Some Info on Interferon Signaling
The expression of HCV proteins induces an ER stress response.
The consequence of prolonged ER stress is the release of Ca2+ from the ER into the cytosol. Cytosolic Ca2+-transients activate Ca2+ dependent kinases, which phosphorylate the transcription factor CREB.
Phosphorylated CREB binds to the CRE-element in the PP2Ac promoter and induces transcription.
Elevated PP2Ac level inhibits the enzymatic activity of PRMT1.
Two consequences of reduced PRMT1 activity are the
• hypomethylation of STAT 1 and
• the hypomethylation of NS3 helicase.
Hypomethylated STAT1 shows increased association with PIAS1 and decreased binding to IFNa-target genes upon IFNa treatment.
The consequence of the inhibited IFNa-signaling is a reduced antiviral response, which contributes to the development of chronic liver infection, which later on can progress to liver cirrhosis and HCC.
On the other hand, the unwinding activity of hypomethylated NS3 is increased compared to methylated NS3.
The higher unwinding activty of NS3 causes an increase in viral replication.
Therefore the upregulation of PP2Ac has two advantages for the virus:
• reduced cellular antiviral response and
• increased viral replication.
Many viruses have evolved strategies to protect themselves against the IFN system2. Viruses can interfere with the IFN system by blocking IFN synthesis, by inhibiting IFN signaling or by inhibiting the functions of IFN-induced proteins such as dsRNA-dependent protein kinase (PKR).
The most important signal transduction pathway for IFNs is the Jak-STAT pathway3. IFNa and IFN (3 activate STAT1, STAT2 and often STAT3. Signal transducers and activators of transcription (STAT) proteins are activated by members of the Jak kinase family through the phosphorylation of a single tyrosine residue4. Activated STATs form dimers, translocate into the nucleus and bind specific DNA elements in the promoters of target genes.
This activation cycle is terminated by tyrosine dephosphorylation in the nucleus, followed by the decay of dimers and the nuclear export of STATs.
Negative regulators of this signal transduction pathway have been found at three levels.
First, the suppressor of cytolcine signaling (SOCS) family members SOCS 1 and SOCS3 prevent phosphorylation and activation of IFN induced STATs by inhibiting the IFN receptor associated Jak kinases.
Second, downstream of STAT activation by tyrosine phosphorylation, IFN induced gene transcription can be inhibited by protein inhibitor of activated STAT1 (PIAS1). PIAS1 inhibits binding of STAT1 dimers to the response elements in the promoters of target genes. The binding of PIAS 1 to STAT1 is regulated by methylation of STAT1 by protein arginine methyl-transferase PRMT1 l T.
Arginine methylation inhibits binding of PIAS1 to STAT1, whereas demethylation of STAT1 enhances its association with PIAS 1.
A third step of negative regulation occurs through dephosphorylation and deactivation of STATs in the nucleus. Recently, the 45 lcDa isoform of protein tyrosine phosphatase TC-PTP was identified as the nuclear STAT1 phosphatase.
The inventors have found that the catalytic subunit of protein phosphatase 2A (PP2Ac) was overexpressed in liver extracts of HCV transgenic mice. Interestingly, expression of an N-terminally modified catalytic subunit of PP2A in the human hepatoma cell line Huh7 resulted in hypomethylation of STAT1 leading to inhibition of STAT1- DNA binding through increased binding to PIAS 1. The relevance of these findings for the human disease was confirmed in liver biopsies from patients with chronic hepatitis C.
Moreover, the inventors have found that treatment with a methyl group donor can restore IFN signaling. S-adenosyl-L-methionine (SAMe, also called AdoMet or S- Adenosylmethionine) is a methyl group donor produced naturally in all living organisms.
Under normal circumstances, it is produced in the cells by the transfer of an adenosyl group (derived from ATP) to methionine by the enzyme methionin adenosyl transferase.
After enzymatic transfer of its methyl group, SAMe is metabolized to homocysteine, a potential toxic substance. Homocysteine can by recycled to SAMe by transfer of a methyl group from betaine by betaine-homocysteine methyltransferase (BHMT). By using a combination of SAMe and betaine, the inventors found a significant increase in the induction of interferon stimulated genes by IFNa.
The inventors have found that treatment of cultured cells with SAMe increases the methylation of STAT1 and increases IFN signaling. Since methylated STAT1 can not be bound by its inhibitor PIAS1, it is a better IFN signal transducer.
If you want to read more on this here are some links
(WO/2005/071101) TREATMENT OF HEPATITIS C INFECTION BY INCREASING STAT1 METHYLATION
http://www.wipo.int/pctdb/en/wo.jsp?wo=2005071101&IA=IB2005000158&DISPLAY=DESC
Interferon alpha Signaling in Viral Hepatitis
http://pages.unibas.ch/diss/2008/DissB_8424.pdf
Molecular Mechanisms of Insulin Resistance in Chronic Liver Disease
http://pages.unibas.ch/diss/2008/DissB_8384.pdf
Should have also mention I will also be taking the following Supplements and dosage
Mainly to reduce Tx Insulin Resistance and Oxidative Stress
SAMe..................: 1600mg BID
TMG (Betaine)......: 5 grams BID
R-ALA..................: 600 mg BID
NAC.....................: 2 grams BID
CoQ10..................: 200mg
Taurine.................: 1000mg BID
Vitamin C
Vitamin E
Vitamin D3
Vitamin B12
Vitamin B6
Folic Acid
Multi Vitamin – no Iron)
Magnesium
Probiotic
CS
Sounds like a great plan!
3rd time's a charm
I wish you minimal sx's and SVR!!!
enigma
Looks like you have done all the research and passed it by your doctor and was given the green light, “outside the box” and good to go. Hope you keep a journal through the journey and hope to see UND early and SVR at the end. I am sure the doc is going to monitor you through out, Good Luck!
jasper
Best of luck to you CS...I am glad you are apparently looking at this tx as it relates to bi/tri-phasic viral decline based on viral kinetic studies..My feeling is, you should be open to dosage/tx adjustments based on these studies...but that will (IMO) require many pcr's during the phasic declines to actually chart the results...again, best of luck
pro
I wish you success CS. Sounds like a terrific plan and all the very best to you. You've put a tremedous amount of time and energy into your plan and your efforts will pay off.
Trin
Excellent plan!!
Don't worry about mixing Ribas from different manufactures... I suspect it is a marketing/ sales trick.
All the all the way SVR!!!
Well with Pegintron d@mn near impossible. You see when pegintron is mixed it only lasts 24 hours when stored in the fridge
Hey CS - I started with the baby redi-pen and intron (hated that redipen) then when I switched over to Commitment to Care they sent me non-mixed pegintron. Little tablets and you draw out the right amount of saline from one little bottle then plop the pill into it and once it mixed you draw it all up and inject it.
It seems to me that it would be really easy to just chop those giant tabs in half - of course it might not be EXACT but I'm sure you can get it close enough always erring on the side of a bit too much right?
I don't think you'd waste any peg if they can order it for you that way.
You know we are all 100% in your corner. You should be commended (jez it's early I almost typed out condemned!) for all the effort you have put forth and admired for the way you have not even given up. I pray to God that this is it.
If it wasn't for the colon/endo scope preparation, I'd say you had your sh!t together. Just a few questions/observations about the IFN.
Since you were a non-responder, it seems like double dosing (shock and awe) until undetectable seems a little more logical - just to get to that point in the first place.
I understand the difficulty with the mixing of Peg-Intron. Pegasys would be easier.
Have you thought a what point you would consider Infergen?
I'm confused by the copegus/rebetol thing. I thought they were generic and bio-equivalent.
Good luck in whatever you do. It seems that the hcv education you've amassed should serve you well.
Well, I thought I was aggressive on my 3rd round! LOL I am on board with your plan my friend. Shock and awe for us tough to treat guys may be the answer. Godspeed.
Wow CS you've got your own drug/vitamin-supplement store there!!! ;-)
I wish you all the best. Whatever it takes to get to UND! Then you can move forward from there.
Keep us informed about your progress.
If you have time can you fill us in on your previous response kinectics? I went to your profile but was unable to find the info amongst all the data.
Null response? Partial response?
How is your liver doing?
Cheers!
HectorSF
OK, March 3rd it is then. I will put it in my calender. Question: Baseline viral load?
You worked so hard putting this together and I look forward to hearing great news early on..
Thanks for everything,
MO
Given your decision against doing PIs this time around, I think you have a solid plan with SOC plus, or let's call it SOC plus, plus :)
As to testing, I would definitely do both pre-tx baseline and a week 1 test (by the time you get your week 2 test back it might almost be week 4) and weekly thereafter until UND. How sensitive a test will you be using?
Don't have the data in front of me, but you also might want to look into the 24-hour PCR which can have strong predictive value. I assume you have discussed with HR, or done indendent research on the value/hidden dangers of supplements during treatment such as SAMe & TMG. I have no position, here, just asking if you've factored this all in and run your stated reasoning by others.
The only thing I see missing is an exit strategy, unless I missed it in one of your posts. For example, will you stop if not UND (via sensitive testing) at week 4? There could be any number of exit strategies depending on your liver damage and simply how you rate the relative risks versus rewards of treatment, but from experience -- like in the stock market -- it's sometimes better to plan your exit before the heat of battle when other factors can take over.
Oh, yeah, rescue drugs, mainly epo. You could probably gauge how much you might need it from last time except I assume youre doing more riba now. Unless you don't think anemia could be a problem, I'd have the rx's filled and in the fridge from day one. And if you had a problem last time, why not take the epo prophalactively at the time you start pre-dosing?
All the best,
-- Jim
"The safety and efficacy of REBETOL Capsules with interferons other than INTRON A or
PEG-INTRON products have not been established."
"has not been established" - I am thinking that is all there is to it. Rebetol has not gone through the required testing for any other combination of drugs. And actually it says "with interferons other than...", it doesn't talk about other ribas.
Thanks for posting Will look forward to reading your journals Did you run it by HR?
Best Wishes I am sure we will all be following your progress to SVR
baja
C.S.
Joe and I wish you well and hope this will be very successful for you.
Joe has never got to nondetectible. His viral load was 645 last week. We see the Dr. on monday and this should end another unsuccessful round for him. On the bright side, his alt and ast has been low normal for several months now. We just hope it helped his liver a little and will give us time. He is doing quite well and we aren't depressed or anything.
Take care ,
Ev
I admire your balls to the walls plan on this round of TX and am sure you have mapped out the cmax of the INF and riba in the dosing regimen but am wondering if you have graphed the peaks and troughs of each and then together through out the 8 weeks. I think I am starting to sweat a little here. 13 shots in 8 weeks to me is kind of like a steam boiler with the thermostat turned all the way up and if you have not seen one, the pipes start rattling and then start bouncing making loud noises and you’re last thoughts while heading for the door is if your going to get out the hell out of dodge fast enough. I sure hope the old relief valve is working properly, lol.
jasper
Intron-A is basically the same exact type of interferon as is used in Peg-Intron; prior to them decided to Pegulate it (i.e. make it longer lasting and once a week); Intron-A is taken as a single shot 3x a week, but used to also be used in maintenance therapy. I used to be on Intron-A 3X a week prior to them ever inventing the Peg-Intron. You could, hypothetically use Intron-A in your taper. Just a thought...
Susan400
God bless and God speed. jerry
On my 3rd round I did pre dose riba, did double dose pegasys till undetect at week four and then did 180 every five days until week 12, then did 180 once a week until the end, during the first 12 weeks I got up as high as 21 mg/kg on the riba, was going to taper off at end but said f-it and just stopped, but by then had been less than five viral for at least 48 weeks!!!!!!!!!!!!!!!!!!!!! Was lucky enough to get the SVR, but it really hurt my body!!!!!!!!!!!!!!!!!!!!!!!! Good luck!!!!!!!!!!!!!!!!!!!
Crossing my fingers for ya
smaug
onwards! all the best with your new plan of attack.
Re:
>I have been advised that I shouldn’t mix Copegus with Rebetol.
check out the molecular formula, molecular weight, iupac name, etc. from the two inserts : they are, atom for atom, the same molecule. The only difference is the marketing spin and the inert fillers they pack the capsules with.
Also re methylation, the JAK-STAT pathways, etc. These are fundamental mechanism shared among many many pathways in the cell. The IFN anti-viral response is ancient and complex. Ancient and complex biology survives because, unlike one-trick ponies such as the new PIs, it is adaptible. It may be true that a supplement that promotes methylation significantly enhances IFN efficacy, but IMHO that premise is best swallowed with a bit of salt.
On the other hand, take a look at the VL charts at the bottom of GB's recent Blue Pills thread. The best antidote for a sluggish IFN response may well be to give it less virions to eliminate...