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Pentoxifylline in amphotericin B toxicity rat model
K M Wasan1, K Vadiei, G Lopez-Berestein
1Department of Pharmaceutics, University of Houston, Texas.
Abstract:
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.
Insights
Pentoxifylline (PTX) mitigates amphotericin B (AmpB)-induced nephrotoxicity in rats by reducing vascular congestion. This hemorheologic agent preserves renal function and prevents significant declines in inulin clearance when coadministered with AmpB.
Area of Science:
- Nephrology
- Pharmacology
- Toxicology
Background:
- Amphotericin B (AmpB) is a critical antifungal agent, but its use is limited by significant nephrotoxicity.
- The precise mechanisms underlying AmpB-induced kidney damage, including hemodynamic alterations, remain incompletely understood.
- Pentoxifylline (PTX), a hemorheologic agent, has shown potential in modulating inflammatory and vascular responses.
Purpose of the Study:
- To investigate the protective effects of pentoxifylline (PTX) against acute amphotericin B (AmpB)-induced nephrotoxicity in a rat model.
- To elucidate the potential role of PTX in mitigating AmpB-related vascular congestion and preserving renal function.
Main Methods:
- Acute and chronic studies were conducted in rats using intravenous AmpB with or without intraperitoneal PTX.
- Renal function was assessed by inulin clearance (CLIN) and electrolyte handling.
- Renal morphology, specifically vascular congestion in the medulla and glomeruli, was evaluated histologically.
Main Results:
- AmpB administration significantly decreased inulin clearance (CLIN), an effect attenuated by coadministration of PTX.
- Histological analysis revealed marked vascular congestion in rats treated with AmpB alone, which was significantly reduced by PTX.
- In chronic studies, PTX coadministration prevented the substantial decline in CLIN observed in rats treated with AmpB and saline.
Conclusions:
- Pentoxifylline (PTX) demonstrates a protective effect against acute amphotericin B (AmpB)-induced nephrotoxicity.
- The renoprotective benefit of PTX appears to be mediated, at least in part, by its ability to reduce vascular congestion in the kidney.
- These findings suggest PTX as a potential adjunct therapy to mitigate AmpB-related renal damage.