I had the pleasure to meet Dr. Walker after his oral presentation on Uridine and mitchondrial toxicity at the Lipodystrophy Conference in Paris. I was very excited to see his in vitro data on how this supplement may protect liver cell mitochondria exposed to D4T (Zerit) and DDC (Hivid). He gladly agreed to be interviewed for our newsletter. I am looking forward to seeing more data on this exciting approach that may make it possible for many of us to take nucleosides without the long term mitochondrial toxicity related side effects.
Dr. Ulrich A. Walker underwent his medical school education at the University of Tübingen/Germany and at the University of Michigan (AnnArbor/ MI) and graduating in 1991. He recieved his specialization in Internal Medicine, Rheumatology and Allergology at the University of Freiburg/ Germany. He did postdoctoral studies (3 years) with focus on mitochondrial genetics and metabolism at the Neuromuscular Research Centre in Melbourne/ Australia and at Columbia University (NYC, NY). He has also been director of a research lab on mitochondrial genetics and metabolism since 1999 and is currently anAssociate professor in Internal Medicine at the University of Freiburg/Germany since 2003. Dr Ulrich has also been a consultant doctor and medical director of the HIV outpatient care unit at the University of Freiburg/Germany since 2000.
NV: Doctor Walker, What is Uridine?
UAW: Uridine is a particular “nucleoside” which is used by our body to produce DNA. Uridine is also required for many other metabolic pathways – for example uridine is needed to produce glycogen. Uridine is a natural substance in our body. Humans are normally able to produce uridine, but the ability to do so requires intact mitochondria.
NV: How does Uridine reduce mitochondrial toxicity caused by nucleosides?
UAW: Our current research supports the following concept: One class of anti-HIV drugs are the so called “nucleoside reverse transcriptase inhibitors” (NRTIs). As the name implies, the NRTIs are themselves nucleosides (“nukes”). The NRTIs are “bad nukes”, as they are toxic to mitochondria. This is because they inhibit gamma polymerase, an enzyme that is essential for the replication of mitochondrial DNA. As a consequence, the levels of mitochondrial DNA in mitochondria decline. Mitochondrial DNA however is necessary for the proper function of the respiratory chain (this is were we “breathe internally,” consume oxygen and make ATP as the energy for our body. Another consequence of respiratory chain dysfunction is that the body cannot make uridine and other natural nucleosides (the “good nukes”).
Therefore, the NRTI-nucleosides (“the bad nukes”) are more abundant in relation to the natural nucleosides (“the good nukes”) at gamma polymerase. This excess of the bad nukes makes mitochondrial function even worse, because a vicious circle is closed. Uridine replenishes the good nukes and therefore abolishes this vicious circle.
NV: Your research shows that the dose use invitro studies was 200 micromoles. What does that translate to in a 150 Lb man?
UAW: We have shown full protection at a concentration of 200 µM but there were some indications of improvement starting at about 50 µM. Other researchers looked at the effect of zidovudine (AZT) on blood cells in vitro and in mice and have shown protection at 50 µM.
Uridine can be bought at the chemist but the costs there are prohibitive to be used long-term by anybody. NucleomaxX is a dietary supplement that comes in sachets to be dissolved in water, milk or juice. It contains Mitocnol, a sugar cane extract with high amounts (18%) of nucleosides. We have discovered, that a single sachet of NucleomaxX increases the dose to more than 100 µM (for example in myself (190 Lb) to 105 µM. Repeated doses increase the serum concentrations even more.
NV: Your research so far shows promising results in liver cells that have been exposed to D4T, DDC, AZT+3TC. Are you planning to conduct studies to see the effect on fat, muscle and nerve cells?
UAW: Several studies looking at liver, fat, peripheral nerves, lactate, anemia and leucopenia in humans have been approved or are currently submitted.
NV: Are you currently performing any in vivo studies? If so, what are the variables you are looking at?
UAW: Other than the studies in humans discussed above, we are currently looking at mice, measuring mitochondrial DNA and mitochondrial function in every relevant tissue. We have not yet finished our experiments but I can say that the mice drink NucleomaxX without any apparent problem and that high uridine serum levels are achieved.
NV: What is the human dose?
UAW: We don’t know for certain yet. The experience from our in vitro work and from a very limited number of HIV-patients suggests that uridine resets the mitochondrial clock, thus supporting an intermittent dosing schedule. NucleomaxX is recommended to be taken on three consecutive days on each month. 7.
NV: How can anyone order the product?
UAW: Please refer to the NucleomaxX website www.nucleomaxX.com.
NV: Your research shows that Uridine may not work for mitochondrial toxicity related to DDI. Could you tell us why?
UAW: Nucleosides can be divided into two chemical classes, namely the “pyrimidines” (such as stavudine, zidovudine, zalcitabine, lamivudine) and the “purines”, such as DDI (didanosine). Uridine itself is also a pyrimidine and thus does not block vicious circles caused by purines at the mitochondrial gamma polymerase. 9. You mention that the use of supplements like carnitine , thiamine, riboflavin and Coenzyme Q-10 have shown disappointing results in protecting the mitochondria against nucleosides. The HIV positive community in the US is using these products a lot. Should we stop using them? What would the effect be in we combined these supplements with Uridine? Would they work synergistically?
We have tested the above-mentioned supplements in our system but did not find any benefit. You may continue these supplements if you like as they are not harmful. I just would not put too much hope (and money) into them. I have no information on synergism.
NV:. There was a concern that Uridine may affect blood levels of nucleosides. It seems that your in vitro studies show that Uridine may increase blood levels and enhance the antiviral effect of nucleosides. Could you elaborate?
UAW: The increase of uridine blood levels is a desired effect. Our in vitro work and work by others did not show a significant interaction with the anti-HIV efficacy of antiretrovirals, but I think this still needs a watchful eye.
NV: Even though Uridine improves mitochondrial function of liver cells exposed to DDC, it seemed that the mitochondrial DNA was not restored to baseline values. Does this have any significance?
UAW: Probably not. This is because mitochondria seem to work badly only when mitochondrial DNA drops below a certain threshold (about 20% of baseline). Therefore mitochondrial function in our experiments was fully restored despite the fact that the levels of mitochondrial DNA did not fully return to baseline.
NV: Could Uridine be used to prevent AZT induced anemia and leucopoenia?
UAW: Yes, studies in vitro and studies in mice have shown this.
NV: What are the potential side effects of Uridine?
UAW: The dose-limiting effect in Uridine studies so far was a mild diarrhea with excessive doses. The diarrhea stopped immediately when Uridine was discontinued. We have not yet observed this with NucleomaxX.
NV: You mentioned in Paris that the old studies of Uridine were done in IV formulations and that you have a more bioavailable oral formulation. Can you expand on this?
UAW: This is probably a misunderstanding because intravenous Uridine is more bioavailable than oral Uridine.
NV: Any plans for US studies?
UAW: One study will look at lipodystrophy under Stavudine and is currently being submitted.
NV: Thank you Doctor.