Estudo de dose adequada da droga RO42-1611 (Arteflene) no tratamento da malária por Plasmodium falciparum

A resistência crescente do P. falciparum aos antimaláricos habitualmente empregados, torna urgente a avaliação de novas drogas. O Ro 42-1611 é um antimalárico derivado da planta chinesa Arlabotrys uncinatus. Usado apenas na África em três trabalhos no tratamento da malária por P. falciparum, tem sua ação desconhecida em sul-americanos com esta doença. Apesar do efeito antimalárico ter sido comprovado, ainda não se encontrou a dose adequada para o tratamento supressivo do P. falciparum. Avaliar a tolerância, a toxicidade e a eficácia de três diferentes doses do Ro 42-1611 no tratamento da malária por P. falciparum é o que objetiva este trabalho. O estudo foi realizado em Marabá-Pará, caracterizando-se por ser aberto, prospectivo e randomizado; incluiu pacientes voluntário s, adultos, masculinos, de peso corporal até 80 kg; febris ou com outros sintomas constitucionais de malária e com gota espessa positiva para P. falciparum ( ≥ 200 e ≤ 50.000 parasitas/mm³ de sangue). Grupos de estudo: I -1.500 mg de 12/12 horas por 1 dia; II -1.500 mg de 12/12 horas por2 dias e III -1.500 mg de 12/12 horas por 3 dias. Todos os pacientes foram tratados em regime hospitalar, sendo avaliados no pré-tratamento através de: dados pessoais e biométricos, sinais e sintomas, uso de medicação concomitante, temperatura axilar, freqüência respiratória, pressão arterial, eletrocardiograma, parasitemia, exames hematológicos e bioquímicos. A partir do início da terapêutica, a avaliação destes parâmetros foi feita seguindo protocolo próprio, incluindo a anotação de efeitos colaterais. A análise de variância de Friedman foi usada para avaliar os valores obtidos nos exames hematológicos e bioquímicos. Foram selecionados 16 pacientes, sendo 5 alocados no grupo I, 6 no II e 5 no III. Idade variou de 17 a 41 anos (média: 26,6), peso corporal de 44 a 72 kg (média: 54,9), parasitemia assexuada inicial de 200 a 40.000 formas/mm³ de sangue, sendo os grupos homogêneos quanto a estas variáveis. A febre desapareceu no mínimo com 9 e no máximo com 48 horas a partir do início da terapêutica. A avaliação do traçado eletrocardiográfico e da pressão arterial não mostrou alterações significativas. O desaparecimento da parasitemia assexuada ocorreu em média com 53,6 horas, não se evidenciando diferenças estatísticas i significantes entre os grupos (p=0,7264). Houve uma diminuição significativa entre o pré-tratamento (D0) e o terceiro (D2) e oitavo (D7) dias de acompanhamento quanto os níveis de hematócrito (p=0,0046), um aumento no número de leucócitos entre D2 e D7 (p=0,0171) e plaquetas entre D0 e D7, assim como entre D2 e D7 (p< 0,0001). Entre D0 e D7 detectou-se diminuição nos níveis de bilirrubina total (p=0,0024), fosfatase alcalina (p=0,0195) e uréia (p=0,0168). Efeitos colaterais foram em geral leves ou moderados e de curta duração. Do total de pacientes, 87,5% obtiveram desaparecimento da parasitemia assexuada, porém apenas 2 (12,5%) curaram, ambos incluídos no grupo III. Nenhum dos esquemas posológicos usados foi adequado para a cura desta doença. Talvez em estudos posteriores usando a droga em maior dose ou por maior número de dias ou ainda associando-a a outros antimaláricos, possa obter-se eficácia adequada.

Concentrações plasmáticas de primaquina e metemoglobinemia em pacientes com malária por Plasmodium vivax

A malária vivax é uma doença que a cerca de 40% da população mundial, utiliza-se no tratamento desta, cloroquina (150 mg) e primaquina (15 mg). Esta é uma 8- aminoquinolina com ação esquizonticida tecidual. Dentre seus efeitos adversos se destaca a capacidade de oxidar a hemoglobina, de maneira dose dependente, que é agravada nos indivíduos com deficiência da glicose-6-fosfato desidrogenase. Ao se considerar a ausência de estudos referentes aos teores de metemoglobina e sua correlação com as concentrações plasmáticas de primaquina nos pacientes com malária vivax, justifica-se a realização deste estudo empregando-se como ferramentas a monitorização das concentrações sanguíneas de primaquina e sua correlação com os teores de metemoglobina. Neste sentido, foi realizado seguimento clínico-laboratorial de 20 pacientes com malária vivax antes (D0) e após três (D3), sete (D7) e quatorze (D14) dias iniciado o tratamento, bem como a validação do método para determinação de primaquina por cromatografia líquida de alta eficiência (CLAE). A metemoglobinemia foi avaliada pela técnica de Hegesh et al. (1970) e a glicose-6-fosfato desidrogenase pelo teste colorimétrico de Brewer et al. (1962). A metodologia validada demonstrou parâmetros aplicáveis à determinação de primaquina, cujos teores médios em D3, D7 e D14 foram de 227±106 ng/mL, 191±97 ng/mL e 160±128ng/mL. Não foram obervadas diferenças significativas nas concentrações do fármaco quanto ao sexo dos pacientes participantes e nos diversos dias do estudo. Os teores médios de metemoglobina em D0, D3, D7 e D14 foram de 1,15±0,9%, 4,1±2%, 5,7±2% e 3±1,4%, respectivamente. Foi observado aumento no teor de metemoglobina após administração do fármaco, sem diferença quanto ao sexo. Não foi observada correlação significativa entre os teores de metemoglobina e as concentrações plasmáticas de primaquina em ambos os sexos. Os coeficientes de correlação de Pearson para os sexos masculino e feminino foram 0.8296 e 0.8137, respectivamente. Foi observada deficiência da expressão da enzima glicose-6- fosfato desidrogenase em seis pacientes do sexo masculino sem diferenças entre os teores de metemoglobina e das concentrações plasmáticas de Primaquina, quando comparados com pacientes com expressão normal da enzima.

O isoflurano e a associação remifentanil e isoflurano usados após isquemia reperfusão causa proteção renal em ratos?

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Sevoflurano e dexmedetomidina em isquemia e reperfusão renais no rato

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Microemulsões biocompatíveis de anfotericina B para administração oral: estudo estrutural, liberação in vitro e farmacocinética pré-clínica

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Treinamento aeróbio e diabetes experimental em ratos: perfil endócrino-metabólico no cerebelo

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Different fasting periods in tiletamine-zolezepam-anethetized cats: Glycemia, recovery, blood-gas and cardiorrespiratory parameters

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Electrocardiographic evaluation of the degree of sedation and the isolated use of methadone in healthy dogs

Objective: The present study aimed to investigate the influence of methadone on cardiorespiratory parameters, electrocardiogram and clinical sedation in dogs. Further possible side effects are reported.Study designProspective experimental cross-over study.DogsEight, 1-4-year-old, various breeds of dogs of both genders weighing 9-36kg.MethodsEach dog was treated three times: methadone 0.3mgkg(-1) (M0.3), 0.5mgkg(-1) (M0.5) and 1.0mgkg(-1) (M1.0) intramuscularly. Respiratory rate, heart rate and arterial blood pressure were recorded as well as electrocardiographic evaluation of lead II. Clinical sedation in each treatment received a score (0-3) after drug administration and at 30minute intervals until scores and measurements returned to baseline values.ResultsA significant decrease in heart rate was seen with each dose of methadone and bradycardia (HR<60bpm) was noted in a few dogs at each dose. A clinically significant arrhythmia occurred in one dog at 1mgkg(-1) that required reversal with butorphanol. There was no significant difference in SAP, MAP and DAP between treatments. Some side effects such as salivation, defecation, vocalization and panting, after administration of methadone were observed. There were no differences in mean values of heart rate, P-wave and QRS complex duration and QT interval between treatments.Conclusion and clinical relevanceMethadone administration was associated with panting and a decrease in heart rate at all doses tested in this study. The cardiac rhythm should be monitored carefully in dogs when methadone is administered on its own, especially at higher doses.

Methods to evaluate and strategies to improve the biocompatibility of dental materials and operative techniques

Objective. The general aim of this article is to describe the state-of-the-art of biocompatibility testing for dental materials, and present new strategies for improving operative dentistry techniques and the biocompatibility of dental materials as they relate to their interaction with the dentin-pulp complex.Methods. The literature was reviewed focusing on articles related to biocompatibilty testing, the dentin-pulp complex and new strategies and materials for operative dentistry. For this purpose, the PubMed database as well as 118 articles published in English from 1939 to 2014 were searched. Data concerning types of biological tests and standardization of in vitro and in vivo protocols employed to evaluate the cytotoxicity and biocompatibility of dental materials were also searched from the US Food and Drug Administration (FDA), International Standards Organization (ISO) and American National Standards Institute (ANSI).Results. While there is an ongoing search for feasible strategies in the molecular approach to direct the repair or regeneration of structures that form the oral tissues, it is necessary for professionals to master the clinical therapies available at present. In turn, these techniques must be applied based on knowledge of the morphological and physiological characteristics of the tissues involved, as well as the physical, mechanical and biologic properties of the biomaterials recommended for each specific situation. Thus, particularly within modern esthetic restorative dentistry, the use of minimally invasive operative techniques associated with the use of dental materials with excellent properties and scientifically proved by means of clinical and laboratory studies must be a routine for dentists. This professional and responsible attitude will certainly result in greater possibility of achieving clinical success, benefiting patients and dentists themselves.Signcance. This article provides a general and critical view of the relations that permeate the interaction between dental materials and the dentin-pulp complex, and establish real possibilities and strategies that favor biocompatibility of the present and new products used in Dentistry, which will certainly benefit clinicians and their patients. (C) 2014 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Effects of different mydriatics on intraocular pressure, pupil diameter, and ruminal and intestinal motility in healthy sheep

Objective To determine the effects of the administration of subconjunctival 1% atropine (SA), topical 1% atropine (A), 0.5% tropicamide (T), 1% homatropine (H), 10% phenylephrine (P), and 2% ibopamine (I) on intraocular pressure (IOP), pupil diameter (PD), ruminal motility (RM) and intestinal motility (IM) in sheep.Animal studied Ten spayed ewes of Santa Ines breed.Procedures Six experiments were performed separately at 1-week intervals. One eye was randomly selected and received one drop of A, T, H, P, I, or subconjunctival injection of atropine at 8 a. m. On the following days, IOP and PD were evaluated every 8 h until the pupil returned to its normal diameter. Ruminal motility and intestinal motility were evaluated only within the first 13 h.Results The IOP did not change significantly in the treated eyes compared with the control eyes and baseline at any time point (P > 0.05). A longer-lasting pupil dilation was observed after the administration of A (96 h), SA (79 h), H (24 h), and T (24 h). Within the first 30 min after treatment, RM and IM decreased, by 78% and 82% (H), 76% and 86% (SA), 46% and 58% (A), and 62% and 70% (T) (P < 0.001), respectively, with a tendency to return to baseline values following 13 h of drug administration. Both 10% phenylephrine and 2% ibopamine did not have any effect on the parameters evaluated (P > 0.05).Conclusions Topical and subconjunctival 1% atropine, 0.5% tropicamide, and 1% homatropine significantly reduced RM and IM, and induced pupil dilation but did not change IOP in eyes of healthy sheep. The sympathomimetics phenylephrine (10%) and ibopamine (2%) did not change the parameters evaluated.

Associações anestésicas baseadas em fármacos dissociativos reduzem a pressão intraocular (PIO) em coelhos

The aim of this study was evaluate the effects of three anesthetic combinations, ketamine-midazolam, ketamine-xylazine and tiletamine-zolazepam, on IOP in rabbits. In a experimental, blind, randomized, crossover study, six rabbits were anesthetized with each of 3 treatments in random order. Groups KM (ketamine, 30 mg/kg + midazolam, 1 mg/kg); KX (ketamine, 30 mg/kg + xylazine, 3 mg/kg); and TZ (tiletamine + zolazepam, 20 mg/kg). The drugs were mixed in the same syringe injected intramuscularly (IM) into the quadriceps muscle. IOP was measured before drug administration (baseline) and at 5-minute intervals for 30 minutes. The data were analyzed by a 2-way repeated measures ANOVA followed by Bonferroni test. All groups had significant decreases in IOP compared to baseline (p < 0.001). There was no difference between groups at any of the time points assessed (p > 0.05). Administration of either ketamine-midazolam, ketamine-xylazine, or tiletamine-zolazepam similarly decrease IOP in rabbits within 30 minutes of injection.

Desenvolvimento de nanopartículas de quitosana para adminstração nasal de zidovudina

Zidovudine (AZT) is the drug most commonly used in AIDS treatment, isolated or in combination with other antiretroviral agents, but it has certain limitations due to its therapeutic dose-dependent haematological toxicity. In addition, it has low oral bioavailability, since it undergoes pre-systemic metabolism. The nasal route has been used as an alternative route for drug administration, because it can promote its direct absorption to blood circulation, avoiding hepatic metabolism. However, this route presents as a factor limiting the mucociliary clearance mechanisms that remove quickly the formulation of the nasal cavity. To prolong the residence time of formulations, in this direction, has been proposed the development of mucoadhesive systems. Among the various existing systems, the use of chitosan (QS), as mucoadhesive polymer, has been widely exploited in the preparation of nanoparticles (NPs). The objective of this study was to develop and characterize QS’s NPs for intranasal administration of AZT. For both NPs have been developed by ionic crosslinking of QS with sodium tripolyphosphate (TPP). These NPs were characterized by studies of particle size distribution, zeta potential, morphology, mucoadhesion tests, assessing the ability of encapsulation of the drug and permeation profile of AZT. The evaluation of AZT in the NPs was determined by UV-Vis spectroscopy. Mucoadhesion measures were made using a texture analyzer, using a mucin disk and porcine mucous membrane , and permeation assay were conducted using porcine nasal mucous membrane adapted to the Franz cell. These results suggest that the systems in hand have great potential for nasal AZT administration

Treatment of Dyslipidemia with Statins and Physical Exercises: Recent Findings of Skeletal Muscle Responses

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Synergist interaction between angiotensin II and DOCA on sodium and water balance in rats

Blockade of central angiotensin receptors with the specific antagonist [Leu8]-ANG II abolished water ingestion and water and sodium excretion induced by infusion of angiotensin II (ANGII) into the lateral ventricle (LV) of rats. The antagonist reduced but did not suppress the salt appetite induced by ANGII infusion. Subcutaneous injection of deoxycorticosterone acetate (DOCA) caused increases in water and 3% NaCl ingestion and decreases in sodium excretion. When central ANGII infusion was combined with peripheral DOCA, the water intake was similar to that induced by ANGII alone and the ingestion of 3% NaCl was increased, whereas sodium excretion was inhibited. When ANGII was infused alone, a detailed temporal analysis of fluid and sodium balance showed a negative balance similar those saline controls that persisted throughout the experiment. Combined administration of ANGII and DOCA induce significant changes in water and sodium balance. Sodium and water maintained a positive balance through out the 8-h experiment. The data support an interaction of central ANGII and DOCA on sodium intake and water and sodium balance. © 1994.

Effect of furosemide treatment on the central and peripheral pressor responses to cholinergic and adrenergic agonists, angiotensin II, hypertonic solution and vasopressin

The present study was performed to investigate the effect of treatment with furosemide on the pressor response induced by intracerebroventricular (i.c.v.) injections of cholinergic (carbachol) and adrenergic (norepinephrine) agonists, angiotensin II (ANGII) and hypertonic saline (HS, 2 M NaCl). The changes induced by furosemide treatment on the pressor response to intravenous (i.v.) norepinephrine, ANGII and arginine vasopressin (AVP) were also studied. Rats with a stainless-steel cannula implanted into the lateral ventricle (LV) were used. Two injections of furosemide (30 mg/kg b.wt. each) were performed 12 and 1 h before the experiments. Treatment with furosemide reduced the pressor response induced by carbachol, norepinephrine and ANGII i.c.v., but no change was observed in the pressor response to i.c.v. 2 M NaCl. The pressor response to i.v. ANGII and norepinephrine, but not AVP, was also reduced after treatment with furosemide. These results show that the treatment with furosemide impairs the pressor responses induced by central or peripheral administration of adrenergic agonist or ANGII, as well as those induced by central cholinergic activation. The results suggest that the treatment with furosemide impairs central and peripheral pressor responses mediated by sympathetic activation and ANGII, but not those produced by AVP. © 1992.