Pharmacokinetic and pharmacodynamic responses in adult patients with Chagas disease treated with a new formulation of benznidazole

Pharmacological treatment of Chagas disease with benznidazole (BNZ) is effective in children in all stages, but it is controversial in chronically infected adults. We report the pharmacokinetics and pharmacodynamics in six adult patients with Chagas disease treated with the new BNZ formulation (ABARAX®) in doses between 2.5-5.5 mg/Kg/day. All but one patient had plasmatic BNZ concentrations within the expected range. All patients finalised treatment with nondetectable Trypanosoma cruziquantitative polymerase chain reaction, which remained nondetectable at the six month follow-up. Our data suggests parasitological responses with the new BNZ and supports the hypothesis that treatment protocols with lower BNZ doses may be effective.

Benznidazole biotransformation in rat heart microsomal fraction without observable ultrastructural alterations: comparison to Nifurtimox-induced cardiac effects

Benznidazole (Bz) and Nifurtimox (Nfx) have been used to treat Chagas disease. As recent studies have de-monstrated cardiotoxic effects of Nfx, we attempted to determine whether Bz behaves similarly. Bz reached the heart tissue of male rats after intragastric administration. No cytosolic Bz nitroreductases were detected, although microsomal NADPH-dependent Bz nitroreductase activity was observed, and appeared to be mediated by P450 reductase. No ultrastructurally observable deleterious effects of Bz were detected, in contrast to the overt cardiac effects previously reported for Nfx. In conclusion, when these drugs are used in chagasic patients, Bz may pose a lesser risk to heart function than Nfx when any cardiopathy is present.

Benznidazole vs benznidazole in multilamellar liposomes: how different they interact with blood components?

In spite of its widespread use, benznidazole's (BNZ) toxicity and low efficacy remains as major drawbacks that impair successful treatments against Chagas disease. Previously, attempting to increase the selectivity and reduce its toxicity on infected tissues, multilamellar liposomes (MLV) composed of hydrogenated soybean phosphatidylcholine (HSPC): distearoyl-phosphatidylglycerol (DSPG): cholesterol (CHOL) 2:1:2 mol:mol loaded with BNZ (MLV-BNZ) were designed. In this work we compared different properties of MLV-BNZ with those of BNZ. Opposite to other hydrophobic drugs, the results indicated that slight changes of BNZÎs association degree to proteins and lipoproteins should not modify the percentage of unbound drug available to exert pharmacological action. On the other hand, when loaded in MLV, BNZ reduced its association to plasma proteins in 45 percent and became refractory to the sinking effect of blood, dropping 4.5 folds. Additionally, when loaded in MLV, BNZ had higher volume distribution (160 ± 20 vs 102 ± 15 ml/kg) and total clearance (35.23 ± 2.3 vs 21.9 ± 1.4 ml/h.kg), and lower concentration-time curve (7.23 ± 0.2 vs 9.16 ± 0.5 æg.h/ml) than BNZ. Hence, these studies showed that for MLV-BNZ, the amount of BNZ can be substantially increased, from 25 to 70 percent, being this formulation more rapidly cleared from circulation than free drug; also due to the lower interaction with blood components, lower side effects can be expected.

Stability-indicating assay of secnidazole in the presence of its degradation products

Four new selective, precise and accurate first derivative spectrophotometric, RP-HPLC, TLC densitometric and colorimetric methods were described for the determination of secnidazole in the presence of its degradation products, 2-methyl-5-nitroimidazole and hydroxy propanol. These methods were suitable for stability testing of secnidazole in bulk powder retaining their accuracy in the presence of up to 70% and 90% of its degradation product. The proposed methods were applied for the analysis of pharmaceutical formulations and the recoveries were 99.40-100.52%. The results obtained agreed with the reported method

Comportamento voltamétrico e mecanismo de ação biológica de nitroimidazóis / Mechanism of biological action and voltammetric behaviour of nitroimidazoles

Os derivados nitroimidazólicos são fármacos que apresentam amplo espectro de ação e possuem mecanismo de redução complexo. A ação biológica dos nitrocompostos é dependente da redução do grupo nitro. O radical nitro aniônico e o derivado hidroxilamínico são os principais intermediários responsáveis pela ação citotóxica dos nitroimidazóis. Este artigo de revisão discute o mecanismo de ação biológica dos nitroimidazóis e de que modo as técnicas voltamétricas apresentam-se como altenativa para a compreensão do mecanismo de redução desse grupo de fármacos e suas correlações com atividade biológica, seletividade tóxica e eficiência terapêutica. Aborda, também, os principais aspectos do comportamento voltamétrico do metronidazol, tendo o eletrodo de gota de mercúrio como eletrodo de trabalho, além dos recentes avanços no uso de eletrodo de carbono vítreo modificado com DNA aplicado à análise e ao estudo do mecanismo de ação de fármacos