Ivabradine possesses anticonvulsant and neuroprotective action in mice.

We analyzed whether ivabradine (IVA), a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, clinically used for angina and arrhythmia, had anticonvulsant, antioxidant and neuroprotective properties against classical seizure models. Potential molecular targets to IVA anticonvulsant effects were evaluated by molecular docking. Mice were treated with IVA (1, 10 or 20 mg/kg, IP) for 3 days, and 30 min after the last administration were injected with pentylenetetrazole (PTZ - 85 mg/kg, IP), pilocarpine (PILO 400 mg/kg, SC), picrotoxin (PICRO 10 mg/kg, IP). The following measures were performed: presence of seizures, latency for the first seizure, latency for death, percentage of survival. Antioxidant activity was investigated by determination of lipid peroxidation (MDA), reduced glutathione (GSH) and nitrite levels in the prefrontal cortex (PFC), hippocampus and striatum (ST). Immunohistochemistry analysis for cleaved caspase-3, a pro-apoptotic and degenerative marker, in hippocampal subregions namely cornu ammonis (CA)1, CA3 and dentate gyrus (DG), were also performed. IVA attenuated PTZ- and PICRO-induced seizures while presented an antioxidant effect in all brain areas studied. IVA markedly reduced cleaved caspase-3 expression in the CA1 and DG region of PICRO- and PTZ-treated mice, respectively. Molecular docking demonstrated that IVA has high energetic affinity and binding compatibility for GABAA receptor without causing channel obstruction. However, no reproducibility in the binding of IVA to N-methyl-d-aspartate (NMDA) receptor was detected. In conclusion, IVA has anticonvulsant, antioxidant and neuroprotective effects against PTZ- and PICRO-induced seizures. Also, a high affinity of IVA to GABAA receptor was predicted, representing a potential underlying mechanism to these observable effects.

Central effects of lipoic acid associated with paroxetine in mice.

Antidepressants, including selective serotonin reuptake inhibitors, are commonly prescribed for the treatment of affective disorders such as anxiety and depression. The purpose of this study was to investigate the central effects of acute administration of paroxetine (PXT) combined with lipoic acid (LA) on various behavioral models in mice. Paroxetine (10 and 20 mg/kg), LA (100 mg/kg), or vehicle was administered, intraperitoneally, 30 minutes before the tests. The results showed that PXT (10 mg/kg) alone and in combination with LA increased locomotor activity. In the anxiety models studied, an anxiolytic effect was observed after the administration of LA and PXT. In the tail suspension test, PXT at both doses and in combination with LA caused a significant decrease in immobility time. These results indicate possible anxiolytic and antidepressant effects of LA associated with PXT. These data suggest that coadministration of LA and PXT may improve anxiolytic and antidepressant responses, and being more effective than each drug alone. However, further studies are necessary to investigate the mechanism by which antioxidants exert antidepressant or anxiolytic action.

[The cost of liver transplantation at a university hospital of Brazil].

OBJECTIVE: To investigate if liver transplants were cost effective at a University Hospital of Ceará. METHODS: We evaluated data from the medical records of 62 liver transplant patients performed in 2007, from the day of admission for the transplant to the date of discharge or death. Indicators such as length of hospital stay and location ,quantity of medical material and medication used, as well as the investigations and procedures performed were determined. RESULTS: The population was mostly male from the Northeast of Brazil with an mean age of 45 years. The mean total cost of a liver transplant was US$20,605.01. The largest part was payment for the professional team involved in the liver removal and transplant, followed by hospital stay , medication used during surgery and hospitalization, and products (medication and materials) used in the liver removal. According to the current schedule, the SUS made the following payments to HUWC; US$1,322.97 for liver removal, US$3,223.56 for medical fees and US$32,235.68 for the package including the complete surgical procedure, hospital expenses and care up to the seventh day of hospitalization. CONCLUSION: Results were similar to those found by other Brazilian transplant centers. Liver transplantation in Ceará is an economically viable procedure based upon the financial transfer from SUS.

Atividade farmacológica da monocrotalina isolada de plantas do gênero Crotalaria / Pharmacological activity of monocrotalina isolated from plants of the genus Crotalaria

Crotalaria retusa é uma planta encontrada no Nordeste brasileiro, pertence ao gênero Crotalaria e à família Leguminosae, e possuem mais de seissentas espécies no mundo e mais de quarenta no Brasil. As variedades tóxicas mais conhecidas são C. spectabilis, C. crispata, C. retusa, C. dura e C. globifera. Plantas do gênero Crotalaria são de interesse porque são usadas na medicina popular. Esses gêneros são ricos em alcaloides pirrolizidínicos (AP), que são as principais toxinas e apresentam efeitos pneumotóxicos, nefrotóxicos, cardiotóxicos, fetotóxicos, carcinogênicos, inflamação, hemorragia e fibrose. A monocrotalina é o principal alcaloide pirrolizidínico encontrado nessas plantas e é ativamente oxidada in vivo pelo citocromo P450 no fígado, formando intermediários altamente reativos tipo pirrólicos que são responsáveis pela ligação cruzada do DNA-DNA e DNA-proteína. O presente trabalho teve como objetivo fazer um levantamento bibliográfico via internet, utilizando bancos de dados, programas de pesquisa científica e pesquisa em livros relacionados, acerca da atividade farmacológica e do mecanismo de ação da monocrotalina extraída de plantas do gênero Crotalaria, ressaltando desde os aspectos botânicos da planta, estrutura química dos alcaloides pirrolizidínicos, exemplos experimentais de toxicidade e provável mecanismo de ação.

Crotalia retusa is a plant found in Brazilian Northeast and belongs to the genus Crotalaria and the family Leguminosae, which comprises more than 600 species throughout the world and more than forty in Brazil. The most known toxic species are C. spectabilis, C. crispata, C. retusa, C. dura and C. globifera. Plants of the Crotalaria genus are of great interest because they are used by humans for folk medicine. These plants are rich in pyrrolizidine alkaloids (PA), which are the main toxins that cause effects such as pneumotoxic, nefrotoxic, cardiotoxic, fetotoxic, carcinogenic, inflammation, hemorrhage and fibrosis. Monocrotaline is the main pirrolizidinic alkaloid found in plants and is actively oxidated in vivo by the cytochrome P450 in the liver, yielding highly reactive pyrrolic type intermediates, which are responsible for DNA-DNA and DNA-protein cross-links reaction. The aim of this work is to make a bibliographic survey via internet, using databases, scientific research programs and related books, about pharmacological activity and mechanism of action of monocrotaline extracted from plants of Crotalaria genus, emphasizing plant botanical aspects, chemical structure of pirrolizidinic alkaloid, experimental examples of toxicity and probable action mechanism.

Cocaine-induced status epilepticus and death generate oxidative stress in prefrontal cortex and striatum of mice.

Oxidative stress (OS) has been related to cocaine's actions and also to numerous nervous system pathologies, including seizures. The purpose of this work was to determine the alterations in glutathione (GSH) content, nitrite/nitrate and MDA levels after cocaine-induced toxicity. Male Swiss mice were injected (i.p.) with cocaine 90 mg/kg and observed during 1h. After this cocaine overdose some animals presented status epilepticus (SE) while some died after seizures. These animals were divided in two groups, SE and death. A group with an association of the antioxidant Vitamin E (Vit E, 400mg/kg, i.p.) plus Coc 90 (Vit E plus Coc 90) was undertaken to assess the neuroprotective effect of Vit E. Neurochemical analyses were carried out in prefrontal cortex (PFC) and striatum (ST). GSH levels increased only after cocaine-induced death in both areas studied. Cocaine-induced SE has increased nitrite/nitrate content in PFC and ST, while after death the increase was only in PFC. MDA (the lipid peroxidation marker) was elevated after SE and death in ST and only after death in PFC. Antioxidant treatment significantly reduced the GSH, nitrite/nitrate in ST and MDA levels. Only nitrite/nitrate content in PFC has not been decreased by Vit E pretreatment. The results relate that oxidative stress occurs after cocaine-induced toxicity mainly after death indicating that probably the increase of OS in the animal's brain leads to seizures and death, also showing a protective effect of Vit E in this process. Together with previous results this study contributes to the knowledge of cocaine-induced toxicity and possible in the near future to the use of antioxidants in the prevention of cocaine-induced CNS toxicity.

O custo do transplante hepático em um hospital universitário do Brasil / Cost of liver transplantation at a university hospital of Brazil

OBJETIVO: Investigar se os transplantes de fígado realizados em um hospital universitário do Ceará eram custos-efetivos. MÉTODOS: Foram avaliados os prontuários dos 62 pacientes transplantados hepáticos em 2007, do dia da internação para o transplante até a data da alta hospitalar ou óbito. Foram determinados indicadores como o número de dias e local de internação, a quantidade de material e medicamentos utilizados, os exames complementares e os procedimentos realizados. RESULTADOS: A maioria da população era do sexo masculino, procedente do Nordeste e com idade média de 45 anos. O custo médio do transplante hepático foi de US$ 20.605,01. O item que onerou predominantemente o custo foi o repasse para equipe profissional envolvida na captação e transplante; seguido pelas diárias, medicamentos da cirurgia e internamento; e produtos (materiais e medicamentos) utilizados na captação. Quanto ao repasse do SUS, o HUWC recebeu US$1.322,97 para a captação, US$ 3.223,56 para os honorários médicos e US$ 32.235,68 pelo pacote do transplante hepático que inclui do procedimento cirúrgico até o sétimo dia de internamento. CONCLUSÃO: Os valores encontrados foram semelhantes aos determinados por outros centros transplantadores brasileiros. O transplante hepático no Ceará é um procedimento economicamente viável tomando como base o repasse financeiro do SUS.

OBJECTIVE: To investigate if liver transplants were cost effective at a University Hospital of Ceará. METHODS: We evaluated data from the medical records of 62 liver transplant patients performed in 2007, from the day of admission for the transplant to the date of discharge or death. Indicators such as length of hospital stay and location ,quantity of medical material and medication used, as well as the investigations and procedures performed were determined. RESULTS: The population was mostly male from the Northeast of Brazil with an mean age of 45 years. The mean total cost of a liver transplant was US$20,605.01. The largest part was payment for the professional team involved in the liver removal and transplant, followed by hospital stay , medication used during surgery and hospitalization, and products (medication and materials) used in the liver removal. According to the current schedule, the SUS made the following payments to HUWC; US$1,322.97 for liver removal, US$3,223.56 for medical fees and US$32,235.68 for the package including the complete surgical procedure, hospital expenses and care up to the seventh day of hospitalization. CONCLUSION: Results were similar to those found by other Brazilian transplant centers. Liver transplantation in Ceará is an economically viable procedure based upon the financial transfer from SUS.

Determination of amino acid levels in the rat striatum, after administration of ethanol alone and associated with ketamine, a glutamatergic antagonist.

The main goal of this study was to determine the amino acids (glutamate, aspartate, glutamine and tyrosine) levels in the rat striatum, after ethanol administration alone and/or associated with ketamine. In protocol 1 (Et+ketamine-1), ethanol was administered to male Wistar rats until the 7th day, and at the next day the group received only ketamine (25mg/kg, i.p.) up to the 14th day. In protocol 2 (Et+ketamine-2), ethanol was also administered up to the 7th day, and was associated with ketamine from the 8th up to the 14th day. In other groups, animals were treated daily with ethanol (4 g/kg, p.o.), for 7 or 14 days or ketamine daily for 7 days. Controls were administered with distilled water for 7 days. Results showed that, in protocol 1, aspartate (ASP) levels increased after ketamine administration, as compared to the controls. This effect was inhibited in the group Et+ketamine-1. Ethanol (7 days) increased glutamate (GLU) levels, as compared to control, and this effect did not differ significantly from that observed in the ketamine group. When ketamine was administered after the ethanol withdrawal (protocol 1), no alterations in those amino acid concentrations were seen, as compared to the control and ketamine groups. A tendency for increasing GLU levels was observed, after administration of ethanol (14 days) or ketamine alone or associated (protocol 2), when compared to control values. In protocol 2, TYR levels decreased as related to controls and to the 14-day ethanol-treated group. We can assume that ketamine presents only an antagonist effect, in animals pretreated with ethanol, followed by ketamine administered from the 8th day on. This is due to the fact that NMDA receptors are already sensitized, leading to a decrease in these receptors functions and consequently to ASP and GLU releases.

Study of antinociceptive effect of isolated fractions from Petiveria alliacea L. (tipi) in mice.

The acetate (FA), hexanic (FH), hydroalcoholic (FHA) and precipitated hydroalcoholic (FHAppt) fractions from the root of Petiveria alliacea L. were evaluated for antinociceptive effect using the abdominal constriction induced by acetic acid, hot-plate, formalin tests. The open field and rota rod tests were used to evaluate psychomotor function and myorelaxant activity. The fractions were administered intraperitoneally in mice at doses of 100 and 200 mg/kg. Inhibitions of abdominal constrictions were observed with all doses of the fractions, as compared to control. FH and FHAppt, at both doses, reduced the nociception produced by formalin in the 1st (0-5 min) and 2nd (20-25 min) phases, however FHA (100, 200 mg/kg) and FA 200 mg/kg presented significant inhibition on the 1st and 2nd phases, respectively, of this test. A reduction of the locomotor activity was observed in the open field test with all the fractions. These fractions failed to affect the motor coordination in the rota rod test. Results showed that the different fractions of Petiveria alliacea L. have different antinociceptive potentials as demonstrated in the experimental models of nociception in mice, supporting folk medicine use of this plant.

Effect of anxiolytic, antidepressant, and antipsychotic drugs on cocaine-induced seizures and mortality.

Cocaine abuse may lead to overdose (related to seizures and/or status epilepticus) and to diseases (schizophrenia, depression, and anxiety). This work was designed to study the influence of drugs used to treat psychopathologies associated with cocaine abuse on cocaine-induced seizures and mortality in mice. Fluoxetine (10, 20, 40 mg/kg), imipramine and buspirone (5, 10 mg/kg), pimozide (10, 20 mg/kg), lithium (56.3, 112.5 mg/kg), and naltrexone (25, 50 mg/kg) were administered intraperitoneally, 30 minutes prior to cocaine (90 mg/kg, ip). The animals were observed (30 minutes) to determine: latency to first seizure, number of seizures, and number of deaths after cocaine overdose. Fluoxetine, imipramine, buspirone, and pimozide had pro- or anticonvulsant effects depending on the dose. Smaller doses protected and higher doses increased cocaine-induced seizures and/or mortality. Naltrexone worsened and lithium protected against seizures. Thus, these results suggest that caution should be taken in the selection of pharmacotherapy and dosages for patients with cocaine addiction because of the possibility of potentiating cocaine toxicity.

Cocaetileno um metabolito da associaçäo cocaina e etanol / Cocaethylene a metabolite of cocaine and ethanol association

A cocaina, droga psicoestimulante, e usada frequentemente em associacao com outras drogas de abuso (alcool, heroina, sedativos, maconha, entre outras). Entre estas, o consumo simultaneo de cocaina e alcool tem aumentado significativamente nos ultimos anos em todo o mundo. Com o objetivo de estudar a associacao entre essas drogas, foi realizada uma pesquisa bibliografica via Internet, utilizando programas de pesquisa cientifica (Pubmed e Lilacs), alem...