Mike Youle reported on this study of using LAC to improve peripheral neuropthy and evaluate its effectiveness by immunohistochemical quantification of cutaneous innervation.  Innervation is nerve supply to muscle, skin, etc.

Peripheral neuropathy affects 10-35% of HIV patients, and 11-55% of patients on NRTIs. NRTIs impair neuronal mitochondrial DNA synthesis and repair. Youle said there is a high incidence of peripheral neuropathy in patients but it has stopped going up because ddC is not used anymore. He'd like to recycle ddC, but feels its not an option due to the high incidence of peripheral neuropathy.. We're not quite sure what the underlying pathogenesis is for peripheral neuropathy, but there appears to be some underlying mitochondrial dysfunction involved. Treatment often consists of withdrawing nucleoside analogues or giving such drugs as anti-epileptics, elavil, pain killers, antiinflammatories like tylenol, and others. But on the whole these drug interventions have not proved themselves to be particularly beneficial. At the moment there is no effective pathogenesis based treatment.

Youle offered a potential explanation for the pathogenesis of symptoms. In poly neuropathy, you're basically seeing sensory neuronal death and perhaps an altered central processing, as well as cutaneous sensory organ loss with denervation atrophy. And perhaps some mitochondrial metabolic disturbance which might be making this worse.

The technique of immunohistochemistry (IC) has been used in leprosy and diabetes since the early 1990s. IC uses dyes that have antibodies to nerve tissue to detect the presence of affected nerve tissue that is obtained by biopsy. Youle said IC correlates with clinical tests, but is more sensitive in studies of leprosy and diabetes. In diabetes he said IC detects decreased cutaneous innervation earlier in disease course than clinical tests of nerve function. So if you biopsy people who then go on to develop more severe peripheral neuropathy you can see a change at the level of the skin.

LAC is designated as a drug in some countries, but is available over the counter in others. Youle reviewed why he thinks LAC may be helpful in peripheral neuropathy in AIDS. He said there is some in vitro and in vivo data suggesting LAC may play a physiological role, such as affecting FFA (free fatty acid) transport into mitochondria.

He said LAC is a physiological transport molecule for free fatty acids across mitochondrial membranes and enhances retrograde neurotropic support of sensory neurons. Many people have tried to use carnitine which is available in all countries, but Youle said probably you need acetyl carnitine in peripheral neuropathy. It appears as though no one is particularly certain why acetyl carnitine is preferable but it could that something to do with different carnitine requirements within each cell line.

LAC may play a neuroprotective role. Youle reviewed data references suggesting that there has been seen improved cell survival in vitro, improved nerve regeneration in animal models, and LAC reduces diabetic neuropathy in animal models. He referred to perhaps the largest study of LAC which was conducted in diabetes, and in which 1100 patients were treated with LAC or placebo. Although there was a trend towards significance of benefit with LAC in that study, there was no statistical significant benefit seen with LAC. He suggested the reason for this outcome may be because in diabetes there is no mitochondrial damage, in diabetes itís a vascular problem. There appears to be decreased serum levels for people treated with nucleoside analogues and who experience neuropathy. There has been one published study showing that LAC improves symptoms of symmetrical polyneuropathy in HIV.

Youle posed these questions: do neuropathic symptoms reflect a loss of cutaneous innervation? Is IC an objective, reliable, reproducible, and quantitative assessment tool?

This study was designed to evaluate the effect of LAC on epidermal nerve fibre density. Does oral LAC treatment for patients with HIV related neuropathy improve symptoms of symetrical polyneuropathy, and restore cutaneous nerve innervation?

This study is an open, observational cohort study (n=4) that assessed the efficacy of 6 months of oral LAC therapy (1500mg twice daily) upon established HIV drug related HIV peripheral neuropathy (grade 3-4). These 4 patients had NRTI related neuropathy. Three patients remained on NRTIs throughout the study period. There are 20 patients in total who have had 6 months of therapy and are being biopsied. Youle mentioned a few patients who took LAC for 8 weeks and saw no improvement, but he suggested that it may take considerably longer to improve the type of damage that has occurred.

Skin biopsies from a standardized site in the leg at baseline and following 6 months of LAC were evaluated. Innervation within epidermis, dermis, and sweat glands was quantified by image analysis of immunohistochemistry using fibre-type specific antibodies (PGP, GCRP, VIP). The biopsied tissue was stained with neuromarkers or nerve fibers (PGP, GCRP, VIP). He found that neuropathic symptoms (particularly dysaesthetic pain) improved as measured by the testing in all patients. He showed several before and after pictures which he said indicated improvements. He mentioned that there were clear clinical benefits in all the patients seen and treated for the 6 month period, but this controlled clinical study is an attempt to prove it scientificaly.

Youle explained that the test was done blinded in the sense that a machine was doing the testing. Also, the person performing testing was not aware of whether it was the first biopsy or a subsequent biopsy. As you can see in the table, Youle commented there is a marked increase and improvement in most of the values. The apparently large 750332% increase occurred because there was undetectable nerve fibers in the first test, so any increase produces this large change.

DRUG INTERACTIONS: I don't know of any drug interactions between LAC and antiretroviral therapies. In light of the unexpected NIH findings that St. John's Wort had a serious interaction with indinavir, the FDA issued a letter of caution suggesting not to use indinavir with St. John's Wort. As far as I know no study of interactions has been conducted between antiretroviral therapies and LAC.

Youle Concluded:

• Immunohistochemical quantification demonstrates a significant restoration of cutaneous innervation after 6 months of oral LAC