Comparative neurotoxicities of amphotericin B and its mono-methyl ester derivative in rats.
The intracisternal administration of amphotericin B (AmB) and its mono-methyl ester derivative (AME), via direct intraventricular injection (0.01 to 5 mg/ml, 6 microliters) in adult female Wistar rats, revealed that AmB was significantly more toxic than AME, as measured by weight loss, lethargy, death, and central nervous system histopathology. Light and electron microscopy confirmed a greater neurotoxicity for AmB, manifested as edema and modest gliosis extending along and beyond the injection tract. Neuronal degeneration and myelin damage were present in AmB-treated (1 mg/ml) animals but were present only modestly in animals treated with AME at a fivefold greater concentration. Intravenous administration of AmB to adult female Wistar rats as five daily doses of 5 mg/kg of body weight resulted in significant weight loss and some deaths. Histopathologic examination of the brains, spinal cords, and sural nerves of surviving animals revealed neurotoxicity manifested by neuronal degeneration, gliosis, and myelin edema. In sharp contrast, similar treatment with AME at a 10-fold greater dose resulted in neither death nor significant neurotoxicity. The administration of five daily doses of a mixture of AME-AmB (9:1; wt/wt) at 50 mg/kg of body weight resulted in neurotoxicity. These results indicate that AmB exhibits significantly greater in vivo neurotoxicity than AME.
Department of Pharmacology and Toxicology, College of Pharmacy, Rutgers-The State University of New Jersey, Piscataway 08855-0759.
K R
KR
Reuhl
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M
Vapiwala
M T
MT
Ryzlak
C P
CP
Schaffner
D000666:Amphotericin B / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D000935:Antifungal Agents / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D001927:Brain Diseases / Q000139:chemically induced / Q000473:pathology; D004338:Drug Combinations; D005260:Female; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D009410:Nerve Degeneration / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
D000935:Antifungal Agents; D004338:Drug Combinations; C017501:methylamphotericin B; D000666:Amphotericin B