed by indirect calorimetry, and blood glycerol concentration was taken as an index of lipolysis. After oral administration of 2 mg mazindol no significant changes were observed in the energy expenditure or lipolysis, either at rest or during exercise. In the second group, the influence of 2 mg mazindol, taken orally, on gastric emptying (GE) of a radiolabeled solid meal was examined with the use of a gamma camera. The drug significantly inhibited GE--the median GEt1/2 was 119 min after placebo vs. 230 min after mazindol. The mean +/- SE of the emptying index was 1.13 +/- 0.26 min-1 after placebo vs. 0.53 +/- 0.14 min-1 after mazindol. Mazindol elicited a delaying effect on the late phase of GE, as confirmed by a significant decrease of the shape parameter (S) of the power-exponential fitted GE curves, 2.09 +/- 0.22 after placebo vs. 1.61 +/- 0.24 after mazindol, and by the comparison of the amount of food emptied from the stomach: 30.7 +/- 6.1% after placebo vs. 17.8 +/- 4.0% after mazindol, at 80 min, and 38.9 +/- 6.2% after placebo vs. 20.6 +/- 4.3% after mazindol, at 90 min of the GE measurement.
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.
Mazindol is a potent inhibitor of neuronal dopamine (DA) and norepinephrine (NE) uptake. DA and NE uptake sites in rat brain have been differentially visualized using [3H]mazindol autoradiography. At appropriate concentrations, desipramine (DMI) selectively inhibits [3H]mazindol binding to NE uptake sites without significantly affecting binding to DA uptake sites. The localization of DMI-insensitive specific [3H] mazindol binding, reflecting DA uptake sites, is densest in the caudate-putamen, the nucleus accumbens, the olfactory tubercle, the subthalamic nucleus, the ventral tegmental area, the substantia nigra (SN) pars compacta, and the anterior olfactory nuclei. In contrast, the localization of DMI-sensitive specific [3H]mazindol binding, representing NE uptake sites, is densest in the locus coeruleus, the nucleus of the solitary tract, the bed nucleus of the stria terminalis, the paraventricular and periventricular nuclei of the hypothalamus, and the anteroventral thalamus. The distribution of DMI-insensitive specific [3H]mazindol binding closely parallels that of dopaminergic terminal and somatodendritic regions, while the distribution of DMI-sensitive specific [3H]mazindol binding correlates well with the regional localization of noradrenergic terminals and cell bodies. Injection of 6-hydroxydopamine, ibotenic acid, or colchicine into the SN decreases [3H]mazindol binding to DA uptake sites in the ipsilateral caudate-putamen by 85%. In contrast, ibotenic acid lesions of the caudate-putamen do not reduce [3H]mazindol binding to either the ipsilateral or contralateral caudate-putamen. Thus, the DA uptake sites in the caudate-putamen are located on the presynaptic terminals of dopaminergic axons originating from the SN.
The effects of intracerebroventricular administration of 6-hydroxydopamine (6-OHDA) and 5,7-dihydroxytryptamine (5,7-DHT) on sodium-sensitive [3H]mazindol binding were investigated in the rat hypothalamus and corpus striatum. In the hypothalamus, specific [3H]mazindol binding was inhibited by low concentrations of sodium and stimulated by high-sodium concentrations, whereas in the corpus striatum, only a sodium-dependent stimulation of [3H]mazindol binding was observed. Lesions with 6-OHDA significantly reduced sodium-dependent [3H]mazindol binding in the corpus striatum, but had no effect on the binding of [3H]mazindol in the absence of sodium. Lesions of serotonergic neurons with 5,7-DHT, however, had no effect on [3H]mazindol binding in the striatum, but resulted in a significant increase in the number of [3H]mazindol binding sites in the hypothalamus. These data suggest that [3H]mazindol may bind to two anatomically distinct binding sites, one that is stimulated and the other inhibited by sodium. The sodium-stimulated binding sites appear to be located on dopaminergic terminals in the striatum, and in the hypothalamus, the sodium-inhibited sites appear to be regulated by serotonergic neuronal activity.
In order to elucidate the mechanism of action of the anorectic drug, mazindol, effects of electrophoretically applied mazindol were examined on glucose-sensitive and non glucose-sensitive neurons in the rat lateral hypothalamic area (LHA), which is functionally important in food intake control. Mazindol was found to significantly suppress the firing rate of glucose-sensitive neurons. Ouabain a Na-K pump inhibitor, attenuated mazindol induced suppression of neuronal firing rate. Intracellular recordings revealed hyperpolarization of the membrane with no change in membrane conductance by perfusion of brain slice with 0.1 mM mazindol in bath. This was similar to the effect of 30 mM glucose. Results suggest that the inhibitory action of mazindol is mediated by activation of the Na-K pump. Spiroperidol, a dopamine antagonist, did not affect the inhibitory response to mazindol, suggesting direct action of mazindol on LHA neurons, independent of dopamine.
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.
Effects of mazindol on the contraction induced by nerve stimulation and agonist drugs were investigated to examine the inhibition of catecholamine uptake by mazindol in the vas deferens. Mazindol at 10(-9)-10(-7) M potentiated a single electrical pulse-elicited neurogenic contraction which consisted of a twitch and phasic contraction. This potentiation was almost completely antagonized by prazosin. Mazindol leftwardly shifted the dose-response curve to norepinephrine in a dose-dependent manner; the dose-ratio was 6.2-fold and 83.2-fold at 10(-9) M and 10(-7) M mazindol, respectively. The dose-response curves to dopamine and methacholine were also slightly shifted by mazindol. In the dibenamine-treated vas deferens, mazindol did not affect the dose-response curve to methacholine. These results suggest that mazindol potently inhibits the norepinephrine uptake without acting on the smooth muscle cells in the rat vas deferens.
The effect of mazindol on insulin and glucagon secretion was studied in ventromedial hypothalamic lesioned (VMH) obese rats with hyperinsulinemia and VMH sham rats. Three weeks after the VMH or sham operation, VMH and sham rats were divided into two groups: one was fed diet containing mazindol (50 mg/kg) and the other was fed diet without mazindol. They were housed three more weeks before the experiment. Mazindol reduced significantly body weight increase and calorie intake in VMH rats, but not in sham rats. In addition, the fasting plasma insulin level and the arginine-induced insulin secretion in VMH rats treated with mazindol were significantly lower than those in the VMH rats without treatment of mazindol. On the other hand, in both in vivo and in vitro experiments, mazindol produced no significant change in the insulin secretion of sham-operated rats. These results suggest that mazindol suppresses hypersecretion of insulin in VMH rats probably through an anorectic effect and/or suppression of vagal hyperactivity.
This study addressed the possibility of a unique binding interaction between cocaine and the dopamine transporter as compared with other blockers of dopamine uptake. Cocaine binding sites in a fresh P2 fraction of mouse striatum were labeled with [3H]CFT, a phenyltropane analog of cocaine also known as WIN 35,428, and compared with sites labeled with [3H]mazindol or [3H]GBR 12935. Under the conditions used, homogeneous binding was observed that was inhibited monophasically by cocaine, CFT, and mazindol; the same potencies were observed with the three radioligands. Saturation analysis in the presence and in the absence of unlabeled inhibitor (CFT, mazindol, cocaine) indicated a change in the Kd but not the Bmax, consonant with a competitive mechanisms. Tris-HCl reduced the affinity of each radioligand and unlabeled inhibitor without changing the Bmax. N-Ethylmaleimide reduced the binding of all radioligands equally and cocaine offered protection. The dissociation rate of [3H]CFT and [3H]mazindol binding was not affected by the presence of mazindol and CFT, respectively. The Bmax of [3H]CFT and [3H]mazindol binding was the same; the relatively higher value for [3H]GBR 12935 binding in analyses involving varying tritiated GBR 12935 only, was due primarily to an underestimation of the specific activity of [3H]GBR 12935. All results are in agreement with a one-site model in which cocaine, CFT, mazindol, and GBR 12935 share a common binding site in mouse striatum.
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.
Biochemical and pharmacological studies suggest that the binding of [3H]mazindol is functionally related to the dopamine uptake carrier complex in rodent striatum. In order to study further the relationship between the substrate recognition site for dopamine uptake and the high-affinity binding site for mazindol the uptake of [3H]dopamine and the binding of [3H]mazindol was studied in BALB/cBy mouse striatum in various buffers (Tris, HEPES, bicarbonate-phosphate). Kinetic analysis showed that the Kd of the binding of [3H]mazindol and the Km of the uptake of [3H]dopamine was changed by different sodium concentrations and/or by the presence of Tris, while the Bmax and the Vmax remained essentially the same. However, the shape of the Na+ dependency curves was not the same for mazindol binding and dopamine uptake in the various buffers. The inhibitory effect of other cations such as K+ and Tris was also different on binding and uptake under similar experimental circumstances. Dopamine did not slow down the dissociation of mazindol from its site and this effect was not sodium-sensitive. These complexities can be accommodated by a model that involves overlapping sites for mazindol and dopamine on the dopamine uptake carrier complex, and translocation-reorientation steps.
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.
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.
Effect of an anorexiant, mazindol, on glucose absorption was investigated. Ten weeks-old female Sprague-Dawley rats were divided into mazindol treated (fed on powder diet containing 100 mg/kg of mazindol) and control groups. Four weeks later, experiments of continuous observation of glucose absorption and glucose transport were performed in each group using the everted sac method. During 180 min of continuous observation of glucose absorption, significantly lowered glucose concentrations of the serosal medium were observed in the mazindol treated group at oral and caudal ends of the upper, caudal end of the middle, and caudal ends of the lower small intestine, whereas no significant differences in glucose concentrations of the mucosal medium were observed between the two groups. After 60 min incubation for monitoring the glucose transport, significantly decreased glucose concentrations of serosal medium were observed in mazindol treated group at oral and caudal ends of the upper, caudal ends of the middle and caudal ends of the lower small intestine, whereas no significant differences in glucose concentrations of mucosal medium were observed. The results suggested that there is little effect on glucose absorption, but the metabolism of glucose or the remaining glucose in the small intestinal wall is increased by mazindol treatment.
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.