Aa
Nitazoxanide (Alinia) & Silibinin
I was reading this information about viral resistance to DAAs and noticed this information on Alinia and Silibinin. It's probably been posted on the board before but I can't find it. - Dave
Nitazoxanide (Alinia)
Nitazoxanide is a thiazolide anti-infective with activity against anaerobic bacteria, protozoa, and viruses. It is approved for treatment of cryptosporidiosis and lambliasis in the United States. In vitro nitazoxanide was shown to inhibit HCV replication and the mechanism of action was proposed to be induction of double-strand RNA activated protein kinase.118 In a placebo-controlled study monotherapy with nitazoxanide for 24 weeks led to a mean reduction of HCV-RNA viral load in genotype 4-infected patients by 1.55 log10 IU/mL with 30% of patients having undetectable HCV RNA at the end of treatment.19 Studies in genotype 1-infected patients with a lead-in monotherapy with nitazoxanide for 4 weeks have been performed. However, no virologic response data in genotype 1-infected patients during monotherapy with nitazoxanide have been reported (Figure 1D).21, 119 Patients experiencing viral breakthroughs were not reported from monotherapy studies. However, in vitro studies suggested the potential of resistance to nitazoxanide most likely was conferred by changes in host proteins and not by mutations in the virus.118
Silibinin
The mechanism of action of silibinin is unknown but inhibition of NS5B polymerase as well as antiviral and anti-inflammatory activities shown in NS5B polymerase assays, in human peripheral blood mononuclear cells, and the HCV replicon, respectively, have been reported.120, 121 Monotherapy studies with daily intravenous application of silibinin in genotype 1-, 2-, and 3-infected patients for up to 14 days showed good antiviral activities (Figure 1D).22 Studies in larger cohorts of patients including resistance analysis are underway.
Nitazoxanide (Alinia)
Nitazoxanide is a thiazolide anti-infective with activity against anaerobic bacteria, protozoa, and viruses. It is approved for treatment of cryptosporidiosis and lambliasis in the United States. In vitro nitazoxanide was shown to inhibit HCV replication and the mechanism of action was proposed to be induction of double-strand RNA activated protein kinase.118 In a placebo-controlled study monotherapy with nitazoxanide for 24 weeks led to a mean reduction of HCV-RNA viral load in genotype 4-infected patients by 1.55 log10 IU/mL with 30% of patients having undetectable HCV RNA at the end of treatment.19 Studies in genotype 1-infected patients with a lead-in monotherapy with nitazoxanide for 4 weeks have been performed. However, no virologic response data in genotype 1-infected patients during monotherapy with nitazoxanide have been reported (Figure 1D).21, 119 Patients experiencing viral breakthroughs were not reported from monotherapy studies. However, in vitro studies suggested the potential of resistance to nitazoxanide most likely was conferred by changes in host proteins and not by mutations in the virus.118
Silibinin
The mechanism of action of silibinin is unknown but inhibition of NS5B polymerase as well as antiviral and anti-inflammatory activities shown in NS5B polymerase assays, in human peripheral blood mononuclear cells, and the HCV replicon, respectively, have been reported.120, 121 Monotherapy studies with daily intravenous application of silibinin in genotype 1-, 2-, and 3-infected patients for up to 14 days showed good antiviral activities (Figure 1D).22 Studies in larger cohorts of patients including resistance analysis are underway.
i got the info from an editorial article the writer was consulted directly by Dr. Berg.
it was in the Jan, issue of the German Liver mag "Lebenzeichen" issued by German
Liver assoc.
it was in the Jan, issue of the German Liver mag "Lebenzeichen" issued by German
Liver assoc.
thanks, Bali. No worries - anytime you have time/energy to post on please do. Insofar as it's available now, it becomes another interesting option. The news about approval in Austria is very good. This must be recent. Hopefully the trial being run by Ferenci in Vienna
http://clinicaltrials.gov/ct2/show/NCT00684268
can now yield more results.
Re the Biermer/Berg study the numbers reported at AASLD10 (abstract 989) seem somewhat different:
"Background: High-dose intravenous silibinin has demonstrated significant antiviralactivity against Hepatitis C virus. When administered intravenously silibinin reaches concentrations that have been shown to directly inhibit the HCV-RNA-polymerase in vitro. We have reported on the rescue treatment with short-term silibinin adminstration in partial responders to standard antiviral treatment. Methods: Seventeen patients with minimal persistent viremia during interferon-based therapy that had met discontinuation criteria due to virologic nonresponse received two infusions of silibinin (20 mg/kg bw in 500 ml NaCl) on two consecutive days. An initial virologic response to silibinin was defined as negative TMA testing within one week after silibinin infusions. In patients with an initial response peginterferon alpha plus ribavirin (SoC) was continued. Results: All patients had been treated with peginterferon alfa 2a / ribavirin and four patients additionally received an HCV specific protease inhibitor for the first four weeks of treatment. 9 out of 17 patients showed a plateau of HCV RNA levels ranging from detectable but not quantifiable (< 15 IU/mL) to 2015 IU/mL for at least eight weeks on continuous treatment (total treatment duration 16-58 weeks). The remaining two patients suffered a virologic rebound after cessation of the protease inhibitor (HCV RNA 484 IU/ml at treatment week 6 (pat. 1) and 6890 IU/ml at week 5 (pat. 2)). Six patients could not achieve an initial virologic response to silibinin and discontinued all antiviral therapy. In eleven patients a complete initial virologic response to silibinin could be induced. Among those responders only one patient showed a breakthrough one week after the silibinin rescue treatment but all other patients remained TMA undetectable as long as SoC was continued (12 – 44 weeks). Three patients had to prematurely discontinue SoC therapy for non-virologic reasons: HCC recurrence 13 weeks after silibinin, fatal bleeding from esophageal varices 12 weeks after silibinin, leaving the country with no refrigeration-devices 22 weeks after silibinin. Up to now four patients completed SoC (20 – 44 weeks after SIL) with one patient achieving an SVR, two being TMA negative at week 12 of follow up, one suffering from a viral relapse and three patients still being on treatment. Further virologic follow-up data of the cohort will be presented at the meeting. Conclusion: On-treatment augmentation with intravenous high dose silibinin might be an interesting rescue approach in oder to improve treamtent outcome for difficult to treat patients with chronic hepatitis C showing nonresponse to standard of care."
("A short course of high-dose intravenous silibinin as rescue treatment for hepatitis C patients with inclomplete virologic response to peginterferon alpha / ribavirin treatment" abstract 989).
It seems there was only one actual relapse among the data available three of the other non SVRS were due to discontinuation.
http://clinicaltrials.gov/ct2/show/NCT00684268
can now yield more results.
Re the Biermer/Berg study the numbers reported at AASLD10 (abstract 989) seem somewhat different:
"Background: High-dose intravenous silibinin has demonstrated significant antiviralactivity against Hepatitis C virus. When administered intravenously silibinin reaches concentrations that have been shown to directly inhibit the HCV-RNA-polymerase in vitro. We have reported on the rescue treatment with short-term silibinin adminstration in partial responders to standard antiviral treatment. Methods: Seventeen patients with minimal persistent viremia during interferon-based therapy that had met discontinuation criteria due to virologic nonresponse received two infusions of silibinin (20 mg/kg bw in 500 ml NaCl) on two consecutive days. An initial virologic response to silibinin was defined as negative TMA testing within one week after silibinin infusions. In patients with an initial response peginterferon alpha plus ribavirin (SoC) was continued. Results: All patients had been treated with peginterferon alfa 2a / ribavirin and four patients additionally received an HCV specific protease inhibitor for the first four weeks of treatment. 9 out of 17 patients showed a plateau of HCV RNA levels ranging from detectable but not quantifiable (< 15 IU/mL) to 2015 IU/mL for at least eight weeks on continuous treatment (total treatment duration 16-58 weeks). The remaining two patients suffered a virologic rebound after cessation of the protease inhibitor (HCV RNA 484 IU/ml at treatment week 6 (pat. 1) and 6890 IU/ml at week 5 (pat. 2)). Six patients could not achieve an initial virologic response to silibinin and discontinued all antiviral therapy. In eleven patients a complete initial virologic response to silibinin could be induced. Among those responders only one patient showed a breakthrough one week after the silibinin rescue treatment but all other patients remained TMA undetectable as long as SoC was continued (12 – 44 weeks). Three patients had to prematurely discontinue SoC therapy for non-virologic reasons: HCC recurrence 13 weeks after silibinin, fatal bleeding from esophageal varices 12 weeks after silibinin, leaving the country with no refrigeration-devices 22 weeks after silibinin. Up to now four patients completed SoC (20 – 44 weeks after SIL) with one patient achieving an SVR, two being TMA negative at week 12 of follow up, one suffering from a viral relapse and three patients still being on treatment. Further virologic follow-up data of the cohort will be presented at the meeting. Conclusion: On-treatment augmentation with intravenous high dose silibinin might be an interesting rescue approach in oder to improve treamtent outcome for difficult to treat patients with chronic hepatitis C showing nonresponse to standard of care."
("A short course of high-dose intravenous silibinin as rescue treatment for hepatitis C patients with inclomplete virologic response to peginterferon alpha / ribavirin treatment" abstract 989).
It seems there was only one actual relapse among the data available three of the other non SVRS were due to discontinuation.
Silibin Ivs have recently been approved in Austria ! but not in any other EU country.
It is approved in Austria ( approval code : Zulassungs-NR 17.730) for proven Non-Responders
as an adjunct to Peg/Rib recommended dosage 20mg per kg bodyweight , 2-4hr IVs daily
minimum duration 14 days. Depending on response it can be repeated after waiting for
a minimum of 4 weeks.
In Germany the approval for it so far is not forseeable yet.
The small study from Dr. Biermer and Dr. Berg in Berlin and Leipzig showed
SI Ivs with Peg/Rib being able of turning around a non response in some cases.
Out of 20 non responders 12 reached UND , 3 reached SVR so far , 4 did not SVR
and with 5 other patients they are still waiting for results
It is approved in Austria ( approval code : Zulassungs-NR 17.730) for proven Non-Responders
as an adjunct to Peg/Rib recommended dosage 20mg per kg bodyweight , 2-4hr IVs daily
minimum duration 14 days. Depending on response it can be repeated after waiting for
a minimum of 4 weeks.
In Germany the approval for it so far is not forseeable yet.
The small study from Dr. Biermer and Dr. Berg in Berlin and Leipzig showed
SI Ivs with Peg/Rib being able of turning around a non response in some cases.
Out of 20 non responders 12 reached UND , 3 reached SVR so far , 4 did not SVR
and with 5 other patients they are still waiting for results
you seem to be more functional than i (wk47) am.
got another copy of my german liver mag send yesterday and it has a double page spread
on milk thistle and silibin ivs.
i read some of it yesterday but i have a terrible migraine and have not slept in
weeks or months. i will go over it again , to bad its in german i could try scan it and send you
a pdf. it only said it was expensive no specific price and also that the infusions
take many hrs and need to be done at a clinic..
overall it is still being investigated but so far the results are mixed and seemingly
limited to MAYBE lower once VL prior to inf tx or as a rescue drug to keep decline
going. yes they were able to knock out the virus after transplant in one case
bottomline so far the effects of silibin ivs are temporary.
on some of those studies you posted above they still waiting on final results.
even oral milk thistle i believe is still investigated but at much higher dose
again no results yet
i will read thru it again when my head clears......
thanks for your understanding
b
got another copy of my german liver mag send yesterday and it has a double page spread
on milk thistle and silibin ivs.
i read some of it yesterday but i have a terrible migraine and have not slept in
weeks or months. i will go over it again , to bad its in german i could try scan it and send you
a pdf. it only said it was expensive no specific price and also that the infusions
take many hrs and need to be done at a clinic..
overall it is still being investigated but so far the results are mixed and seemingly
limited to MAYBE lower once VL prior to inf tx or as a rescue drug to keep decline
going. yes they were able to knock out the virus after transplant in one case
bottomline so far the effects of silibin ivs are temporary.
on some of those studies you posted above they still waiting on final results.
even oral milk thistle i believe is still investigated but at much higher dose
again no results yet
i will read thru it again when my head clears......
thanks for your understanding
b
>however so far the virus has always returned after Silibin IV therapy.
> It might find a use when during regular tx the viral decline
> suddenly stops.Silibin IVs are also very expensive.
please post any additional information you have on IV sil - I tried to follow this up when I was more functional but ran out of steam. I will probably start checking again if not able to add a PI in June/July as now planned.Overall, I was left with the impression IV-sil seems very promising and mysteriously under-explored.
- Is it available in the pharmacy in Germany? I know it is not in Austria and I believe not in Italy. In the US it has been used with an FDA IND for treatment of liver failure associated with mushroom poisoning
- what's known about costs ?
- I know Madaus, the german manufacturer, was bought by Italian firm Rottapharm. Are they now making the drug available? (apparently earlier last year they were not)
The four abstracts re IV sil presented at last AASLD seemed very encouraging:
1)Undetectable HCV RNA after Silibinin iv treatment is associated with high on treatment response rates in HCV nullresponders (abs 835)
http://trs.scivee.tv/node/2051
2)Silibinin monotherapy prevents graft infection after orthotopic liver transplantation in a patient with chronic hepatitis C. (abs 943)
http://trs.scivee.tv/node/2160
(also published as a journal paper in
http://www.ncbi.nlm.nih.gov/pubmed/21106270)
3) A short course of high-dose intravenous silibinin as rescue treatment for hepatitis C patients with inclomplete virologic response to peginterferon alpha / ribavirin treatment (abs 989)
http://trs.scivee.tv/node/986
4) Differential in vitro Effects of Intravenous Versus Oral Formulations of Silibinin on the HCV Life Cycle and Inflammation (abs 1870)
http://trs.scivee.tv/node/3929
See also the earlier journal report:
Successful HCV eradication and inhibition of HIV replication by intravenous silibinin in an HIV-HCV coinfected patient.
http://www.ncbi.nlm.nih.gov/pubmed/20709593
I have not used milk thistle in this tx because, in agreement with abs 1870, it seemed a clear antiviral effect is only associated with IV level dosage. The oral supplement is associated with protective hepatic function but doesn't seem to do much to the virus. IV dosage on the other hand is another story
Also Interesting is Berg's case-study comment on Ferenci's initial '08 paper
Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy.
http://www.ncbi.nlm.nih.gov/pubmed/18771667
"Herein, we present a case report of a 65-year-old woman who had previously failed any antiviral treatment strategies. Two courses of pegylated interferon and ribavirin had been applied unsuccessfully in 2002 and 2004. In February 2008, low-dose maintenance therapy with 50 μg pegylated interferon-alfa-2b had to be terminated because of a solitary hepatocellular carcinoma (3 cm in diameter) that developed in compensated liver cirrhosis. Because the patient refused liver transplantation, a local ablative therapy was performed that resulted in complete ablation of the tumor. Confronted with the need to eradicate effectively the HCV infection to reduce the risk of tumor recurrence and disease progression, we adapted the silibinin protocol as described by Ferenci et al.1 We started first a monotherapy with ribavirin to evaluate the highest tolerable dosage and also to reach a steady-state plasma ribavirin level before starting silibinin and pegylated interferon-alfa. During the 4-week ribavirin monotherapy (800 mg/d) a 0.6-log drop in viremia was observed (from 1,610,000 to 363,330 IU/mL; Figure 1). After silibinin was initiated intravenously at 20 mg/kg bodyweight with daily infusions over 2 hours, a further marked reduction in HCV RNA levels was reached (day 8: 1,105 IU/mL corresponding to an additional 2.4-log decline). Ribavirin was continued during silibinin administration. On day 8, we initiated weekly subcutaneous injections with 180 μg pegylated interferon alfa-2a. At day 17, 3 days after stopping the 14-day silibinin course, undetectable HCV RNA levels were obtained. No re-increase of HCV RNA was found after stopping intravenous silibinin.
...
In conclusion, the application of high-dose, intravenous silibinin in an HCV-positive, cirrhotic patient refractory to 3 courses of interferon-based therapy led to a rapid virologic response as documented by undetectable HCV RNA levels. The significant antiviral effect may have been augmented by the concurrent use of ribavirin. This case report could, therefore, favor further studies that compare the antiviral efficacy of silibinin with and without concurrent ribavirin use."
http://www.ncbi.nlm.nih.gov/pubmed/19486953
Being the paranoid sort of person I am becoming, I tend to believe this is not getting more attention because the modified silibinin molecule used in the IV preparation (modified to make it water soluble) is not patentable and Roche/Merck/BMS and co want it to stay in the lab.
> It might find a use when during regular tx the viral decline
> suddenly stops.Silibin IVs are also very expensive.
please post any additional information you have on IV sil - I tried to follow this up when I was more functional but ran out of steam. I will probably start checking again if not able to add a PI in June/July as now planned.Overall, I was left with the impression IV-sil seems very promising and mysteriously under-explored.
- Is it available in the pharmacy in Germany? I know it is not in Austria and I believe not in Italy. In the US it has been used with an FDA IND for treatment of liver failure associated with mushroom poisoning
- what's known about costs ?
- I know Madaus, the german manufacturer, was bought by Italian firm Rottapharm. Are they now making the drug available? (apparently earlier last year they were not)
The four abstracts re IV sil presented at last AASLD seemed very encouraging:
1)Undetectable HCV RNA after Silibinin iv treatment is associated with high on treatment response rates in HCV nullresponders (abs 835)
http://trs.scivee.tv/node/2051
2)Silibinin monotherapy prevents graft infection after orthotopic liver transplantation in a patient with chronic hepatitis C. (abs 943)
http://trs.scivee.tv/node/2160
(also published as a journal paper in
http://www.ncbi.nlm.nih.gov/pubmed/21106270)
3) A short course of high-dose intravenous silibinin as rescue treatment for hepatitis C patients with inclomplete virologic response to peginterferon alpha / ribavirin treatment (abs 989)
http://trs.scivee.tv/node/986
4) Differential in vitro Effects of Intravenous Versus Oral Formulations of Silibinin on the HCV Life Cycle and Inflammation (abs 1870)
http://trs.scivee.tv/node/3929
See also the earlier journal report:
Successful HCV eradication and inhibition of HIV replication by intravenous silibinin in an HIV-HCV coinfected patient.
http://www.ncbi.nlm.nih.gov/pubmed/20709593
I have not used milk thistle in this tx because, in agreement with abs 1870, it seemed a clear antiviral effect is only associated with IV level dosage. The oral supplement is associated with protective hepatic function but doesn't seem to do much to the virus. IV dosage on the other hand is another story
Also Interesting is Berg's case-study comment on Ferenci's initial '08 paper
Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy.
http://www.ncbi.nlm.nih.gov/pubmed/18771667
"Herein, we present a case report of a 65-year-old woman who had previously failed any antiviral treatment strategies. Two courses of pegylated interferon and ribavirin had been applied unsuccessfully in 2002 and 2004. In February 2008, low-dose maintenance therapy with 50 μg pegylated interferon-alfa-2b had to be terminated because of a solitary hepatocellular carcinoma (3 cm in diameter) that developed in compensated liver cirrhosis. Because the patient refused liver transplantation, a local ablative therapy was performed that resulted in complete ablation of the tumor. Confronted with the need to eradicate effectively the HCV infection to reduce the risk of tumor recurrence and disease progression, we adapted the silibinin protocol as described by Ferenci et al.1 We started first a monotherapy with ribavirin to evaluate the highest tolerable dosage and also to reach a steady-state plasma ribavirin level before starting silibinin and pegylated interferon-alfa. During the 4-week ribavirin monotherapy (800 mg/d) a 0.6-log drop in viremia was observed (from 1,610,000 to 363,330 IU/mL; Figure 1). After silibinin was initiated intravenously at 20 mg/kg bodyweight with daily infusions over 2 hours, a further marked reduction in HCV RNA levels was reached (day 8: 1,105 IU/mL corresponding to an additional 2.4-log decline). Ribavirin was continued during silibinin administration. On day 8, we initiated weekly subcutaneous injections with 180 μg pegylated interferon alfa-2a. At day 17, 3 days after stopping the 14-day silibinin course, undetectable HCV RNA levels were obtained. No re-increase of HCV RNA was found after stopping intravenous silibinin.
...
In conclusion, the application of high-dose, intravenous silibinin in an HCV-positive, cirrhotic patient refractory to 3 courses of interferon-based therapy led to a rapid virologic response as documented by undetectable HCV RNA levels. The significant antiviral effect may have been augmented by the concurrent use of ribavirin. This case report could, therefore, favor further studies that compare the antiviral efficacy of silibinin with and without concurrent ribavirin use."
http://www.ncbi.nlm.nih.gov/pubmed/19486953
Being the paranoid sort of person I am becoming, I tend to believe this is not getting more attention because the modified silibinin molecule used in the IV preparation (modified to make it water soluble) is not patentable and Roche/Merck/BMS and co want it to stay in the lab.
Silibinin is the primary active ingredient in Milk Thistle, and has gained some attention over the years for not only anti-viral properties but also anti-fibrotic properties. Lots of potential for silibinin: there are currently even phase III clinical trials going on investigating it's possible efficacy in preventing hepatic failure:
http://clinicaltrials.gov/ct2/show/NCT00915681
"The mechanism of action of silibinin is unknown..." as is it's potential.
Thanks, Dave. Good stuff. :)
http://clinicaltrials.gov/ct2/show/NCT00915681
"The mechanism of action of silibinin is unknown..." as is it's potential.
Thanks, Dave. Good stuff. :)
nice to have so many things in one place.
wondering what is going on with the time release version of Alinia
should`nt they be recruiting for phase 3 trial by now?
Silibin can be quite effective in supressing the virus
however so far the virus has always returned after Silibin IV therapy.
It might find a use when during regular tx the viral decline
suddenly stops.Silibin IVs are also very expensive.
wondering what is going on with the time release version of Alinia
should`nt they be recruiting for phase 3 trial by now?
Silibin can be quite effective in supressing the virus
however so far the virus has always returned after Silibin IV therapy.
It might find a use when during regular tx the viral decline
suddenly stops.Silibin IVs are also very expensive.
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