Research supported antifibrotics - do they exist?

[Hepatitis Researcher]

The problems of treatment failure for SOC/IFN nonresponders and the possibility of reducing future supercombo-SVRchances by introducing archived resistance mutations when using "Pseudomonotherapy" - (that is here defined as using  a single  antiviral agent that is not protected against resistance development by its combo with an IFN/riba component (IFN by definition in this scenario is not sufficiently effective in reducing viral replication so that all the burden to tame the adaptive quasispecies evolution falls on the antiviral)) together with the 61% and 65% SVR rates for the latest triple modality in Geno 1s, have raised concern and the awareness for the need for alternate/additional treatment modalities in many HCV patients and their health care providers. Waiting for future antiviral developments is one route frequently recommended, but for the patients  in current need, our repertoire of additional meaningful approaches needs to be carefully reevaluated. Using antifibrotics to halt fibrosis progression is one concept not proven in large trials but it might well be effective in many, because the mechanisms for fibrosis generation are not intrinsically linked to HCV persistence, but rather to secondary response mechanisms evoked in the chronically inflamed liver, with the stellate cell activation holding center stage in this scenario. The following is one of several possible add on modalities.

[drofi]

Lieber HR,
inzwischen bin ich in dem Umfeld hep sehr aktiv und bemuehe mich nur bestens nachpruefbare Informationen als Multiplikator weiterzugeben. Daher haette ich mich auch ueber gute Daten zu PPC gefreut. Natuerlich gibt es sehr viele Komponenten, die eventuell einen positiven Effekt auf die Fibroseprogression haben, und wahrscheinlich auch eine geringe Toxizitaet haben, aber das ist aus meiner Sicht keineswegs eine ausreichende Basis um verzweifelten kranken Menschen die Anwendung zu empfehlen. Beispiele sind Silymarin, antoxidative Vitamine, acetylcystein, ursodeoxycholsaure, colchicine, s-adenosysl-methionin und sogar carnitin. Im Grunde gibt es aber zu keiner der Substanzen wirklich überzeugende Daten. Ueber die Wirksamkeit einer Erhaltungstherapie habe ich mir noch keine abschliessende Meinung bilden koennen, die Ergebnisse der HALT-C etc sind enttauschend, aber es gibt ja etliche andere Studien, die dem entgegenstehen. Da bin ich noch abwartend. Hinweise auf moegliche Wirksamkeit von Substanzen reichen meiner Ansicht nach nicht aus für eine Empfehlung. Schon gar nicht in einem Laienforum, in dem so viele verzweifelte Menschen mitlesen, denen andere dann ohne Skrupel den letzten Cent aus der Tasche ziehen. Daher bin ich beim Thema Wirksamkeit und Unbedenklichkeit so kompromisslos. In Ihrem speziellen Fall trifft das aber sicher den falschen Ansprechpartner, denn Ihre Absichten sind ausschliesslich ehrenhaft, das ist mir ganz klar.
Mir persoenlich geht es gut, ich bin motiviert 72 Wochen mit  anschliessender Lowdose phase zu therapieren und bin zuversichtlich Erfolg zu haben.

Viele herzliche Gruesse, drofi

[GoofyDad]

Thanks for the lesson. I'm starting to get there.... but if you will indulge one more question, I'm still not clear on this: Is the advantage of the unsaturated PPC molecule vis-a-vis the saturated PC molecule that the PPC can slip into the membrane easier -- or is it that once PPC is integrated into a membrane the PPC enhanced membrane has more fluidity?

I wasn't much of a student - eight grade biology was the end of the line for me. That may help  explain my need for the applied sledgehammer learning technique......    

[Hepatitis Researcher]

The key thing to watch is the appearance of any kind of neoplastic disorder - very unlikely. The exact reason why your Immunoglobulin subtypes  are somwhat out of line is very hard to find and I doubt that your doc will or can make many any specialized efforts in that regard. Even a flow cytometry test to see if - within your lymphocytes - the B cell population is on the low side is not a routine test.
The best available test for disturbances in your immune system/hematopoetic system is a bone marrow biopsy, but there is probably no indication for this at this point.Since clinically there seems to be no major rheumatologic disorder present, it will not be pursued by a rheumatologist.

The superhigh B12 level is strange, I assume you take no mega supplements of this, or you would have mentioned it.I am not familiar with any autoimmune disorder with immune complexes containing VitB12.

[Hepatitis Researcher]

Drofi:
Quote: "To be sarcastic, in Germany the  HCV standard therapy apparently consists already of nucleosidanalogs"

Yes, it does. IFN and RIBAVIRIN.
Didn't you know that Ribavirin is a nucleosidanalog?
http://en.wikipedia.org/wiki/Ribavirin

hr. Drofi. Sie wissen ,dass ich ribavirin kenne. Nichtsdestotrotz war die Ausdruckweise in der Deutschen Webseite unpassend und sachlich inkorrekt. Man haette sagen sollen Interferon und ja bitte, ein Nukleosidanalog ( das ja immerhin im Verhaeltnis zu Interferon wohl zweitrangig ist (mit einer direkten antiviralen Wirkung von 0.5 log im Schnitt). Diese unnoetigerweise mangelhafte Ausdruckweise in der kritischen Beschreibung der Vergleichsstudie spricht fuer unfachmaennische Bearbeitung dieses Textes, das werden Sie sicher auch so sehen. Gibt zu denken.
Nicht zuletzt stehen die kommenden Nukleosidanaloga als Polymerasehemmer nun auch  im Zentrum des Interesses und dann wird der Plural wohl eines Tages Berechtigung haben.

Alles in Allem sind viele Leute in diesem Forum ueberempfindich und ueberreaktiv.Wird wohl das Interferon und die fuer viele duestere Lage sein.

Viel Glueck und herzliche Gruesse. Wie ist die Lage jetzt bei Ihnen mit der VL Entwicklung?
.

[scratchinghead]

Any chance of getting a grant from somewhere to run a study of your own?

[Hepatitis Researcher]

The knowledge regading PPC is mainly from Dr. Charles Liebers work, he has published several animal studies on the antifibrotic effect of this compound. It is also from abstracts at prior liver meetings, posters viewed there and a personal, over an hour discussion wit Dr. Lieber which allowed me to better judge his qualifications, trust his conclusions and get his ovrall " feel" for this compound. The rest is from what publications are available on Pubmed and the overall trend re lack of any toxicity, likelihood of contribution to liver health by concept and role in membrane biology. There are no further large human trials, since none will pay for those, since this is not an item where you can charge $20 per pill as with the antivirals and if you did, patients would obtain it from other sources once you would have spent the money to further prove its usefulness. I fully realize that this is not enough to convince any authorities in Germany or here ("evidence based medicine") to allow it to be officially labeled and indicated as antifibrotic , indeed, its contribution in this regard might be smaller that we think or even worst case, nonexistent. However, weighing all the available evidence, combined with the virtually nonexistent toxicity, the availability and its low cost it seems a valuable component to someone with inflammatory liver and/or  fibrosis. Please also note, that the above PPC trial tested its efficac y re SVR%  improvement, not antifibrosis, and it seemed well conducted to me. .

I did not comment prior to your request for further links, but first only to the other compound that you linked, since I can only do so much in my limited time.

The compound from the website, that you mentioned, might well work excellent against stellate activation vio reduction of macrophage /Kupfer cell activation pathways in the liver that play as you know a pivotal role in the profibrotic pathway. I am still interested in finding out -possibly from you with bettrer access to european patents-  if you have the time - what the chemical class and basis for this codenamed product is, to possibly get some first idea if it should be included in the antifibrotic compounds of interest list.. If you have access to the compound intself, you could send it to Antox Gmbh in Munich, which will determine its inflammation inhibitory potential for your very own or somebody elses lymphocytes/monocytes using state of the art assays for transcription intensity meaurements under the influence of this agent. If it would work well in that assay, one could next turn to the question of toxicity. The balance between effectiveness and toxicity is quite important in the pursuit and use of such antifibrotics. Totally harmless like PPC  - you can try it, not much lost. Totally effective and totally harmless:  buy stock before anybody elso knows about it. Very effective but very problematic as some  in pharmaceutical development pursued antifibrotics were and are : Weigh your risks, wait until  approval or halting of development.  

I have no personal bond or pride or any advantage from any of these antifibrotic "components".Nor can i precisely gauge the relative contributory power of any of these, I wish there were any side to side comparisons in the numerous animal trials done.  But I do know that the cocktail has worked very well, with dramatic reduction from cirrhosis to stage one fibrosis, confirmed by numerous fibroscans and a liver biopsy in at least two patient cases thus far.