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Does Valtrex block mitochondrial reproduction?

JalapenoLuv

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Valtrex is an antiviral drug which was shown in a pilot study to improve mental symptoms and fatigue after taking it for six months. The improvements lasted three months more after patients stopped taking it but longer outcomes data isn't available.

Mitochondrial damage is a hallmark of CFS. One concern I have about Valtrex is that it has been found to prevent mitochondrial reproduction. Over time, this should lead to a lowering of the total number of mitochondria in affected cells and a worsening of CFS fatigue symptoms.

“Mitochondrial DNA synthesis in Molt-4 cells was particularly sensitive to ddC. The ratio of mitochondrial to cellular DNA was decreased 80% after 5 days of treatment with 0.05 puM ddC; however, there was no apparent increase in the doubling times of the treated cells. (Martin, JL. Antimicrob. Agents Chemother. 1994, 38(12):2743)."
 

JalapenoLuv

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Valtrex is not valganciclovir (Valcyte). Very different drugs.

Sorry, I listed the wrong generic name; but it is Valtrex (valacyclovir). Valtrex uses a DNA polymerase inhibitor called
thymidine kinase which is listed on Martin's paper as reference 16. Martin writes:

"Thymidine analogs were also examined as inhibitors of mitochondrial DNA synthesis. FLT reduced the ratio of mitochondrial to cellular DNA by 59% after 7 days of treatment...Significant cell death was observed after 5 days of treatment..." (Ibid. Martin p. 2745.)
 

Ema

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I don't find this paper to be conclusive evidence of much of anything much less that Valtrex inhibits the mitochondria.

Conse-quently,thereare not sufficient data in the literature on any antiretroviral nucleoside analog to provide a sound mechanis- tic basis for concluding that inhibition of isolated polymerase-y will be predictive of inhibition of mitochondrial DNA synthesis in vitro or in vivo.

Where does it say that Valtrex is a thymidine analog?
 

JalapenoLuv

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Microbiology
Mechanism of Action
Valacyclovir is a nucleoside analogue DNA polymerase inhibitor. Valacyclovir hydrochloride is rapidly converted to acyclovir which has demonstrated antiviral activity against HSV types 1 (HSV-1) and 2 (HSV-2) and VZV both in cell culture and in vivo.

The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue.
 

Ema

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Microbiology
Mechanism of Action
Valacyclovir is a nucleoside analogue DNA polymerase inhibitor. Valacyclovir hydrochloride is rapidly converted to acyclovir which has demonstrated antiviral activity against HSV types 1 (HSV-1) and 2 (HSV-2) and VZV both in cell culture and in vivo.

The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue.
How does having an affinity for viral TK make it a thymidine analog?
 

JalapenoLuv

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On page 2743 of Martin, the Materials and Methods section lists acyclovir, so it was tested. It is toxic to mitochondria.
 
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Ema

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On page 2743 of Martin, the Materials and Methods section lists acyclovir, so it was tested. It is toxic to mitochondria.
The Materials and Methods section lists the abbreviation for acyclovir...it says nothing about how it was tested.

If you look down to Table 3, it is not listed as one of the compounds that was tested.

But regardless, the researchers themselves say that nothing can be derived from these results regarding toxicity to the mitochondria in real life.

The results presented herein demonstrated no clear quantita- tive or qualitative correlation between the inhibition of DNA polymerases,particularly mitochondrial DNA polymerasey, and the inhibition of mitochondrial DNA synthesis in Molt-4 cel culture.

Furthermore,these data indicate that inhibition of either isolated DNA polymerases or mitochondrial DNA synthesis in vitro may not be predictive of in vivo toxicity (Table3)(17).

Further the conclusion goes on to say:

Although all of the nucleoside analogs included in the present study are structurally related,they have diverse bio- logical properties.This diversity includes differences in mech- anises of cel permeation, differences in anabolic and catabolic pathways, differences in inhibition of cellular and mitochon- drialDNA synthesis...

So you can't just lump them all together, even if they had proven one nucleoside analog to be toxic to the mitochondria because they don't all act in the same way.
 

JalapenoLuv

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The precautionary principle—that any action designed to reduce risk should not await scientific certainty—applies here. Just because something may not be predictive in vivo, you have to take in vitro experimentation seriously.

Martin described the effect as potent.

A look at table 2 shows the data.

He said that AZTTP didn't have an effect and it's K value for polymerase alpha was 140, the highest of the group. ACVTP (valtrex)'s effect on the other hand he called potent, and it is listed as 0.96. That is a difference of 140x!

Frankly, this really scares me. The doses given for CFS patients are very high, 1-1.5g 3x/day. So I can't see this being safe in any way.

The prudent thing to do is to not use the drug until it is proven nontoxic to human mitochondria in vivo.

I have used it and my impressions are that it decreased my mitochondrial function by 75%, just as the study predicted. I experienced fatigue and decreased urge to breathe. However, I realize that my observations are not applicable to the side effects reported because of the uniqueness of the experimental regimen I am doing. Simply, most CFS patients aren't recovering their mitochondria count and the lack is masking any increases in fatigue. More fatigue on top of existing fatigue isn't perceptible.

It is very risky to take this drug in light of this negative in vitro data. Moreover, perceived fatigue improvements haven't been documented to last longer than three months.

Having done it myself, I do not recommend this treatment.

Here are comments from other PR members who had fatigue from valtrex:

I took Famciclovir for over a year 500 mg 3 a day. My reactived EBV,CMV, HHV6,HHV7 HAS NOT IMPROVED. I have been taking Valacyclovir 1GM 3 a day for a week. Can't hardly stay awake feel like I got ran over by who knows what!!!! Extreme headache,sore throat, hard to breathe. Has anyone else had this? If so what did you do?

I take valcyte and valtrex, and the combination really kicked my ass. Definitely felt run over by who knows what - completely flattened. (NOTE-MAYBE IT WASN'T THE COMBINATION BUT THE DURATION ON THE DRUG) I thought it was the valcyte, but when I ran out of the valtrex, I felt much better. (Surprised me because in the past valtrex alone seemed to have no effect at all, good or bad) One huge mistake I made was taking one of the anti virals at bedtime. I was waking up feeling unbelievably bad, death warmed over. I have stopped that and feel better upon waking.

One of the limitations for Valtrex is immunocompromised patients:

Immunocompromised patients other than for the suppression of genital herpes in HIV-infected patients with a CD4+ cell count ≥ 100 cells/mm³. (rxlist for valtrex)

I did a survey where 45% of the CFS patients reported they aren't getting fevers and head colds, indicating their immune systems are compromised. Therefore, this is a second reason why valtrex would be contraindicated.
 
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Ema

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That's fine if a treatment is not for you.

But this study does not say *any* of the things you attribute to it as far as I can see.

I'm all for a case study but even I have to scratch my head over how one could possibly discern a 75% decrease in mito function.

Please don't present something as a fact when it is not. It just muddies the waters because this paper does not even prove that Valtrex or acyclovir is toxic in vitro. Ddc is not the same as Valtrex.
 

JalapenoLuv

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I'm all for a case study but even I have to scratch my head over how one could possibly discern a 75% decrease in mito function.

That was my error, using the figure for dGTP in the Polymerase alpha column you actually get a value of 96.4% reduction comparing ddGTP (27) to ACVTP (0.96).

Again not respecting the precautionary principle and ignoring data puts patients at risk. I won't do that and I'm not misleading people about these effects.

80% of drugs approved by the US FDA are withdrawn at five years. I have no doubt that pharmaceutical companies lobby hard to get data like this ignored, especially when the indication for it is short term use. Using valtrex long term is off label and unapproved.

I'm curious what Dr. Edwards thinks about the valtrex study.
 
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Sushi

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I did a survey where 45% of the CFS patients reported they aren't getting fevers and head colds, indicating their immune systems are compromised. Therefore, this is a second reason why valtrex would be contraindicated.

I think that statement is misleading. First of all, that survey and only 11 votes--total--from members on this forum. 5 indicated that they no longer get fevers and/or head colds. This cannot really be said to represent 45% of "the CFS patients."

Also, of those who responded, several had tests showing that their immune systems were partially hyperactive. They and their doctors thought that this was a likely explanation for them not getting colds and fevers.

Sushi
 

JalapenoLuv

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Formally the survey needed 30 people to be statistically significant and it isn't controlled so it has to be seen with that limitation. An ideal study would be to take 80 patients and inject them with pyrinogens to see if they can get a fever. But the point is that many people are reporting they have signs of immune compromise.
 

Ema

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I'm not ignoring data but I'm not creating it either where it is not. I'm all for further study of Valtrex. If indeed, it could be shown to be toxic to mitochondria, that would be important information.

The benefits of reducing long standing chronic infections would still have to be weighed against these potential risks though. I think for some people, the benefits obviously outweigh the risk considering that a substantial number of people have improved on antivirals.