New Approach, Old Drug Show Promise Against Hepatitis C, Research Shows

[mikesimon]

".....The advance involves two new discoveries. One is that a protein called NS4B is instrumental in binding some of the genetic material, or RNA, and allowing the hepatitis C virus to replicate. The other is that the former anti-itching drug clemizole hydrochloride could hinder that protein, resulting in a tenfold decrease in virus replication with no apparent harm to infected liver-like cells. Because the drug has already been used by people, it is eligible for human testing....."

See: http://www.sciencedaily.com/releases/2008/08/080831151350.htm

Mike

[jdwithhcv]

Interesting article.  Thanks Mike.

jd

[Marcia2202]

Some interesting stuff

[burned74]

thanks so much for this valuable info.

If I to do tx again before Teleprevir comes out, it sounds like this would be a great add-on to SOC, maybe even with alinia. It might be a good add on with teleprevir.

[moahunter]

It is intersting to me that many of the drug candidates poping up, are not new drugs, but rather existing ones. Ribarvirin was like this also, and it makes one wonder if there isn't even more out there which would help. I guess it is logical per all the cocktail ideas, that if you throw enough poison at this virus, it will die. It is a bit frustrating though, that there seems to be little prospect of removing Riba from the mix, IMO riba is the drug that makes treatment the ordeal it is. I had few problems when I was on mono-therapy, but Riba seems to be the symptom magnifier per my experience anyway.

[GoofyDad]

The goal is to improve on the current treatment, a combination of the general antiviral drugs interferon and ribavirin. Those only work about half the time, but have uncomfortable, flulike side effects.

>uncomfortable, flulike side effects.
That would be one way to describe it.

[kickboxingmom]

Thanks for that.Interesting stuff.
Tammy

[IAmTheWalrus]

Thanks, Mike. Very interesting.

[dointime]

Thanks for posting Mike.  This is great news, especially the new lab technique that facilitates more efficient and faster research.

dointime      

[frijole]

It is all greek to me but I agree, Goof - I think we could embellish the uncomfortable fullike symptoms a tad

[merryBe]

cool stuff. this kinda reminds me of the new stuff on the P450 chromosome and how stimulating it increases fibrosis. Soon they'll have much better antiviral/antifibrotics combos and we can all get well!!

Learning which chemicals to stimulate and suppress.....sheesh, what a complex world our bodies are!!

[merryBe]

after several attempts, I think the Nature Biotech article must have been delayed, can't find it anywhere.

also can't find any current RX dosing info for this....is it that obsolete that no rx's are available?

I did find a bulk source for it at Spectrum chemicals, but would still need to know dosing info to try it that way.

It might be easier to just do it that way than to try to convince my doctor, after the battle to get on Alinia it would be a hard sell...although it is his buddies at Stanford doing the research...and that's what won him over finally last time...

hmmm...as far as flu like....heck, taken at night, I may be able to eliminate one or both sleep aides. Besides, with all the current sides, like one more would matter?

If anyone finds out more info on this please post it, I would think a ten fold reduction in viral replication should put it at the top of any treaters points to ponder.
It's getting the chemical into the cell that concerns me....how well does it do that.

If anybody finds the original research of Aug 31 please post it here.
and thanks Mike for finding this one....really a plus.
mb

[merryBe]

Article abstract

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Nature Biotechnology
Published online: 31 August 2008 | doi:10.1038/nbt.1490


Discovery of a hepatitis C target and its pharmacological inhibitors by microfluidic affinity analysis
Shirit Einav1,2,5, Doron Gerber3,5, Paul D Bryson2, Ella H Sklan2, Menashe Elazar2, Sebastian J Maerkl3,4, Jeffrey S Glenn2 & Stephen R Quake3



--------------------------------------------------------------------------------

AbstractMore effective therapies are urgently needed against hepatitis C virus (HCV), a major cause of viral hepatitis. We used in vitro protein expression and microfluidic affinity analysis to study RNA binding by the HCV transmembrane protein NS4B, which plays an essential role in HCV RNA replication. We show that HCV NS4B binds RNA and that this binding is specific for the 3' terminus of the negative strand of the viral genome with a dissociation constant (Kd) of 3.4 nM. A high-throughput microfluidic screen of a compound library identified 18 compounds that substantially inhibited binding of RNA by NS4B. One of these compounds, clemizole hydrochloride, was found to inhibit HCV RNA replication in cell culture that was mediated by its suppression of NS4B's RNA binding, with little toxicity for the host cell. These results yield new insight into the HCV life cycle and provide a candidate compound for pharmaceutical development.

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Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, CCSR 3115A, 269 Campus Drive, Stanford, California 94305, USA.
Department of Bioengineering, Stanford University and Howard Hughes Medical Institute, Stanford, California 94305, USA.
Present address: School of Engineering, École Polytechnique Fédérale de Lausanne, Building BM 2111, Station 17, 1015 Lausanne, Switzerland.
These authors contributed equally to this work.
Correspondence to: Jeffrey S Glenn2 e-mail: jeffrey.***@****

Correspondence to: Stephen R Quake3 e-mail: ***@****


the whole article costs 32 bucks....don't think it would help me with dosing info at this stage of their research so I'll pass.

Looks like I need a really OLD PDR to discover what dosages were used.
the research on this is all from the sixties. Old stuff.

Also, it looks like several repatent searches are being applied for, which means the price will skyrocket. Probably Burroughs doing that and a competitor or 2.  It's tempting to just get bulk from Spectrum while it's still generic, sounds crazy, but hey...maybe I've still got a PDR in the attic...hmm

mb

[nygirl7]

I would think a ten fold reduction in viral replication should put it at the top of any treaters points to ponder.
-----------------------------------

It would be very important to factor this in to the "how long do I need to treat for" questions that's for sure as it would make a 2 log drop by week 12 obsolete but perhaps not be a true indicator of ones real condition.

I would really stop and think about it UNTIL somebody tested and knew - be careful.

[merryBe]

Point well taken, my theory would be if cell permeation is the number one hindrance (as HR has suggested many times) then an antihistamine that even eats into the silicone it's been tested on might mean its ten fold effect is because of it's ability to break through cell walls and lipid shells on the virions, probably both.

For me already being UND there's less to worry about, although it is those lingerers that have half of us relasping.
For those treating for the 2, 3, or 4th time, I'd be on this like white on rice. If it could cut down your tx time, and remember every round of tx does it's own damage, then it would make sense of find out what you could.
The human trials have already been done for heart, and skin problems so the safety is well established. It seems to stabalize certain heart rhythms, so heart patients would need more monitoring, and perhaps less of their current meds but that would depend on which kind of arhythmia they have, since only one is effected by this drug.

I'll continue to look into this, and see if an rx could be obtained and report back what I find.

[Hepatitis Researcher]

The Clemizole paper is quite detailed and does give hints what to expect in a clinical use for HCV.
The concentration at which a 90% inhibition of viral replication in the cell line used occurred was 20 micromoles - that is fairly high and not easy to achieve with an oral drug unless for example 1 to 2 grams a day are used. This of course depends on the pharmacodynamics factors and needs to be measured in the early clinical development stages.

The concentration needed to inhibit the NS4B binding to HCV RNA by 50% (IC50) however is only 24 nanomols, almost 1000times lower.

Thus the drug inhibits its molecular target very well, but does not enter the cells in sufficient amounts, therefore huge extra doses are needed to bring enough of the drug to the site of action. The researchers hope to develop modifications that will increase intracellular bioavailibility.

Resistance development was also tested and found to occur. Therefore a meaningful  use of this compound could only be envisioned as part of a multidrug approach, or at extremely low viral loads.

[fretboard]

Well TY for chiming in with that information, now that I know that it would take too much orally I can get back to my reality and stop trying to locate it.  What interest me is they had just mentioned a couple months back two drugs that are already on the market and are already in trials.  That would be the fluvastatin and alinia, hope I spelled those right and I'm not mis-informed.  Is there anything that a person could take that would "decrease in virus replication with no apparent harm to infected liver-like cells"?  It's difficult to accept that this virus has been around, for me dx'ed in 92 and nobody has come up with a semi-cure so that one could safely use until they have all their ducks in a row to tx.  They gotta be close...  thanks again  

[scratchinghead]

thanks, too.

[merryBe]

Hi HR, glad to see you still stopping in from time to time.

so 1000th of a gram or 2. isn't that like ten or 20 milligrams? Not a phamacist so not sure of my math here.

those dosages are quite safe are they not?

I'm drawn to the idea that cutting back on the two sleep aides I'm currently on to deal with this disease and the Riba-mania....namely Ambien and Remeron might be lowered were I to have this on board, and getting an inhibitory bump in the process makes more sense.

I'm concerned also about the remeron as it has some action on the P450 chromosome, though I haved been able to find out much about how much safer tetracyclics are than SSRI's the whole family is these classifications has me concerned.

So wouldn't an antihistamine be a better choice from that standpoint as well, as far as P450 goes?

[willing]

always good to see you posting..I was curious to hear your thoughts on two topics, both related to HCV in PBMCs, that have come up recently.

The first concerns mitogen culturing of PBMCs to stimulate viral replication prior to PCR.  Three studies over the past few months have refuted detection of post-SVR/spontaneous clearance HCV in PBMCs as documented in the earlier Pham,Radkowski,Castillo reports:

http://www.ncbi.nlm.nih.gov/pubmed/18593587
http://www.ncbi.nlm.nih.gov/pubmed/18220272
http://www.ncbi.nlm.nih.gov/pubmed/18448695

None of the above applied mitogen culturing of cells, though the Pham/Michalak protocol description makes it clear that this is a key part of reliable detection in lymphoid cells:

http://www.medscape.com/viewarticle/563337_1

"In the case of occult HCV infection, culture of PBMCs for 72 h with phytohemagglutinin (5 µg/ml) to stimulate T cells, pokeweed mitogen (5 µg/ml) to induce B and T cells and/or lipopolysaccharide (1 µg/ml) to activate monocytes and B cells, led to the identification of HCV-RNA in the vast majority of individuals who were otherwise seemingly HCV-RNA nonreactive."

I just noticed Pham/Michalak wrote a comment to the Bernardin study raising the issue and the authors, though claiming a more rigorous dilution calibration, don't seem to dispute the omission.

Also, another very recent study
http://www.ncbi.nlm.nih.gov/pubmed/18594984
which did apply mitogen/cytokine culturing reports finding post-SVR PBMC HCV RNA.

Do you think failure to apply cell culturing is simply an omission,  or that this is being intentionally resisted (eg as a source of possible contamination?)

The second topic is commercial availability of PBMC-detecting tests. Surely, current technology for detecting RNA in serum is very near its limit. Furthermore, most SVRs clear HCV from serum somewhere between weeks 4 and 12 leaving absolutely no guidance about progression of the fight for the rest of tx. If in fact infected cells, in lymph, liver and elsewhere, die/clear at a much slower rate, as one would expect and as suggested for example in

http://www.ncbi.nlm.nih.gov/pubmed/18712814

the availability of PBMC tests would give patients a good, though not definitive, correlation to gauge where they were in the fight (and provide additional support for tapering, for example).

[Hepatitis Researcher]

The use of mitogens will stimulate numerous components of the replicating machinery, including some that "remnant HCV" might need to proceed though is very hampered molecular machinery. Thus a positive test/find under mitogen conditions is much more likely. Furthermore there is the remote possibility that some, at least partial, integration of the HCV genome, by some spurious reverse transcription, as supplied by our numerous genomic transposons, is leading to PCR detectability of those sequences under these conditions.
The whole issue is however a bit on the philosophical side, since the stability of SVR , even under immunosuppressive regimens, is testimony to the fact that these remaining sequences do not have the power to mount a renewed high level of replication.

As to the PBMC tests after serum UND results, those might not reflect the truly important variable which is likely to be the further shrinking of the genome pool size of HCV in the liver after UND and even less the gradual remodeling of this remaining quasi-species pool into a more immunogenic/less epitope avoiding/less speedy and efficient replicating variety - deeply hidden facts that might be the truly deciding factors in achieving SVR in the end, aside from simple quantity of total number of remaining "HCV" genomes reduction...

[willing]

thanks -  seems a bit odd that someone setting out to measure residual HCV in PBMCs, as those three papers did,  wouldn't either include that step or discuss why they had not done so.

Re  PBMC-based VL, I was thinking successive readings would  provide some indication of changes in cellular-level infection whereas currently, after serum-UND is reached, there's nothing. True, this is not what one really wants to measure, but if there's even rough correlation it would be an improvement over guessing. Post-svr resurgence is not a realistic concern, but decisions about extending, tapering and dose adjustments have to be made every day and seem to turn on the extent of remaining infection and  fitness of the remaining virus.

Interesting twist about partial integration - a major gap in the 'occult infection' claim is that so far only the 'occult' and not the 'infection' has been shown.

[TnHepGuy_]

Very good to see you here again. And always great to read of your thoughts and insights.

"The whole issue is however a bit on the philosophical side, since the stability of SVR , even under immunosuppressive regimens, is testimony to the fact that these remaining sequences do not have the power to mount a renewed high level of replication."


What do you make of the following papers, then?

http://www3.interscience.wiley.com/journal/121382474/abstract?CRETRY=1&SRETRY=0

http://www.amjmedsci.com/pt/re/ajms/abstract.00000441-200807000-00025.htm;jsessionid=LHTPYt312czWMM5v1GbWKdjVhMmtKpG3dvx9yTs1dyxKzhpjGvjz!609209752!181195628!8091!-1?index=1&database=ppvovft&results=1&count=10&searchid=1&nav=search

http://www.ncbi.nlm.nih.gov/pubmed/16107964?ordinalpos=62&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum


And in transplant settings?

http://www.ncbi.nlm.nih.gov/pubmed/12927925?dopt=Abstract

http://www.ncbi.nlm.nih.gov/pubmed/15964345?dopt=Abstract

http://www.ncbi.nlm.nih.gov/pubmed/15589744?dopt=Abstract


Separately, what are your thoughts on this finding of occult in kidney tissue?

http://www3.interscience.wiley.com/journal/120091231/abstract


TnHepGuy

[Hepatitis Researcher]

Thank you for the links. I am am aware of these reports and also that there is, as expected a grey zone of reactivatibility, since there will be a great variety of types of leftover HCV genomes with different fitness from  none (so that immunosuppression CANNOT REACTIVATE IT)  to quite fit ( SO THAT NOTHING WILL HAPPEN WHILE IMMUNE SURVEILLANCE IS HIGH but recurrence at strong immunosuppression), that need to be considered combined with their epitope inherent Tcell immunogenicity.

The emotional need for a feeling of total safety from recurrence is understandable and thus these topics need - in the context of this forum- presentation in a somewhat simplified, black and white format. In that sense: SVR is stable, do not worry. If you have immunosuppressive treatment - worst case scenario you can retreat.

[DoubleDose]

Now I am a little bit confused.  Since this has been a very volatile subject on this forum, as you may be aware from prior threads, I want to try to clarify what you are saying just a little bit more.  You state that SVR is stable, but at the same time it seems to me that you also indicate that SOME HCV genomes, leftover after SVR in the body, with greater levels of fitness, actually can re-activate or recur, thus causing an active HCV infection again.  You indicate that if this were to happen, one could retreat, so I interpret this as meaning that, while rare, it is possible to trigger an active infection again in some SVR's, under extreme immunosuppression.  

If the above is accurate, would this then imply that HCV is placed in a state of virtually permanent remission when SVR is achieved, but that it is not  ever totally eradicated in SVR's?  I do want to try to get some expert opinion from you on this, because this issue has inflamed tempers in the past, and been the cause of  lengthy, and often rancorous threads.
I suspect personally that SVR is extremely durable and stable, BUT that the virus is still present in differing forms, and at extremely low levels in most SVR's....thus leading to a situation best described as long term remission.  Even though virtually a permanent state, this remission could in rare cases allow for relapse, and NOT just re-infection.  This is my interpretation.  (might extreme, chronic alcohol abuse also provoke a potential relapse in some rare cases, just as immunosuppressive drugs could do??)

What would be the best way to characterize it from your perspective?  Thanks for your input.

DoubleDose