Valcyte: does it work because of its antiviral or immunomodulatory properties (or both)?

[leokitten]

I saw Dr. Montoya today and asked him whether the improvements I've been experiencing were due to anti-viral or anti-inflammatory effects. He says he doesn't know.

He's trying to get funding for brain-scan studies, to look for more evidence of structural abnormalities in the brain, which may be linked to inflammation. He is also wondering if too many crashes might cause permanent tissue damage.

There was already a small but well done 11C-(R)-PK11195 PET study of a few ME/CFS patients and controls.

Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study.

The above technique is the current best way to look for microglia and astrocyte activation, ie neuroinflammation in the brain. They found compelling evidence of neuroinflammation but because of the small sample size this would need to be repeated in a much larger cohort with ICC/CCC selection criteria.

Valcyte is well known to inhibit microglial activation and therefore suppress neuroinflammation:

Antiviral drug ganciclovir is a potent inhibitor of microglial proliferation and neuroinflammation

http://www.msdiscovery.org/news/new...vir-inhibits-neuroinflammation-mouse-model-ms

So I believe that in addition to its immunosuppressive/modulating properties in the body the fact that it's also suppressing neuroinflammation in the brain this is definitely helping ME patients a lot.

Unfortunately though I personally don't think Valcyte is actually altering the core underlying cause(s) of the ME/CFS so it's not a cure. Also it has to be taken on and off forever which is not a good solution since it is somewhat toxic and carcinogenic.

 

[IreneF]

There was already a small but well done 11C-(R)-PK11195 PET study of a few ME/CFS patients and controls.

Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study.

The above technique is the current best way to look for microglia and astrocyte activation, ie neuroinflammation in the brain. They found compelling evidence of neuroinflammation but because of the small sample size this would need to be repeated in a much larger cohort with ICC/CCC selection criteria.

Valcyte is well known to inhibit microglial activation and therefore suppress neuroinflammation:

Antiviral drug ganciclovir is a potent inhibitor of microglial proliferation and neuroinflammation

http://www.msdiscovery.org/news/new...vir-inhibits-neuroinflammation-mouse-model-ms

So I believe that in addition to its immunosuppressive/modulating properties in the body the fact that it's also suppressing neuroinflammation in the brain this is definitely helping ME patients a lot.

Unfortunately though I personally don't think Valcyte is actually altering the core underlying cause(s) of the ME/CFS so it's not a cure. Also it has to be taken on and off forever which is not a good solution since it is somewhat toxic and carcinogenic.

No, it's not a cure, but I think it's the best thing out there.

 

[SOC]

He is also wondering if too many crashes might cause permanent tissue damage.

I wonder if this might be one of the reasons my daughter can achieve 90+% functionality and no PEM while I, with the same treatment, am significantly more impaired.

In the early days, before I knew what was going on, I pushed myself and lived for years in a constant state of PEM. My daughter had mild ME with very few PEM episodes for the first 5 years. As soon as she got worse, we enforced a strict activity management program to keep her PEM episodes to a minimum. She recovered much more quickly with treatment and achieved a much higher level of function.

Of course she's also younger than me, which probably helps, was less severely ill, and was seriously ill for less time. The last two could be related to fewer crashes and less tissue damage as well, I imagine.

 

[IreneF]

I wonder if this might be one of the reasons my daughter can achieve 90+% functionality and no PEM while I, with the same treatment, am significantly more impaired.

In the early days, before I knew what was going on, I pushed myself and lived for years in a constant state of PEM. My daughter had mild ME with very few PEM episodes for the first 5 years. As soon as she got worse, we enforced a strict activity management program to keep her PEM episodes to a minimum. She recovered much more quickly with treatment and achieved a much higher level of function.

Of course she's also younger than me, which probably helps, was less severely ill, and was seriously ill for less time. The last two could be related to fewer crashes and less tissue damage as well, I imagine.

It does seem like younger people and people who haven't been sick for very long do better.

 

[leokitten]

I wonder if this might be one of the reasons my daughter can achieve 90+% functionality and no PEM while I, with the same treatment, am significantly more impaired.

In the early days, before I knew what was going on, I pushed myself and lived for years in a constant state of PEM. My daughter had mild ME with very few PEM episodes for the first 5 years. As soon as she got worse, we enforced a strict activity management program to keep her PEM episodes to a minimum. She recovered much more quickly with treatment and achieved a much higher level of function.

Of course she's also younger than me, which probably helps, was less severely ill, and was seriously ill for less time. The last two could be related to fewer crashes and less tissue damage as well, I imagine.

I think it's yet another piece of proof that this truly is an autoimmune illness. Like all other autoimmune illnesses ME/CFS has this relapse/remitting structure and if left untreated it continues to do more and more damage that over time becomes irreversible even with eventual treatment.

 

[halcyon]

Also it has to be taken on and off forever which is not a good solution since it is somewhat toxic and carcinogenic.

This disease is carcinogenic too, so pick your poison I guess.

 

[leokitten]

This disease is carcinogenic too, so pick your poison I guess.

I agree, but I believe that taking Valcyte every day for the rest of your life increases the likelihood of getting cancer more than having ME/CFS does.

 

[Hip]

I agree, but you will get cancer much faster by taking Valcyte for too long than just by having ME/CFS.

Where does this info come from?

I read that Valcyte has only been shown to cause cancer in certain animal cells which do not exist in humans.

Interestingly, Valcyte is being tested as a treatment for cancer.



What I would like to know is whether any ME/CFS patient with high titers to coxsackievirus B, but not to herpes family viruses, has benefited from Valcyte to a similar degree that those with active herpes viruses benefit.

Valcyte has three known actions that may have relevance for ME/CFS: it is an antiviral against herpes family viruses, it is a immunomodulator, and it is an anti-inflammatory that potently inhibits microglial activation.

So for coxsackievirus B, although the antiviral action of Valcyte will not be much use, the immunomodulatory and anti-inflammatory actions might provide benefits.

I know Dr Chia does not seem to use Valcyte, but I wonder if anyone has tried this drug for coxsackievirus B associated ME/CFS.

 

[heapsreal]

I agree, but you will get cancer much faster by taking Valcyte for too long than just by having ME/CFS.

If your going to scare monger atleast back it up with some type of research not just an opinion.

your opinion could stop someone from using a Treatment which could greatly help them.

 

[minkeygirl]

Please explain why Valcyte makes you get cancer? Show us where you got this.

 

[leokitten]

If your going to scare monger atleast back it up with some type of research not just an opinion.

your opinion could stop someone from using a Treatment which could greatly help them.

I take Valcyte @heapsreal!

Could you and @minkeygirl please actually read the entire thread and all the context before giving your two cents?!?!

I was only saying that Valcyte is quite toxic and is not a good idea to take for life. READ THE ENTIRE THREAD!

Dr. Montoya and others say the same thing, it's not a drug that you should take every day for your entire life, can other people please back me up to show @heapsreal and @minkeygirl that they just bully without reading or thinking??

Valcyte is a known carcinogen:

http://www.valcyte.com/hcp/important-safety-information

http://www.drugs.com/pro/valcyte.html

Animal data indicate that administration of ganciclovir is carcinogenic. Valcyte should therefore be considered a potential carcinogen in humans

Read starting at page 10, also starting at page 16:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021304s004lbl.pdf

274 Teratogenesis, Carcinogenesis and Mutagenesis
275 Because of the mutagenic and teratogenic potential of ganciclovir, women of
276 childbearing potential should be advised to use effective contraception during treatment.
277 Similarly, men should be advised to practice barrier contraception during, and for at least
278 90 days following, treatment with Valcyte tablets (see PRECAUTIONS:
279 Carcinogenesis, Mutagenesis and Impairment of Fertility‡, and Pregnancy:
280 Category C‡).
281 In animal studies, ganciclovir was found to be mutagenic and carcinogenic. Valcyte
282 should, therefore, be considered a potential teratogen and carcinogen in humans with the
283 potential to cause birth defects and cancers

268 Animal data indicate that administration of ganciclovir causes inhibition of
269 spermatogenesis and subsequent infertility. These effects were reversible at lower doses
270 and irreversible at higher doses (see PRECAUTIONS: Carcinogenesis, Mutagenesis
271 and Impairment of Fertility‡). It is considered probable that in humans, Valcyte at the
272 recommended doses may cause temporary or permanent inhibition of spermatogenesis.
273 Animal data also indicate that suppression of fertility in females may occur.

Valcyte is toxic enough that there are so many warnings to not take more than the recommended daily dose because overdose can cause you a lot of serious damage. This is not true of for example Valtrex or Famvir you can accidentally take more and nothing serious will happen to you.

Valcyte is toxic and carcinogenic due to the fact that unlike other nucleoside analogues it is not as cleanly preferential to viral DNA vs eukaryotic (your) DNA. So it inserts itself into your DNA causing DNA damage, more in certain cell types than others. This over time is carcinogenic.

Again, I take Valcyte and know I have no other choice, but all I've been saying if you read my posts is that I would like there to be a better, less toxic, more targeted choice. How can I fearmonger when I take the drug myself?

 

[leokitten]

Where does this info come from?

I read that Valcyte has only been shown to cause cancer in certain animal cells which do not exist in humans.

Interestingly, Valcyte is being tested as a treatment for cancer.

Almost all cancer drugs/chemotherapy (except for the newer targeted therapies) are also carcinogens. Chemotherapy drugs work by inserting themselves into the DNA replication and repair process and cause DNA damage and mutations in order to kill malignant cells, they do so by the fact that faster dividing cells are copying their DNA much more frequently. But they are not 100% clean, they cause plenty of DNA damage to non-malignant cells and are therefore carcinogenic.

Valcyte is considered chemotherapy, it works in much the same way except that it's supposed to preferentially target herpesvirus DNA. But it's not 100% clean and does also damage our cells DNA. This is why it's also possibly effective for cancer.

I take Valcyte and I know it's the one of the best things we have out there currently.

If everyone read the entire thread I said that if Valcyte's effectiveness in ME/CFS is its immunosuppressive/immunodulaotry effects then this is a dirty approach, a non-targeted approach with a drug that is generally toxic to white blood cells. It's not a drug that anyone would recommend taking for the rest of your life, it's too toxic and requires taking breaks for extended periods of time.

Roche/Genentech, Dr Montoya and others all believe you cannot take this drug at full dosage every day for your entire life, it's just too toxic and will likely promote cancer faster than by just having ME/CFS alone.

 

[Hip]

@leokitten
I appreciate what you saying about the potential dangers of Valcyte carcinogenicity, and these of course should be borne in mind; but as far as I am aware, there is no empirical evidence that Valcyte increases cancer risks in humans, only speculations that it might.


One thing that might possibly make a safe substitute for Valcyte is the long list of microglial activation inhibitor supplements and drugs I compiled in this post.

Obviously we do not know which out of the antiviral, immunomodulatory, and microglial activation inhibition effects of Valcyte is playing the major role in improving ME/CFS symptoms; however, if the microglial activation inhibition has a significant role, then you may be able to get similar benefits to Valcyte by taking some of the microglial inhibitor supplements in my list.

You could always add to these microglial inhibitors some immunomodulatory supplement, such as inosine say, to try to better mimic the effects of Valcyte. That way you will be getting both microglial inhibition and immunomodulation from safe supplements, providing two of the three effects of Valcyte.


The first time I tried taking a cocktail of 20 of microglial activation inhibitor supplements all together (the cocktail I used is detailed in this post), it rapidly precipitated a mini crash that lasted for a week, and so I stopped taking them.

This initially made me think that taking a lot of microglial inhibitor supplements is perhaps not a good thing; but then I considered that lots of ME/CFS patients feel much worse when first starting Valcyte as well. So this made me think that I should try to push through any ill effects created by these microglial inhibitors, and see if once the bad effects (hopefully) pass, I start to feel better.

 

[leokitten]

@leokitten
I appreciate what you saying about the potential dangers of the Valcyte carcinogenicity, and these of course should be borne in mind; but as far as I am aware, there is no empirical evidence that Valcyte increases cancer risks in humans, only speculations that it might.

I apologize but I have to disagree it's not speculation, not having 100% irrefutable evidence in humans is not then just speculation. It's not ethically possible to prove drugs like Valcyte are carcinogenic in humans. As opposed to major carcinogens, with minor carcinogens which take a long time/cumulative dose to increase the likelihood that they cause oncogenic DNA damage then it's very difficult to do pharmacoepidemiological studies to show over the long term it was this drug and not something else that caused cancer. This doesn't mean that it's not carcinogenic, we do have animal evidence and see human adverse effects that are similar to other known human carcinogens.

 

[minkeygirl]

Asking for proof is not bullying. If you care going to make a statement like that it's not too much to ask for back up, which as far as I can see you still haven't offered up. Just your speculation. @Hip has included info to support his statements.

As @halcyon said "we pick our poison" . I'd prefer to feel better for a few years (aka not housebound and stuck on the sofa) than live in misery because I'm afraid of side effects in 20 years? I've been sick since 95, am already 63. I'm not that concerned about what could happen 10 years down the road.

I'm not interested in just existing for the sake of it.

 

[Hip]

I apologize but I have to disagree it's not speculation, not having 100% irrefutable evidence in humans is not then just speculation.

I am sure you know that in the language and conventions of science, everything is speculation until either there is good empirical evidence available that demonstrates a phenomenon exists, or a phenomenon is predicated by theory that is so reliable and robust that the prediction is beyond question.

So if you say Valcyte will cause cancer in humans, in science that means either you have empirical evidence for this, or you have a theory is so reliable that its predictions are unquestionable.

In the case of Valcyte, as far as I can see, there is neither. So the use of the word "will" is not really in keeping with scientific convention.


But saying things like "it is conceivable that Valcyte may increase cancer incidence," or "there is a theoretical risk Valcyte may cause cancer" would be fine.

 

[leokitten]

I am sure you know that in the language and conventions of science, everything is speculation until either there is good empirical evidence available that demonstrates a phenomenon exists, or a phenomenon is predicated by theory that is so reliable and robust that the prediction is beyond question.

So if you say Valcyte will cause cancer in humans, in science that means either you have empirical evidence for this, or you have a theory is so reliable that its predictions are unquestionable.

In the case of Valcyte, as far as I can see, there is neither. So the use of the word "will" is not really in keeping with scientific convention.


But saying things like "it is conceivable that Valcyte may increase cancer incidence," or "there is a theoretical risk Valcyte may cause cancer" would be fine.

Apologies, saying something is carcinogenic is not saying "it will cause cancer in humans". I have edited my text to be more clear in the only place in this entire thread where it was misunderstood, and the only reason I used those words was to quickly say i believe its cancer-causing effect was greater than ME/CFS's cancer-causing effect if you were to take Valcyte at full dosage every day for the rest of your life.

It's funny, but for all the challenge I'm getting from my one statement I don't see anyone challenging @halcyon statement that ME/CFS it's carcinogenic even though this isn't true when you hold it to the same standard.

There was one epidemiological study done by my colleagues who work with me at NIH/NCI showing an slightly increased likelihood of getting NHL in elderly ME/CFS patients only. ME/CFS was not associated with elevated cancer risk overall, and if people read the paper ME/CFS had a reduced risk of other cancers:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3434293/

Neither CFS1 nor CFS2 was associated with cancer overall (both ORs=0.99) (Table 2). Using the broadest definition of exposure, CFS1 was most strongly associated with elevated risk of NHL (OR=1.29, 95% CI=1.16–1.43, p-value=1.7 × 10−6), kidney cancer (OR=1.27, 95% CI=1.07–1.49, p-value=0.005), and pancreatic cancer (OR=1.25, 95% CI=1.07–1.47, p-value=0.006), and there was an inverse association with breast cancer (OR=0.85, 95% CI=0.74–0.98, p=0.025) and cancers of the oral cavity and pharynx (OR=0.70, 95% CI=0.49–1.00, p=0.049) (Table 1). CFS2 was similarly associated with elevated risk of NHL (OR=1.22, 95% CI=1.09–1.37, p=4.6 × 10−4), kidney cancer (OR=1.29, 95% CI=1.09–1.53, p-value=0.004), and pancreatic cancer (OR=1.27, 95% CI=1.07–1.50, p-value=0.006), and reduced risk of breast cancer (OR=0.85, 95% CI=0.74–0.99, p=0.034) and cancers of the oral cavity and pharynx (OR=0.65, 95% CI=0.44–0.97, p=0.033). Additionally, CFS2 was associated with reduced risk of gall bladder and bile duct (OR=0.71, 95% CI=0.51–0.97, p=0.032).

There were also significant associations between CFS1 (the broader definition) and a few other cancers, including cancers of the pancreas, kidney, and breast. However, because the p-values for these other associations were higher (p-values from 0.006 to 0.049) than that for NHL (p-value=0.0000017), and because we had no a priori hypotheses for these other associations, we would tend to discount these as chance findings. Indeed, using a Bonferroni p-value cutoff of 0.001 (i.e., 0.05/40 cancer types), only the association with NHL would remain significant after correction for multiple comparisons.

So it's not accurate to say that "ME/CFS is carcinogenic" in the general way that it was put.

 

[halcyon]

It's funny, but for all the challenge I'm getting from my one statement I don't see anyone challenging @halcyon statement that ME/CFS it's carcinogenic even though this isn't true when you hold it to the same standard.

I will admit that I'm not familiar with the study or studies but I thought it was pretty well accepted that there is an increased risk of NHL in ME patients. Also, Dr. John Richardson has published statistics from his enterovirus patient cohort, noting increased incidence of gliomas, astrocytomas, and carcinomas.

 

[Hip]

It's funny, but for all the challenge I'm getting from my one statement I don't see anyone challenging @halcyon statement that ME/CFS it's carcinogenic even though this isn't true when you hold it to the same standard.

Perhaps you just happened to hit on raw nerve in all the people taking Valcyte, as I expect there may be some concern at the back everyone's mind on this, and that's why there was a strong response to your statement.

I have not yet tried Valcyte myself, but its various potentially serious side effects, and the theoretical possibility that it may be carcinogenic in humans, would be my concern when I do.

I don't think anyone is disagreement with the idea that there may be some carcinogenic risks involved in taking Valcyte.



Just to quote various authoritative sources on Valcyte and carcinogenicity:

No long term carcinogenicity studies have been conducted with valganciclovir. However, ganciclovir is a potential carcinogen and due to the rapid conversion of valganciclovir to ganciclovir, it is also considered a potential carcinogen.
http://www.drugs.com/mmx/valganciclovir.html

High concentrations of ganciclovir have produced carcinogenic effects in animal models. As a result, ganciclovir is considered a potential carcinogen in humans.
http://www.medscape.com/viewarticle/712277_6

Ganciclovir has caused tumors in laboratory animals. Although there is no information in humans, ganciclovir should be considered cancer-causing (carcinogenic).
http://www.medicinenet.com/ganciclovir-injection/article.htm

Valcyte may cause cancer. Valcyte causes cancer in animals. It is not known if Valcyte causes cancer in people.
http://www.gene.com/patients/medicines/valcyte

Ganciclovir was carcinogenic in the mouse at oral doses that produced exposures approximately 0.1x and 1.4x, respectively, the mean drug exposure in humans following the recommended intravenous dose of 5 mg/kg, based on area under the plasma concentration curve (AUC) comparisons.

All tumours were of epithelial or vascular origin except for histiocytic sarcoma of the liver.

No carcinogenic effects were seen at 1 mg/kg/day.

At the higher dose there was a significant increase in the incidence of tumors of the preputial gland in males, fore stomach (nonglandular mucosa) in males and females, and reproductive tissues (ovaries, uterus, mammary gland, clitoral gland and vagina) and liver in females.

At the lower dose, a slightly increased incidence of tumors was noted in the preputial and harderian glands in males, forestomach in males and females, and liver in females. Ganciclovir should be considered a potential carcinogen in humans

Ganciclovir caused point mutations and chromosomal damage in mammalian cells in vitro and in vivo. In an 18 month study, ganciclovir was carcinogenic in mice after oral doses of 20 mg and 100 mg daily.
http://datasheets.scbt.com/sc-203963.pdf

 

[leokitten]

I will admit that I'm not familiar with the study or studies but I thought it was pretty well accepted that there is an increased risk of NHL in ME patients. Also, Dr. John Richardson has published statistics from his enterovirus patient cohort, noting increased incidence of gliomas, astrocytomas, and carcinomas.

I'm just trying to show people on this forum that they are so quick to criticize and say there is no evidence when I say a general statement that Valcyte is carcinogenic, but when someone says in such a general way that ME/CFS is carcinogenic of course there is no criticism.