Enteroviruses - revisited

[globalpilot]

I thought I'd start a thread where we could share research on enteroviruses. Several of us, including myself, have been found to have excessive amounts of dsRNA in our gut biopsies by Dr. Chia.

Here is a start:

http://jvi.asm.org/content/73/12/10113.full#abstract-1
Molecular Mechanisms of Coxsackievirus Persistence in Chronic Inflammatory Myopathy: Viral RNA Persists through Formation of a Double-Stranded Complex without Associated Genomic Mutations or Evolution

- this study looks at myopathy but does reference CFS. It explains how coxsackie may persist (in a dsRNA form)

"The mechanism of enterovirus replication is not completely understood, but it is possible that downregulation of RNA polymerase activity occurs in damaged myofibers through changes in cellular proteins that participate as elements of the viral replication complex, resulting in production of double-stranded persistent RNA. As a potent inducer of interferon and other cell mediators, double-stranded RNA may itself be pathogenic (25). Activation of interferon-inducible protein kinase has multiple effects on cellular proteins, which, in addition to inhibiting viral replication, include upregulating the transcription of cytokine genes through activation of NF?B. In virus-induced myopathies, tissue injury could result directly from inducible nitric oxide synthase produced by muscle or through production of cytokines and other mediators such as those that have been implicated in the pathogenesis of fatigue syndromes (20). Equivalent levels of plus and minus strands of enterovirus RNA have been observed in patients with chronic fatigue syndrome (15), and what we have found in mouse muscle may now provide a basis for understanding the processes which are at work in human diseases (33). Whether pathogenicity in CIM is derived directly from the presence of viral RNA or requires some degree of translation is not known. The lack of deleterious mutations and the fact that all regions of the viral genome were amplified leaves open the possibility that under appropriate but as yet unknown conditions, persistent coxsackievirus RNA possesses the capacity to produce viral proteins or infectious virus, thereby promoting an ongoing immunopathic response in muscle. "

 

[Waverunner]

This thread is a very good idea. I'm very interested in the implication of enteroviruses in ME/CFS.

 

[Timaca]

Coxsackie B is part of my problem. My oxymatrine journey can be found here: http://hhv6foundation.proboards.com/index.cgi?board=antiviral&action=display&thread=200 In a nutshell it appears (by antibody titers) that I am battling various pathogens (HHV-6, EBV, Coxsackie B, Cpn and HSV1). In June of 2009, Coxsackie B4 was as high as the lab measures at ARUP lab (>=1:640) and B3 was quite high too 1:320. Oxymatrine brought those titers down (B4 to 1:40 and B3 to <1:10), and I felt better (not well but better). In April 2010, I got quite ill, and my WBC and platelets dropped well below the reference range. The doctors ran some labs on me and found that The Coxsackie B3 and B4 had jumped back to >=1:640 and 1:320. (In 3 weeks time they jumped from as low as they had ever been to that high again.) So we know my problem was Coxsackie related. B3 is now 1:80 and B4 1:160 so they are dropping again. And my Cpn IgA is dropping too due to the antibiotics I'm on. But, HSV 1 IgG is as high as the lab measures and IgM is "detected" sometimes also giving a low titer. So, in me, it's not just one pathogen causing me problems (apparently).

For more info on Coxsackie B and enteroviruses see: http://chronicfatigue.stanford.edu/infections/entero.html
http://enterovirusfoundation.org/
http://www.evmedresearch.com/

Best, Timaca

 

[globalpilot]

I wonder why one person with enterovirus (yourself) would show high antibodies to various pathogens and another (myself) doens't show high antibodies. I didn't even show high antibodies to coxsackie. maybe we have different immune system abnormalities. I think, in myself, this infection may have become established when I was very young (not breastfed which confers IgA immunity against enteroviruses and lots of time at a lake).

Coxsackie B is part of my problem. My oxymatrine journey can be found here: [urlyourhttp://hhv6foundation.proboards.com/index.cgi?board=antiviral&action=display&thread=200[/url] In a nutshell it appears (by antibody titers) that I am battling various pathogens (HHV-6, EBV, Coxsackie B, Cpn and HSV1). In June of 2009, Coxsackie B4 was as high as the lab measures at ARUP lab (>=1:640) and B3 was quite high too 1:320. Oxymatrine brought those titers down (B4 to 1:40 and B3 to <1:10), and I felt better (not well but better). In April 2010, I got quite ill, and my WBC and platelets dropped well below the reference range. The doctors ran some labs on me and found that The Coxsackie B3 and B4 had jumped back to >=1:640 and 1:320. (In 3 weeks time they jumped from as low as they had ever been to that high again.) So we know my problem was Coxsackie related. B3 is now 1:80 and B4 1:160 so they are dropping again. And my Cpn IgA is dropping too due to the antibiotics I'm on. But, HSV 1 IgG is as high as the lab measures and IgM is "detected" sometimes also giving a low titer. So, in me, it's not just one pathogen causing me problems (apparently).

For more info on Coxsackie B and enteroviruses see: http://chronicfatigue.stanford.edu/infections/entero.html
http://enterovirusfoundation.org/
http://www.evmedresearch.com/

Best, Timaca

 

[globalpilot]

Here is another one showing enteroviruses have antiapoptotic features:

http://jvi.asm.org/content/83/14/7273.full
Antiapoptotic Activity of the Cardiovirus Leader Protein, a Viral Security Protein?

- Since then, a wealth of data has been accumulated that shows that the activation of apoptotic pathways is a widespread, though not universal, response to picornavirus infection. Thus, apoptosis-inducing capacity was reported for coxsackieviruses B3, B4, and B5 (22, 54, 82), enteroviruses 70 and 71 (25, 27, 60, 88), human rhinoviruses 1B, 9, 14, and 16 (32, 92, 100), foot-and-mouth disease virus (53, 76), avian encephalomyelitis virus (62, 63), and hepatitis A virus (16, 43) and was the subject of several recent reviews (15, 102). The antiapoptotic activity of picornaviruses was studied predominantly by using poliovirus (3, 8, 13, 72) and coxsackievirus B3 (21, 36, 85).
- 2A protease proteins of enterovirus and rhinovirus (unrelated to 2A proteins of cardioviruses), though apparently essential (70), also perform a set of anti-defensive functions very similar to those exhibited by L proteins of cardioviruses and aphthoviruses, namely the inhibition of host translation (59), the disruption of controllable nucleocytoplasmic traffic (12, 75), the suppression of interferon action (71), and others (56).

 

[globalpilot]

DICER enzyme - cleave double stranded RNA

http://en.wikipedia.org/wiki/Dicer

 

[globalpilot]

Here is a study showing how the body deals with dsRNA in pancreatic beta cells. I don't know if the same would apply to the gut where Dr Chia is finding enterovirus dsRNA. But, it seems there is a specific mechanism for apoptosis of these cells and for those with persistent dsRNA this procedure must not be working properly. I wonder if the virus downregulates this procedure. If so, stopping viral translation should stop this problem. Maybe the emblica root can accomplish this.

http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002267
Exposure to the Viral By-Product dsRNA or Coxsackievirus B5 Triggers Pancreatic Beta Cell Apoptosis via a Bim / Mcl-1 Imbalance
- We have presently clarified the signaling pathways leading to beta cell apoptosis following exposure to the viral mimetic double-stranded RNA (dsRNA) and a diabetogenic enterovirus (Coxsackievirus B5). Internal dsRNA induces cell death via the intrinsic mitochondrial pathway. In this process, activation of the dsRNA-dependent protein kinase (PKR) promotes eIF2? phosphorylation and protein synthesis inhibition, leading to downregulation of the antiapoptotic Bcl-2 protein myeloid cell leukemia sequence 1 (Mcl-1). Mcl-1 decrease results in the release of the BH3-only protein Bim, which activates the mitochondrial pathway of apoptosis.

 

[Hip]

List of Antivirals for Enteroviruses: Coxsackievirus B and Echovirus

Here is a list of supplements and drugs that are antiviral for coxsackievirus B and echovirus, two enteroviruses strongly associated with chronic fatigue syndrome / myalgic encephalomyelitis (ME/CFS).

Note though that antiviral effects in vitro (in cell line tests) may not necessarily translate to effects in vivo (in the body), when the drug or supplement is taken orally. This is because with in vitro studies, they use a certain concentration of the drug or supplement in a cell line to achieve an antiviral effect. But that concentration may be too high to achieve in the body when the drug or supplement is taken orally.

In fact by some pharmacokinetic calculations I performed on these substances, I found out that most of the antiviral supplements and off-label drugs in my list below will not have any significant antiviral effect in vivo, when you actually take the supplement or drug. See this post for more info.

Dr John Chia has found that the enteroviruses most commonly found as active infections in ME/CFS patients are: 1

• CVB3 and CVB4 first and foremost
• Then less frequently CVB2, EV6, EV7 and EV9; and then much less frequently EV11

Antiviral Drugs for Coxsackievirus B:

interferon alpha (immunomodulatory drug) for CVB3 1
ribavirin (antiviral drug) antiviral for CVB3 1
OSW-1 (saponin) broad-spectrum antiviral for enteroviruses including CVB3, poliovirus, rhinovirus 1
umifenovir (Arbidol, Russian antiviral drug) antiviral for CVB3, CVB5 1 2 and CVB4 1
fluoxetine (antidepressant drug) antiviral for CVB1, CVB2, CVB3 1 2 and CVB4 1
pirlindole (Pyrazidol, MAO-A antidepressant) antiviral for CVB3, and antiviral for other CVBs and echoviruses 1
dipyridamole (vasodilator) broad-spectrum antiviral for picornaviruses including CVB3 1 2
itraconazole (anti-fungal) broad-spectrum antiviral for enteroviruses including CVB3, CVA16, poliovirus, enterovirus-71, enterovirus 68, rhinovirus 1 2
bosentan (pulmonary hypertension drug) antiviral for CVB3 (and likely all CVBs) 1 More info here.
valsartan (ARB blood pressure drug) antiviral for CVB3 (and likely all CVBs) 1 More info here.
olmesartan (ARB blood pressure drug) antiviral for CVB3 1
lovastatin (statin drug) antiviral for CVB3 1
mycophenolate (immunosuppressive drug) antiviral for CVB3 1
oseltamivir (Tamiflu, antiviral for influenzavirus) antiviral for CVB3 and CVB4 1 (see Table 1 in the raoulic acid full paper)
amiloride (diuretic drug) antiviral for CVB3 1 2 3 4
arsenic trioxide (leukemia drug) antiviral for CVB3 1 2
glyceryl trinitrate and isosorbide dinitrate antiviral for CVB3 1
gemcitabine (chemotherapy drug) antiviral for CVB3 and CVB3 replicons (non-cytolytic CVB3) 1
valproic acid ameliorates CVB3 myocarditis 1
alpha-galactosylceramide protects from CVB4 type 1 diabetes 1
trichostatin (a histone deacetylase inhibitor) inhibits CVB3 in vivo 1
chloroquine antiviral for CVB3 1
micafungin inhibits replication of CVB replicon 1



Note that Dr John Chia found that interferon and ribavirin are effective against CVB3 and CVB5 infections, but found these drugs were not effective against CVB4 infections. 1 2


Antiviral Drugs for Echovirus:

ribavirin (antiviral drug) antiviral for EV5, EV11 and EV18 1 2 3
amantadine (antiviral drug) antiviral for EV5 and EV18 1 2
fluoxetine (antidepressant drug) antiviral for EV1, EV9 and EV11 1
itraconazole (anti-fungal) broad-spectrum antiviral for enteroviruses including EV11 1 2
dipyridamole (vasodilator) broad-spectrum antiviral for picornaviruses 1 2
pirlindole (Pyrazidol, MAO-A antidepressant) antiviral for echoviruses 1


Antiviral Supplements and Compounds for Coxsackievirus B:

N-acetyl-cysteine (NAC) shown antiviral in vivo in mice for CVB3. 1
dihydroquercetin (DHQ, a flavonoid) is a antiviral (as good as ribavirin) for CVB4. 1 Used by Dr Chia.
Aegle marmelos (bael fruit, bilva) antiviral (as good as ribavirin) for CVB1 to CVB6 1
Emblica officinalis (Phyllanthus emblica, amla) root antiviral for CVB3 1 2
shuang huang lian (Chinese herbal formula) antiviral for CVB3 1 2
garlic antiviral for CVB3 1
curcumin antiviral for CVB3 1
chlorogenic acid (6% in coffee; 50% in green coffee bean) antiviral for CVB3 and CVB5 1 2
baicalein (from Scutellaria baicalensis, Chinese skullcap) antiviral for CVB3 1
Paris polyphylla (Qi Ye Yi Zhi Hua, Chong Lou) antiviral for CVB3 and enterovirus 71 1
raoulic acid (from Raoulia australis) antiviral for CVB3 and CVB4 1
Dodonaea viscosa (hopbush) antiviral for CVB3 1
oroxylin A (from Scutellaria baicalensis) may be antiviral for CVB3 1 and for enterovirus 71 1
oxymatrine (from Sophora flavescens root) immunomodulator for coxsackievirus B 1
ursolic acid antiviral for CVB1 and enterovirus 71 1
apigenin antiviral for CVB1 and enterovirus 71 1
emodin (from Japanese knotweed, aloe vera, rhubarb) antiviral for CVB3, CVB4 and CVB5 1 2 3
Spatholobus suberectus (Ji Xue Teng) antiviral for CVB3 and CVB5 1 2 3 4
Sophora tonkinensis (Shan Dou Gen) antiviral for CVB3 and CVB5 1
Terminalia chebula (haritaki, He Zi) antiviral for CVB3 and CVB5 1
Trichosanthes root (Tian Hua Fen, Chinese cucumber) antiviral for CVB3 1
Rhodiola rosea (golden root) antiviral for CVB3 1
Astragalus membranaceus antiviral for CVB3 1
Bupleurum (Chai Hu) antiviral for CVB1 1
Glycine max (black soybean extract, Dan Dou Chi) antiviral for CVB1 1
DHEA (dehydroepiandrosterone) protective during CVB4 infection 1
5-androstenediol 100 times more protective than DHEA during CVB4 infection 1 2 (more info)
sodium selenite (a form of selenium) antiviral for CVB5 1
Epimedium (horny goat weed) antiviral for CVB4 and CVB5 1 2 3
acemannan (aloe polymannose from aloe vera leaves) antiviral for CVB3 1
Azadirachta indica (neem leaf) antiviral for CVB1 to CVB6 (but most effective for CVB4) 1
sophoridine (from Sophora flavescens root, Ku Shen) antiviral for CVB3 1 2
oxymatrine (from Sophora flavescens root, Ku Shen) antiviral for CVB3 and immunomodulator for coxsackievirus B 1 2
Isatis tinctoria (dyer’s woad, Da Qing Ye, Ban Lan Gen) antiviral for CVB3 1
Indirubin derivative E804 antiviral for CVB3 1
yakammaoto (Chinese herbal formula) antiviral for CVB4 1
cinnamaldehyde (cinnamon essential oil is about 90% cinnamaldehyde) antiviral for CVB3 1
hyaluronic acid antiviral for CVB5 1
Quassia amara antiviral for CVB2 1
Rheum palmatum root (Chinese rhubarb, Turkish rhubarb) antiviral for CVB3 1
fatty acid synthase inhibitors (these include: amentoflavone, oleic acid, keemun tea, Parasitic loranthus, EGCG, orlistat) are antiviral for CVB3 1 2
EGCG (from green tea) antiviral for CVB3 1
clinoptilolite (a natural zeolite) antiviral for CVB5 1
selenium deficiency increases virulence of CVB3 1
vitamin E deficiency increases virulence of CVB3 1
copper deficiency increases virulence of CVB3 1
nicotinamide (aka: niacinamide, vitamin B3) antiviral for CVB4 and CVB5 1
ginsenosides antiviral for CVB3 1
wild berry fruit extracts antiviral for CVB1 1
berberine antiviral for CVB3 1
chrysin antiviral for CVB3 1
Re Du Ning antiviral for CVB3 1
Spirulina platensis antiviral for CVB4 1
Houttuynia cordata antiviral for CVB3 and CVB6 1
fucoidan antiviral for CVB4 1
Bifidobacterium adolescentis probiotic antiviral for CVB3 1
Lactobacillus plantarum probiotic antiviral for CVB4 1
Eucalyptus camaldulensis antiviral for CVB and EV6 1
jiadifenoic acids C potent antiviral for all CVB 1
2-(α-Hydroxybenzyl)-benzimidazole antiviral for CVB4 and EV12 1
Zinc finger antiviral protein antiviral for CVB3 1
Pyrrolidine dithiocarbamate antiviral for CVB3 1
gallic acid antiviral for CVB3 and CVB4 1
Ardisia chinensis antiviral for CVB3 1
oxoglaucine antiviral for CVB1 1
manassantin B antiviral for all CVB 1
Mdivi-1 (a mitochondrial fusion inhibitor) antiviral for CVB 1
Acokanthera schimperi antiviral for CVB3 1
glucomannan from konjac root antiviral for CVB 1
arginine ameliorates acute and chronic CVB3 myocarditis 1
Eucalyptus camaldulensis and Eucalyptus torelliana antiviral for CVB 1
galangin antiviral for CVB1 1
ethyl 3-hydroxyhexanoate shown antiviral in vivo in mice and in vitro for CVB3 1



Antiviral Supplements and Compounds for Echovirus:

shuang huang lian (Chinese herbal formula) antiviral for EV11 1
garlic antiviral for EV11 1
oxymatrine (from Sophora flavescens root) immunomodulator for echovirus 1
betulin and betulinic acid (from birch bark and Chaga mushroom) antiviral for EV6 1
Spatholobus suberectus Dunn (Ji Xue Teng) antiviral for EV9 and EV29 1 2
Sophora tonkinensis (Shan Dou Gen) antiviral for EV9 and EV29 1
latex from fig fruit (Ficus carica) antiviral for EV11 1
beta-lapachone (from Lapacho) antiviral for EV19 1
clinoptilolite (a natural zeolite) antiviral for EV7 1
lactoferrin antiviral for EV5 1
bismuth salts (such as bismuth subsalicylate) antiviral for EV12 1
Re Du Ning antiviral for EV11 1
serum albumin (of bovine and human origin) antiviral for EV7 and other echoviruses 1
EGCG (from green tea) antiviral for EV11 1
Lactobacillus species probiotics antiviral for EV7 and EV19 1



Antivirals for Enteroviruses and Picornaviruses in General:

lamivudine (Epivir) an antiviral used by Dr Chia for enterovirus infections, although he found Epivir is not effective for EV6 and EV7. 1
EGCG (extract from green tea) antiviral for enteroviruses 1
hinokitiol (found in hiba wood essential oil) antiviral for picornaviruses 1
guanidine a potent but very toxic antiviral for picornaviruses 1 2 3
eupafolin potential anti-enteroviral agent with anti-inflammatory activities 1
idarubicin a broad-spectrum anti-enterovirus 1



Non-Chemical Antivirals:

B cells from CVB-immune mice clear coxsackievirus B 1



Antiviral Mechanisms:

From the studies referenced above, the following info was extracted:

• Fluoxetine and its metabolite norfluoxetine markedly reduced the synthesis of coxsackievirus RNA and protein. It might work by targeting the enterovirus 2C protein.
• Pirlindole inhibits the RNA replication of coxsackieviruses and echoviruses. It likely works by targeting the enterovirus 2C protein. In a study, pirlindole was specifically shown to inhibit CVB replicons (non-cytolytic viruses).
• Curcumin potently inhibits coxsackievirus replication through dysregulation of the ubiquitin-proteasome system (UPS). Proteasome inhibitors reduce CVB replication via inhibition of viral RNA transcription and protein synthesis. 1
• Itraconazole (Sporanox) is a broad spectrum anti-enterovirus compound that inhibits viral RNA replication by targeting oxysterol-binding protein. 1
• OSW-1 is a potent broad spectrum anti-enterovirus compound that inhibits viral RNA replication by targeting oxysterol-binding protein. 1
• Arbidol (umifenovir) decreased the CVB5 RNA level in infected host cells. 1
• Arbidol inhibits the high expression of IL-10 induced by CVB4; this IL-10 is key to the chronic persistence of CVB4, and Arbidol's IL-10 inhibition helps clear this virus. 1 More info in this post. Note that the antiviral tenofovir strongly inhibits IL-10. 1
• Ribavirin has a number of antiviral mechanisms, including causing lethal mutagenesis of the viral genome. 1
• Dipyridamole has little or no antiviral activity, but is capable of remarkably enhancing the antiviral activity of IFN-α. 1
• Spatholobus suberectus extracts have remarkable anti-CVB3 activity in vitro. CVB3 messenger RNA (mRNA) is significantly inhibited by Spatholobus suberectus.
• Trichosanthes kirilowii (the ethyl acetate extract) has a significant protective effect on HeLa cells infected with CVB3 (an in vitro study).
• Aegle marmelos Corr (bael fruit powder, bilva powder) has similar efficacy to ribavirin. Marmelide, from Aegle marmelos Corr, interfered with early events of the replicative cycle like adsorption and penetration.
• Hinokitiol imports zinc ions into the cell, which exerts antiviral effects by interfering with the viral life cycle.
• Astragalus may inhibit the replication of CVB3 RNA

Note: when a study demonstrates a compound has antiviral efficacy against a specific enterovirus serotype, such as for example CVB3, that is because the study only investigated that particular serotype; but the same compound may potentially also have efficacy against other serotypes (but this is not known for sure).


General Notes:

• Curcumin has a short half life of 3 to 6 hours, so you need to take curcumin 3 or 4 times a day.
• The anti-enteroviral compound in Emblica officinalis (amla) is called phyllaemblicin B. A study on phyllaemblicin B found it has strong antiviral effects against CVB3.
• The anti-enteroviral compound in Rhodiola rosea is called salidroside.
• The anti-enteroviral compound in Epimedium (horny goat weed) is called icariin. The icariin content of horny goat weed around 0% to 2.7%. 1
• The anti-enteroviral compounds in Sophora flavescens root (Ku Shen) are oxymatrine, matrine and sophoridine. As well as antiviral effects, oxymatrine and matrine also have an immunomodulatory action that can fight enteroviruses.
• The anti-enteroviral compound in Aegle marmelos Corr is called marmelide. Maximum safe daily dose of Aegle marmelos Corr (bael fruit powder, bilva powder) is 40 grams (this is by my calculations, based on data from the Aegle marmelos study). A study on the marmelide component from the herb Aegle marmelos (bael fruit) showed it is more potent than ribavirin against CVB1 to CVB6.
• A study on dihydroquercetin (a flavonoid supplement) show it is as strong or stronger than ribavirin in its antiviral effect against CVB4.
• A study on curcumin showed it is potently antiviral for CVB3.
• A study on the medicinal plants Dodonaea viscosa, Rumex nervosus and Rumex abyssinicus found they have strong activity against CVB3.
• EGCG inhibits folate.
• Emodin is a laxative.
• Trichosanthes root is toxic in higher amounts.
• Sodium selenite (a form of selenium) is not to be confused with sodium selenATE (another form of selenium).
• The Chinese herbal formula Qi Hong = Astragalus membranaceus + Rhodiola rosea + Sophora flavescens.
• The Chinese herbal formula Shuang Huang Lian = Lonicera japonica + Scutellaria baicalensis + Fructus Forsythiae + Saccharum. The main antiviral compounds in this formula are forsythoside A, baicalin and chlorogenic acid. 1 2 Note that baicalin is not to be confused with baicalein (both are found in Scutellaria baicalensis). A study on Shuang Huang Lian found it was more potent than ribavirin.
• Yakammaoto is a Chinese herbal formula containing 9 ingredients: Ephedra sinica, Pinellia ternate, Zingiber officinale, Tussilago farfara, Aster tataricus, Ziziphus jujube, Belamcanda chinensis, Asarum sieboldii, and Schisandra chinensis.
• Isatis tinctoria is sometimes also called Isatis indigotica.
• OSW-1 is a natural compound extracted from the bulbs of the plant Ornithogalum saundersiae that has been studied mainly for its anti-cancer activity.
• Garlic is best not co-administered with Chinese skullcap. 1
• Ursolic acid has a poor oral bioavailability of only 0.6%, 1 likely due to being metabolized by the gut wall and liver, as well as being poorly absorbed by the intestine. 1 An apple contains around 50 mg of ursolic acid in the peel. 1 Ursolic acid has been shown to damage DNA (although it also has an anti-cancer action), which is thought may constitute a serious problem. 1


Antivirals Able to Cross the Blood-Brain Barrier:

Since ME/CFS may involve an enteroviral infection within the central nervous system, anti-enteroviral compounds that can penetrate the blood-brain barrier might be of particular benefit. I found studies showing that the following antiviral compounds can cross the blood-brain barrier:

• Fluoxetine crosses the blood-brain barrier, and furthermore fluoxetine concentrates into the brain and central nervous system at levels 20 times higher than in the blood. So low oral doses of 20 to 40 mg of fluoxetine have been shown to produce high concentrations of 14 μM in the brain (much higher than its EC50 concentration of 2.3 μM). 1 However, the antiviral effects of fluoxetine are unfortunately not linearly dose dependent (see Fig 1 of this study), and it turns out that even a 30 μM concentration provides no more antiviral effect than 2.3 μM.
• Oseltamivir
• Dipyridamole
• Lovastatin
• Amantadine
• Icariin from Epimedium (horny goat weed) might cross the blood-brain barrier into brain tissues. 1
• Baicalein from Chinese skullcap is able to penetrate the blood-brain barrier. 1
• Indirubin from Isatis tinctoria herb (Da Qing Ye), and from Indigo naturalis powder (Qing Dai), is able to cross the blood-brain barrier. 1
• Curcumin
• Chlorogenic acid


Non-Cytolytic Enteroviruses: the Intracellular Side of an Enterovirus Infection:

In chronic infections, enteroviruses such as coxsackievirus B and echovirus can exist in two distinct forms: the regular lytic form of the virus (comprising viral particles), and a non-cytolytic form (comprising simply naked viral RNA), which lives inside cells as a chronic, smoldering intracellular infection. It is thought that as well as the lytic form, the non-cytolytic form of enterovirus may also play causal role in ME/CFS. 1

Since non-cytolytic enteroviruses comprise naked enteroviral RNA rather than the more usual viral particles, antivirals which work by viral particle entry inhibition or uncoating inhibition mechanisms will not have any direct effect on non-cytolytic enterovirus infections.

However, I believe that viral genome replication inhibitor antivirals will work for both lytic and non-cytolytic enteroviruses. And any antiviral that increases interferon alpha will I think fight non-cytolytic enteroviruses, because interferon alpha activates the intracellular immune response which targets such non-cytolytic infections.

In a study, pirlindole was specifically shown to inhibit CVB replicons (non-cytolytic viruses).

More information about non-cytolytic enteroviruses is given here.

Non-cytolytic enteroviruses are also known as: non-cytopathic enteroviruses, terminally-deleted enteroviruses, defective enteroviruses, defective interfering enteroviruses and replicons.


EC50 Values of Antivirals:

When measuring the potency of an antiviral through in vitro experiments in cells lines, the EC50 (effective concentration) test is often used. The EC50 is the concentration of an antiviral compound in solution that will lead to a 50% reduction in viral replication in the cell line. The IC50 (inhibitory concentration) in the context of antivirals I believe is the same as EC50.

The EC50 is typically expressed in micrograms of the antiviral compound per milliliter of solution (μg/ml), or alternatively expressed in micromoles (μM). (To convert μM to μg/ml, multiply by the molecular weight, and divide by 1000).

Below are some EC50 figures for various antivirals tested in vitro. Note that the lower the EC50 figure, the stronger the antiviral.

The actual usefulness of an antiviral compound depends on its therapeutic index (aka: selectivity index), which is equal to the ratio: CC50 / EC50. Here, the CC50 is the cytotoxic concentration — the concentration of the antiviral that kills 50% of the cells in the cell line. For a useful antiviral, you obviously want the CC50 concentration to be quite a bit higher than the EC50.

EC50 Values for Antivirals (values shown in bold, and expressed as μg/ml). Note that smaller values represent a more potent antiviral:

Arbidol: HEp-2 cells: CVB3 = 13.1, HEp-2 cells: CVB5 = 6.6 1 2
Oseltamivir (Tamiflu): Vero cells: CVB3 = 6.8, CVB4 = 18 1
Raoulic acid: Vero cells: CVB3 = 0.33, CVB4 = 0.40 1
Ribavirin: HeLa cells: CVB3 = 1.9, Vero cells: EV5 = 22, EV18 = 7.6 1 2 3
Amantadine: Vero cells: EV5 = 1.0, EV18 = 5.0 1 2
Phyllaemblicin B (from Emblica officinalis): HeLa cells: CVB3 = 7.8 1
Marmelide (from Aegle marmelos): Vero cells: CVB1 to CVB6 = 63 (by comparison, study found ribavirin IC50 = 2000) 1
OSW-1: BGM cells: CVB3 = 0.002 1
Paris polyphylla extract: HeLa cells: CVB3 = 157 (by comparison, study found ribavirin IC50 = 129) 1
Baicalein (from skullcap herb): BGMK cells: CVB3 = 7.8 and SI = 34 (by comparison, study found ribavirin IC50 = 16 and SI = 15) 1
Ursolic acid: BCC-1/KMC cells: CVB1 = 0.4 (SI = 251); enterovirus 71 = 0.5 (SI = 201) 1


Indirubin derivative E804: and Akt Inhibitor IV: HeLa cells: 25 μM led to 2 log reduction in CVB3 1
Platelet-derived growth factor receptor tyrosine kinase inhibitor III (E5(1)): HeLa cells: 25 μM led to 4 log reduction in CVB3 1


Anti-Enteroviral Drugs in the Research Pipeline:

The following pharmaceuticals have shown anti-enterovirus or anti-picornavirus activity, and are currently under research, but are not as yet available.

TTP 8307 — potently inhibits CVB3 and poliovirus by interfering with the synthesis of viral RNA
V-073 / SCH-48973 (pocapavir) — capsid inhibitor for poliovirus, CVB and echovirus
GPC-N114 — RNA polymerase inhibitor, broad-spectrum anti-enterovirus, potent for CVB3 in vitro
Ro 09-0179 — flavone from Agastache rugosa, antiviral for rhinoviruses and CVB
SDZ 35-682 — a capsid-binding agent, potently inhibits several rhinoviruses and EV9
MDL-860 — broad-spectrum anti-picornavirus activity, including CVB3
TBZE-029 — inhibits CVB3, EV9, CVA9 and enterovirus 68
AG-7088 (rupintrivir) — rhinovirus protease inhibitor
R77975 (pirodavir) — rhinovirus inhibitor
LY-122772 (enviroxime) — rhinovirus and enterovirus inhibitor
WIN 63843 (pleconaril, Picovir) — a capsid-binding agent for rhinovirus and enterovirus
WIN 51711 (disoxaril) — rhinovirus and enterovirus inhibitor
WIN 54954 — broad-spectrum anti-picornavirus drug.
T-705 (favipiravir, Avigan) — RNA polymerase inhibitor, antiviral for poliovirus and rhinovirus
BTA-798 (vapendavir) — inhibits rhinovirus
Ro 4-4602 (benserazide) — inhibits the 3C protease of coxsackievirus B
Rega Compound 17 — inhibits in vitro replication of CVB3, CVB4, CVB5 and CVB6. Ref: here.
Rega Compound A — completely eradicates CVB4 from the tissues and organs of mice
Rega compound 1 and 2 — broad-spectrum anti-enterovirus drug
GSK583 antiviral for CVB5, but too toxic to use 1

 

[fairlight]

global-thank you for starting this thread and the great info posted. I am also a patient of Dr. Chiia's and have high levels of enteroviruses shown on biopsies of the gut.

Hip-thank you for the great info you've posted. Do you know why the diuretic drug amilorid is used against enteroviruses? Thanks.

The hep c drug will cost $60,000. :-(

 

[Enid]

Thanks to you all for this very interesting and informative thread. Never doubted the enteroviral origins (but which) in my case.

 

[Hip]

global-thank you for starting this thread and the great info posted. I am also a patient of Dr. Chiia's and have high levels of enteroviruses shown on biopsies of the gut.

Hip-thank you for the great info you've posted.

The hep c drug will cost $60,000. :-(

Hi Fairlight

Wow, $60,000 seems a lot for this new hep C drug though if this new drug completely cures ME/CFS, it puts this in a different perspective. I believe Dr Chia thinks it may eradicate the enterovirus infection from our cells, thus possibly leading to a cure.

Do you know the name of this new hep C drug, by the way? I am trying to find more information about this new drug, to read up on it. Perhaps you could ask Dr Chia the name of it when yo next see him? I am not sure why this new hep C drug is not getting more attention, given it has a theoretical possibility of curing ME/CFS.

Do you know why the diuretic drug amilorid is used against enteroviruses?

I don't think amiloride is generally prescribed to fight enteroviruses, but a study I uncovered said that it does have an anti-enterovirus effect. I did try amiloride, but without much success though it did reduce my anxiety levels noticeably, for some unknown reason.

 

[Jenny]

Hi Fairlight

Wow, $60,000 seems a lot for this new hep C drug though if this new drug completely cures ME/CFS, it puts this in a different perspective. I believe Dr Chia thinks it may eradicate the enterovirus infection from our cells, thus possibly leading to a cure.

Do you know the name of this new hep C drug, by the way? I am trying to find more information about this new drug, to read up on it. Perhaps you could ask Dr Chia the name of it when yo next see him? I am not sure why this new hep C drug is not getting more attention, given it has a theoretical possibility of curing ME/CFS.





I don't think amiloride is generally prescribed to fight enteroviruses, but a study I uncovered said that it does have an anti-enterovirus effect. I did try amiloride, but without much success though it did reduce my anxiety levels noticeably, for some unknown reason.

Hi Hip

Ribavarin isn't particularly new - it's been used to treat Hep C for many years. A newer drug is telaprevir which is now used in combination with ribavarin and pegalated interferon.

My husband started treatment for his Hep C with this combination 2 weeks ago - he's on a trial to see whether people who've had a liver transplant (and therefore on immune suppresant drugs) benefit from it. He's been given around a 50% chance of success given that earlier treatment with interferon and ribavarin failed many years ago, and that his liver is now being attacked again, 4 years after transplant.

He's feeling very ill on the treatment - but can still do much more than me!

The trial will continue for nearly a year if he does OK. I've no idea how much these drugs cost, but I'm amazed at the resources being put into this trial. He has blood tests 2 or 3 times a week, monitoring of heart, kidneys etc, regular pep talks over the phone from docs.

If only...............

 

[Hip]

Hi Hip

Ribavarin isn't particularly new ...

No, it is not ribavirin I am referring to. I am talking about a newly-developed hep C drug, that I believe is still in clinical trials, and not on the market yet.

Dr Chia thinks this new hep C drug may eradicate the enterovirus infection from within our cells, possibly leading to a cure of ME/CFS.

I would just like to know the name of this new hep C drug (or its code number, if it has not got a name yet).

 

[Jenny]

No, it is not ribavirin I am referring to. I am talking about a newly-developed hep C drug, that I believe is still in clinical trials, and not on the market yet.

Dr Chia thinks this new hep C drug may eradicate the enterovirus infection from within our cells, possibly leading to a cure of ME/CFS.

I would just like to know the name of this new hep C drug (or its code number, if it has not got a name yet).

OK. There are over 60 Hep C drugs in various stages of development.

 

[Hip]

OK. There are over 60 Hep C drugs in various stages of development.

Hopefully Fairlight will know the name of this new hep C drug.

As you say, there are many new hepatitis C drugs under development (this web page lists them).

 

[CBS]

No, it is not ribavirin I am referring to. I am talking about a newly-developed hep C drug, that I believe is still in clinical trials, and not on the market yet.

Dr Chia thinks this new hep C drug may eradicate the enterovirus infection from within our cells, possibly leading to a cure of ME/CFS.

I would just like to know the name of this new hep C drug (or its code number, if it has not got a name yet).

Was it DRACO? Dr. Chia has discussed this as a potential treatment for enteroviruses that could be available in 4-6 years. http://www.plosone.org/article/info:doi/10.1371/journal.pone.0022572

 

[Hip]

Was it DRACO? Dr. Chia has discussed this as a potential treatment for enteroviruses that could be available in 4-6 years. http://www.plosone.org/article/info:doi/10.1371/journal.pone.0022572

I don't think it was DRACO, which is only in the early stages of research, and which is also a broad spectrum antiviral. What I read in this article here is that it was specifically a hepatitis C drug under development that will be able to wipe out the enterovirus RNA inside human cells.

 

[FunkOdyssey]

Has anyone tried higher doses of sodium selenite (400-600 mcg daily) for extended lengths of time (6+ months)? Selenium status seems to determine vulnerability to a wide range of viruses, and this particular form of selenium, sodium selenite, shuts down coxsackievirus B replication impressively well. Check out Keshan disease, where CVB3 causes myocarditis and sodium selenite treats it handily.

Also there is the possibility that coxsackievirus actively depletes host stores of selenium to favor its persistence: http://www.ncbi.nlm.nih.gov/pubmed/17590522

As early as 1977, Nicholl and Thomas [15] discovered that 10 of 38 patients with acute myocardial infarction, who were admitted to King Edward VII Hospital in Midhurst, England during a 2-month period, displayed serological evidence of very recent Coxsackie B infection. This relationships has been reconfirmed several times since, for example, by Kipshidze and colleagues [16] and Friman and Fohlman [17]. It also seems likely that selenium is protective against myocardial infarction triggered by Coxsackie B infection. Kok and coworkers [18], for example, compared toenail selenium levels in 84 patients who had suffered acute myocardial infarction with those from the same number of population controls. Toenail selenium gives an insight into consumption of this trace element in the previous year. This analysis demonstrated that there was a marked trend of increasing risk of infarction as selenium toenail levels declined. This would explain the high rates of myocardial infarction mortality seen in young AIDS patients [19] who are invariably selenium deficient [20].

If the hypothesis being evaluated here is correct, Coxsackie B viruses should continue to remove selenium from their hosts after infection. This is certainly possible since Taylor and coworkers [21] have demonstrated that this virus possesses a gene that is a homologue of glutathione peroxidase, a selenoenzyme. As it replicates, therefore, it appears inevitable that Coxsackie B virus will deplete its host of selenium. Certainly, the Coxsackie B virus is linked to Keshan disease [22] an endemic cardiomyopathy that occurs in the selenium deficiency belt that crosses China from northeast to southwest. Indeed, mortality from myocardial infarction can be notably reduced by selenium supplementation during recovery. Kuklinski and colleagues [23] for example, randomized 61 patients with myocardial infarction into either selenium and coenzyme Q10 or placebo treated groups. During a one-year followup period, six patients in the control group died from re-infarction, whereas only one patient from the verum group died and that was from a non-cardiac cause. This data strongly suggests that selenium and perhaps coenzyme Q10 supplementation should be accepted as an adjunct treatment for myocardial infarction [24].

 

[Hip]

I have taken 400 mcg of selenium daily on an empty stomach for a good two years now, as a general antiviral. I currently take the selenomethionine form of selenium, but I have also tried the sodium selenate and sodium selenite forms too.

As you say, the sodium selenite form of selenium has good antiviral effects against coxsackievirus B:
Selenite inhibition of Coxsackie virus B5 replication: implications on the etiology of Keshan disease

Note: this study says zinc counteracts the antiviral effect of selenite (zinc inhibits the toxicity of selenite, and the antiviral effects of selenite derive from its toxicity).


And selenium deficiency is linked to increased virulence of coxsackievirus B: see these studies:
Increased virulence of a human enterovirus (coxsackievirus B3) in selenium-deficient mice.
Selenium and viral virulence.

So I keep taking selenium to help fight coxsackievirus B.

I have also tried taking high doses of sodium selenite, up to 1,600 mcg daily. Unfortunately, this dosage had the side effect of creating significant irritability, so I had to discontinue. Though if I can find a workaround for this irritability side effect, I would try this high dose of sodium selenite again.

Generally, the recommended safe maximum daily amount of selenium is 800 mcg. However, people taking sodium selenite as an anti-cancer agent take up to 6,000 mcg daily(!), and seem to have no problems even after years on this super high dosage. Many studies show sodium selenite has potent effects specifically against chemotherapy-resistant cancers, and I know someone who had a chemotherapy-resistant cancer that doctors said would kill him in a matter of months, but he is still alive and well years later from daily super high dose of sodium selenite.


Note that my ME/CFS has improved quite a bit over the last two years. Two years ago, I would often get a couple of days a week in which I was so tired I'd sleep all night, and then sleep most of the day too; but now I almost never sleep during the day — though I still need 10 to 12 hours sleep at night.

In terms of the supplements likely responsible for this increased health: the only supplement that I have taken consistently almost every day for the last two years of improving health is selenomethionine 400 mcg daily. I have also taken N-acetylglucosamine (NAG) 750 mg consistently each day for the last year, and I believe NAG has been extremely helpful for my ME/CFS, and particularly for my anxiety symptoms (I wax lyrical about NAG on this thread). I have also taken horsetail herb (silica) daily for the last 18 months to control my recurrent kidney infection.

 

[Charles555nc]

Do you think that taking sodium selenite in the morning and then antioxidants at night (so as not to detoxiify the anti viral effects) would be a good game plan?

I tested positive for coxsackie B virus.