Potential for uridine to treat mitochondrial toxicity: still only in vitro data
31 January 2005. Related: Conference reports, Side effects, Lipodystrophy and metabolic complications, Lipodystrophy Workshop (IWADRW) 6th Washington 2004.
Simon Collins, HIV i-Base
Ulrich Walker from University of Freiburg and colleagues from INSERM and Pierre and Marie Curie Universite, Paris, presented interesting in vitro results looking at the effect of uridine on adipose cell function. [1]
At last years Workshop Walker presented interesting data were presented suggesting the potential for uridine to reverse ddC or d4T-associated mitochondrial dysfunction. The studies used Mitocnol, a dietary supplement derived from sugar cane, to raise levels of uridine. An in vitro study showed a protective effect in the presence of each drug in hepatocytes and normalised cell proliferation, lactate and intracellular lipids by adjusting mtDNA-levels to about 65% of NRTI-unexposed control cells. A single dose PK study showed that plasma uridine levels were achievable. [2]
The year data was presented on preadipocytes exposed to ddI or ddC +/- uridine for 21 days before and 7 days after differentiation. Without uridine, adipocytes showed reduced lipid accumulation containing reduced size and number of lipid droplets, and high rates of rates of apoptosis (by 5.6-fold and 2.2 fold in ddC and d4T exposed cells respectively).
Uridine had no effect by itself, but on ddC and d4T-exposed cells, normalised lipid morphology and rate of apoptosis.
Pharmacokinetic data was provided from a study in eight HIV-negative volunteers (4 men, 4 women) following single dose NucleomaxX (36g, dissolved in orange juice). Mean serum uridine levels increased from 5.6 uM at baseline to 152.0 uM (Cmax after 1.3 hours), dropping to 19.3 uM and 7.5 uM at 8 and 24 hours respectively. No side effects were reported. [3]
Comment
It was disappointing though not to have any further data in HIV-positive individuals at the meeting.
However. several larger studies in HIV-positive patients are already underway in Europe and the US, looking at countering mitochondrial toxicity in patients maintained on d4T- or AZT-containing regimens, and a further study in Germany is looking at NucleomaxX for polyneuropthy.
Uridine replacement may only be effective for lipoatrophy by abrogating an effect of ongoing nucleoside use and its mechanism of action is not expected to help nucleosides such as ddI.
References:
- Walker UA, Capeau J, Caron M et al. Uridine abrogates the adverse effects of stavudine and zalcitabine on adipose cell functions. 6th Lipodystrophy Workshop, Washington, 2004. Abstract 14. Antiviral Therapy 2004; 9:L10.
http://www.aegis.org/DisaplayConf/?Abstract=87272 - Uridine as a potential treatment for NRTI related mitochondrial toxicity. See
https://i-base.info/htb/7000. - Walker UA, Venhoff N, Zilly M et al. Uridine pharmacokinetics of Mitocnol, a sugar cane extract. 6th Lipodystrophy Workshop, Washington, 2004. Abstract 30. Antiviral Therapy 2004; 9:L21.
http://www.aegis.org/DisaplayConf/?Abstract=87256