L-Acetyl Carnitine (LAC) improves symptoms of peripheral neuropathy (PN): evidence for increases in cutaneous innervation

Simon Collins, HIV i-Base

Although somewhat tenuously linked to clinical pharmacology, the implications for this study are sufficiently important to justify early presentation at any HIV-related meeting.

Peripheral neuropathy can be one of the most difficult symptoms to manage, and one that significantly effects the quality of life. Estimates range from 10-35% of HIV positive patients and from 11-55% patients who use ddC, d4T, ddI or 3TC. For people who have no other remaining choices for antiretroviral therapy, or where the severity of symptoms has been underestimated and neuropathy has progressed, there are currently no effective pathogenesis based therapies.

The mechanism for nucleoside analogue -related PN is thought to be impaired neuronal mitochondrial DNA synthesis and repair which disrupts energy metabolism causing die-back of long peripheral axions. L-acetyl carnitine is an amino acid that enhances retrograde neurotrophic support of sensory neurons, and which suffers a decrease in serum levels in HIV neuropathy. This open observational cohort study by Mike Youle performed lower leg skin biopsies on four patients with established PN (Grade 2-4) before and after 6 months oral LAC treatment (1500mg BID). Frozen sections were immunostained using fibre-type specific primary antibodies (PGP, GCRP, VIP) and FITC-labelled secondary sera, and were examined by fluorescence microscopy and optimised by digital photography. All sections were stained and analysed at the same time. The system used for computerised image analysis for each of three skin areas (epidermis, dermis and ecrine sweat glands) has already been validated for use in diabetes-related neuropathy.

Results showed an increase in area of immunostaining of 40% (p=0.22) for all fibre types and 493% (p=0.002) for small sensory fibres. The study noted a trend towards greater percentage increases with increased duration of neuropathy. In sweat glands the mean increase was 293% (p<0.001) for all nerve fibres and 273% (p<0.001) for sympathetic efferents.

All patients reported an improvement in symptoms and three of these four patients had continued nucleoside treatment throughout the study. Clinical grade of dysaesthetic pain improved from grade 3-4 at baseline to grade 1-2 following treatment with LAC. [11]

References:

Aarnoutse R et al. International Interlaboratory quality control (QC) program for therapeutic drug monitoring (TDM) in HIV infection: first results. Abstract 1.4. First International Workshop on Clinical Pharmacology, 30-31 March 2000. Noordwijk, Netherlands.
Merry C et al. TDM of PI Therapy: PK-PD considerations – Abstract 6.1. First International Workshop on Clinical Pharmacology, 30-31 March 2000. Noordwijk, Netherlands.
Burger D, Hoetelmans R, Hugen P et al – ATHENA: A Randomised, Controlled Clinical Trial to Evaluate whether Therapeutic Drug Monitoring (TDM) Contributes to Reduced HIV-related Morbidity and Mortality. Abstract 6.6 First International Workshop on Clinical Pharmacology, 30-31 March 2000. Noordwijk, Netherlands.
BFletcher C et al. Concentration Controlled Antiretroviral Therapy. Abstract 6.2. First International Workshop on Clinical Pharmacology, 30-31 March 2000. Noordwijk, Netherlands.
Urquhart J – The Challenges of Patient Non-Compliance with Antiretroviral Drug Regimens. Plenary 2. First International Workshop on Clinical Pharmacology, 30-31 March 2000. Noordwijk, Netherlands.
De Maat MMR et al. A Potential Interaction between St Johns Wort and Nevirapine. Abstract 2.8. First International Workshop on Clinical Pharmacology, 30-31 March 2000. Noordwijk, Netherlands.
Lamotte et al. Amprenavir Plasma Concentrations are Dramatically Increased by Association to Ritonavir in Baby Doses in HIV-infected Patients: Possible Combination with Efavirenz. Abstract 2.7. First International Workshop on Clinical Pharmacology, 30-31 March 2000. Noordwijk, Netherlands.
Sadler et al – Phamacokinetic Drug-Interaction between Amprenavir and Ritonavir inHIV-Seronegative Individuals. Abstract 77 – 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA.
Aarnoutse et al. PK Study to Investigate the Influence of Efaviranz on a BID Regimen of Indinavir/Ritonavir (800/100mg) in Healthy Volunteers. Abstract 2.3. First International Workshop on Clinical Pharmacology, 30-31 March 2000. Noordwijk, Netherlands.
Hsu A et al. Interaction of ABT-378/ritonavir with Protease Inhibitors in Healthy Volunteers. Abstrat 2.4. First International Workshop on Clinical Pharmacology, 30-31 March 2000. Noordwijk, Netherlands
Hart AM, Terenghi G, Johnson M, Youle M – L-Acetyl Carnitine (LAC) Therapy Increases Cutaneous Innervation and Improves Symptoms in Antiretrovital Therapy Related HIV peripheral neuropathy. Abstract 7.2 First International Workshop on Clinical Pharmacology, 30-31 March 2000. Noordwijk, Netherlands.