TRATAMENTO DA HIPERTENSAO ARTERIAL LEVE E MODERADA COM FOSINOPRIL. COMPARACAO DE EFEITOS ADVERSOS COM OUTROS ANTI-HIPERTENSIVOS

Purpose - To evaluate the adverse reactions of fosinopril with other antihypertensives used as monotherapy. Methods - Out-patients (n = 2,568) with diagnostic of mild to moderate hypertension, diastolic blood pressure (DBP) 95-115 mmHg, with no antihypertensive treatment for 15 days, were included to treatment initially with fosinopril (F) 10mg, once daily, for six weeks. After this period, patients with DBP >95mmHg had the dosage, once daily, increased to 20 mg, while the others were maintained with the same dosage for six more weeks. Adverse reactions of 822 patients treated as monotherapy were grouped as absent, musculoskeletal, cardiovascular, cough, gastrointestinal, neurological, genital-urinary dysfunctions and dermatological and compared with 1,568 with F. Monotherapy consist in α-methyldopa (100 patients); β-blocker (129); calcium blocker (106); diuretic (394); and another ACE inhibitors (93). Results - At the end of the period without treatment, the blood pressure (BP), 165 ± 16/105 ± 7 mmHg decreased significantly at 6(th) week to 144 ± 15/91 ± 9 mmHg (p < 0.05 vs week 0) with further lowering to 139 ± 13/86 ± 7 mmHg till the end of 12(th) week. BP response (DBP ≤90 mmHg) was obtained in 89% of the patients with F. Absence of adverse reactions were ≥70% in patients with F compared to other drugs. Conclusion - Fosinopril has demonstrated therapeutic efficacy and less adverse reactions compared to antihypertensives used previously as monotherapy.

EFICACIA E TOLERABILIDADE DA ASSOCIACAO CAPTOPRIL + HIDROCLOROTIAZIDA NO TRATAMENTO DA HIPERTENSAO ARTERIAL LEVE A MODERADA. ESTUDO MULTICENTRICO

Purpose. To evaluate the antihypertensive efficacy and tolerability of captopril 50 mg + hydrochlorothiazide 25 mg daily in mild to moderate primary hypertension. Methods. Out-patients (n = 471) with mild to moderate hypertension, diastolic blood pressure (DBP) 95-115 mmHg, with 15 days of washout, were included to the treatment initially with half tablet of the association of captopril 50 mg + hydrochlorothiazide 25 mg once daily, for 30 days. After this period, patients with DBP > 90 mmHg had the dosage duplicated, while the others had the same dosage for 60 days more. Evaluation was performed 15 days before and then every month during active drug. Results. Twenty six patients were withdrawn, 13 (2,7%) by adverse effects and 13 by protocol violation. At the end of the wash-out period, the blood pressure (BP), 162 ± 16/103 ± 6 mmHg decreased significantly at the 30th day to 146 ± 14/92 ± 8 mmHg (p < 0,001 vs 0th day); 139 ± 12/86 ± 7 mmHg at the 60th day, (p < 0,001 vs 30th day), and further to 136 ± 11/84 ± 5 mmHg (p < 0,001 vs day 0) till the end of the 90th day. Antihypertensive efficay (DBP ≤ 90 mmHg and decreased for the DBP ≥ 10 mmHg) was obtained in 82% of the patients. There was no difference in BP control considering race, hypertension level, previous antihypertensive treatment and obesity. Cough (4%) was the main adverse event. Conclusion. Captopril + hydrochlorothiazide was effective and safe in the treatment of mild to moderate hypertension. The favorable response was observed in 82% of the patients independently of race, hypertensive level, previous antihypertensive treatment and obesity. Low incidence of side effects was reported, with no difference from others reported in the literature.

Assessment of vitamin A status in chronic obstructive pulmonary disease patients and healthy smokers

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

Reorganizacao do processo condilar da articulacao temporomandibular apos condilectomia unilateral, em camundongos tratados com zidovudina (AZT)

In order to analyze the reorganization of the condylar process after unilateral condylectomy in animals which have received AZT, 30 albino mice, 30 days old were used. The condylectomized animals were divided in two groups, one have received distilled water and the other AZT, orally during 10 days. After 5, 10, 15, 30 and 45 days of the surgery the animals of both groups were sacrificed, their heads removed and fixed in 10% formalin. After decalcification the pieces received histological routine treatment to be included in paraffin. The slices were stained by hematoxylin/eosin method. The analysis of results showed that: 1. the condylar repair is similar on both groups; 2. the results reaffirm those found in the literature, that the articulation after condylectomy is located in an anterior position and that the articular disc is not a determinant factor on condylar reorganization.

Nausea e vomito em laparoscopia ginecologica: Efeitos do oxido nitroso e da metoclopramida

Background and Objectives - Gynecological laparoscopy causes high postoperative morbidity, mainly due to occurrences such as nausea and vomiting. They result from a great multiplicity of etiologies and drugs used in anesthesia may function as contributing factors. Both the emetic properties of nitrous oxide and the efficacy of metoclopramide as antiemetic agent are controversial. This study was undertaken to determine the effects of both drugs, when used alone or in combination. Methods - Eighty three physical status ASA I and II women were studied. They were premedicated with midazolam before induction of anesthesia with alfentanil and propofol. Anesthesia was maintained with isoflurane with or without nitrous oxide in oxygen. Muscle relaxation was achieved with atracurium. There were 4 groups of patients: GI: midazolam, alfentanil, propofol, atracurium, isoflurane/oxygen; GII: midazolam, alfentanil, propofol, atracurium, isoflurane/nitrous oxide/oxygen; GIII: metoclopramide, midazolam, alfentanil, propofol, atracurium, isoflurane/oxygen; GIV: metoclopramide, midazolam, alfentanil, propofol, atracurium, isoflurane/nitrous oxide/oxygen. The incidence of nausea and vomiting was assessed both in the recovery room (RR) and in the ward. Results - There were no significant differences as regards age, weight and height of the patients and duration of anesthesia and surgery. Nausea and vomiting were more frequent in patients who received N2O (GII, 50%; GIV, 33%), as compared to those who didn't receive this agent (GI and GII, 9.5% and 14.35%, respectively). Metoclopramide decreased the incidence of nausea and vomiting in the recovery room, in patients who didn't receive N2O (GII). These patients remained in the recovery room for 90 minutes. Conclusions - N2O increases the incidence of nausea and vomiting and metoclopramide is effective in reducing these complications only in the recovery room.

Lipossomas: Estrategia biotecnologica para liberacao controlada e direcionamento intracelular de farmacos com efeito antimicobacteriano

This text highlights the state of research related with the application of liposomes in the control of drug delivery and drug target to intracellular bacterial diseases, such as the tuberculosis. Liposome have several pharmaceutical applications and this article is primarily focused on the potential of this agregate on drug encapsalation especially antimycobacterial compounds. Case studies in which liposomes have successfully been used to improve pharmacological drug effect are presented. Mechanisms involved in intracellular drug delivery, possibilities of application, research and development efforts to address these objectives are discussed.

The deep mycoses in HIV infection

The deep mycoses are uncommon infections, usually acquired from the inhalation or ingestion of fungal spores, sometimes from the soil in areas of endemicity, such as in the Americas and south-east Asia, or from decaying vegetable matter. They are also seen in immunocompromised persons and, increasingly, in HIV-infected persons. Respiratory involvement is frequent, with granuloma formation, and mucocutaneous involvement may be seen. Oral lesions of the deep mycoses are typically chronic but non-specific, though nodular or ulcerative appearances are common. Person-to-person transmission is rare. In HIV disease, the most common orofacial involvement of deep mycoses has been in histoplasmosis, cryptococcosis, aspergillosis and zygomycosis. Diagnosis is usually confirmed by lesional biopsy although culture may also be valuable. Treatment is with amphotericin or an azole.

Haematological and biochemical alterations in leprosy patients already treated with dapsone and MDT

Dapsone (DDS) is useful in the treatment of a number of inflammatory conditions which are characterized by neutrophil infiltration. It is the drug of choice for the treatment of leprosy and prophylaxis of malaria. Haematological side effects of methaemoglobinaemia and haemolysis have been long recognized. However, the frequency and severity of these side effects in patients already treated with DDS as a single drug or as part of a multidrug therapy (MDT) have not been well documented. We report herein an investigation of the effect of dapsone long-term treatment on the haematological and biochemical alterations in leprosy patients undergoing dapsone as a single drug (DDS group) or as part of a multidrug therapy in combination with rifampin and clofazimine (MDT group). Methaemoglobinaemia and haemolytic anaemia were the principal side effects observed. Reticulocytes were found to be elevated (> 1.5%) in 90% of the patients. Heinz bodies were also detected (6.6% of the patients). The osmotic fragility test showed a reduction in cell resistance and in the evaluation of white cells a severe eosinophilia was found. Hepatic, pancreatic and renal evaluation by the determination of biochemical parameters showed rare and occasional changes of no apparent clinical significance. We conclude that haematological side effects of dapsone are significant even at doses currently used to treat leprosy (100 mg/day) and that rifampin and clofazimine do not increase the incidence of these effects during long-term treatment.

Peridural com ropivacaina a 1%: Experiencia com volume proporcional a estatura

Background and Objectives - Ropivacaine - a local amino amide anesthetic agent - is a plain S enantiomer which makes it a potent and low toxicity drug. The aim of our study was to evaluate 1% ropivacaine for epidural block in lower doses than those described in the literature. Methods - Thirty-eight patients, physical status ASA I and II, aged 15 to 70 years, weighing 50 to 100 kg were selected. Premedication consisted of 15 mg oral midazolam given 60 min before anesthesia induction. In the OR, after standard monitoring a catheter was inserted intravenously to administer 10 ml.kg-1 Ringers lactate solution. Epidural puncture was performed with the patient in the sitting position and 1% ropivacaine was administered in a volume corresponding to 10% of patient's height in centimeters. With the patient in the supine position, motor blockade intensity, temperature sensitivity and sensory block extension at 1, 3, 5, 7, 10, 15, 20, 30 minutes after drug injection were evaluated. Blood pressure, heart rate and adverse side effects during the course of anesthesia and in the post-anesthetic period were also observed. In the recovery room patients were followed-up until motor blockade intensity temperature sensitivity and sensory block had returned to level L2. Results - Mean values were 41.4 years of age, 68.8 kg of body weight and 165 cm height. Upper thermal blockade level was T4 and upper sensory block level was T6. Most patients showed motor block level 1 (Bromage scale) after 30 minutes of observation. Motor block mean duration was 254 minutes and temperature sensitivity 426 minutes. Only three patients had complications: two cases of hypotension and one of bradycardia. Conclusions - In the volumes used in this study, ropivacaine produced adequate analgesia and a less intense lower limb motor block which, however, was sufficient to allow for surgical procedures with low incidence of side-effects.

Determination of the geometrical diarylpropenamine isomers in feces by high-performance liquid chromatography

Diarylpropenamine derivatives are a class of compounds which have been evaluated as potential drug candidates. Here a specific and reproducible HPLC method for the determination of cis- and trans-isomers of the unsubstituted derivative, 3-(4'-bromo-[1,1'-biphenyl]-4-yl)-3-(4-X-phenyl-N,N-dimethyl-2-propen-1-amine (I, where X=H) in feces is described. The analyte I and internal standard, nitro derivative (II, where X=NO2), were isolated from the basified biological matrix using a liquid-liquid extraction with ethyl acetate followed by a solid-phase procedure performed on a silica cartridge. The organic phase was evaporated to dryness, the residue was reconstituted in mobile phase and injected into the HPLC system. The analytes were eluted with ethyl acetate-hexane-triethylamine (59:40:1) in HPLC column (silica) and detected by UV spectrophotometry at 272 nm. Linearity, precision and accuracy data for feces standards after extraction were acceptable. The method has been applied to analyses of feces samples from rats dosed with I, in which it could be anticipated that fecal excretion is quantitatively the major route for I elimination. Copyright (C) 1999 Elsevier Science B.V.

The effects of Chlorella vulgaris in the protection of mice infected with Listeria monocytogenes. Role of natural killer cells

In this work we have demonstrated the effects of oral administration of Chlorella vulgaris (CV) on Natural Killer cells (NK) activity of mice infected with a sublethal dose of viable Listeria monocytogenes. The treatment with C. vulgaris produced a significant increase on NK cells activity in normal (non-infected) animals compared to the animals that received only vehicle (water) (p < 0.0001). Similarly, the infection alone produced a significant increase on NK cells activity, which was observed at 48 and 72 hours after the inoculation of L. monocytogenes. Moreover, when CV was administered in infected animals, there was an additional increase in NK cells activity which was significantly higher than that found in the infected groups (p < 0.0001) CV treatment (50 and 500mg/Kg) of mice infected with a dose of 3x105 bacteria/animal, which was lethal for all the non- treated controls, produced a dose-response protection which led to a 20% and 55% survival, respectively (p < 0.0001).

Influence of simvastatin on bone regeneration of tibial defects and blood cholesterol level in rats

The purpose of this study was to evaluate the effects of simvastatin, by oral or subcutaneous administration, on tibial defects regeneration and blood cholesterol level in rats. A surgical defect was made on the right tibia of 40 male animals assigned to 4 groups (n=10), based on two routes of administration and on the use or not of simvastatin: subcutaneous injection of simvastatin (7 mg/kg) (group AT) or only the vehicle of drug suspension (group AC), above the defect area, for 5 days; and 20 mg/kg of simvastatin macerated on water (group BT) or only water (group BC), orally, daily, during the whole observation period. The animals were sacrificed after 15 or 30 days, when blood samples were analyzed to check plasma cholesterol levels. Tibiae were removed and, after decalcification and routine laboratorial processing, histological and histomorphometrical analyses were carried out. ANOVA was used for statistical analysis at 5% signficance level. The histological and histomorphometrical analyses showed significant differences only between the experimental periods (p<0.05). Animals sacrificed after 30 days showed better bone repair (p<0.05). There was no statistically significant difference (p>0.05) for blood cholesterol levels between the groups. In conclusion, simvastatin administration either orally or subcutaneously did not improve bone repair of experimental tibial defects and did not alter blood cholesterol levels in rats.

Rapid determination of gemcitabine in plasma and serum using reversed-phase HPLC

Gemcitabine (2'2'-difluorodeoxycytidine) is a pyrimidine analog used in the treatment of a variety of solid tumors. After intravenous (i.v.) administration, it is rapidly inactivated to 2'-deoxy-2',2'-difluorouridine (dFdU). A sensitive analytical method for the quantitation of gemcitabine is required for the assessment of alternative dosage and treatment schemes. A rapid and robust RP-HPLC assay for analysis of gemcitabine in human and animal plasma and serum was developed and validated using 2'-deoxyuridine (dU) and 5-fluoro-2'-deoxyuridine (5FdU) as internal standards. It is based on protein precipitation, the use of an Atlantis dC18 column of 100 mm length (inner diameter, 4.6 mm; particle size, 3 microm) and isocratic elution using a 10 mM phosphate buffer, pH 3.0, followed by isocratic elution with the same buffer containing 3% of ACN. For gemcitabine, RSD values for intraday and interday precision were < 4.4 and 5.3%, respectively, the LOQ was 20 ng/mL, and the assay was linear in the range of 0.020-20 microg/mL with an accuracy of > or =89%. The recovery for gemcitabine, dU and 5FdU was 86-98%. The assay was applied to determine gemcitabine levels in plasma samples of patients collected during and shortly after conventional infusion of 25-30 mg/kg body mass (levels: 2.0-18.9 microg/mL) and rats that received lower doses (1.5 mg/kg) via i.v., subcutaneous and oral drug administration (levels: 0.20-2.60 microg/mL). It could also be applied to estimate dFdU levels in human plasma.

Potencies of human immunodeficiency virus protease inhibitors in vitro against Plasmodium falciparum and in vivo against murine malaria

Parasite resistance to antimalarial drugs is a serious threat to human health, and novel agents that act on enzymes essential for parasite metabolism, such as proteases, are attractive targets for drug development. Recent studies have shown that clinically utilized human immunodeficiency virus (HIV) protease inhibitors can inhibit the in vitro growth of Plasmodium falciparum at or below concentrations found in human plasma after oral drug administration. The most potent in vitro antimalarial effects have been obtained for parasites treated with saquinavir, ritonavir, or lopinavir, findings confirmed in this study for a genetically distinct P. falciparum line (3D7). To investigate the potential in vivo activity of antiretroviral protease inhibitors (ARPIs) against malaria, we examined the effect of ARPI combinations in a murine model of malaria. In mice infected with Plasmodium chabaudi AS and treated orally with ritonavir-saquinavir or ritonavir-lopinavir, a delay in patency and a significant attenuation of parasitemia were observed. Using modeling and ligand docking studies we examined putative ligand binding sites of ARPIs in aspartyl proteases of P. falciparum (plasmepsins II and IV) and P. chabaudi (plasmepsin) and found that these in silico analyses support the antimalarial activity hypothesized to be mediated through inhibition of these enzymes. In addition, in vitro enzyme assays demonstrated that P. falciparum plasmepsins II and IV are both inhibited by the ARPIs saquinavir, ritonavir, and lopinavir. The combined results suggest that ARPIs have useful antimalarial activity that may be especially relevant in geographical regions where HIV and P. falciparum infections are both endemic.

High-amylose carboxymethyl starch matrices for oral sustained drug-release : in vitro and in vivo evaluation

Les amidons non modifiées et modifiés représentent un groupe d’excipients biodégradables et abondants particulièrement intéressant. Ils ont été largement utilisés en tant qu’excipients à des fins diverses dans des formulations de comprimés, tels que liants et/ou agents de délitement. Le carboxyméthylamidon sodique à haute teneur en amylose atomisé (SD HASCA) a été récemment proposé comme un excipient hydrophile à libération prolongée innovant dans les formes posologiques orales solides. Le carboxyméthylamidon sodique à haute teneur en amylose amorphe (HASCA) a d'abord été produit par l'éthérification de l'amidon de maïs à haute teneur en amylose avec le chloroacétate. HASCA a été par la suite séché par atomisation pour obtenir le SD HASCA. Ce nouvel excipient a montré des propriétés présentant certains avantages dans la production de formes galéniques à libération prolongée. Les comprimés matriciels produits à partir de SD HASCA sont peu coûteux, simples à formuler et faciles à produire par compression directe. Le principal objectif de cette recherche était de poursuivre le développement et l'optimisation des comprimés matriciels utilisant SD HASCA comme excipient pour des formulations orales à libération prolongée. A cet effet, des tests de dissolution simulant les conditions physiologiques du tractus gastro-intestinal les plus pertinentes, en tenant compte de la nature du polymère à l’étude, ont été utilisés pour évaluer les caractéristiques à libération prolongée et démontrer la performance des formulations SD HASCA. Une étude clinique exploratoire a également été réalisée pour évaluer les propriétés de libération prolongée de cette nouvelle forme galénique dans le tractus gastro-intestinal. Le premier article présenté dans cette thèse a évalué les propriétés de libération prolongée et l'intégrité physique de formulations contenant un mélange comprimé de principe actif, de chlorure de sodium et de SD HASCA, dans des milieux de dissolution biologiquement pertinentes. L'influence de différentes valeurs de pH acide et de temps de séjour dans le milieu acide a été étudiée. Le profil de libération prolongée du principe actif à partir d'une formulation de SD HASCA optimisée n'a pas été significativement affecté ni par la valeur de pH acide ni par le temps de séjour dans le milieu acide. Ces résultats suggèrent une influence limitée de la variabilité intra et interindividuelle du pH gastrique sur la cinétique de libération à partir de matrices de SD HASCA. De plus, la formulation optimisée a gardé son intégrité pendant toute la durée des tests de dissolution. L’étude in vivo exploratoire a démontré une absorption prolongée du principe actif après administration orale des comprimés matriciels de SD HASCA et a montré que les comprimés ne se sont pas désintégrés en passant par l'estomac et qu’ils ont résisté à l’hydrolyse par les α-amylases dans l'intestin. Le deuxième article présente le développement de comprimés SD HASCA pour une administration orale une fois par jour et deux fois par jour contenant du chlorhydrate de tramadol (100 mg et 200 mg). Ces formulations à libération prolongée ont présenté des valeurs de dureté élevées sans nécessiter l'ajout de liants, ce qui facilite la production et la manipulation des comprimés au niveau industriel. La force de compression appliquée pour produire les comprimés n'a pas d'incidence significative sur les profils de libération du principe actif. Le temps de libération totale à partir de comprimés SD HASCA a augmenté de manière significative avec le poids du comprimé et peut, de ce fait, être utilisé pour moduler le temps de libération à partir de ces formulations. Lorsque les comprimés ont été exposés à un gradient de pH et à un milieu à 40% d'éthanol, un gel très rigide s’est formé progressivement sur leur surface amenant à la libération prolongée du principe actif. Ces propriétés ont indiqué que SD HASCA est un excipient robuste pour la production de formes galéniques orales à libération prolongée, pouvant réduire la probabilité d’une libération massive de principe actif et, en conséquence, des effets secondaires, même dans le cas de co-administration avec une forte dose d'alcool. Le troisième article a étudié l'effet de α-amylase sur la libération de principe actif à partir de comprimés SD HASCA contenant de l’acétaminophène et du chlorhydrate de tramadol qui ont été développés dans les premières étapes de cette recherche (Acetaminophen SR et Tramadol SR). La modélisation mathématique a montré qu'une augmentation de la concentration d’α-amylase a entraîné une augmentation de l'érosion de polymère par rapport à la diffusion de principe actif comme étant le principal mécanisme contrôlant la libération de principe actif, pour les deux formulations et les deux temps de résidence en milieu acide. Cependant, même si le mécanisme de libération peut être affecté, des concentrations d’α-amylase allant de 0 UI/L à 20000 UI/L n'ont pas eu d'incidence significative sur les profils de libération prolongée à partir de comprimés SD HASCA, indépendamment de la durée de séjour en milieu acide, le principe actif utilisé, la teneur en polymère et la différente composition de chaque formulation. Le travail présenté dans cette thèse démontre clairement l'utilité de SD HASCA en tant qu'un excipient à libération prolongée efficace.