Arek Tabak

N-acetylcysteine increases the glutathione content and protects rat alveolar type II cells against paraquat-induced cytotoxicity

A protective effect of N-acetylcysteine in oxidative lung damage was reported by a number of workers; however, the mechanism underlying this effect was not thoroughly elucidated. The present research investigates the protection by N-acetylcysteine against paraquat-induced cytotoxicity to alveolar type II cells, which are known to be specific targets of paraquat toxicity in vivo. We found that addition of 1 mM N-acetylcysteine to alveolar type II cells incubated with 1 mM paraquat reduced the cytotoxic index from 17.4 +/- 1.3% to 9.3 +/- 1.5%. This effect could not be explained by the interference of N-acetylcysteine with the active uptake of paraquat by type II cells. Incubation of these cells with N-acetylcysteine enhances their glutathione content, thus reducing the paraquat- induced depletion of glutathione in these cells. These results suggest that N-acetylcysteine exerts its protective effect by acting as a precursor for glutathione in alveolar type II cells.

Evaluation of a Liposome System for the Delivery of Desferrioxamine to Lungs in Rats

Abstract— Liposomes with various lipid composition and sizes, prepared by two different techniques were evaluated for their potential to deliver desferrioxamine to lungs as a treatment against oxidative lung damage. Multilamellar vesicles (MLV) and reverse evaporation vesicles were prepared out of a lipid mixture containing dipalmitoyl phosphatidylcholine, stearyl amine, cholesterol and vitamin E. The administration of desferrioxamine‐encapsulated liposomes to rats by the intravenous route at a dose of 100 mg kg−1, significantly prolonged the presence of desferrioxamine in all the tested organs when compared with the administration of free desferrioxamine. The injection of reverse evaporation vesicles extruded through a 2 μm polycarbonate membrane exhibited a longer residence time of the desferrioxamine and of liposomal vitamin E in lungs compared with the other types of liposomes tested. The examination of liposome components in the bronchoalveolar lavage fluid (BALF) and the alveolar macrophages recovered from BALF revealed that about 7 × 10−3% of the administered desferrioxamine dose was recovered by this technique at 3 and 17 h after liposome administration. This high residual concentration in the alveolar space confirms the hypothesis that liposomes can be delivered to the lung tissue when encapsulated in alveolar macrophages.

A simple approximation for Busulfan dose adjustment in adult patients undergoing bone marrow transplantation

Busulfan is an alkylating agent used in preparative regimens before bone marrow transplantation (BMT). Busulfan concentrations in plasma, expressed as the area under the concentration–time curve (AUC), were reported to correlate with treatment outcome. Because busulfan is administered in 16 doses of 1 mg/kg every 6 hours for 4 days, the opportunities to “correct” the dose as a consequence of the measured AUC are limited to the 16-dosage protocol. In the present research busulfan pharmacokinetics were prospectively evaluated in 27 adult patients treated according to the above protocol by measuring the first, second, and fifth dose AUC. The pharmacokinetic analysis was based on a noncompartment model for extravascular absorption, but calculations according to a 1-compartment model gave similar results. A simple mathematical approximation allowed prediction of the AUC of the second dose from that of the first and the busulfan concentration at trough. Fifteen patients had the dose adjusted at the fourth dose to obtain an AUC within the “therapeutic window” of 950–1500 μM-min. This procedure was then validated by the measurement of the fifth dose AUC. It appears that this simple pocket calculator method allows a rapid evaluation of the need and the extent of dose adjustment and proved to be a valuable tool to improve busulfan administration in pre BMT treatment.

Monitoring of busulfan area under the curve : Estimation by a single measurement

Because the busulfan area under the concentration–time curve (AUC) has been correlated with the outcome of bone marrow transplantation (BMT) and the occurrence of veno-occlusive disease after BMT, a rapid determination of AUC is needed to ensure its suitable dosage. The present work describes a method based on combining aliquots from the 10 blood samples collected for an AUC busulfan determination and performing a single determination of the resulting mixture. In 42 patients undergoing a preparative regimen for bone marrow transplantation this combined sample AUC was compared with the regular determined AUC obtained from 10 consecutive samples drawn at various time intervals after dosing. It is apparent that the AUCs calculated by pharmacokinetic analysis using a noncompartmental model package and those obtained by analyzing the sample mixture are very similar (r = 0.961). The proposed method allows rapid adjustment of the busulfan dose, reducing the number of uncorrected dosages during therapy.