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Beneficial effects of oral uridine in mitochondrial toxicity
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Correspondence in AIDS: Volume 18(7) 30 April 2004 pp 1085-1086
Walker, Ulrich Aa; Langmann, Peterb; Miehle, Nikolausa; Zilly, Michaelb; Klinker, Hartwigb; Petschner, Franziskaa
aMedizinische Universitätsklinik, Department of Rheumatology and Clinical Immunology, Freiburg, Germany; and bUniversity of Wuerzburg, Department of Infectious Diseases, Wuerzburg, Germany.Received: 19 August 2003; revised: 11 September 2003; accepted: 16 September 2003.
Note from Jules Levin: Data on this treatment was reported at the Lipodystrophy Workshop in Paris in 2003. It's my understanding that clinical studies are underway.
Some long-term side-effects of antiretroviral therapy are now attributed to the mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors (NRTI) and specifically their ability to deplete mitochondrial DNA. Using the human hepatoma (HepG2) cell line, we have discovered that the nucleoside uridine prevents and treats mtDNA depletion by pyrimidine NRTI (such as zalcitabine or stavudine). In this hepatocyte model, uridine increased mtDNA levels and fully abrogated consequent hepatocyte death, elevated lactate production and intracellular steatosis. Several investigators have also found beneficial effects of uridine in zidovudine-related haematopoietic toxicity, both in vitro and in animals. Depending on the system studied, uridine was effective at concentrations of 50-200 M. Various steps of mitochondrial nucleoside utilization may be involved in the protective effect, but the competition of uridine or its metabolites with NRTI at gamma-polymerase is the most plausible explanation. Pharmacokinetic studies of uridine in humans suggest that high uridine serum concentrations can be achieved by oral or intravenous dosing. Oral dosing is limited by a mild osmotic diarrhoea at 10-12 g/m2 uridine. Uridine supplementation was also safely used long term in numerous patients suffering from hereditary orotic aciduria, an inborn error of pyrimidine de-novo synthesis. Investigations performed in vitro and in mice indicated that high concentrations of uridine do not interfere with the antiretroviral activity of the NRTI.
Taken together, these data suggest that strategies aimed at increasing uridine may be promising in the treatment of some symptomatic or life-threatening mitochondrial toxicities in HIV-infected patients.NucleomaxX is a food supplement consisting of mitocnol, an extract from sugar canes with a high content (17%) of nucleosides (http://www.nucleomaxX . com). Drinking the contents of a single sachet (36 g) of NucleomaxX increases the physiological serum concentration of uridine in humans from approximately 5 mM to more than 100 mM. We have used NucleomaxX first in an HIV patient with mitochondrial steatohepatitis and symptomatic elevation of creatine kinase under long-term antiretroviral treatment with stavudine.
A 54-year-old caucasian man (168 cm, 75 kg) was started on antiretroviral medication 4 years ago, when he was diagnosed with HIV-1/AIDS as a result of Pneumocystis carinii pneumonia, pulmonary tuberculosis and oesophageal candidiasis. When he first presented to our institution 2 years ago, his initial CD4 cell count of 25 cells/ml had risen to 682 cells/ml and his previous stavudine-containing antiretroviral regimen had been switched to lamivudine 150 mg twice a day, stavudine 40 mg twice a day, abacavir 300 mg twice a day and efavirenz 600 mg a day. We continued this regimen because side-effects were not clinically apparent initially and because HIV was undetectable in the blood. After several months, he developed myalgias, and a continuous increase in creatine kinase, lactate, and transaminases. Tests for hepatotropic viruses, alpha-1 antitrypsin deficiency and haemochromatosis were negative, and there was no indication of alcohol abuse. There was no indication of cholestasis, but abdominal ultrasound revealed signs of massive liver steatosis. The patient was then started on NucleomaxX for suspected stavudine-related mitochondrial toxicity (three sachets a day for 4 days). After 2 weeks, at his next visit, liver and muscle enzymes as well as the myalgias had improved rapidly, despite unchanged medication. Lactate had normalized after 7 weeks. Stavudine was then switched to tenofovir. There were no subsequent clinical or laboratory abnormalities, HIV replication remained below the limit of detection (< 50 copies/ml blood) and ultrasound showed a substantial improvement of steatotic signs.
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