Attenuation of amphotericin-B nephrotoxicity in the candidiasis rat model

Dose-limiting nephrotoxicity has hampered the clinical usefulness of amphotericin-B (AmpB). Recently, vascular decongestants, such as pentoxifylline, have shown benefit in reducing drug-associated renal damage of AmpB in rats. The present study investigated a dose-dependent protection of a structurally similar methylxanthine, HWA-448, in the candidiasis rat model given a single dose of AmpB. Forty-eight hours after inoculation with Candida albicans, each rat was treated with 0.8 mg/kg of AmpB or sterile water; animals were further randomized to receive 0.5, 1, 5, or 10 mg/kg i.v. of HWA-448 or saline given every 12 h for 3 doses. Kidney fungal counts, morphology, and renal function were compared between treatment groups upon completion of the study. Rats administered AmpB with HWA-448 had markedly improved renal function compared with those given AmpB alone; these effects were independent of the administered dose of HWA-448. The antifungal effect of AmpB was not impaired with concomitant HWA-448. Marked accumulation of granulomas and organisms was found in all rat groups. In summary, coadministration of low doses of HWA-448 attenuated the dose-limiting nephrotoxicity without impairing the antifungal effect of AmpB.