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European Journal of Pharmacology Jul 1997The antinociceptive potential of mazindol, an anorectic drug, and lidocaine, an amide-type local anesthetic, were investigated in the mouse formalin test with concurrent...
The antinociceptive potential of mazindol, an anorectic drug, and lidocaine, an amide-type local anesthetic, were investigated in the mouse formalin test with concurrent motor function assessment. In addition, the role of dopamine and opioid receptors in mediation of the antinociceptive action of these drugs was examined. The i.p. injection of mazindol (1.25-10 mg/kg) and lidocaine (10-30 mg/kg) induced significant antinociceptive responses in both phases of the test. Cocaine (20 mg/kg, i.p.), used as positive control, also inhibited the pain responses caused by formalin. Haloperidol (0.2 mg/kg, i.p.), and sulpiride (5 mg/kg, i.p.), a dopamine D2 receptor antagonist, reduced the antinociceptive actions of mazindol and cocaine, while SCH 23390, R(+)-7-chloro 8-hydroxy-3methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3 benzazepine (0.03 mg/kg, i.p.), a dopamine D1 receptor antagonist, did not affect these responses. Only the antinociception associated with mazindol was reversed by naloxone (2 mg/kg, i.p.). The same pretreatments failed to modify lidocaine-induced antinociception. The drug conditions used in this study did not reveal any motor impairment in the rotarod test. These observations suggest an involvement of dopaminergic mechanisms, mainly via dopamine D2 receptors, in the antinociceptive action of mazindol in the formalin test, but the nature of mechanisms involved in the lidocaine responses remains unsolved.
Topics: Anesthetics, Local; Animals; Benzazepines; Cocaine; Dopamine Antagonists; Dopamine Uptake Inhibitors; Drug Interactions; Haloperidol; Lidocaine; Male; Mazindol; Mice; Naloxone; Narcotic Antagonists; Nociceptors; Pain Measurement; Receptors, Dopamine; Receptors, Opioid
PubMed: 9253942
DOI: 10.1016/s0014-2999(97)00182-9 -
Naunyn-Schmiedeberg's Archives of... Jul 2004The norepinephrine transporter (NET) is the carrier that drives the neuronal norepinephrine uptake mechanism (uptake1) in mammalian hearts. The radioligand [3H]mazindol... (Comparative Study)
Comparative Study
The norepinephrine transporter (NET) is the carrier that drives the neuronal norepinephrine uptake mechanism (uptake1) in mammalian hearts. The radioligand [3H]mazindol binds with high affinity to NET. In this study, the kinetics of [3H]mazindol binding to NET were measured using a rat heart membrane preparation. Results from these studies were used to set up saturation binding assays designed to measure cardiac NET densities (Bmax) and competitive inhibition assays designed to measure inhibitor binding affinities (KI) for NET. Saturation binding assays measured NET densities in rat, rabbit, and canine hearts. Assay reproducibility was assessed and the effect of NaCl concentration on [3H]mazindol binding to NET was studied using membranes from rat and canine hearts. Specificity of [3H]mazindol binding to NET was determined in experiments in which the neurotoxin 6-hydroxydopamine (6-OHDA) was used to selectively destroy cardiac sympathetic nerve terminals in rats. Competitive inhibition studies measured KI values for several NET inhibitors and substrates. In kinetic studies using rat heart membranes, [3H]mazindol exhibited a dissociation rate constant koff=0.0123+/-0.0007 min(-1) and an association rate constant kon=0.0249+/-0.0019 nM(-1)min(-1). In saturation binding assays, [3H]mazindol binding was monophasic and saturable in all cases. Increasing the concentration of NaCl in the assay buffer increased binding affinity significantly, while only modestly increasing Bmax. Injections of 6-OHDA in rats decreased measured cardiac NET Bmax values in a dose-dependent manner, verifying that [3H]mazindol binds specifically to NET from sympathetic nerve terminals. Competitive inhibition studies provided NET inhibitor and substrate KI values consistent with previously reported values. These studies demonstrate the high selectivity of [3H]mazindol binding for the norepinephrine transporter in membrane preparations from mammalian hearts.
Topics: Animals; Binding, Competitive; Dogs; Dose-Response Relationship, Drug; Heart Rate; Hydroxydopamines; Kinetics; Mazindol; Methods; Myocardium; Norepinephrine Plasma Membrane Transport Proteins; Rabbits; Radioligand Assay; Rats; Rats, Sprague-Dawley; Sodium Chloride; Species Specificity; Symporters; Tritium
PubMed: 15300361
DOI: 10.1007/s00210-004-0949-y -
Biological Psychiatry Jun 1992
Topics: Adult; Cocaine; Humans; Male; Mazindol; Schizophrenia; Substance-Related Disorders
PubMed: 1525287
DOI: 10.1016/0006-3223(92)90171-u -
Endocrine Journal Dec 1996The 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...
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.
Topics: Adult; Aged; Appetite Depressants; Blood Glucose; Body Mass Index; Body Weight; Diet, Reducing; Energy Intake; Female; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Insulin; Mazindol; Middle Aged; Obesity, Morbid
PubMed: 9075607
DOI: 10.1507/endocrj.43.671 -
Acta Neuropsychiatrica Jun 2014Mazindol is a sympathomimetic amine, widely used as an anorectic agent in the treatment of obesity. This drug causes psychostimulant effects because of its...
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.
Topics: Animals; Brain; Central Nervous System Stimulants; Energy Metabolism; Male; Mazindol; Mice; Obesity
PubMed: 25142190
DOI: 10.1017/neu.2013.43 -
Deutsche Medizinische Wochenschrift... Aug 1990
Comparative Study Review
Topics: Adolescent; Adult; Amphetamine; Cataplexy; Child; Clomipramine; Diagnosis, Differential; Female; Humans; Imipramine; Male; Mazindol; Methylphenidate; Narcolepsy; Phenmetrazine
PubMed: 2201510
DOI: 10.1055/s-2008-1065149 -
The Journal of International Medical... 1975Fifty 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... (Clinical Trial)
Clinical Trial Comparative Study
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.
Topics: Adult; Diethylpropion; Female; Humans; Male; Mazindol; Middle Aged; Obesity; Weight Loss
PubMed: 162676
DOI: 10.1177/030006057500300310 -
Addictive Behaviors 1979
Clinical Trial Randomized Controlled Trial
Topics: Adult; Body Weight; Double-Blind Method; Eating; Female; Humans; Indoles; Male; Mazindol; Obesity
PubMed: 495247
DOI: 10.1016/0306-4603(79)90033-9 -
Physiology & Behavior Jan 1991Brain microdialysis was used to determine if lateral hypothalamic serotonin (5-HT) is involved in the mazindol-induced anorexia in rats. Direct application of mazindol...
Brain microdialysis was used to determine if lateral hypothalamic serotonin (5-HT) is involved in the mazindol-induced anorexia in rats. Direct application of mazindol through a microdialysis membrane both significantly increased the 5-HT levels in the lateral hypothalamus and suppressed food intake by fasted rats. The increase in 5-HT concentration was dose related and the concentration of mazindol for half-maximal response was 4.6 microM. Pretreatment with methysergide, a potent 5-HT receptor-blocking agent, significantly antagonized the mazindol-induced anorexia. These results suggest that the anorectic action of mazindol might be mediated, at least in part, through serotonergic mechanisms in the hypothalamus.
Topics: Animals; Appetite; Circadian Rhythm; Dose-Response Relationship, Drug; Eating; Feeding Behavior; Hypothalamic Area, Lateral; Male; Mazindol; Methysergide; Rats; Rats, Inbred Strains; Serotonin
PubMed: 2017466
DOI: 10.1016/0031-9384(91)90243-h -
Naunyn-Schmiedeberg's Archives of... Dec 1989Biochemical and pharmacological studies suggest that the binding of [3H]mazindol is functionally related to the dopamine uptake carrier complex in rodent striatum. In... (Comparative Study)
Comparative Study
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.
Topics: Animals; Binding, Competitive; Buffers; Corpus Striatum; Dopamine; Female; In Vitro Techniques; Indoles; Kinetics; Male; Mazindol; Mice; Mice, Inbred BALB C
PubMed: 2615854
DOI: 10.1007/BF00717737