Immunochemical evidence against the involvement of cysteine conjugate beta-lyase in compound A nephrotoxicity in rats.

BACKGROUND: Compound A, a degradation product of sevoflurane, causes renal corticomedullary necrosis in rats. Although the toxicity of this compound was originally hypothesized to result from the biotransformation of its cysteine conjugates into toxic thionoacyl halide metabolites by renal cysteine conjugate beta-lyase, recent evidence suggests that alternative mechanisms may be responsible for compound A nephrotoxicity. The aim of this study was to evaluate these issues by determining whether mercapturates and glutathione conjugates of compound A could produce renal corticomedullary necrosis in rats, similar to compound A, and whether renal covalent adducts of the thionacyl halide metabolite of compound A could be detected immunochemically. METHODS: Male Wistar rats were administered, intraperitoneally, N-acetylcysteine conjugates (mercapturates) of compound A (90 or 180 micromol/kg) or glutathione conjugates of compound A (180 micromol/kg) with or without intraperitoneal pretreatments with aminooxyacetic acid (500 micromol/kg) or acivicin (250 micromol/kg). Rats were killed after 24 h, and kidney tissues were analyzed for toxicity by histologic examination or for protein adducts by immunoblotting or immunohistochemical analysis, using antisera raised against the covalently bound thionoacyl halide metabolite of compound A. RESULTS: Mercapturates and glutathione conjugates of compound A both produced renal corticomedullary necrosis similar to that caused by compound A. Aminooxyacetic acid, an inhibitor of renal cysteine conjugate beta-lyase, did not inhibit the toxicity of the mercapturates, whereas acivicin, an inhibitor of gamma-glutamyltranspeptidase, potentiated the toxicity of both classes of conjugates. No immunochemical evidence for renal protein adducts of the thionacyl halide metabolite was found in rats 24 h after the administration of the mercapturates of compound A or in the kidneys of rats, obtained from a previous study, 5 and 24 h after the administration of compound A. CONCLUSION: The results of this study are consistent with the idea that a mechanism other than the renal cysteine conjugate beta-lyase pathway of metabolic activation is responsible for the nephrotoxicity of compound A and its glutathione and mercapturate conjugates in male Wistar rats.

Atypical extrapulmonary presentations of severe respiratory syncytial virus infection requiring intensive care.

The patterns and nature of a four-month epidemic of severe respiratory syncytial virus (RSV)-associated disease were analyzed using presenting, demographic, clinical, and therapeutic data. Of 218 infants with RSV infection admitted to Rainbow Babies and Childrens Hospital, 49 (22.4%), most born prematurely, entered the pediatric intensive care unit (PICU). Fluorescent antibody and/or enzyme-linked immunosorbent assay documented RSV infection. PICU patients underwent airway stabilization; 53.5% were intubated and evaluated for sepsis. Patients with positive bacterial cultures received antibiotics; 18% were given ribavirin. Patterns of infection included hypothermia, septic shock appearance, apnea, pneumonia, and wheezing due to bronchiolitis. The average age difference between patients with hypothermia (23.3 days) and those with pneumonia (11.2 months) was statistically significant. There were no significant differences in average age, gestational age at birth, number intubated, worst pH and PCO2, duration of intensive care, or treatment modalities between infants with bronchopulmonary dysplasia who received ribavirin and those who did not.