Acetyl-carnitine deficiency in AIDS patients with neurotoxicity on treatment with antiretroviral nucleoside analogues.
OBJECTIVE
A severe dose limiting axonal peripheral neuropathy may develop in subjects on treatment with the nucleoside analogues didanosine (ddl), zalcitabine (ddC), and stavudine (d4T). The impairment of mitrochondrial DNA synthesis is crucial to the pathogenesis of this disorder although other mechanisms have not been ruled out. The depletion of acetyl-carnitine, which regulates the metabolism and function of peripheral nerves could contribute to the neurotoxicity of these compounds.


METHODS
Non-randomized, cross-sectional study of selected patients.


METHODS
We measured the serum levels of acetyl- and total carnitine in 12 subjects with axonal peripheral neuropathy developed on treatment with different regimens of neurotoxic nucleoside analogues (ddl, ddC, d4T). Subjects who did not develop peripheral neuropathy while staying on treatment with ddl (n = 10) or zidovudine (n = 11) served as the control groups. HIV-negative subjects with axonal on demyelinating autoimmune neuropathies (n = 10) and healthy individuals (n = 13) were additional control groups.


RESULTS
Subjects experiencing axonal peripheral neuropathy on treatment with ddl, ddC and d4T had significantly reduced levels of acetyl-carnitine in comparison to the control groups. No difference was observed in the levels of total carnitine between study subjects and the control groups.


CONCLUSIONS
Our results demonstrate that subjects who developed peripheral neuropathy while staying on treatment with ddl, ddC and d4T had acetyl-carnitine deficiency. The normal levels of total carnitine in the study group appear to indicate the specificity of the defect and rule out coexisting relevant nutritional problems. The critical role of acetyl-carnitine for the metabolism and function of the peripheral nerves supports the view that the acetyl-carnitine deficiency found in these subjects may contribute to the neurotoxicity of ddl, ddC and d4T, even though the interference with mitochondrial DNA synthesis is regarded as the main cause of their toxicity.
Famularo
G
G
Department of Infectious Diseases, University of L'Aquila, Italy.
Moretti
S
S
Marcellini
S
S
Trinchieri
V
V
Tzantzoglou
S
S
Santini
G
G
Longo
A
A
De Simone
C
C
D000108:Acetylcarnitine / Q000097:blood / Q000172:deficiency*; D000163:Acquired Immunodeficiency Syndrome / Q000097:blood / Q000188:drug therapy*; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001369:Axons / Q000473:pathology; D003430:Cross-Sectional Studies; D016049:Didanosine / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010523:Peripheral Nervous System Diseases / Q000097:blood / Q000139:chemically induced*; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D018119:Stavudine / Q000009:adverse effects / Q000627:therapeutic use; D016047:Zalcitabine / Q000009:adverse effects / Q000627:therapeutic use
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D000108:Acetylcarnitine; D016047:Zalcitabine; D018119:Stavudine; D016049:Didanosine