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Summary: Drugs tested against XMRV to date (in vitro)

Discussion in 'XMRV Testing, Treatment and Transmission' started by cfs since 1998, Mar 31, 2010.

  1. cfs since 1998

    cfs since 1998 *****

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    The following drugs were tested in vitro only. Their effectiveness against XMRV in vivo or for ME/CFS in general has not been established. Taking HIV drugs before more research is available is not advised and could cause resistance mutations or dangerous side effects.

    Not Effective:
    • 3TC/lamivudine (NRTI) [1,2,3]
    • ABC/abacavir/Ziagen (NRTI) [2,3]
    • amdoxovir (NRTI) [3]
    • AZA (NRTI) [3]
    • AZG (NRTI) [3]
    • carbovir/CBV (NRTI) [3]
    • CS-92 (NRTI) [3]
    • d4c (NRTI) [3]
    • d4T/stavudine/Zerit (NRTI) [1,2,3]
    • ddc/dideoxycytidine/zalcitabine/Hivid (NRTI) [3]
    • ddl/didanosine/Videx (NRTI) [2,3]
    • DXG (NRTI) [3]
    • emtricitabine/FTC (NRTI) [3]
    • FLT (NRTI) [3]
    • efavirenz/Sustiva/Stocrin (NNRTI) [1,3]
    • nevirapine/Viramune (NNRTI) [1]
    • TIBO analog (NNTRI) [3]

    • amprenavir (PI) [3]
    • atazanavir (PI) [3]
    • darunavir (PI) [3]
    • indinavir/Crixivan (PI) [1,3]
    • lopinavir (PI) [3]
    • nelfinavir (PI) [3]
    • ritonavir/Norvir (PI) [1,3]
    • saquinavir (PI) [1,3]
    • tipranavir (PI) [3]

    • 118-D-24 (integrase inhibitor) [1]

    • acyclovir [3]
    • aspirin [3]
    • bicalutamide [3]
    • cidofovir/Vistide [3]
    • chloroquine [3]
    • DHEA [3]
    • ldUrd [3]
    • entecavir [3]
    • foscarnet [2,3]
    • ribavirin [3]
    • ganciclovir [3]
    • methylene blue [3]
    • penciclovir [3]
    • telbivudine [3]
    • vidarabine [3]

    Effective:
    • AZT/azidothymidine/zidovudine/Retrovir (NRTI) [1,2,3]
    • TDF/tenofovir disoproxil fumarate/Viread (NRTI) [2,3]
    • raltegravir/Isentress (integrase inhibitor) [2,3]
    • L-000870812 (integrase inhibitor) [3]
    • androgen inhibitors casodex and flutamide suppressed viral growth 3-fold [4]

    Notes:
    • raltegravir seems to be the most potent XMRV inhbitor of all drugs tested [2,3]. IC50 was 2.5-fold lower than HIV [2].
    • AZT inhibits XMRV at a similar concentration as HIV (0.45M versus 0.3M) [2].
    • Tenofovir at a concentration of 30nM had minimal inhibition of XMRV [1]. However, later studies showed TDF inhibition of XMRV [2,3]. IC50 was similar to but 3.9-fold higher than the IC50 of HIV [2].
    • Raltegravir, L-000870812, TDF and AZT/ZDV displayed strong synergistic effects in combination [3].


    References:
    1. Sakuma et. al. Xenotropic murine leukemia virus-related virus is susceptible to AZT. Virology. 2010 Feb 5
    2. Paprotka et. al. Inhibition of Xenotropic Murine Leukemia Virus-Related Virus by APOBEC3 Proteins and Antiviral Drugs. J Virol. 2010 Mar 24
    3. Singh et. al. Raltegravir Is a Potent Inhibitor of XMRV, a Virus Implicated in Prostate Cancer and Chronic Fatigue Syndrome. PLoS One. 2010 Apr 1
    4. Dong et. al. Androgen stimulates transcription and replication of xenotropic murine leukemia virus-related virus. J Virol. 2010 Feb
  2. cfs since 1998

    cfs since 1998 *****

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    The first study only looked at each drug at one particular concentration, the second determined the IC50 (50% Inhibitory Concentration) of each drug, so I'd say the second is more comprehensive. However since the concentration of tenofovir needed to inhibit XMRV was four times that of HIV would that mean taking quadrouple the dose used in HIV? That seems rather dangerous.

    It appears standard HIV dosage is 300mg once per day. From this pharmacokinetic study, 300mg tenofovir once daily dosage in adults produced a concentration of about 300mcg/ml peak, 100mcg/ml at 12 hours (which is about the HIV IC50), and 50mcg/ml at 24 hours. The highest dose studied, 600mg once daily, produced concentrations double that of the 300mg/day group. So for XMRV you might need 1200mg once per day or 600mg twice per day. I don't think there's evidence that this drug is safe at such a high dose.
  3. outofstep

    outofstep

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    tenofovir

    Apparently it can cause build-up of lactic acid in the body. Dr. Shungu is finding in his studies that people w/ CFS already have abnormally high levels of lactate.
  4. HopingSince88

    HopingSince88 Senior Member

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    Thought I would look into the cost of raltegravir and found this

    this quote from: http://www.thepharmaletter.com/file/f6170bb01b669a7b4e479217ef5f438d/raltegravir-tablets.html

    Wholesale price $810 for 60 tablets (dose is 2 tabs per day)

    Above based on standard script for HIV. I would hope that the 2.5 lower concentration would allow for lower dose script and lower cost?
  5. subtr4ct

    subtr4ct Senior Member

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    outofstep: Thanks for this info. Can you point me to any references for these statements?

    Mrs. subtr4ct had a run-in with what we suspect was d-lactic acidosis. If tenofovir would exacerbate this kind of problem, and its in vitro effectiveness is in dispute (see post #1), then it is sounding less attractive.
  6. outofstep

    outofstep

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    lactic acidosis

    Sorry to hear about your missus subtr4ct! Don't know how to do links on here, but if you go to nyp.org and do a search on Dikoma Shungu you'll get all of their links for his study info. In light of this research it made me concerned about tenofovir when I saw that lactic acidosis was listed as a side-effect, don't know if any XMRV researchers have looked into the CFS/lactate/tenofovir connection yet though.
  7. acer2000

    acer2000 Senior Member

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    Isentress sure does sound promising. Although I'd be happier if they'd test GcMAF or similar therapies that seem to have been shown in some cases to actually knock out the infection - not requiring you to take an expensive drug for life. Not sure if it would work out that way for XMRV, but if the WPI is on the side of patients, they should at least try!
  8. MaryAnn

    MaryAnn

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    Since HIV was recently found to "hide out" in bone marrow, patients need to take their meds for life. However, the news articles point out that researchers are now looking into how to rid the virus completely.
  9. Knackered

    Knackered Guest

    They've only been shown to work in vitro though right? Are there any validated reports of them making people better?
  10. acer2000

    acer2000 Senior Member

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    Yeah I mean that would be great. The only thing I fear is that more research isn't going into curative therapies because its more profitable to keep people on expensive drugs for a lifetime. I hope the WPI in their chats with drug companies keeps this in mind and searches for potentially curative therapies, even if its a long term project.

    Antiretrovirals, while they are better than being dead or very ill, aren't without long term side effects. Many people report cognitive decline, premature aging, etc.. after being on them for years. Viruses become resistant to therapies that slow replication. Also most of the world (ie Africa, Asia, South America) can't afford 13,000$ a year drugs. I mean you can buy a whole car in India for $7,000. You can't put a price on health, but still...
  11. Hope123

    Hope123 Senior Member

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    Here is the link for Dr. Shungu's work, which is supported by the CAA. His findings are in brain fluid (CSF) which is different from the lactic acidosis of tenofovir (which is in blood) so I'm not sure we can generalize this. Also, in general, relying on one or two studies for anything isn't great.

    http://www.cfids.org/cfidslink/2009/030403.pdf

    If Isentress can stop XMRV from integrating into host chromosomes, even if our symptoms are caused by production of XMRV proteins rather than by replication, I wonder if it might be of assistance as production of proteins requires transcription and translation?
  12. cfs since 1998

    cfs since 1998 *****

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    That is correct. However, since the pharmacokinetic properties of these drugs are known from going through the approval process for HIV, in theory they should inhibit XMRV in vivo as well. Of course, if XMRV doesn't cause CFS or if there are other factors or if resistance develops they won't work. I posted this because I think the long list of drugs that did not work in vitro is information that is just as interesting as the ones that do work. I plan to update the list as new research emerges.

    Not that I know of.

    I would be very hesitant to try any of these drugs at this point in time. Even though the possibility of resistance is said to be smaller than HIV, that is speculation; I would rather not risk developing resistance to the only drugs I have a chance with.
  13. Knackered

    Knackered Guest

    I agree 100%.

    I've felt like death lately but I'd rather feel like this for a while longer than risk never being able to get rid of my symptoms. Maybe it'd be wise to put a litle disclaimer pointing this out o your original post.
  14. parvofighter

    parvofighter Senior Member

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    Canada
    Thanks!

    And thanks CFS-since-1998 for starting this thread. Great idea!:Retro smile:
  15. fred

    fred The game is afoot

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    Post removed as it duplicated previous entry.
  16. julius

    julius Watchoo lookin' at?

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    Canada
    So much good news coming out this month. I am floored. Nice catches parvo.

    CFS since, maybe add casodex and flutamide (and maybe dutasteride) to your list. This is from Dong & Silverman's "Androgen stimulates Transcription and Replication of XMRV" http://www.ncbi.nlm.nih.gov/pubmed/19906923?dopt=Abstract

    Basically, they inhibit replication by up to 3-fold by inhibiting the conversion of testosterone into dihydrotestosterone.

    And if you're interested in natural treatments, saw palmetto has the same mode of action as these drugs and is often prescribed for the same reasons. Here's a write up on the Mayo website http://www.mayoclinic.com/health/saw-palmetto/NS_patient-sawpalmetto/DSECTION=evidence
  17. Andrew

    Andrew Senior Member

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    I think this might add one or two.

    "The group, led by Ila R. Singh, M.D., Ph.D., associate professor of pathology at the University of Utah School of Medicine, tested 45 antivirals including 28 marketed drugs in cultured human breast cancer and prostate cancer cells. They found that the integrase inhibitor, raltegravir (the API in Isentress), was the most potent XMRV inhibitor, although another integrase inhibitor L-000870812 and the nucleoside reverse transcriptase inhibitors zidovudine and tenofovir disoproxi fumarate also blocked XMRV replication.

    "When combined, the compounds also displayed synergistic effects and required even lower doses to be effective. This further throws up the possibility that mix-and-match approaches to treating XMRV infection could be a useful tool against the emergence of resistant viruses, the authors point out."

    http://www.genengnews.com/news/bnitem.aspx?name=79300789
  18. Dolphin

    Dolphin Senior Member

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    Methylene blue

    Thanks CFS since 1988.

    I don't think methylene blue should be in the "no or minimal inhibition" group based on Figure 3 of [3]. It's EC90 result was actually the best. Although it looks like it could be quite cytotoxic if I'm reading the paper correctly but perhaps it too might have synergistic properties??
  19. cfs since 1998

    cfs since 1998 *****

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    That's a good point although since they are not antivirals they're not in the same category. I will have read that paper again and think about it.

    Those are there. Singh's paper is reference #3.

    For each drug the classification was according to the author's comments in the full text of the appropriate study rather than straight numerical values. (The classifications used to say "not effective" and "effective" so maybe I should change them back.) Anyway, in the Results section of Singh's paper, under "Inhibitors of viruses other than HIV-1", the authors basically say methylene blue etc. are unacceptably toxic at necessary concentrations.
  20. Dolphin

    Dolphin Senior Member

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    Well technically this is what it says:
    The TI ratio for IdUrd is 2.2/7.3. For methylene blue it is 0.42/7.2. Ideally, I'd prefer another column that said the problem was toxicity but I'm putting in the record with the message so will happily shut up!
    ETA: The TI ratio is worse than the four they highlighted although if the TI ratio was CC50/EC90 it would be not much worse than Tenofovir.

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