Temporal development of 2 ',3 '-dideoxyinosine (ddI)-induced peripheral myelinopathy

The anti-HIV therapeutic dideoxyinosine (ddI) has been reported to produce a painful, dose-limiting peripheral myelinopathy in HIV-infected patients a fter chronic administration. We have previously demonstrated ddI-induced my elinopathy in a non-HIV-infected rat model after 20 weeks of dosing, charac terized by myelin splitting and intramyelin edema. The present study examin ed 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) anim als 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 n eutral phosphate-buffered formalin, dehydrated in graded alcohols, and embe dded 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 mu g/ml within the first hour after dosing and fell rapidly to less than 1 mu g/ml (clinical range 1 -2 mu g/ml) within 3 h after dosing. The abnormalities observed in the scia tic nerve were few, if any, after 5 or 10 weeks, but very prominent after 1 5 weeks of dosing. Four of the six ddI-treated rats exhibited abnormal morp hology as evidenced by myelin splitting and ballooned myelin sheaths. Altho ugh abnormal morphology was present at 20 weeks of dosing, the effect was n ot as robust as at 15 weeks. This suggests that the nerve may partially rec over from the effects of ddI with time. Published by Elsevier Science Inc.