Evaluation of brain and nerve pathology in rats chronically dosed with ddI or isoniazid.
The antiviral adenosine analog, 2',3'-dideoxyinosine (ddI), and the antitubercular nicotinic acid analogue, isoniazid, have recently received widespread clinical application in the treatment of acquired immunodeficiency syndrome (AIDS). Clinical studies indicate that the primary dose limiting side effect of both drugs is neurological in nature. Most clinical studies are confounded by the fact that the observed neuropathy must be evaluated in the presence of the ongoing disease process associated with human immunodeficiency virus (HIV) infection. The purpose of this study was to develop and validate a rat model of ddI-and isoniazid-induced neuropathy in the absence of any disease-induced pathology. Myelin splitting and intramyelin edema were the most frequent abnormalities observed in the sciatic nerves of ddI-dosed animals, whereas whorls, extracellular debris, macrophages, and reduced myelinated axon number were seen following chronic isoniazid administration. Isoniazid also resulted in myelinopathy of the CNS. Thus, contrary to previous reports, the rodent is a suitable model for ddI- and isoniazid-induced neuropathies.
Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA.
L C
LC
Schmued
C M
CM
Albertson
A
A
Andrews
J A
JA
Sandberg
J
J
Nickols
W
W
Slikker
D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity; D000995:Antitubercular Agents / Q000633:toxicity; D001369:Axons / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D016049:Didanosine / Q000009:adverse effects / Q000633:toxicity*; D004487:Edema; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D007538:Isoniazid / Q000633:toxicity*; D008297:Male; D008407:Mast Cells / Q000473:pathology; D009186:Myelin Sheath / Q000473:pathology; D009431:Neural Conduction / Q000187:drug effects*; D009498:Neurotoxins / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology* / Q000502:physiology
D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D009498:Neurotoxins; D016049:Didanosine; D007538:Isoniazid