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  1. #1
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    Default A Proposed CFS Treatment: Valsartan's Off-label Antiviral Effects

    Two existing blood pressure drugs, bosentan and valsartan, have been shown to significantly inhibit Coxsackie B virus in vitro — as much as a 5-fold and 10-fold reduction in viral load respectively. See here:

    Antiviral effect of Bosentan and Valsartan during coxsackievirus B3 infection of human endothelial cells.

    So these drugs might be useful antivirals for those with enterovirus-associated chronic fatigue syndrome (CFS).

    Valsartan looks easier to use than bosentan, as bosentan use requires regular liver function checks by your doctor when you take it. And valsartan seems to be the more potent antiviral of the two.

    I am going to try valsartan, as a guinea pig, and see if it improves my CFS (which I believe is enterovirus-associated).

    The antiviral action of these two drugs is indirect: it is mediated by lowering the expression of coxsackie-adenovirus receptors (CAR) on the cellular membrane. Coxsackievirus B uses the CAR receptor to enter cells; so with reduced CAR populations, the infection is also reduced.

    Any unwanted blood pressure lowering effects from valsartan might be counteracted by simultaneously taking blood pressure raising supplements like licorice, ginseng, or salt. Drinking more water can also raise blood pressure.

    Note that the above study was performed in vitro, so these antiviral actions may not necessary pan out in vivo.

    The cells targeted by valsartan and bosentan are:

    Epithelial cells — which line the mucous membranes of the whole respiratory-gastrointestinal tract.
    Endothelial cells — which line the inside of the blood vessels.

    Epithelial cells in the gut are, I believe, a major reservoir for coxsackievirus B infection, so these drugs would appear to hit this virus right in its home territory.



    Any thoughts on whether this antiviral approach might work in vivo, or more precisely, in me?

    And apart from the lowering of blood pressure, and the known potential side-effects of valsartan (which include headache, dizziness, sensitivity to bright light), can anyone envisage any other side effects that might occur from valsartan?

    The study authors themselves mention that "future attempts to figure out the potential use of both bosentan and valsartan as antivirals should also take into consideration that inhibition of CAR might cause unwanted side effects." Would reducing CAR populations have any negative effects in CFS?

    Valsartan is an angiotensin II type 1 receptor antagonist. There has been some vague speculation that reducing the effects of angiotensin II may benefit CFS patients (ref: here), so this would be a positive side effect of valsartan's use in CFS.

    Valsartan's absorption is around 25%, and its half-life is 6 to 9 hours (ref: here). The slightly low absorption may well act in favor of this proposed CFS treatment, as a lot of the enterovirus infection in CFS is found in the gut lining, so this low absorption presumably equates to a higher concentration of valsartan in the gut.


    Treatment Limitations: Slugs and Snails

    The limitation of this proposed valsartan treatment is that, although it may potentially prevent infection of epithelial cells by full enterovirus virions, unfortunately, a major subpart of chronic enterovirus infection comprises not whole virions, bur rather naked strands of enterovirus dsRNA that persistently occupy human cells, and replicate inside these cells.

    As this dsRNA replicates, it does not make viral shells (capsids) to house itself in, as happens in normal viral replication where a full virions are built; but rather this dsRNA just duplicates itself; it just makes more and more naked dsRNA.

    If the full enterovirus virion is like a snail, with the snail's shell representing the viral capsid, and the snail's body representing the enteroviral RNA genome inside the capsid, then this naked dsRNA is a bit like a snail without its shell. A slug, if you like.

    Refs: 1, 2, 3.

    Unlike the regular enterovirus virions, this enterovirus dsRNA does not cause lysis of the cell (so the infected cell is not destroyed), but nevertheless, enterovirus dsRNA living inside cells alters the functioning of those cells. For this reason, enterovirus naked dsRNA is also known as a non-cytopathic or non-cytolytic enterovirus.

    Incidentally, this persistent enterovirus naked dsRNA infection is also a major etiological suspect in chronic muscle diseases: Viral dsRNA as a Mediator of Chronic Muscle Diseases.

    This proposed valsartan treatment for CFS would only potentially tackle the enterovirus full virion infection, not the accompanying enterovirus dsRNA infection.

    In other words, this treatment may kill off the snails (virions), but not the slugs (persistent dsRNA), found in chronic fatigue syndrome.

    But if some other treatment can be found for the persistent dsRNA infection, then you might start seeing results, as combined "snail & slug" killing treatment for CFS.

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    Nice - I didn't know anything about these drugs. I wonder if there is a similar effect from Propranolol/beta blockers and from timing of administration of the blood pressure drug - higher nocturnal blood pressure seems to be highly correlated with depressive and suicidal mood, as I recall, which indicates a possible viral involvement. It seems to be due to a systemic dysruption in the central/peripheral nerves. If Gabaergic drugs operate via reducing activity, there may be something interacting with viral replication - perhaps reduced cellular ROS or something along those lines. Some GABAergics do seem to be antiviral. I think there is an effect and general property here, and it may be enhanced by a diurnal pattern.

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    Aha - Some clinical evidence of the hypothesis of a... [Med Hypotheses. 2011] - PubMed - NCBI

    Med Hypotheses. 2011 May;76(5):689-91. Epub 2011 Feb 26.
    Some clinical evidence of the hypothesis of an indirect antiviral effect of propranolol through immunoactivation.

    Peuschel KE.
    Source

    CNP, Rue Sophie-Mairet 29, 2300 La Chaux-de-Fonds, Switzerland. karin@swissmail.com

    Abstract

    The hypothesis of an indirect antiviral effect on the immune system of propranolol has been confirmed on a small scale by treating viral infections with herpes simplex I, shingles and influenza virus infections diagnosed clinically; in one case influenza virus infection was confirmed with a specific influenza test. Herpes simplex infections were treated successfully with propranolol in 2 days, influenza infections in 2 to 3 days, chronic shingles lesions in a month. Other interesting effects of propranolol have been observed, for example on the skin, the liver, the pancreas and on the nervous system.
    Copyright © 2011 Elsevier Ltd. All rights reserved.

    PMID:21354709

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    This somewhat ties into FunkOs dislike of noradrenergics. However, I think that both NE agonism and antagonism is desired, not equally for all groups, and the most important effect is probably acheived through diurnal timings, and this may alter completely the action of NE drugs. This remains to be proven.

    On the GABAergic dimension, I think exactly the same thing is desirable, and the NE antagonists and GABA active drugs may have a similar activity. Reducing psychological stress, which both betablockers and gabaergics do, seems to be indicated in preventing viral activity. In rodents, herpes reactivation was strongly increased in social but not physical stress. I think the reason here is that social stress is ongoing and disrupts rest, which I think has a core antiviral function.

    Some of the stress in CFS may be learnt, from discomfort in the GI tract. There seems to be evidence that in IBS, the pain involved induces anxiety, since anxiety becomes associated with discomfort sensations, and discomfort sensations causes anxiety.

    Even here, I think a role for the peripheral nervous system, and NE sensitive nerves, is also strongly indicated, and they may well be targets of certain viruses or other agents.

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    A central problem for Valsartan: lowering blood pressure may not be desirable in CFS, except as part of sleep - although evidence suggests at least 2 or three subtypes of CFS, one which seems to have a deficiency/disruption of NE signalling. This is one of the reasons I quite like noradrenergic agonists in the day, but propranolol at night. The drugs still dont have an ideal half-life however, and these aren't necessarily the only ways to tackle this.

  6. #6
    Senior Member FunkOdyssey's Avatar
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    I think the potential concern with ARB's in CFS is that they may worsen POTS symptoms by not only reducing BP but also by reducing blood volume. I read about the mechanism for the reduced blood volume somewhere and I've forgotten. I think it was Cheney who explained it in one of his presentations.

    This looks really promising if CAR-dependent enteroviruses are a problem for you though.
    "Also, can I rig some sort of enema out of household items?" -Tussman

    "I don't have the stamina for a 3-some, and I am a one-pump chump" -Ubiyca

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    Yeah, exciting find for that.

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    Ah, I've just noticed Hip had already discussed the blood pressure lowering effects.

    Well, one way to get rid of unwanted RNA and potentially DNA viruses is to enhance the cells internal clean up of proteins. Lithium could be an example of an agent able to influence this positively.

    Glutathione complicates the picture - raising it too much may reduce autophagy, however, it does seem that the cell ATP level is important. This comes from some studies, but also a line of reasoning:

    Cellular infection with bacteria of the alpha-proteobacterial class has had huge impact on our evolution. These can pump out a lot of ATP, so if you had a cell whose autophagy/cleanup was impaired by ATP, then you couldn't control these agents (which became mitochondria).

    There is evidence that healthy autophagy is vital for controlling infections, although its possible to have too much of a good thing, as cancer cells typically have a sort of autostimulating autophagy. Many viruses and bacteria try to target this system, boosting aspects of it for enhancing the supply of nutrients but also impairing the normal autophagal-lysosomal destruction of the pathogen at various points.

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    I'm fairly sure that naked virions can incur a cytopathic effect, however:

    Methods and Results—To determine whether low-level enteroviral gene expression similar to that observed with viral persistence can induce myocytopathic effects without formation of infectious virus progeny, the full-length infectious cDNA copy of CVB3 was mutated at the VP0 maturation cleavage site. This prevented formation of infectious virus progeny. In myocytes transfected with this mutated cDNA copy of the viral genome, both positive- and negative-strand viral RNAs were detected, demonstrating that there was replication of the viral genome by the RNA-dependent RNA polymerase. The level of viral protein expression was found to be below limits of detection by conventional methods of protein detection, thus resembling restricted virus replication. Nonetheless, the CVB3 mutant was found to induce a cytopathic effect in transfected myocytes, which was demonstrated by inhibition of cotransfected MLC-2v luciferase reporter activity and an increase in release of lactate dehydrogenase from transfected cells.
    Conclusions—This study demonstrates that restricted replication of enteroviral genomes in myocytes in a pattern similar to that observed in hearts with persistent viral infection can induce myocytopathic effects without generation of infectious virus progeny.



    http://vir.sgmjournals.org/content/91/8/1959.full.pdf

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    May I suggest you take this drug at night to mitigate the blood pressure lowering effect, it has a not too bad half life, at least compared to antihistamines. I have reason to believe this blood pressure lowering effect is best optimised diurnally and diurnal rhythms of blood pressure and peripheral nervous activity plays a role in the restorative action of sleep against stress and infections, and could be a target in treating mood and anxiety dissorders ie, that nocturnal blood pressures via neural signalling are not merely a result, but bidirectionally involved with these symptoms, possibly involving an interaction in the peripheral nerves and the immune system, or antiviral mechanisms in the neurons.

    Chronotherapy with valsartan/hydrochlorothiaz... [Chronobiol Int. 2011] - PubMed - NCBI




    Chronobiol Int. 2011 Aug;28(7):601-10. Epub 2011 Aug 8.
    Chronotherapy with valsartan/hydrochlorothiazide combination in essential hypertension: improved sleep-time blood pressure control with bedtime dosing.

    Hermida RC, Ayala DE, Mojón A, Fontao MJ, Fernández JR.
    Source

    Bioengineering and Chronobiology Laboratories, University of Vigo, Campus Universitario, Vigo, Spain. rhermida@uvigo.es

    Abstract

    Administration of angiotensin receptor blockers at bedtime results in greater reduction of nighttime blood pressure than dosing upon awakening, independent of the terminal half-life of each individual medication. To obtain blood pressure (BP) target goals most patients require treatment with more than one hypertension medication. However, the potential differing effects on BP regulation of combination therapy depending on the time-of-day of administration have scarcely been investigated. Accordingly, the authors prospectively evaluated the administration-time-dependent BP-lowering efficacy of valsartan/hydrochlorothiazide (HCTZ) combination therapy. The authors conducted a randomized, open-label, blinded-endpoint trial on 204 subjects with essential hypertension (95 men/109 women), 49.7 ± 11.1 (mean ± SD) yrs of age. The BP of participants in this trial was not properly controlled with respect to published ambulatory BP criteria after initially randomized to valsartan monotherapy (160 mg/day), whether routinely ingested upon awakening by one group or at bedtime by another group for 12 wks. Thus, HCTZ (12.5 mg/day) was added to valsartan as a single-pill formulation, maintaining the original treatment-time, i.e., upon awakening or at bedtime, of participants of the two groups, for another 12 wks. BP was measured by ambulatory monitoring for 48 h at inclusion and after each 12-wk span of therapy. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately define the beginning and end of daytime activity and nocturnal sleep so that the respective BP means for every participant at each evaluation could be precisely determined. Combination therapy resulted in a similar statistically significant reduction of the 48-h BP mean from baseline for both treatment-time groups (17.0/11.5 mm Hg in systolic/diastolic BP after combination therapy on awakening; 17.9/12.1 mm Hg reduction after combination treatment at bedtime; p > .542 between groups). The awake BP mean was reduced to a comparable extent in both treatment-time groups (p > .682). However, bedtime compared to morning dosing better reduced the asleep means of systolic BP (20.1 vs. 16.0 mm Hg; p = .015) and pulse pressure (6.5 vs. 4.0 mm Hg; p = .007 between groups). Accordingly, the proportion of subjects with a baseline non-dipper BP profile was significantly reduced from 59% to 23% only after bedtime combination treatment (p < .001). Moreover, the proportion of subjects with properly controlled ambulatory BP after combination therapy was significantly greater with bedtime than upon-awakening treatment (55 vs. 40%, p = .037). The improved efficacy in lowering the asleep BP mean, increased sleep-time relative BP decline, and greater proportion of controlled patients suggest that valsartan/HCTZ combination should be preferably administered at bedtime for treatment of subjects with essential hypertension requiring combination therapy to achieve proper BP control.

    PMID:21823969 [PubMed - in process]
    -nice, potential synnergies in health and antiviral treatment with chonotherapy, as they call it.

  11. #11
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    I'm guessing you don't need constant high levels of the drug in your system to downregulate the CAR's, so nighttime dosing would probably work.
    "Also, can I rig some sort of enema out of household items?" -Tussman

    "I don't have the stamina for a 3-some, and I am a one-pump chump" -Ubiyca

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    Aye good point - maybe the CAR receptor interacts with other metabolic signals or cytokines or whatever, so it may even work better at night?

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    yeah, this actually would make a fair ammount of sense - cardiac damage is related to hypertension, and complement levels, and it may therefore be a case where insufficient rest could lead to a cycle of inflammatory ROS and viral replication - since ROS seems to encourage that. Obviously, the night during SWS is the only relative 'downtime' the heart tissue gets.

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    Access : Coxsackievirus B3 and adenovirus infections of cardiac cells are efficiently inhibited by vector-mediated RNA interference targeting their common receptor : Gene Therapy

    This is just more on CAR and coxsakie B.

    The paper on google describes something about norepinephrine but its not described in that abstract.

    Nothing yet on that particular interaction, which would have a diurnal aspect, but NE able to induce cardiac hypertrophy, which isn't automatically a good thing - IIRC hypertrophy is reported in CS.

    http://www.ncbi.nlm.nih.gov/pmc/arti...df/1021609.pdf

    I've broadened the search to diurnal rhythms and viruses:

    A blast from the 1960's: http://jn.nutrition.org/content/95/3/357.full.pdf

    I think thats just the beginning though.

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    Serum H2S is increased in Coxsackie B3 virus-induced myocarditis in mice and a

    Serum H2S - although this may be endogenously induced by an inlammatory response, it can also be produced in the gut. I dug up research that showed that gut H2S seems to not derrive from sulphur in food (sorry, no excuse to avoid those sprouts), but instead is produced ffrom mucous in the intestines, probably increased by inlammation and action by H2S producing bacteria. This may have no baring, or turn out to be relevant, I have no idea.

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    Quote Originally Posted by C Norris View Post
    May I suggest you take this drug at night to mitigate the blood pressure lowering effect, it has a not too bad half life, at least compared to antihistamines. I have reason to believe this blood pressure lowering effect is best optimised diurnally and diurnal rhythms of blood pressure and peripheral nervous activity plays a role in the restorative action of sleep against stress and infections, and could be a target in treating mood and anxiety dissorders ie, that nocturnal blood pressures via neural signalling are not merely a result, but bidirectionally involved with these symptoms, possibly involving an interaction in the peripheral nerves and the immune system, or antiviral mechanisms in the neurons.

    Chronotherapy with valsartan/hydrochlorothiaz... [Chronobiol Int. 2011] - PubMed - NCBI

    -nice, potential synnergies in health and antiviral treatment with chonotherapy, as they call it.

    Quote Originally Posted by FunkOdyssey View Post
    I'm guessing you don't need constant high levels of the drug in your system to downregulate the CAR's, so nighttime dosing would probably work.
    Thanks guys, that's a very good idea taking this drug at bedtime. Since you are lying horizontally during sleep, this might presumably mitigate some of the effects of low blood pressure. I actually developed slightly high blood pressure since getting chronic fatigue syndrome from this viral infection, so this makes things easier. I have no sign of POTS either.

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    It would also be good to find ways of down-regulating coxsackievirus and adenovirus receptor (CAR) expression on neurons, as this would fight coxsackievirus B infections of the central nervous system — an infection which may produce the major part of CFS symptoms.

    It is interesting that this this study found that CAR expression was higher on new neurons, compared to mature neurons. Neurons thus presumably become less less susceptible to coxsackievirus B5 once mature.

    (I guess this fact makes neurogenesis more difficult in coxsackievirus B infected brains, as incipient neurons may suffer high rates of coxsackievirus B infection, due to their higher CAR expression).

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    interesting. In alzheimers, there is a surprising ammount of hippocampal neurogenesis, but the cells seem to dysunction and commit an inflammatory death. Additionally, remaining hippocampal neurons have chromosomal abberations like that of Downs Syndrome, which further suggests a virus, one dependent on cell division which it may enhance.

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    Quote Originally Posted by C Norris View Post
    interesting. In alzheimers, there is a surprising ammount of hippocampal neurogenesis, but the cells seem to dysunction and commit an inflammatory death. Additionally, remaining hippocampal neurons have chromosomal abberations like that of Downs Syndrome, which further suggests a virus, one dependent on cell division which it may enhance.
    Apparently herpes simplex virus 1 is associated with Alzheimer's disease in individuals that possess the APOE4 form of the APOE gene. The APOE4 gene enables the herpes virus to enter the brain. Source: Wikipedia

    I believe herpes virus can enter the brain via the trigeminal or olfactory nerves.

    One interesting thing I read about coxsackievirus B is that it can travel along the vagus nerve, from the gut to the brain in 3 days.

    I thought it might be a good idea to look at what brain structures are adjacent to the entry point of the vagus nerve into the brain. If the vagus nerve is a main route of entry of coxsackievirus B into the brain in CFS, you might expect that the first symptoms experienced when the brain is first infected by this virus in CFS would relate to malfunctions in brain structures adjacent to the vagus entry point.

    Similarly for Alzheimer's, and the herpes simplex virus entry points into the brain via the trigeminal or olfactory nerves.

    Here is a map of the 12 cranial nerve entry points into the brain.

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    Yeah, quite a few viruses can climb up the vagus nerve, including flu virus. I've looked into that myself, but its well worth going back over it.

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