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The anti-HIV therapeutic dideoxyinosine (ddI) has been reported to produce a painful, dose-limiting peripheral myelinopathy in HIV-infected patients after chronic administration. We have previously demonstrated ddI-induced myelinopathy in a non-HIV-infected rat model after 20 weeks of dosing, characterized by myelin splitting and intramyelin edema. The present study examined the time course needed to produce the ddI-induced neuropathy. Adult male Sprague-Dawley rats were gavaged with vehicle or 415 mg/kg ddI twice daily for up to 20 weeks. Groups of treated (n = 6-8) and control (n = 3-5) animals were killed after 5, 10, 15, and 20 weeks of dosing and the distal end of the sciatic nerve was removed. The nerve was postfixed by immersion in neutral phosphate-buffered formalin, dehydrated in graded alcohols, and embedded in plastic embedding media. One-micrometer-thick sections were cut and stained with toluidine blue and basic fuchsin. Plasma levels of ddI on the day the animals were killed were greater than 10 microgram/ml within the first hour after dosing and fell rapidly to less than 1 microgram/ml (clinical range 1-2 microgram/ml) within 3 h after dosing. The abnormalities observed in the sciatic nerve were few, if any, after 5 or 10 weeks, but very prominent after 15 weeks of dosing. Four of the six ddI-treated rats exhibited abnormal morphology as evidenced by myelin splitting and ballooned myelin sheaths. Although abnormal morphology was present at 20 weeks of dosing, the effect was not as robust as at 15 weeks. This suggests that the nerve may partially recover from the effects of ddI with time. Published by Elsevier Science Inc.

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.