Aa
Interesting: some success with I.V. licorice
Here is a summary: Summary. Chronic hepatitis C patients often fail to respond to interferon-based therapies. This phase III study aimed at confirming the efficacy and safety of glycyrrhizin in interferon + ribavirin-based therapy non-responders. A randomised, double-blind, placebo-controlled, comparison of glycyrrhizin, administered intravenously 5×/or 3×/week, and 5×/week placebo for 12 weeks to 379 patients, was followed by a randomised, open comparison of glycyrrhizin i.v. 5×/versus 3×/week for 40 weeks. Primary endpoints were: (1) the proportion of patients with ≥50% ALT (alanine aminotransferase) reduction after 12 weeks double-blind phase, and (2) the proportion of patients with improvement of necro-inflammation after 52 weeks as compared with baseline. The proportion of patients with ALT reduction ≥50% after 12 weeks was significantly higher with 5×/week glycyrrhizin (28.7%, P < 0.0001) and 3×/week glycyrrhizin (29.0%, P < 0.0001) compared with placebo (7.0%). The proportion of patients with improvement in necro-inflammation after 52 weeks was 44.9% with 5×/week and 46.0% with 3×/week, respectively. Glycyrrhizin exhibited a significantly higher ALT reduction compared to placebo after 12 weeks of therapy and an improvement of necro-inflammation and fibrosis after 52-weeks treatment. Generally, glycyrrhizin treatment was well tolerated. And here is the link: http://www.medscape.com/viewarticle/767511?src=rsshttp://www.medscape.com/viewarticle/767511?src=rss
Hey Dennis, this is very interesting. Before I treated I used to use licorice
Hope you are doing better
Dee
Hope you are doing better
Dee
See if this is meaningful for you as I'm avoiding pasting the multi page article. One of the reasons I'm not interpreting it for you is I have to run out plus my "sort of ADD, day-night reversal, up, down, and sideway mood changeable kaleidoscope of a personality" challenges credible interpretation (still undetected at 2 weeks post 48 though!) My best: This study demonstrates that treatment with GL reduces ALT levels. After the 12 week double-blind treatment phase ALT values were significantly improved in comparison to placebo. Suppression of necro-inflammation as well as improvement of fibrosis was observed in patients treated with GL either 5×/week or 3×/week for 52 weeks. Despite the fact that no changes in serum HCV-RNA levels were seen during the double-blind or open phase, GL leads to a decrease in ALT values compared to the two placebo arms.
The combination of peg-IFN and RBV has been the standard of care (SOC) for patients with chronic hepatitis C since 2001. However, certain patient populations in particular non-responders to prior IFN-based therapies show very poor response rates to these therapies with less than 16% of patients clearing HCV RNA.[21,22] Thus, alternative options are needed. Treatment that could halt or diminish the progression of fibrosis would be beneficial. However, three major studies, HALT-C, EPIC-3 and COPILOT, failed to show efficacy of low dose pegylated interferon on fibrosis progression in patients who previously failed to IFN based therapies.[5,23]
Innovative agents that are in clinical development include HCV protease, HCV polymerase and HCV NS 5A inhibitors as well as the host targeting agent (HTA) alisporivir.[24] Currently, phase III study results of two HCV protease inhibitors are available.[25,26] They have to be combined with peg-IFN + RBV and therefore there are no solutions for IFN intolerant patients at the moment. Two phase III studies, REALIZE and RESPOND-2, explored the benefits of telaprevir and boceprevir in previous peg-IFN + RBV failure patients, respectively.[6,25] Response rates were higher among patients who had previously relapsed than those who were non-responders, partial as well as null responders.[27] Still more than half of non-responder patients will fail to upcoming triple therapies with first generation HCV protease inhibitors and response rates are particular poor for subjects with advanced fibrosis or cirrhosis, HCV genotype 1a and African Americans. Treatment regimens with all oral anti-HCV therapies combining protease inhibitors, polymerase inhibitors as well as NS 5A inhibitors are in earlier stages of clinical development.[28] As a remaining alternative out of the currently available therapies, GL is considered worth re-evaluating its utility in the treatment of IFN non-responder or IFN non-tolerant chronic hepatitis patients.
The result of this study suggests that GL may be helpful in patients who did not respond to previous IFN based therapies or who cannot tolerate interferon. GL led to a significant reduction of ALT levels in comparison to placebo after 12 weeks of treatment. Further decrease of ALT was observed during the 40 weeks of open phase. First experience with GL in IFN non-responders in European chronic hepatitis C patients was reported by Schalm et al. (2003).[29] The recent study was performed to provide data from a larger European patient population and to assess the effect of GL on ALT and on liver histology. ALT is a marker of inflammatory activity in the liver.[30] Moriyama et al. (2005) reported that patients achieving ALT levels less than twice the ULN after IFN therapy had a reduced risk of progression to HCC.[31] Several studies have shown that long-term treatment with GL decreases elevated ALT levels in chronic hepatitis, while development of HCC was reduced.[15] Rino et al. (2006) demonstrated that consistent reduction of elevated ALT level with GL significantly decreased the risk of developing HCC from 66% to 41%.[32]
Necro-inflammation and fibrosis scores improved significantly after GL treatment. Combining the results for improved modified HAI grade and no further deterioration, histological efficacy of GL reaches 63.3% (5×/week GL) and 61% (3×/week GL), respectively. In regard to fibrosis scores, the combined results reached 67%. However, a control group has not been part of the study design since two biopsies 52 weeks apart in peg-IFN plus ribavirin non-responders receiving placebo for 52 weeks was not regarded ethical.
Necro-inflammation scores were improved although they did not reach the targeted endpoints of ≥60% improvement. A closer look at the results of necro-inflammation sub-scores confirmed the positive effects of GL. In particular, the results of periportal or periseptal interface hepatitis scores and the focal (spotty) lytic necrosis, apoptosis, and focal inflammation indicate a favorable inhibition. No such effects have been demonstrated in IFN non-responders before.[3] When this study was planned, there were no reliable histological data available on non-responders. An improvement rate of 60% was considered feasible (by assumption) based on a limited source of information available, but in hindsight this proved too optimistic,[33] particularly in IFN non-responding, difficult-to-treat patients.
The treatment rationale for hepatitis C should include not only reduction in liver disease progression and HCC development but also an improvement in health-related quality of life (HRQOL). HRQOL was significantly decreased in patients with chronic hepatitis C with advanced fibrosis and cirrhosis and treatment with peg-IFN + RBV improved HRQOL as assessed by SF-36 questionnaire.[34] In our study, HRQOL-improvements were observed in both study phases, exceeded placebo effect in patients receiving GL and appeared to be dose dependent. Despite the reported negative impact of long-term intravenous application on QOL, a good compliance of GL therapy was confirmed by low drop-out rates. Based on the mode of action of GL, adverse events, laboratory parameters and vital signs were compatible with symptoms of pseudoaldosteronism. While the incidence of AEs was slightly higher than that observed in the past clinical studies[10,11] treatment with GL was found generally well tolerated and this study confirmed the safety profile of GL.
Limitations of this study need to be considered. No long-term follow-up of patients was performed to investigate if the potential beneficial effects on disease activity had also a long-term impact on progression of liver disease. This information would be required to determine the optimal treatment duration of GL also considering cost-benefit ratios. Moreover, treatment with GL required frequent intravenous injections over a prolonged period of time and thus might be feasible in clinical practice only in some countries.
In conclusion, it was shown that GL reduces ALT and prevents disease progression in a proportion of chronic hepatitis C patients who did not respond to or tolerate previous IFN based therapies. Improvement of ALT levels in IFN non-responders and IFN intolerant patients irrespective of HCV-RNA can be achieved in a proportion of patients. Since frequent i.v. injection (5×/week or 3×/week) required for a GL therapy can possibly be a burden for chronic hepatitis patients, development of a formulation which allows less frequent administration or non-parenteral application would be a significant step forward.
The combination of peg-IFN and RBV has been the standard of care (SOC) for patients with chronic hepatitis C since 2001. However, certain patient populations in particular non-responders to prior IFN-based therapies show very poor response rates to these therapies with less than 16% of patients clearing HCV RNA.[21,22] Thus, alternative options are needed. Treatment that could halt or diminish the progression of fibrosis would be beneficial. However, three major studies, HALT-C, EPIC-3 and COPILOT, failed to show efficacy of low dose pegylated interferon on fibrosis progression in patients who previously failed to IFN based therapies.[5,23]
Innovative agents that are in clinical development include HCV protease, HCV polymerase and HCV NS 5A inhibitors as well as the host targeting agent (HTA) alisporivir.[24] Currently, phase III study results of two HCV protease inhibitors are available.[25,26] They have to be combined with peg-IFN + RBV and therefore there are no solutions for IFN intolerant patients at the moment. Two phase III studies, REALIZE and RESPOND-2, explored the benefits of telaprevir and boceprevir in previous peg-IFN + RBV failure patients, respectively.[6,25] Response rates were higher among patients who had previously relapsed than those who were non-responders, partial as well as null responders.[27] Still more than half of non-responder patients will fail to upcoming triple therapies with first generation HCV protease inhibitors and response rates are particular poor for subjects with advanced fibrosis or cirrhosis, HCV genotype 1a and African Americans. Treatment regimens with all oral anti-HCV therapies combining protease inhibitors, polymerase inhibitors as well as NS 5A inhibitors are in earlier stages of clinical development.[28] As a remaining alternative out of the currently available therapies, GL is considered worth re-evaluating its utility in the treatment of IFN non-responder or IFN non-tolerant chronic hepatitis patients.
The result of this study suggests that GL may be helpful in patients who did not respond to previous IFN based therapies or who cannot tolerate interferon. GL led to a significant reduction of ALT levels in comparison to placebo after 12 weeks of treatment. Further decrease of ALT was observed during the 40 weeks of open phase. First experience with GL in IFN non-responders in European chronic hepatitis C patients was reported by Schalm et al. (2003).[29] The recent study was performed to provide data from a larger European patient population and to assess the effect of GL on ALT and on liver histology. ALT is a marker of inflammatory activity in the liver.[30] Moriyama et al. (2005) reported that patients achieving ALT levels less than twice the ULN after IFN therapy had a reduced risk of progression to HCC.[31] Several studies have shown that long-term treatment with GL decreases elevated ALT levels in chronic hepatitis, while development of HCC was reduced.[15] Rino et al. (2006) demonstrated that consistent reduction of elevated ALT level with GL significantly decreased the risk of developing HCC from 66% to 41%.[32]
Necro-inflammation and fibrosis scores improved significantly after GL treatment. Combining the results for improved modified HAI grade and no further deterioration, histological efficacy of GL reaches 63.3% (5×/week GL) and 61% (3×/week GL), respectively. In regard to fibrosis scores, the combined results reached 67%. However, a control group has not been part of the study design since two biopsies 52 weeks apart in peg-IFN plus ribavirin non-responders receiving placebo for 52 weeks was not regarded ethical.
Necro-inflammation scores were improved although they did not reach the targeted endpoints of ≥60% improvement. A closer look at the results of necro-inflammation sub-scores confirmed the positive effects of GL. In particular, the results of periportal or periseptal interface hepatitis scores and the focal (spotty) lytic necrosis, apoptosis, and focal inflammation indicate a favorable inhibition. No such effects have been demonstrated in IFN non-responders before.[3] When this study was planned, there were no reliable histological data available on non-responders. An improvement rate of 60% was considered feasible (by assumption) based on a limited source of information available, but in hindsight this proved too optimistic,[33] particularly in IFN non-responding, difficult-to-treat patients.
The treatment rationale for hepatitis C should include not only reduction in liver disease progression and HCC development but also an improvement in health-related quality of life (HRQOL). HRQOL was significantly decreased in patients with chronic hepatitis C with advanced fibrosis and cirrhosis and treatment with peg-IFN + RBV improved HRQOL as assessed by SF-36 questionnaire.[34] In our study, HRQOL-improvements were observed in both study phases, exceeded placebo effect in patients receiving GL and appeared to be dose dependent. Despite the reported negative impact of long-term intravenous application on QOL, a good compliance of GL therapy was confirmed by low drop-out rates. Based on the mode of action of GL, adverse events, laboratory parameters and vital signs were compatible with symptoms of pseudoaldosteronism. While the incidence of AEs was slightly higher than that observed in the past clinical studies[10,11] treatment with GL was found generally well tolerated and this study confirmed the safety profile of GL.
Limitations of this study need to be considered. No long-term follow-up of patients was performed to investigate if the potential beneficial effects on disease activity had also a long-term impact on progression of liver disease. This information would be required to determine the optimal treatment duration of GL also considering cost-benefit ratios. Moreover, treatment with GL required frequent intravenous injections over a prolonged period of time and thus might be feasible in clinical practice only in some countries.
In conclusion, it was shown that GL reduces ALT and prevents disease progression in a proportion of chronic hepatitis C patients who did not respond to or tolerate previous IFN based therapies. Improvement of ALT levels in IFN non-responders and IFN intolerant patients irrespective of HCV-RNA can be achieved in a proportion of patients. Since frequent i.v. injection (5×/week or 3×/week) required for a GL therapy can possibly be a burden for chronic hepatitis patients, development of a formulation which allows less frequent administration or non-parenteral application would be a significant step forward.
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