Pentoxifylline in amphotericin B toxicity rat model.
The mechanism of acute nephrotoxicity following the administration of amphotericin B (AmpB) remains unclear despite a number of studies describing hypermagnesuria, hyperkaluria, and hemodynamic changes. The present experiments attempted to elucidate the mechanism by using a novel hemorheologic probe, pentoxifylline (PTX). Acute studies were performed with rats given single intravenous doses of AmpB (1 mg/kg of body weight) with or without intraperitoneal PTX (45 mg/kg). Renal function, assessed by inulin clearance (CLIN) and electrolyte handling, and morphology were compared with those of controls given sterile water and PTX. A significant decrease in CLIN not observed in rats given AmpB and PTX or in the controls was found in rats given AmpB. Electrolyte handling was not different among groups. Whereas pronounced (3 and 4+ on a scale of mild to significant [1+ to 4+]) vascular congestion was found in rats given AmpB, rats coadministered PTX had mild (1 and 2+) medullary and glomerular vascular congestion. In chronic studies, intravenous AmpB (1 mg/kg per day) or sterile water was coadministered with intraperitoneal PTX (45 mg/kg every 12 h) or saline for 10 days. Mean CLIN of rats coadministered AmpB and PTX was not significantly different from that of PTX control rats (1.61 +/- 0.19 versus 1.31 +/- 0.29 ml/min per g of kidney weight). A 46% decline in CLIN was found in rats treated with AmpB and saline (P less than 0.05). Renal sodium and potassium excretions were increased in both AmpB-treated groups compared with controls. Coupled with histologic evidence of the acute studies, these data suggest that the benefit of PTX in the prevention of AmpB-induced nephrotoxicity is, in part, due to vascular decongestion.
Wasan
K M
KM
Department of Pharmaceutics, University of Houston, Texas.
Vadiei
K
K
Lopez-Berestein
G
G
Verani
R R
RR
Luke
D R
DR
D000666:Amphotericin B / Q000633:toxicity*; D000818:Animals; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D010431:Pentoxifylline / Q000494:pharmacology*; D051381:Rats; D012079:Renal Circulation / Q000187:drug effects; D013805:Theobromine / Q000031:analogs & derivatives*; D013997:Time Factors; D014652:Vascular Diseases / Q000139:chemically induced / Q000503:physiopathology
D000666:Amphotericin B; D013805:Theobromine; D010431:Pentoxifylline