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Rega Compound 17 & Compound A - Potential Cures for Chronic Coxsackie B

Messages
10
Yes, I've seen a few interesting articles about defective virus infections with dengue virus (a flavivirus).

I had a friend in Brazil who caught dengue there about 20 years ago, and he had poor health and fatigue forever after. A study indicated that dengue can cause a post-infectious fatigue syndrome. So this looks like another case of a defective, non-cytolytic virus hanging around in the body and causing a fatiguing illness.

Most interestingly, I came across this paper on defective EBV infections. I've never been able to find any further info on defective EBV, but I wonder whether in the case of EBV-associated ME/CFS, it is this defective EBV that causes the disease.


Just catching up here after many years. I think i posted a strategy on how to eradicate persistent herpes infections including EBV. Cytolytic reactivation with HDAC inhibitors like IV sodium phenylbutyrate combined with valcyte. Total cure in many EBV cancers but killed several patients due to tumor lysis syndrome. I think this could be applied at lower spread out dosages to relieve that issue. For a decade I have believed this could provide a functional cure for some but didnt have the balls to do it myself.

Also, higher dose quercetin leads to EBV lytic reactivation (be careful with this also).
 

Swim15

Senior Member
Messages
369
@Swim15, I copied your post below to this Rega thread.


I've heard nothing new, in spite of Dr Chia saying some time ago that these drugs will be out a couple of years.

I believe this study might refer to one the Rega compounds.

Looks like a pretty serious potential advancement since enteroviruses are the ones we have very little treatment for. Wish there were more compassionate use programs or fucking something to get ahold of something like that
 

Hip

Senior Member
Messages
17,808
I know someone who has seen him several times at a huge cost

And so?

You do know that generally speaking, ME/CFS is largely incurable, and most doctors cannot do much, although some patients are lucky enough to improve to a degree on treatments that leading ME/CFS doctors provide. But no ME/CFS patient should go to a doctor thinking that they are guaranteed to get better.
 
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mitoMAN

Senior Member
Messages
624
Location
Germany/Austria
Has there been a compound CAS number released for this? We could try having it custom made in good old China Town.
edit:
Raga Compound 1
CAS: 1436383-95-7
1, 2-fluoro-4-(2-methyl-8-(3-(methylsulfonyl)benzylamino)imidazo[1,2-a]pyrazin-3-yl)phenol


https://m.chemicalbook.com/ChemicalProductProperty_DE_CB33303776.htm

Possible Suppliers:
https://m.chemicalbook.com/Chemical/ProductProperty?id=CB33303776&N=CHINA&language=de-de#Supplier


@Hip has there been dosages on human trials posted already in some studies? Sorry for being lazy, researching a lot of medications right now that could be custom produced in China and got my mind all over the place. Just thought about Raga and saw this thread popping up.

Also more studies mentioning the pharmacological composition of the other Raga Compounds? 17? A?
 
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Hip

Senior Member
Messages
17,808
Has there been a compound CAS number released for this?

The formulas are secret, as far as I am aware.

If you look at S7 Fig: Core structure derived from compound 17 of this paper, you see some structural info for compound 17. I am not sure if that is disclosing the full structure.


And in this paper, the chemical structure of two further anti-enterovirus compounds named compound 1 and compound 2 are given. These two antiviral compounds I believe were also discovered at the Rega Institute in Belgium, as many of the paper's authors are from Rega.
 
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Springbok1988

Senior Member
Messages
153
I don’t have high hopes for this antiviral as an ME treatment. If the research into persistent CVB applies to those with ME and it is a contributing factor, then the infections persist through double stranded RNA. The Rega compounds work by preventing the viral capsid proteins from coming together. From what I have read, it sounds like the full virion may not play a large role in these types of infections. But there’s still so much left to research about all this.
 

Hip

Senior Member
Messages
17,808
I don’t have high hopes for this antiviral as an ME treatment. If the research into persistent CVB applies to those with ME and it is a contributing factor, then the infections persist through double stranded RNA. The Rega compounds work by preventing the viral capsid proteins from coming together. From what I have read, it sounds like the full virion may not play a large role in these types of infections. But there’s still so much left to research about all this.

Yes, I would imagine that from the perspective of fighting a non-cytolytic enterovirus infection, it would probably be better if these Rega compounds were RNA replication inhibitors.

Though these Rega drugs may help a bit, in certain patients: when the enterovirus antiviral pleconaril was available for investigational use, Dr Chia treated four enterovirus ME/CFS patients with it. Pleconaril also does not inhibit RNA replication (it works by prevent viral attachment to cells and preventing uncoating of viral RNA).

Three patients saw no benefit on pleconaril, but one patient experienced a moderate improvement while taking the drug, along with a fourfold decrease of antibody titers for CVB4 and echoviruses 7 and 11. However, the patient relapsed about one month later, and did not respond to a further month of pleconaril treatment. Ref: 1

Pleconaril was finally never brought to market, so it is no longer available.
 
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Nuno

Senior Member
Messages
112
Yes, I would imagine that from the perspective of fighting a non-cytolytic enterovirus infection, it would probably be better if these Rega compounds were RNA replication inhibitors.

Three patients saw no benefit on pleconaril, but one patient experienced a moderate improvement while taking the drug, along with a fourfold decrease of antibody titers for CVB4 and echoviruses 7 and 11. However, the patient relapsed about one month later, and did not respond to a further month of pleconaril treatment. Ref: 1

Pleconaril was finally never brought to market, so it is no longer available.

Besides Interferons, pleconaril was one of the antivirals with highest strength against CVB according to your pharmacokinetics calculations right?

Do you have any list with these values for the in vivo? Would be interesting to see which are actually the best, and thank you Hip for the services you do on this forum!
 

Hip

Senior Member
Messages
17,808
Do you have any list with these values for the in vivo?

I have a spreadsheet where all the pharmacokinetic calculations are done (I may put this online at some point, but it needs a bit of work and tidying up first).

Anyway, here is a screenshot for the calculated "Potency Factor" for pleconaril against various enteroviruses:

Pleconaril Potency Factors.png


The Potency Factor is a figure I calculated. It measures the mathematically estimated power of the antiviral in vivo, based on in vitro data.

To give you some reference, when I calculate the Potency Factor for standard commercial antiviral drugs like Valrex or Valcyte, they typically come out around about 4,000, give or take a 1,000 or so.

You can see that pleconaril has a rather varied effect on different enteroviruses. And even varied effects of different strains of the same serotype. For example, you have a Potency Factor of only 1 for the Nancy strain of coxsackievirus B3, but a Potency Factor of 540 for another strain of CVB3.


So pleconaril looks rather hit and miss: it works well for some enteroviruses, but poorly for others.


Dr Chia tried pleconaril on a few ME/CFS patients (see this study), but the results were lackluster.
 

Nuno

Senior Member
Messages
112
Interesting @Hip, appreciated.

It does look like a potent antiviral drug in your table, wonder why it didnt lower viral titers on the Chia's patients?

If Ribavirin, Epivir and Interferons show more effect on his patients, wonder what is their pharmacokinetic values.

Also Hip, on another topic, what is your thought on Remdesivir or even better, GS 441524 for enteroviral persistence?
 

Hip

Senior Member
Messages
17,808
It does look like a potent antiviral drug in your table, wonder why it didnt lower viral titers on the Chia's patients?

Pleconaril lowered antibody levels on one patient, as the study indicates, but not the three others who tried it:
Four patients with CFS and either persistently raised antibody titres for CVB or echoviruses and/or positive enteroviral RNA of the peripheral blood leucocytes were treated with Pleconaril, an anti-capsid agent specific for uncoating of enterovirus and rhinovirus, obtained through a compassionate use protocol of Viropharma Inc, Exton, Pennsylvania, USA.

Three patients had no symptomatic improvement while on or after one week of drug treatment, at a dose of 400 mg three times a day, and there was no change of antibody titre after the treatment.

One patient had a moderate symptomatic improvement while taking Pleconaril 200 mg three times a day for one month, along with a fourfold decrease of antibody titres for CVB4 and echoviruses 7 and 11.

However, she relapsed about one month later, and did not respond to a further month of treatment. As of March 2004, the oral form of Pleconaril is no longer available for investigational use.

If you look at the Potency Factors in my table above, you see that the antiviral potency varies widely from enterovirus to enterovirus, with this drug having low (red) or moderate (orange) potency for some enteroviruses, and high (green) potency for other enteroviruses. Even for the same enterovirus serotype, potency varies even for different strains of that virus.

So it could be that the patients who failed to respond to pleconaril were those who had enteroviruses which this drug only has weak potency for.

In other words, for enterovirus ME/CFS patients trying pleconaril, it would be a matter of luck whether this drug is able to have any antiviral effect on the particular viruses they have.



If Ribavirin, Epivir and Interferons show more effect on his patients, wonder what is their pharmacokinetic values.

Using Epivir (lamivudine) off-label to treat enterovirus was Dr Chia's idea. There is no in vitro data for the antiviral effect of Epivir for enterovirus, so no pharmacokinetic calculation can be performed.

We know from Dr Chia's reports that Epivir works for about 1 in 3 enterovirus ME/CFS patients. But even when it does work, the benefits are not major. It is not the sort of drug which will typically move you up one level on the ME/CFS scale of severe, moderate, mild, remission.

Whereas drugs like oxymatrine and tenofovir, which are used by Dr Chia, can move patients up 1 level on that scale, if the patient is lucky enough to have these drugs work for them.

I believe the main three drugs Dr Chia uses for enterovirus ME/CFS are oxymatrine, tenofovir and Epivir, so enterovirus patients might consider trying all of these, one by one.

I tried oxymatrine and Epivir with no effect. I started taking tenofovir but got substantial mental health worsening. I tried tenofovir twice, but the same side effect occurred. So at present I am unable to try tenofovir, but if I can improve brain health and make my mental health more robust, I will hopefully be able to try tenofovir in future.

I know one ME/CFS patient with CVB4, the same virus as mine, who experienced permanent improvements from tenofovir after just a few months treatment. He said tenofovir completely eliminated his PEM, and it remained eliminated even after stopping tenofovir. Another patient trying tenofovir also got permanent improvements from it.

This ability to provide permanent improvements is very significant, because often you find with ME/CFS that antivirals help, but patients relapse after stopping the drug (as we saw above with pleconaril). But the two tenofovir success stories I know (detailed in the recoveries thread) both resulted in permanent improvements which remained after stopping the drug.

Tenofovir is also used off-label for enterovirus by Dr Chia, and there is no in vitro data for the antiviral effect of tenofovir on enteroviruses, so we cannot do any pharmacokinetic calculations. However, it does have some moderate antiviral effects against Epstein-Barr virus, which my pharmacokinetic calculations show (see table below), so tenofovir might have some use in EBV-associated ME/CFS, as well as enterovirus-associated ME/CFS.


Here is a screenshot for the calculated Potency Factor for Epivir and tenofovir against various viruses (hepatitis B virus, HIV, and Epstein-Barr virus):

1632579399065.png


As you can see, tenofovir is highly potent against HIV, with a Potency Factor of over 20 thousand.



For ribavirin, this drug does not have strong antiviral effects, as the table below demonstrates:

1632579631082.png


The reason ribavirin's Potency Factors are low in spite of being sold as an antiviral is likely because ribavirin fights viruses by various immunomodulatory mechanisms, in addition to its direct antiviral effects.

Immunomodulatory mechanisms are not accounted for in the pharmacokinetic Potency Factor calculation, a calculation which is based on in vitro data. In general there is no way to test or measure immunomodulatory effects in vitro, because these effects act on the entire immune system, and you cannot mimic the immune system in vitro in a cell line.

So my pharmacokinetic calculations can only measure the direct antiviral effect of a substance, but they cannot measure any immune boosting effects the substance may have which will also fight the viral infection.

Ribavirin is problematic in long-term use, due to risk of serious side effects, so is not much use in ME/CFS linked to chronic enterovirus.




Also Hip, on another topic, what is your thought on or even better, GS 441524 for enteroviral persistence?

Remdesivir might have some effects against the enteroviruses found in ME/CFS, but its extraordinarily high price would preclude it as an ME/CFS treatment, unless a short course of the drug had permanently benefits. Some antiviral/immunomodulatory drugs like tenofovir seem to permanently improve ME/CFS, but with other drugs, the benefits disappear when you stop taking them.

At around $400 per dose, only a multi-millionaire could afford to take this drug daily on a long-term basis.
 
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