This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Distal symmetric peripheral neuropathy (DSPN) is the most frequent neurologic complication of HIV infection and its treatments. To date, there are no effective treatments for DSPN. The pathology of DSPN involves a length-dependent degeneration of peripheral nerve fibers, however, the pathogenesis remains unknown. In clinical trials, treatment with recombinant human nerve growth factor (rhNGF) improved global pain assessments and pin sensitivity; however, there was no improvement in neuropathy severity as assessed by neurological examination (1, 2). Despite reported symptomatic improvement with rhNGF, it is not approved by the Food and Drug Administration (FDA) for treatment of DSPN in HIV and is not available for use from the manufacturer. In another trial (ACTG 242), neither Mexiletine nor Amitriptyline provided significant pain relief for HIV-associated DSPN. Acetyl-L-carnitine (ALC) is a transport molecule for fatty acids across the mitochondrial membrane via the 'Carnitine Shuttle.' Contrasting evidence exists concerning the benefit of ALC in neuropathy treatment, as described below. A possible mechanism for ALC's effect in treating dideoxynucleoside-associated DSPN involves ALC providing a necessary substrate to improve fatty acid transport across the mitochondrial matrix. It is also possible that ALC works through nerve growth factor (NGF). Other postulated mechanisms of action for ALC include enhanced neuronal metabolism and cholinergic neural transmission, direct effects on post-synaptic inhibition potentials, and direct stimulation of synapses. While the correlation to neuropathy is not clear, research in other tissues supports a beneficial effect of ALC for HIV-1 seropositive individuals. However, contrasting data exist concerning serum ALC levels in patients with DSPN. This open-label dose-escalation pilot study hopes to clarify the initial reports concerning efficacy of DSPN and to determine drug safety and tolerability. Goals: The purpose of the study is to determine whether ALC reduces pain, numbness and/or tingling in the feet and/or legs, and to determine whether it is safe and tolerable in people living with HIV who have taken anti-HIV drugs such as Zalcitabine (ddC), Didanosine (ddI), or Stavudine (d4T). The primary objectives are to determine changes in intraepidermal innervation associated with ALC use by immunohistochemical quantification of skin biopsy nerve fiber density from baseline to week 24, and to assess the safety, toxicity, and tolerability of ALC in the treatment of dideoxynucleoside-associated DSPN. The secondary objectives are to assess the effect of ALC on the degree of mitochondrial depletion through quantification of mitochondrial DNA (mtDNA) in subcutaneous fat (obtained from skin fat biopsies) before and after intervention, and to assess the effect of ALC on the signs and symptoms of dideoxynucleoside-associated DSPN as measured by neurologic examination and the Gracely pain scale. Experimental Design: This is a multicenter, open-label, 24-week pilot study with dose-escalations of ALC for the treatment of DSPN associated with dideoxynucleoside analogues in 36 HIV-infected subjects.
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