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Temporal development of 2',3'-dideoxyinosine (ddI)-induced peripheral myelinopathy
T A Patterson1, L C Schmued, J A Sandberg
1Division of Neurotoxicology, National Center for Toxicological Research/FDA, 72079-9502, Jefferson, AR, USA. tpatterson@nctr.fda.gov
Abstract:
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.
Insights
Dideoxyinosine (ddI), an anti-HIV drug, causes peripheral neuropathy. This study in rats shows significant nerve damage after 15 weeks of ddI, with some recovery by 20 weeks.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- Dideoxyinosine (ddI) is an anti-HIV medication known to cause peripheral neuropathy.
- Previous studies in rats showed ddI induces myelinopathy characterized by myelin splitting and intramyelin edema.
Purpose of the Study:
- To investigate the time course of ddI-induced neuropathy in a rat model.
- To determine the onset and progression of ddI-induced peripheral myelinopathy.
Main Methods:
- Adult male Sprague-Dawley rats received vehicle or ddI (415 mg/kg) twice daily for up to 20 weeks.
- Sciatic nerves were collected at 5, 10, 15, and 20 weeks for histological examination.
- Nerve tissues were processed, sectioned, and stained with toluidine blue and basic fuchsin.
Main Results:
- Few abnormalities were noted at 5 or 10 weeks of ddI administration.
- Prominent myelin splitting and ballooned myelin sheaths were observed in 4 out of 6 rats after 15 weeks.
- While abnormalities persisted at 20 weeks, the severity was less pronounced than at 15 weeks, suggesting partial recovery.
Conclusions:
- Peripheral neuropathy induced by ddI in rats develops significantly after 15 weeks of chronic administration.
- The findings suggest a potential for partial nerve recovery despite continued ddI exposure.