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Neurotoxicity of amphotericin B methyl ester in dogs
W G Ellis1, E Bencken, R A LeCouteur
1Department of Pathology, School of Medicine, University of California, Davis 95616.
Abstract:
Clinical and neuropathologic effects of chronically administered intravenous (iv) amphotericin B methyl ester (AME) were observed in 3 male dogs (2 German shorthaired pointers and 1 pit bull). Each dog received 6.2-7.3 g of AME (299-327 mg/kg body weight) over a period of 11-12 weeks. One dog developed neurologic signs of severe diffuse brain dysfunction and at necropsy all 3 dogs had a marked leukoencephalopathy, most severe in centrum ovale and subcortical white matter of frontal lobes. Brain histopathology included diffuse myelin loss, oligodendrocyte depletion, accumulation of macrophages filled with sudanophilic lipid, fibrillary astrogliosis, and swelling or fragmentation of many axons. Two control dogs administered iv glucose showed no neuropathologic abnormalities. These findings closely resemble the clinical and neuropathologic abnormalities that developed in patients during the first human trial of AME for treatment of fungal infections, but differ from those of animal studies that did not closely simulate the long-term drug administration required for antifungal therapy in humans. It was concluded that before human clinical trial is authorized, experimental protocols for animal studies of drug toxicity should reflect the anticipated human use of the drug, both in dose and duration.
Insights
Chronic intravenous amphotericin B methyl ester (AME) caused severe brain dysfunction and leukoencephalopathy in dogs. Animal study protocols should mimic human drug use for accurate toxicity assessment.
Area of Science:
- Veterinary Neurology
- Toxicology
- Pharmacology
Background:
- Intravenous amphotericin B methyl ester (AME) is an antifungal agent.
- Previous human trials indicated potential neurological side effects.
- Animal models are crucial for understanding drug toxicity.
Purpose of the Study:
- To investigate the clinical and neuropathologic effects of chronic intravenous AME administration in dogs.
- To compare canine AME toxicity with human trial findings.
- To inform future animal study designs for drug toxicity.
Main Methods:
- Three male dogs received chronic intravenous AME (6.2-7.3 g over 11-12 weeks).
- Neurologic examinations and necropsies were performed.
- Brain histopathology was analyzed, including myelin, oligodendrocytes, axons, and glial cells.
- Control dogs received intravenous glucose.
Main Results:
- One dog exhibited severe diffuse brain dysfunction.
- All dogs showed marked leukoencephalopathy, particularly in the frontal white matter.
- Histopathology revealed diffuse myelin loss, oligodendrocyte depletion, axonal damage, and astrogliosis.
- Control dogs had no abnormalities.
Conclusions:
- Chronic intravenous AME administration induces significant leukoencephalopathy and neurological deficits in dogs.
- These findings closely mirror adverse effects observed in human AME trials.
- Animal toxicity studies must accurately simulate the intended human dose and duration of drug administration.