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1.
Acta Pharm ; 71(2): 279-291, 2021 Jun 01.
Article in English | MEDLINE | ID: mdl-33151165

ABSTRACT

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.


Subject(s)
Appetite Depressants/pharmacology , Mazindol/pharmacology , Metformin/pharmacology , Administration, Oral , Animals , Appetite Depressants/administration & dosage , Appetite Depressants/toxicity , Dose-Response Relationship, Drug , Drug Therapy, Combination , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/toxicity , Male , Maze Learning/drug effects , Mazindol/administration & dosage , Mazindol/toxicity , Metformin/administration & dosage , Metformin/toxicity , Rats , Rats, Wistar
2.
Drug Alcohol Depend ; 26(1): 9-17, 1990 Aug.
Article in English | MEDLINE | ID: mdl-2120023

ABSTRACT

The substitution of either bromazepam, diazepam, methaqualone, mazindol, nortriptyline or bupropion for pentobarbital, in dependent rats, was assessed using a continuous drug infusion method. Male, Sprague-Dawley rats were made dependent on pentobarbital during 12 days of continuous, intraperitoneal, pentobarbital infusion. On Day 13, pentobarbital was replaced with either saline, vehicle, or one of the drugs of interest and rats were infused for 24 h. On Day 14, all rats were infused, for 24 h, with saline. Changes in both body weight and behavioral indices of withdrawal were assessed during Day 13 and 14. It was observed that bromazepam and methaqualone substituted for pentobarbital in a dose-dependent fashion. Diazepam also substituted in pentobarbital dependent rats but, inexplicably, the low dose of diazepam provided better substitution than did the higher dose. On the other hand, neither mazindol or nortriptyline substituted for pentobarbital and there was a tendency for exacerbation of the withdrawal signs. Finally, it was noted that the low dose of bupropion appeared to decrease the severity of the withdrawal symptoms. The data supports the view that the substitution of compounds for pentobarbital, in dependent rats, is limited to those compounds which, presumably, possess similar mechanisms of action in the CNS.


Subject(s)
Arousal/drug effects , Phenobarbital , Psychotropic Drugs , Substance Withdrawal Syndrome/physiopathology , Substance-Related Disorders/physiopathology , Animals , Antidepressive Agents/toxicity , Body Weight/drug effects , Brain/drug effects , Bromazepam/toxicity , Bupropion , Diazepam/toxicity , Dose-Response Relationship, Drug , Male , Mazindol/toxicity , Methaqualone/toxicity , Motor Activity/drug effects , Nortriptyline/toxicity , Phenobarbital/toxicity , Propiophenones/toxicity , Psychotropic Drugs/toxicity , Rats , Rats, Inbred Strains
3.
Toxicol Lett ; 81(2-3): 101-5, 1995 Nov 15.
Article in English | MEDLINE | ID: mdl-8553363

ABSTRACT

Mazindol (5-hydroxy-5-p-chlorophenyl-2,3-dihydro-5H-imidazo-2,1-a-isoindole) although not chemically related to the phenylethylamine group, shows a pharmacological profile similar to that of amphetamines. In rats these anorectic drugs enhance dopamine (DA) turnover, which is the mechanism that causes anorexia. It has been hypothesized that amphetamine causes a long-lasting depletion of DA, a decrease of dopaminergic transport pumps and nerve terminal degeneration increasing. These actions provide a cellular environment encouraging the autoxidation of DA that may lead to lipid peroxidation and neuronal damage. Considering that both drugs may cause neuronal damage by oxidative mechanisms, this study was conducted to investigate the action of mazindol and methamphetamine on brain cell antioxidant defense system and to investigate whether animal age is important in the antioxidant response to chronic anorectic administration. The activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), as well as the total glutathione (GSH) content in brains of rats, were measured. The animals (2 groups with 5 and 18 months old) were treated for 5 months (i.p.) with mazindol (10 mg/kg body weight/day), methamphetamine (2.5 mg/kg body weight/day) or saline. The results obtained showed no differences between SOD, CAT, GPx activities and GSH content in the brain of animals treated with saline compared with both drugs, either in 10-month or 23-month groups. On the other hand, brain total GSH content of old animals was found to be lower than that from young ones, independent of the treatment. SOD activity was found to be increased, CAT unchanged and GPx decreased, in the brain of old animals, treated with both drugs or saline. These findings led us to conclude that the chronic administration of mazindol and methamphetamine have no effects on the antioxidant systems studied either in young (10 months) or in old (23 months) rats.


Subject(s)
Antioxidants/metabolism , Appetite Depressants/toxicity , Brain/drug effects , Brain/metabolism , Mazindol/toxicity , Methamphetamine/toxicity , Aging , Animals , Brain/enzymology , Catalase/metabolism , Dopamine Uptake Inhibitors/toxicity , Glutathione/metabolism , Glutathione Peroxidase/metabolism , Male , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism , Superoxide Dismutase/metabolism
4.
J Neurochem ; 60(4): 1444-52, 1993 Apr.
Article in English | MEDLINE | ID: mdl-8095976

ABSTRACT

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)


Subject(s)
Cocaine/toxicity , Mazindol/toxicity , Mesencephalon/drug effects , Methamphetamine/toxicity , Neurons/drug effects , Animals , Binding, Competitive , Cells, Cultured , Cocaine/administration & dosage , Cocaine/pharmacology , Dopamine/metabolism , Immunohistochemistry , L-Lactate Dehydrogenase/metabolism , Mazindol/administration & dosage , Mazindol/pharmacology , Mesencephalon/embryology , Methamphetamine/administration & dosage , Methamphetamine/pharmacology , Neurons/metabolism , Neurons/ultrastructure , Phosphopyruvate Hydratase/analysis , Rats , Tyrosine 3-Monooxygenase/analysis
5.
Arch Int Pharmacodyn Ther ; 214(2): 285-307, 1975 Apr.
Article in English | MEDLINE | ID: mdl-1171662

ABSTRACT

5-Hydroxy-5-(4'-chlorophenyl-2, 3-dihydro-5H-imidazo (2, 1-a)isoindole (mazindol), a novel tricyclic compound, has been shown to suppress food consumption in rats at doses causing weak central stimulation and little effects on blood pressure or heart rate. The substance produces dose-related decreases in the consumption of orange juice in cebus monkeys trained on an operant behavior schedule. The compound did not alter cardiac or pulmonary hemodynamics in the anesthetized dog but provided potentiation of norepinephrine pressor responses. Mazindol also demonstrated potent but incomplete antagonism of reserpine-induced hypothermia in mice, antagonism of tetrabenazine catalepsy in rats, and suppression of mouse-killing behavior of rats. Suppression of mouse-killing was reduced by lesions placed in the septal area of the brain. Brain monoamine oxidase or catechol-o-methyl-transferase activities were not altered, although preliminary experiments showed that mazindol reduced uptake of norepinephrine in brain tissue.


Subject(s)
Appetite Depressants/pharmacology , Indoles/pharmacology , Mazindol/pharmacology , Aggression/drug effects , Animals , Blood Glucose , Body Temperature/drug effects , Brain Chemistry/drug effects , Catalepsy/chemically induced , Dogs , Drug Interactions , Feeding Behavior/drug effects , Female , Guinea Pigs , Hemodynamics/drug effects , Humans , In Vitro Techniques , Lipid Metabolism , Male , Mazindol/toxicity , Mice , Monoamine Oxidase Inhibitors/pharmacology , Motor Activity/drug effects , Rats , Reserpine/pharmacology , Tetrabenazine/pharmacology , Vas Deferens/drug effects
7.
Folha méd ; 110(1): 115-8, jan.-fev. 1995. ilus, tab
Article in Portuguese | LILACS | ID: lil-154035

ABSTRACT

Os efeitos da administraçäo crônica do mazindol (5 e 10 mg/kg i.p. e 60 mg/kg s.c) sobre a evoluçäo ponderal e a atividade da tirosina hidroxilase cerebral foram determinados em ratos machos jovens e idosos. O potencial anorético da droga foi observado através da avaliaçäo comparativa do peso corporal dos animais. A atividade da tirosina hidroxilase no estriato foi utilizada como parâmetro indireto da possível neurotoxicidade do mazindol. Nos ratos jovens notou-se uma perda significativa de peso aos 15 dias de tratamento, com recuperaçäo ascendente deste ao longo do tempo. Nos ratos idosos houve também perda de peso significativa; no entanto, tal recuperaçäo näo foi observada. Näo foram detectadas alteraçöes significativas da atividade enzimática em relaçäo aos grupos controles para ambas as idades. Estes resultados säo analisados a partir de dados encontrados na literatura


Subject(s)
Animals , Male , Rats , Corpus Striatum/drug effects , Mazindol/toxicity , Cerebrum/drug effects , Methamphetamine/toxicity , Rats, Inbred Strains , Nerve Endings , Tyrosine 3-Monooxygenase/analysis , Weight Loss/drug effects
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