Pharmacokinetic and safety evaluation of the use of ciprofloxacin on an isoniazid-rifampicin regimen in rabbits

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

The effect of pyrazinamide and rifampicin on isoniazid metabolism in rats

Hepatotoxicity is the main concern during tuberculosis chemotherapy with the first-line drugs isoniazid (INH), rifampicin (RMP) and pyrazinamide (PYR). Since these hepatotoxic events have been associated with INH metabolites, the study aimed to measure the area under curve (AUC) parameter for INH and its metabolites acetylisoniazid (AcINH), hydrazine (Hz) and acetylhydrazine (AcHz), when groups of rats were pre-treated for 21 days with INH alone or in combination with RMP and/or PYR, in the following amounts per kg body weight: INH 100 mg; INH 100 mg + RMP 100 mg; INH 100 mg + PYR 350 mg; INH 100 mg + PYR 350 mg + RMP 100 mg. It was found that co-administration of RMP, PYR and RMP + PYR caused a significant decrease in the AUC for INH. Co-administration of PYR was the only treatment that caused a significant increase in the AUC for Hz and a decrease in the AUC for its acetylated product AcHz. The AUC for AcINH was not significantly altered in any experimental group. In conclusion, the increased metabolism of INH in all the drug combinations and the significantly higher production of Hz in the group INH + PYR might be linked with exacerbated hepatotoxic effects of these drug associations. Copyright (c) 2007 John Wiley & Sons, Ltd.

The effect of rifampicin and pyrazinamide on isoniazid pharmacokinetics in rats

Tuberculosis chemotherapy involves combination of the drugs isoniazid (INH), rifampicin (RMP) and pyrazinamide (PYR) for a 6-month period. The present work investigated the influence of RMP and PYR on the pharmacokinetic parameters of INH when groups of rats were pre-treated for 21 days with INH alone or in combination with RMP and/or PYR, in the following amounts per kg body weight: INH 100 mg; INH 100 mg + RMP 100 mg; INH 100 mg + PYR 350 mg; INH 100 mg + PYR 350 mg + RMP 100 mg. It was found that the co-administration of PYR caused an increase in the INH distribution volume (V-d/F), half-life of elimination t(1)/2(beta)) and clearance (Cl-T/F), and a decrease in the area under curve 0 to 24 h (AUC). Co-administration of RMP caused an increase in the Cl-T/F and a decrease in the AUC. The combination INH + PYR + RMP caused an increase in the Cl-T/F and a decrease in the AUC. These significant pharmacokinetic interactions between the tuberculostatic drugs might be related to differences in the therapeutic and toxic effects. Copyright 0( 2007 John Wiley & Sons, Ltd.

Simultaneous analysis of the enantiomers of verapamil and norverapamil in rat plasma by liquid chromatography tandem mass spectrometry

An enantioselective micromethod for the simultaneous analysis of verapamil (VER) and norverapamil (NOR) in plasma was developed, validated and applied to the study of the kinetic disposition of VER and NOR after the administration of a single oral dose of racemic-VER to rats. VER, NOR and the internal standard (paroxetine) were extracted from only 100-mu L plasma samples using n-hexane and the enantiomers were resolved on a Chiralpak AD column using n-hexane:isopropanol: ethanol: diethyl ami ne (88:6:6:0.1) as the mobile phase. The analyses were performed in the selected reaction monitoring mode. Transitions 456 > 166 for VER enantiomers, 441 > 166 for NOR enantiomers and 330 > 193 for the internal standard were monitored and the method had a total chromatographic run time of 12 min. The method allows the determination of VER and NOR enantiomers at plasma levels as low as 1.0 ng/mL. Racemic VER hydrochloride (10 mg/kg) was given to male Wistar rats by gavage and blood samples were collected from 0 to 6.0 h(n = 6 at each time point). The concentration of (-)-(S)-VER was three folds higher than (+)-(R)-VER, with an AUC ratio (-)/(+) of 2.66. Oral clearance values were 12.17 and 28.77 L/h/kg for (-)-(S)-VER and (+)-(R)-VER, respectively. The pharmacokinetic parameters of NOR were not shown to be enantioselective. (c) 2007 Elsevier B.V. All rights reserved.

Uma (re)leitura teleológica da filosofia moral em Kant : por uma necessidade de inclusão do homem na natureza

Made from the bases of metaphysics, this dissertation is related do Kant‟s moral philosophy. But the itinerary to reach the main speculation used to develop this current understanding of Kant‟s thoughts, it is nothing but an attempt to make the formal rigor more flexible, which has always been associated to Kantian ethics‟ perspectives. From the awareness of what this formalism could be, while a moral arrangement, it is how we will be able to come upon a teleological Kant. That is the fundamental element to comprehend some of the significant aspects in that ethical system, which necessarily comes through the effort to demonstrate the proximity between reason and sensibility, as well as nature and liberty. In this environment, the journey to achieve the autonomy, as the bedrock of liberty and morality, evokes the support of education in Kantian patterns, which enables a course of improvement of the human being, as an individual e, more significantly, as specie. This evolution progress, which tents to reveal the destiny of the humanity, is evolved in the relationship between necessity and finality, as a condition to make the structure of a project to humanity possible. We should mention that it is a rational, an educational and a moral project to be developed in the course of history. As a consequence, the amount of all these elements permits the development of the man‟s natural disposition as a creature that looks for self knowledge , becoming, afterward, dignified to be qualified as a human being. Finally, this study intent to figure out the necessity of the human being inclusion to nature, which happens throughout the acquirement of the individuals‟ conscience

Influence of N-Hexane Inhalation on the Enantioselective Pharmacokinetics and Metabolism of Verapamil in Rats

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

In vivo CYP2E1 phenotyping as a new potential biomarker of occupational and experimental exposure to benzene

Assessing CYP2E1 phenotype in vivo may be important to predict individual susceptibility to those chemicals, including benzene, which are metabolically activated by this isoenzyme. Chlorzoxazone (CHZ), a specific CYP2E1 substrate, is readily hydroxylated to 6-OH-chlorzoxazone (6-OH-CHZ) by liver CYP2E1 and the metabolic ratio 6-OH-CHZ/CHZ in serum (MR) is a specific and sensitive biomarker of CYP2E1 activity in vivo in humans. We used this MR as a potential biomarker of effect in benzene-treated rats and, also, in humans occupationally exposed to low levels of benzene. Male Sprague-Dawley rats (375-400 g b.w.) were treated i.p. for 3 days with either a 0.5 ml solution of benzene (5 mmol/kg b.w.) in corn oil, or 0.5 ml corn oil alone. Twenty-four hours after the last injection, a polyethylene glycol (PEG) solution of CHZ (20 mg/kg b.w.) was injected i.p. in both treated and control animals. After 2, 5.10,15, 20,30,45, 60, 90, 120, 180, and 240 min from injection, 0.2 ml blood was taken from the tip tail and stored at -20 degrees C until analysis. A modified reverse phase HPLC method using a 5 mu m Ultrasphere C18 column equipped with a direct-connection ODS guard column, was used to measure CHZ and its metabolite 6-OH-CHZ in serum. No statistically significant difference in the MR was observed, at any sampling time, between benzene-treated and control rats. The concentration-versus-time area under the curve (AUC), however, was lower (p < 0.05, Mann-Whitney test), whereas the systemic clearance was higher (p < 0.05) in treated than in control rats. Eleven petrochemical workers occupationally exposed to low levels of airborne benzene (mean +/- SD, 25.0 +/- 24.4 mu g/m(3)) and 13 non-exposed controls from the same factory (mean +/- SD, 6.7 +/- 4.0 mu g/m(3)) signed an informed consent form and were administered 500 mg CHZ p.o. Two hours later a venous blood sample was taken for CHZ and 6-OH-CHZ measurements. Despite exposed subjects showed significantly higher levels of t,t-MA and S-PMA, two biomarkers of exposure to benzene, than non-exposed workers, no difference in the MR mean values +/- SD was found between exposed (0.59 +/- 0.29) and non-exposed (0.57 +/- 0.23) subjects. So, benzene was found to modify CHZ disposition, but not CYP2E1 phenotype in benzene-treated rats, nor in workers exposed to benzene, probably due to the levels of exposure being too low. (C) 2009 Elsevier B.V. All rights reserved.

Stereoselective analysis of carvedilol in human plasma and urine using HPLC after chiral derivatization

An enantioselective high-performance liquid chromatographic method for the analysis of carvedilol in plasma and urine was developed and validated using (-)-menthyl chloroformate (MCF) as a derivatizing reagent. Chloroform was used for extraction, and analysis was performed by HPLC on a C18 column with a fluorescence detector. The quantitation limit was 0.25 ng/ml for S(-)-carvedilol in plasma and 0.5 ng/ml for R(+)-carvedilol in plasma and for both enantiomers in urine. The method was applied to the study of enantioselectivity in the pharmacokinetics of carvedilol administered in a multiple dose regimen (25mg/12h) to a hypertensive elderly female patient. The data obtained demonstrated highest plasma levels for the R(+)-carvedilol(AUCSS 75.64 vs 37.29ng/ml). The enantiomeric ratio R(+)/S(-) was 2.03 for plasma and 1.49 0 - 12 for urine (Aeo-12 17.4 vs 11.7 pg). Copyright (c) 2008 John Wiley & Sons, Ltd.

Light microscopy and ultrastructure of the liver of Astyanax altiparanae Garutti and Britski, 2000 (Teleostei, Characidae).

Livers of thirty specimens of Astyanax altiparanae obtained from a commercial fish farm were subjected to light and transmission electron microscopy, in order to describe the hepatic parenchyma and the intrahepatic exocrine pancreatic tissue. Anatomically, the liver showed only three hepatic lobes. Histological analysis demonstrated that the hepatocytes were spread out as anastomotic cords, arranged in two cellular layers and surrounded by sinusoids. The intrahepatic exocrine pancreatic tissue exhibited an acinar arrangement and was diffused in the hepatic parenchyma. Ultrastructural analysis showed that the hepatocytes had a rounded nucleus and a rough endoplasmatic reticulum, with a parallel disposition to the nuclear membrane. The exocrine pancreatic cells showed secretion granules at the apical portion, and the rough endosplasmatic reticulum was concentrically distributed.

Preferências e escolhas românticas entre universitários

Several studies have found different patterns of preferences to men and women for short term and long term relationship romantic partners. It is known that the preferences vary with the sex of individuals, the expected involvement level of the relationship and according to the perceptions that subjects have about themselves. In the present study, we investigate whether the preferences typically founded for sexes are also founded between Brazilian undergraduate students. We also investigated if the individuals choose partners in accord of the sex preferences and if the ideal preferences are really expressed in real choices. For these investigations, 370 undergraduate students described profiles of an ideal partner for a short-term and a long-term relationship, through the joint evaluation of nine characteristics. Each ideal s profile has been described over three simulations, in which the amount of points available to be invested were limited and gradually reduced. After the descriptions of these profiles, the participants described the current or previous partner (if they were not in a relationship) and performed a self-assessment with the same characteristics used in the description of preferences. Overall, the results obtained in several countries were observed in Brazil. For short-term relationships men prioritize physical attributes and women value physical and personal attributes. For long-term, personal traits gained in importance on masculine preferences and women emphasized personal traits and the partner disposition to acquire resources. We also identified similar preferences profiles for both sexes and that the romantic preferences reflect similarities with the own individual s characteristics, in addition to the typical sexual preferences expected for the Parental Investment Theory. When evaluated their real partners, men considerate them more physically attractive than themselves but less intelligent, good humorous and ambi tion/willing to work. Women, in turn, described their partners as good as them. Finally, we observed equivalence between characteristics of the subjects and those of its partners, this effect being more pronounced among men. The last partners were described only as less sincere. The interpretation of the most part of our results was possible from evolutionist s and socio-cultural s explanations and was discussed under the two perspectives. We conclude this study stressing that the traditional romantic preferences occur in Brazil and that the sex, the kind of relationship and the vision that people have about their own characteristics affect the preferences, which are expressed in the real partner choices

Análise imunoistoquímica da distribuição de Serotonina, transportador de serotonina e receptores de serotonina no hipotálamo do sagui (callithrix jacchus)

The hypothalamus is a diencephalic portion located around the third ventricle below the hypothalamic sulcus, limited by the optic chiasm, and by the mammillary bodies, acting as a center that integrates behavioral and homeostatic functions. Serotonin is a neurotransmitter produced in limited sites in the midbrain and brain stem, but is distributed throughout the central nervous system and has many functions, acting through specific receptors that are also distributed throughout the nervous system. Using immunohistochemical techniques, the aim of this study was to delineate the hypothalamic nuclei of the marmoset (Callithrix jacchus) and study the distribution of serotonin transporter and serotonin receptors in the hypothalamus of this species. We used the Nissl method to determine the cytoarchitecture of the hypothalamic nuclei, and immunohistochemistry to reveal the presence of NeuN as a method to determine the contours of the hypothalamic nuclei. As a result, we found serotonin containing fibers and terminals throughout the rostrocaudal extent of the hypothalamus, more concentrated in some nuclei, and even absent in some. Like serotonin, serotonin transporter was observed between pre-optic area and tuberal region of the hypothalamus, in densities and distribution similar to serotonin. The 5-HT1A and 5-HT1B receptors were found with minor differences among itselves regarding the disposition and intensity of staining.

As praças públicas de Natal/RN no âmbito dos problemas socioambientais urbanos

This paper presents the public square as a subsystem of the city for the potential integration of elements 'natural' and built environment. But sometimes the suitability of projects and the social processes involved are not compatible and favorable to their real functions in urban space. The city of Natal, with a population of 803,739 inhabitants has 253 public parks not uniformly distributed in the urban area, but mostly in central areas and their absence in some peripheral neighborhoods. In this sense, the objective of this paper is to analyze the quality and spatiality of the city's public squares within the urban socio-environmental problems. For this, use of simple random sampling to define the sample and the proportional allocation of districts, totaling 168 squares to be raised. We prepared a form to collect data on the field that includes aspects of leisure, infrastructure and environment. For each square sampled was calculated Square Quality Index (PQI), then calculating the average per IQP neighborhood. The rates found were crossed with census data and Municipal Public Administration by neighborhood, using multivariate analysis. We generated maps, charts and tables, considered appropriate to each question format, focused comparison. The public square appears as an indicator of environmental challenges present in intra-urban spaces of the city. Their spatial distribution is not consistent demand population, both by disposition and by how much. In terms of quality are characterized by different levels of inadequacy and degradation aspects of leisure, environmental and infrastructure, often causing disfigurement, abandonment and improper occupation in such spaces. Multivariate analysis point to a central concentration and their problems in certain administrative units, not only as regards the public squares, but also to aspects of education, income, and other violence, perpetuating the problem. The various levels of inadequacy and degradation of public squares have been more blatant in the poorest neighborhoods of the city, pointing to a structural pattern associated with the intrinsic characteristics of the neighborhood and the socioeconomic profile of the local population. These are problems of social and environmental dimensions, threaded in and influenced the political, economic and broader social process of transformation of the city and the urban. Based on an uneven process in which space necessarily reflect the contradictions inherent in the active forces and interests. Thus evidencing the importance of managing the necessary public effectively engaged with the problems that are present there, in order to equate them, without being prioritized certain areas of the city at the expense of others

Experimental poisoning by Senecio brasiliensis in calves: quantitative and semi-quantitative study on changes in the hepatic extracellular matrix and sinusoidal cells

A matriz extracelular (MEC) desempenha um papel importante em lesões hepáticas crônicas e tem sido estudada em modelos de intoxicação experimental. em bovinos, no entanto, não há estudos específicos sobre a MEC hepática normal ou com lesões crônicas. Por isso, foi desenvolvido um modelo de intoxicação experimental hepático usando Senecio brasilliensis, uma planta que contém alcalóides pirrolizidínicos e causa lesão hepática dependente da dose. Cinco bezerros receberam por via oral, 0.38g/kg de folhas secas por 24 dias. Biópsias hepáticas foram obtidas a cada 15 dias durante 60 dias. Sinais clínicos de complicações digestivas surgiram da terceira semana do experimento. Um bezerro morreu aos 45 dias e os outros quatro foram avaliados até os 60 dias. As biópsias hepáticas foram processadas para microscopia óptica, imuno-histoquímica e microscopia eletrônica de transmissão. No trigésimo dia, as lesões hepáticas eram progessivas caracterizadas por vacuolização hepatocelular, necrose, apoptose, megalocitose, e fibrose centrolobular, pericelular e portal. Foram realizadas avaliações quantitativas e semi-quantitativas de componentes da MEC hepática antes e após o aparecimento das lesões. Foi realizada morfometria do colágeno total e do sistema de fibras elásticas. Colágeno total e colágenos tipos I e III aumentaram progressivamente em todos os locais do fígado. Mudanças na localização, quantidade e disposição do sistema de fibras elásticas foram também observadas. Houve um aumento significativo de células de Kupffer aos 30 dias e de células sinusoidais totais aos 45 e 60 dias. As lesões hepáticas neste experimento foram progressivas mesmo após a remoção da planta. Lesões de fibrose severa foram localizadas principalmente nos espaços porta, seguido por fibrose veno-oclusiva e pericelular. Os colágenos tipo I e tipo III foram observados no fígado normal e no fígado dos bezerros afetados, com predomínio do tipo I. Nos bezerros afetados o aumento do colágeno total e do sistema de fibras elásticas foi paralelo ao aumento no número das células sinusoidais.

Effect of Platelet-Rich Plasma on Peri-Implant Bone Repair: A Histologic Study in Dogs

The present study evaluated the effect of platelet-rich plasma (PRP) on pen-implant bone healing. A total of 9 mongrel dogs received 36 dental implants with sandblasted acid-etched surface in lower jaws in a split-mouth design: in the PRP group (n = 18 implants) the implants were placed in association with PRP, and in the control group (n = 18 implants) the implants were placed without PRP. Biopsies were obtained and prepared for histologic and histometric analysis after 15, 30, and 55 days of healing. The biopsies retrieved at 15 days showed delicate bone trabeculae formed by immature bone with presence of numerous osteoblasts for both groups. At 30 days the trabeculae presented reversal lines and evident lamellar disposition, where some thread spaces were filled by bone and dense connective tissue. At 55 days, bone healing was not altered in the control group, and histologic aspects were variable for the group treated with PRP. There was no significant difference between the groups for bone-to-implant contact (P > .05). PRP did not enhance bone formation around sandblasted acid-etched implants.

Demographic and metabolic characteristics of individuals with progressive glucose tolerance

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