Peripheral neuropathy induced by 2',3'-dideoxycytidine. A rabbit model of 2',3'-dideoxycytidine neurotoxicity.
The nucleoside analog 2',3'-dideoxycytidine (ddC) is a potent inhibitor of the reverse transcriptase of human immunodeficiency virus and a DNA chain terminator. In clinical trials in patients with acquired immunodeficiency syndrome, ddC treatment has been associated with a dose-limiting and dose-dependent, painful, sensorimotor peripheral neuropathy. In search of an animal model for ddC-induced neurotoxicity we studied 36 New Zealand White rabbits (3 males/3 females/group) given 0, 10, 50, 100, 150, or 250 mg/kg/day of ddC, by oral intubation, for 13 or 18 weeks. Rabbits in the 150 and 250 mg/kg/day groups were sacrificed at 13 weeks because of hematopoietic toxicity. After 16 weeks, rabbits in the 50 and 100 mg/kg/day groups showed hindlimb paresis and/or gait abnormalities. Nerve conduction velocities and amplitudes in the 100 mg/kg/day rabbits were reduced by 30 to 50%. The most prominent pathologic changes in peripheral nerve and ventral roots of ddC-treated rabbits were (a) myelin splitting and intramyelinic edema, (b) demyelination and remyelination of axons, and (c) axonal loss. Treatment-related histologic lesions were not observed in spinal cord, brain, or retina. The pathology in these ddC-treated rabbits is consistent with a peripheral myelinopathy and axonopathy. This represents the first clinical, electrophysiologic, and pathologic description of an animal model of a peripheral neuropathy induced by a nucleoside analog.
Anderson
T D
TD
Department of Toxicology and Pathology, Hoffmann-La Roche Inc., Nutley, New Jersey.
Davidovich
A
A
Arceo
R
R
Brosnan
C
C
Arezzo
J
J
Schaumburg
H
H
D000284:Administration, Oral; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005260:Female; D008297:Male; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009431:Neural Conduction / Q000187:drug effects; D010291:Paresis / Q000139:chemically induced / Q000503:physiopathology; D010525:Peripheral Nerves / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000401:mortality / Q000473:pathology; D011817:Rabbits; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D016047:Zalcitabine / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology
D016047:Zalcitabine