Ubisol-Aqua: coenzyme Q10 prevents antiretroviral toxic neuropathy in an in vitro model.

BACKGROUND Peripheral neuropathy is the dose-limiting toxicity of stavudine and didanosine (nucleoside analogs used in HIV treatment) and is attributed to mitochondrial toxicity from these drugs. Acetyl L-carnitine (ALC) and co-enzyme Q(10) are proposed as neuropathy treatments, but evidence to support these is limited. METHODS We examined ALC and a water-soluble formulation of co-enzyme Q(10) (H(Q)O) for the prevention of d4T and ddI neurotoxicity using cultured fetal rat DRG as an in vitro model. RESULTS DdI (33microM) and d4T (50microM) caused clear toxicity (impaired neurite growth) by day 8 of DRG culture. H(Q)O at concentrations 1-100microM completely prevented the toxicity of 33microM ddI in vitro and ALC at concentrations 1-100 microM substantially (but incompletely) prevented ddI toxicity in this model. In contrast, ALC was ineffective at all concentrations tested for preventing the toxicity of 50microM d4T. H(Q)O showed dose-dependent efficacy for preventing d4T toxicity. H(Q)O (1microM) partially prevented d4T toxicity while 10 and 100microM H(Q)O completely prevented d4T toxicity in this model. CONCLUSIONS We find H(Q)O is superior to ALC for preventing the neurotoxicity of d4T (the HIV treatment most associated with neuropathy) and ddI in vitro. Further study is needed to clarify any clinical role for co-enzyme Q(10) co-administration with d4T and ddI and to assess whether this compound may have a role in treating established cases of neuropathy.

[1]  P. Price,et al.  Can we predict neuropathy risk before stavudine prescription in a resource-limited setting? , 2008, AIDS research and human retroviruses.

[2]  M. Hellard,et al.  Neurologic disorders are prevalent in HIV-positive outpatients in the Asia-Pacific region , 2008, Neurology.

[3]  P. Price,et al.  Prevalence of and risk factors for HIV‐associated neuropathy in Melbourne, Australia 1993–2006 , 2007, HIV medicine.

[4]  M. Cudkowicz,et al.  Coenzyme Q treatment of neurodegenerative diseases of aging. , 2007, Mitochondrion.

[5]  M. Youle,et al.  A double‐blind, parallel‐group, placebo‐controlled, multicentre study of acetyl l‐carnitine in the symptomatic treatment of antiretroviral toxic neuropathy in patients with HIV‐1 infection , 2007, HIV medicine.

[6]  J. Brooks,et al.  Clinical Toxicity of Highly Active Antiretroviral Therapy in a Home-Based AIDS Care Program in Rural Uganda , 2007, Journal of acquired immune deficiency syndromes.

[7]  P. Doraiswamy,et al.  Coenzyme Q10: A Review of Its Promise as a Neuroprotectant , 2007, CNS Spectrums.

[8]  R. Marfella,et al.  Acetyl-L-carnitine for symptomatic diabetic neuropathy , 2006, Diabetologia.

[9]  Xenia Dennett,et al.  Skeletal myopathy associated with nucleoside reverse transcriptase inhibitor therapy: potential benefit of coenzyme Q10 therapy , 2005, International journal of STD & AIDS.

[10]  M. Youle,et al.  Long-Term Effect of Acetyl-L-Carnitine for Antiretroviral Toxic Neuropathy , 2005, HIV clinical trials.

[11]  J. Mak,et al.  Mutations That Abrogate Human Immunodeficiency Virus Type 1 Reverse Transcriptase Dimerization Affect Maturation of the Reverse Transcriptase Heterodimer , 2005, Journal of Virology.

[12]  A. Caraceni,et al.  Symptomatic and neurophysiological responses of paclitaxel- or cisplatin-induced neuropathy to oral acetyl-L-carnitine. , 2005, European journal of cancer.

[13]  M. Calvani,et al.  Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. , 2005, Diabetes care.

[14]  S. Jensen-Fangel,et al.  Mitochondrial DNA levels in fat and blood cells from patients with lipodystrophy or peripheral neuropathy and the effect of 90 days of high-dose coenzyme Q treatment: a randomized, double-blind, placebo-controlled pilot study. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[15]  M. Youle,et al.  Acetyl-l-carnitine: a pathogenesis based treatment for HIV-associated antiretroviral toxic neuropathy , 2004, AIDS.

[16]  S. Wesselingh,et al.  Nucleoside analogues and neuropathy in the era of HAART. , 2003, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[17]  A. Hoke,et al.  FK506 is neuroprotective in a model of antiretroviral toxic neuropathy , 2003, Annals of neurology.

[18]  D. Katzenstein,et al.  Plasma carnitine in HIV-associated neuropathy. , 2001, AIDS.

[19]  D. Stein,et al.  Phosphorylation of Nucleoside Analog Antiretrovirals: A Review for Clinicians , 2001, Pharmacotherapy.

[20]  T. Kakuda,et al.  Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. , 2000, Clinical therapeutics.

[21]  J. McArthur,et al.  Incidence of neuropathy in HIV-infected patients on monotherapy versus those on combination therapy with didanosine, stavudine and hydroxyurea , 2000, AIDS.

[22]  M. Sadler,et al.  Peripheral Neuropathy with Nucleoside Antiretrovirals , 1998, Drug safety.

[23]  S. Moretti,et al.  Acetyl‐carnitine deficiency in AIDS patients with neurotoxicity on treatment with antiretroviral nucleoside analogues , 1997, AIDS.

[24]  M. Nelson,et al.  Peripheral neuropathy in HIV , 1997, International journal of STD & AIDS.

[25]  E. Scarpini,et al.  Effect of acetyl-L-carnitine in the treatment of painful peripheral neuropathies in HIV+ patients. , 1997, Journal of the peripheral nervous system : JPNS.

[26]  J. Mellors,et al.  Zidovudine resistance is suppressed by mutations conferring resistance of human immunodeficiency virus type 1 to foscarnet , 1996, Journal of virology.

[27]  J. Malone,et al.  The effects of acetyl-L-carnitine and sorbinil on peripheral nerve structure, chemistry, and function in experimental diabetes. , 1996, Metabolism: clinical and experimental.

[28]  D. Greene,et al.  Primary preventive and secondary interventionary effects of acetyl-L-carnitine on diabetic neuropathy in the bio-breeding Worcester rat. , 1996, The Journal of clinical investigation.

[29]  M. Tagliati,et al.  Nucleoside analogue-associated peripheral neuropathy in human immunodeficiency virus infection. , 1995, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[30]  J Desmyter,et al.  Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. , 1988, Journal of virological methods.

[31]  H. Gendelman,et al.  Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone , 1986, Journal of virology.

[32]  N. Yamamoto,et al.  Infection of HTLV-III/LAV in HTLV-I-carrying cells MT-2 and MT-4 and application in a plaque assay. , 1985, Science.

[33]  U. Moritz,et al.  L-carnitine and haemodialysis: double blind study on muscle function and metabolism and peripheral nerve function. , 1985, Scandinavian journal of clinical and laboratory investigation.

[34]  S. Lindstedt,et al.  The effect of D,L-carnitine supplementation on muscle metabolism, neuropathy, cardiac and hepatic function in hemodialysis patients. A pilot study. , 2009, Acta medica Scandinavica.