Augmented arterial pressure responses to cyclosporine in spontaneously hypertensive rats. Role of cytochrome P-450 3A.

Evidence to support a hypertensinogenic role of family 3A cytochrome P-450 (CYP3A) activity is that troleandomycin, a selective inhibitor of CYP3A, decreases both blood pressure and in vivo corticosterone 6 beta-hydroxylation in spontaneously hypertensive rats (SHR). Renal CYP3A activity is markedly increased in SHR compared with Wistar-Kyoto (WKY) rats. Cyclosporine acutely increases both systolic blood pressure and renal total cytochrome P-450 in SHR. We tested the hypothesis that the augmentation of blood pressure by cyclosporine is mediated by a further increase in renal CYP3A activity. Accordingly, we assessed the effect of troleandomycin administration on cyclosporine-induced systolic blood pressure increase and renal and hepatic microsomal CYP3A activity in SHR. Cyclosporine (5 mg/kg SC) given daily in 11-week-old SHR resulted in substantial augmentation of blood pressure after 6 days. This blood pressure increase was attenuated by troleandomycin (40 mg/kg) given either during or after development of hypertension. Cyclosporine increased renal (60%) but decreased hepatic (25%) microsomal CYP3A activity in SHR. In contrast, cyclosporine failed to produce any detectable increase in either blood pressure or renal CYP3A activity in WKY rats. Troleandomycin completely inhibited renal CYP3A activity measured after cyclosporine treatment of SHR, which correlated with its attenuation of the cyclosporine-induced blood pressure increase. These findings suggest that renal CYP3A could play an important role in acute cyclosporine-induced hypertension.

Serum antibacterial activity after oral suspensions and capsules of triacetyloleandomycin and erythromycin estolate.

Comparison of serum antibacterial activity against a beta-hemolytic streptococcus and a penicillin-resistant staphylococcus was made in a cross-over study in volunteers after ingestion of oral suspensions and capsules of triacetyloleandomycin and erythromycin estolate. Oral suspensions yielded earlier peak titers, but ultimate peak titers and duration of activity were similar to those observed after ingestion of capsules. Antibacterial activity of serum against both organisms was consistently greater with both erythromycin estolate preparations than with the triacetyloleandomycin preparations. These in vitro data were comparable to observations made previously in monkeys infected with the same organisms, although comparative clinical efficacy in monkeys did not reflect these implied therapeutic differences.

Therapy of staphylococcal infections in monkeys. IV. Further comparison of triacetyloleandomycin and erythromycins.

Intravenous inoculation of a penicillin-resistant, phage type 80/81 staphylococcus caused lethal infection in 8 of 15 untreated monkeys. Daily intragastric administration of 50 mg/kg of triacetyloleandomycin, erythromycin estolate, and erythromycin ethylsuccinate was followed by mortalities of 0 of 16, 3 of 16, and 3 of 10, respectively. At dose levels of 25 and 12.5 mg/kg, none of 7 and 4 of 7 receiving triacetyloleandomycin and erythromycin estolate, respectively, died, as compared to 3 of 4 deaths in controls. In vitro sensitivity data and serum antibacterial levels would suggest that triacetyloleandomycin would be the least effective therapeutically. However, this prediction was not fulfilled in these studies of experimental infections in monkeys wherein triacetyloleandomycin was a very effective antimicrobial agent.