Impact of timing of the anorexigen sibutramine administration on reproductive end-points of male rats.

Sibutramine is a non-selective serotonin-norepinephrine reuptake inhibitor orally administered for weight loss. In a previous study, we showed pharmacological mechanisms involved in the reduction of sperm quality and fertility of rats exposed for 30 days to this anorexigen in the light phase of the light-dark (l/d) cycle. It is already known that rodents are nightlife animals, with higher metabolic activity during the dark phase than in the light phase of the light-dark (l/d) cycle. Thus, the present study aimed to investigate whether the deleterious effects on reproductive parameters after sibutramine administration would be enhanced after a shorter period of exposure during the dark phase of the l/d cycle. For this, adult male Wistar rats were treated with sibutramine (10 mg/kg/d) or vehicle for 15 days during the dark phase of the l/d cycle. Sibutramine treatment decreased final body and reproductive organ weights, as well as serum testosterone levels. Sperm transit time through the epididymis was accelerated, and sperm concentration and motility were diminished in the sibutramine-exposed rats. The decrease in sperm concentration was also verified in the epididymal histological sections. In conclusion, the deleterious effects of sibutramine on reproductive parameters of male rats were enhanced when the exposure occurred in the dark phase of the l/d cycle, even after a short exposure duration. Our results reinforce the impact of timing on drug therapeutic action.

Omega-3 fatty acids and mood stabilizers alter behavioral and oxidative stress parameters in animals subjected to fenproporex administration.

Studies have shown that oxidative stress is involved in the pathophysiology of bipolar disorder (BD). It is suggested that omega-3 (ω3) fatty acids are fundamental to maintaining the functional integrity of the central nervous system. The animal model used in this study displayed fenproporex-induced hyperactivity, a symptom similar to manic BD. Our results showed that the administration of fenproporex, in the prevent treatment protocol, increased lipid peroxidation in the prefrontal cortex (143%), hippocampus (58%) and striatum (181%), and ω3 fatty acids alone prevented this change in the prefrontal cortex and hippocampus, whereas the co-administration of ω3 fatty acids with VPA prevented the lipoperoxidation in all analyzed brain areas, and the co-administration of ω3 fatty acids with Li prevented this increase only in the prefrontal cortex and striatum. Moreover, superoxide dismutase (SOD) activity was decreased in the striatum (54%) in the prevention treatment, and the administration of ω3 fatty acids alone or in combination with Li and VPA partially prevented this inhibition. On the other hand, in the reversal treatment protocol, the administration of fenproporex increased carbonyl content in the prefrontal cortex (25%), hippocampus (114%) and striatum (91%), and in prefrontal coxter the administration of ω3 fatty acids alone or in combination with Li and VPA reversed this change, whereas in the hippocampus and striatum only ω3 fatty acids alone or in combination with VPA reversed this effect. Additionally, the administration of fenproporex resulted in a marked increase of TBARS in the hippocampus and striatum, and ω3 fatty acids alone or in combination with Li and VPA reversed this change. Finally, fenproporex administration decreased SOD activity in the prefrontal cortex (85%), hippocampus (52%) and striatum (76%), and the ω3 fatty acids in combination with VPA reversed this change in the prefrontal cortex and striatum, while the co-administration of ω3 fatty acids with Li reversed this inhibition in the hippocampus and striatum. In conclusion, our results support other studies showing the importance of ω3 fatty acids in the brain and the potential for these fatty acids to aid in the treatment of BD.

Evaluation of the toxic activity of anorectic diethylpropion in Chinese hamster ovary cells.

Diethylpropion has been available in the market for treating obesity for over 50 years. Refined studies are lacking to fully elucidate its action spectrum. The aim of our study was to evaluate possible toxic effects of anorectic diethylpropion in Chinese hamster ovary (CHO) cells. Comet assay (detects breaks in the DNA strand), micronucleus test (detects clastogenic/aneugenic damage), and cell survival test (detects cytotoxic damage) were used to evaluate the toxic effects. In comet assay, we found that the damage scores with diethylpropion treatments at the concentrations of 20 and 40 µg/mL were more significant ( p < 0.05) than that of the negative control. When assessing the possible aneugenic and/or clastogenic damage caused by the drug in CHO cells, we found no difference ( p > 0.05) in the values of micronucleated cells when comparing different diethylpropion treatments and the negative control. Regarding the cell viability, for all the diethylpropion concentrations tested, higher values ( p < 0.05) of apoptosis were found compared with those of the negative control. In relation to the number of necrotic cells, no difference ( p > 0.05) was noted between the means of the three concentrations of diethylpropion evaluated and the negative control. In the experimental conditions, we conclude that diethylpropion has weak genotoxic and cytotoxic activities.

Can Spirulina maxima reduce the mutagenic potential of sibutramine?

The worldwide obesity pandemic requires the use of anti-obesity drugs. Sibutramine is an anti-obesity drug that has been used worldwide but is indiscriminately consumed in Brazil. Several studies have demonstrated that sibutramine promotes weight loss and weight maintenance, but several side effects have been associated with its systematic consumption. For this reason, sibutramine was withdrawn from the European and American markets, but still remains legal for use in Brazil. Studies have shown that a 5-10% reduction in body weight results in outstanding health benefits for obese patients. However, in order to promote significant weight loss, it is necessary to use sibutramine for at least 2 years. This long-term exposure has carcinogenic potential, as sibutramine causes DNA damage. Thus, this study evaluated the in vivo mutagenic potential of sibutramine alone (5, 7, 10, 15, and 20 mg/kg) and in association with Spirulina maxima (150 and 300 mg/kg), a cyanobacterium with antioxidant potential, using the polychromatic erythrocyte micronucleus test. Our results reinforced the mutagenic potential of sibutramine alone, which showed a time-dependent action. Combinatory treatments with S. maxima were not able to reduce the genotoxicity of sibutramine. These results were confirmed in vitro with the cytokinesis-blocked micronucleus test. In conclusion, our data showed that new alternative anti-obesity treatments are needed since the consumption of sibutramine can increase the risk of cancer in overweight patients.

O uso de complexos emagrecedores por mulheres em idade reprodutiva e suas implicações na gravidez / The use of complexes to treat the obesityby women in reproductive age and its implications on gestation

Os padrões atuais de beleza têm estimulado o uso de complexos emagrecedores, principalmente por mulheres em idade reprodutiva. Como uma grande parte das gestações não é planejada, esta conduta pode resultar em dano para o embrião/feto. Este trabalho analisa os efeitos dos componentes dessas formulações na gravidez. Foi feita uma revisão da literatura, consultando a bibliografia da área e os bancos de dados PubMed, MedLine, ScienceDirect e Micromedex. Os complexos emagrecedores contêm estimulantes do sistema nervoso central- os anorexígenos (derivados da anfetamina, como femproporex) e os antidepressivos (fluoxetina); depressores do sistema nervoso central (benzodiazepínicos); diuréticos, e produtos de origem vegetal. Os fármacos derivados da anfetamina não devem ser teratogênícos, mas o femproporex demonstrou efeitos adversos na implantação. Já fluoxetina promove a síndrome de abstinência neonatal, enquanto o diazepam pode causar fendas orais, baixo peso ao nascer e mudanças neurocomportamentais. Diuréticos, como furosemida, provocaram anomalias esqueléticas em ratos pela depleção de potássio, e o hidroclorotiazida causa complicações na mãe e no feto. Atualmente, há poucos estudos sobre a segurança no uso das plantas medicinais. Por causa dos diversos efeitos sobre o embrião/feto, as mulheres que fazem uso de complexos emagrecedores devem ser alertadas para os riscos em caso de concepção.

Developmental exposure to fenproporex: reproductive and morphological evaluation.

This study was designed to evaluate the maternal toxicity and teratogenicity of fenproporex, one of the most widely-used anorectic drugs in many countries, including Brazil. Three periods of exposure were evaluated: (a) 30 days before mating; (b) from gestational day (GD) 0 to 14; and (c) 30 days before mating and during pregnancy, until GD 14. Female mice from experimental groups received, by gavage, 15 mg/kg of fenproporex. Treatment with fenproporex increased ambulation of dams in the open-field test and did not influence the mobility in the forced-swimming test. There was no significant difference in maternal weight gain between the controls and fenproporex-treated groups, although fenproporex treatment reduced the gravid uterus weight. No significant difference was observed in postimplantation loss, fetal viability and sex ratio. In addition, this compound did not impair intra-uterine growth. The reduction in the number of implantations in the groups receiving fenproporex indicates that this drug may have an adverse effect on implantation. Fenproporex treatment also increased the number of fetuses presenting small kidneys and cervical ribs. The present results indicate that fenproporex, in the dose and exposure periods tested, appears to exhibit a low maternal toxicity and teratogenic potential in mice.

Behavioral neurotoxicity in adolescent and adult mice exposed to fenproporex during pregnancy.

We investigated the effects of gestational exposure to fenproporex, one of the most used anorectic drugs in Brazil, on the behavior of adolescent and adult pups (30 and 60 days of age, respectively). Pregnant Swiss mice were treated daily, by gavage, with 15 mg/kg of fenproporex chloride or water during the whole gestational period. Male pups were submitted to open-field, forced swimming test, tail suspension test and fenproporex-induced stereotyped behavior. The results demonstrated that gestational exposure to fenproporex induces antidepressant-like effect and decreases fenproporex-induced stereotyped behavior in both adolescent and adult pups. Moreover, fenproporex-exposed adolescent pups tended (P= 0.06) to be more active than control pups. Our data show, for the first time, that gestational exposure to fenproporex leads to long-lasting behavioral toxicity in male mice characteristic of altered dopaminergic transmission.

Effects of diethylpropion treatment and withdrawal on aorta reactivity, endothelial factors and rat behavior.

Diethylpropion (DEP) is an amphetamine-like compound used as a coadjutant in the treatment of obesity and which presents toxicological importance as a drug of abuse. This drug causes important behavioral and cardiovascular complications; however, the vascular and behavioral alterations during DEP treatment and withdrawal, have not been determined. We evaluated the effects of DEP treatment and withdrawal on the rat aorta reactivity to noradrenaline, focusing on the endothelium, and the rat behavior during DEP treatment and withdrawal. DEP treatment caused a hyporreactivity to noradrenaline in aorta, reversible after 2 days of withdrawal and abolished by both the endothelium removal and the presence of L-NAME, but not by the presence of indomethacin. Furthermore, DEP treatment increased the general activity of rats. Contrarily, DEP withdrawal caused a decrease in the locomotor activity and an increase in grooming behavior, on the 2nd and 7th days after the interruption of the treatment, respectively. DEP treatment also caused an adaptive vascular response to noradrenaline that seems to be dependent on the increase in the endothelial nitric oxide system activity, but independent of prostaglandins synthesis. The data evidenced chronological differences in the adaptive responses of the vascular and central nervous systems induced by DEP treatment. Finally, a reversion of the adaptive response to DEP was observed in the vascular system during withdrawal, whereas a neuroadaptive process was still present in the central nervous system post-DEP. These findings advance on the understanding of the vascular and behavioral pathophysiological processes involved in the therapeutic and abusive uses of DEP.

Formulaçöes para emagrecimento: usos e abusos / Use and abuse of drug therapy in obesity

Este trabalho discute a questäo das formulaçöes para emagrecimento. Foi efetuado um levantamento das receitas recebidas por uma farmacológicas presentes nas fórmulas prescritas, sendo ainda discutidos os efeitos tóxicos provocados por essas associaçöes de alto risco. O estudo mostrou que as formulaçöes estudadas continham, em média, cinco componentes. As associaçöes medicamentosas eram, muitas vezes, duvidosas e, em alguns casos, os fármacos estavam presentes em dosagens extremamente altas que poderiam implicar no aparecimento de efeitos tóxicos e/ou na näo manifestaçäo do efeito terapêutico desejado.

Experimental toxicity of verbesina encelioides in sheep and isolation of galegine.

Verbesina encelioides is a widely distributed weed in Argentina. Although it has been suspected as poisonous, there seem to be no previous reports of its toxicity in this country. Its biological activity was evaluated through an experiment in sheep. Four 5-y-old sheep, averaging 33 kg in body weight, were given a single dose of 1.0, 3.2, 5.0 or 6.3 g of dried plant material (17.9% dry matter)/kg body weight orally in a water suspension. Forty-eight hours later, the animals given 5.0 g or 6.3 g showed dullness and lack of appetite. The higher dosed sheep became recumbent a few hours later and died 60 h after dosing without showing further signs. The other animals showed no signs. Necropsy of the dead sheep showed severe lesions in different organs: liver, kidneys, lungs, lymph nodes and digestive tract. Hydrothorax was also observed. The animal receiving 5.0 g/kg was sacrificed after 72 h to determine the degree of recovery or lesions. Microscopically, severe glomerulonephrosis and congestion in the liver, with cellular degeneration and fatty changes were observed. Additionally, hemorrhagic lymph nodes, and hemorrhagic and edematous lungs were noted. No gross nor microscopic lesions were found in the sheep receiving 5.0 g/kg. Mice injected ip with the chromatographic extract died in less than 15 min. Galegine was identified in the plant material. The minimum toxic dose of 5-6 g/kg indicates a high toxicity when compared to other poisonous plants of the southeastern area of Buenos Aires province, Argentina.

Chronic fenfluramine treatment of rats with different ages: effects on brain oxidative stress-related parameters.

Fenfluramine is an anorectic drug widely used for the regulation of food intake that presents some adverse effects at the central and peripheral levels. d-Fenfluramine, an isomer of dl-fenfluramine, is postulated to be more effective and to induce less side effects than the racemic compound. These drugs act preferentially on the serotonergic system. Some authors have suggested that fenfluramine causes a degeneration of serotonergic neurons. Alterations of the serotonergic system are also observed during the aging process, and in this case, a relationship with reactive oxygen species has been already established. In view of these data, the present study was conducted to investigate the relationship between fenfluramine and brain antioxidant defense system in mature and aged animals. Rats aged 4 and 17 months were chronically treated with dl-fenfluramine, d-fenfluramine, or saline. Brain activity of superoxide dismutase and glutathione peroxidase was significantly affected by aging. Catalase activity was altered by the treatment. Total glutathione content and chemiluminescence in the brains were also altered by aging. Glutathione levels were altered as a function of the interaction between age and treatment. These findings suggest that treatment with d- or dl-fenfluramine results in alteration of the anti-oxidant system that could be exacerbated when associated with the aging process.

Antioxidant defense in rat brain after chronic treatment with anorectic drugs.

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.

Epidemiologia do abuso de drogas em Belo Horizonte, MG, Brasil / Epidemiology of drug abuse in Belo Horizonte, MG, Brazil

Desde 1980, o autor é Diretor de um Centro de Orientaçäo sobre Drogas para o tratamento de usuários de tóxicos. Em cerca de dois anos e meio de trabalho em serviço ambulatorial, o Centro atendeu 370 usuários de drogas com a participaçäo de uma equipe multi-disciplinar formada por psiquiatras, psicólogos, assistentes sociais e terapeutas ocupacionais. A droga mais abusada foi a maconha, seguida por dois medicamentos dispensados de receita médica nas farmácias: o analgésico Optalidon (Sandoz) e um xarope contra a tosse, o Pambenyl (Parke-Davis). As outras drogas foram, pela ordem de frequência: álcool (bebidas), solventes voláteis (cola de sapateiro, de aeromodelismo, lança-perfume, limpa-tipos), chá de cogumelo, moderadores do apetite, dextropropoxifeno (Algafan), Fiorinal e cocaína. A maioria dos pacientes é formada por poli-usuários (mais ou menos 60 por cento) e a maior proporçäo jovens (78,6 por cento). O autor discute o problema do abuso dos medicamentos vendidos sem receita médica e salienta as consequências principais do abuso de drogas: perda do trabalho e queda do rendimento escolar.