Efficacy and safety of glycyrrhizic acid and essential phospholipids (Phosphogliv) combination for alcoholic liver disease: results of the double-blind randomized placebo-controlled multicenter post-registration (phase IV) clinical trial «Jaguar» (PHG-M2/P03-12)

Material and methods. The original study included overall 120 patients with ALD, who were randomized in two identical groups. The patients of the main group (group A) received 2 courses of therapy: the first - Phosphogliv 5 mg/day as intravenous bolus injection for 2 wks, followed by the oral intake of 2 capsules t.i.d. for 10 wks (the total treatment duration was 24 wks). Patients of the control group (group B) received placebo in the same regimen. The dynamics of serum alanine transaminase (ALT), aspartate transaminase (AST), liver scores by noninvasive FibroMax test was applied to assess the treatment efficacy and safety, along with change in quality of life of patients. Results. In 24 wks in group A in comparison to the group B significantly lower mean ALT level was found: 35,2±29,4 U/l vs 48,4±36,1 U/l (р =0,044), AST level became normal in higher rate of patients: 69,4% vs 47,7% (р =0,034), that had more prominent decrease in gamma-glutamyltranspeptidase (GGT) level - 47,4±36,5% vs 25,1±63,9% (р =0,039), the rate of patients with Aktitest A2-A3 range decreased - 8,5% vs 21,4% (p<0,05) with no patients remained in FibroTest F3-F4 range; significantly more pronounced improvement by the vitality and social functioning scales of «SF-36» questionnaire was registered. The safety profile was comparable in both groups. Conclusions. Expected effects of the drug include reduction of inflammatory activity in the liver, improvement of cholestasis at longer follow-up period, decrease in fibrosis severity, improvement of quality of life at favorable safety profile.

Фосфоглив®, гепатопротектор, алкогольная болезнь печени, воспаление, фиброз, качество жизни

1. Сернов С. П., Лифшиц В. Б., Субботина В. Г. и др. Эпидемиология алкогольной болезни печени. Саратовский научно-мед журн 2009; 5(4):564-8 .

2. Комова А. Г., Маевская М. В., Ивашкин В. Т. Распространенность диффузных заболеваний печени в Москве. Клин перспект гастроэнтерол гепатол 2014; 5:3-8 .

3. EASL Clinical Practical Guidelines: Management of Alcoholic Liver Disease. J Hepatol 2012; 57(2): 399-420.

4. O’Shea R.S., Dasarathy S., McCullough A. J. Alcohol Liv Dis. Hepatology 2010; 51(1): 307-28.

5. Rambaldi A., Saconato H. H., Christensen E. et al. Systematic review: glucocorticosteroids for alcoholic hepatitis - a Cochrane Hepato-Biliary Group systematic review with meta-analyses and trial sequential analyses of randomized clinical trials. Aliment Pharmacol Ther 2008; 27:1167-78.

6. Mathurin P., Mendenhall C. L., Carithers R. L. Jr. et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH. J Hepatol 2002; 36:480-7.

7. Mathurin P., O’Grady J., Carithers R. L. et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut 2011; 60:255-60.

8. Thursz M. R., Richardson P., Allison M. et al. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med 2015; 372:1619-28.

9. O’Shea R.S., McCullough A. J. Treatment of alcoholic hepatitis. Clin Liv Dis 2005; 9:103-34.

10. Singal A. K., Kodali S., Vucovich L. A. et al. Diagnosis and Treatment of Alcoholic Hepatitis: A Systematic Review. Alcohol Clin Exp Res 2016; 40(7):1390-402. doi: 10.1111/acer.13108.

11. Saberi B., Dadabhai A. S., Jang, Y.Y. et al. Current Management of Alcoholic Hepatitis and Future Therapies. J Clin Translat Hepatol 2016; 4(2):113-22.

12. Purohit V., Bode J. C., Bode C. et al. Alcohol, intestinal bacterial growth, intestinal permeability to endotoxin, and medical consequences: summary of a symposium. Alcohol 2008; 42(5):349-61.

13. Yoh T., Nakashima T., Sumida Y. et al. Effects of Glycyrrhizin on Glucocorticoid Signaling Pathway in Hepatocytes. Dig Dis Sci 2002; 47(8):1775-81.

14. Sun Xiao­peng, Shi Ran­ran, Yuan Xue­qiang. Effect of glycyrrhizin on expression of TNF-α, IL 1 and IL 6 in adjuvant arthritis rat. Heilongjiang Med Pharm 2011: http://en.cnki.com.cn/Article_en/CJFDTOTALKXJY201101015.htm.

15. Abe M., Akbar F., Hasebe A. et al. Glycyrrhizin enhances interleukin-10 production by liver dendritic cells in mice with hepatitis. J Gastroenterol 2003; 38(10): 962-7.

16. El­Tahawy N.F., Ali A. H., Saied S. R. et al. Effect of glycyrrhizin on lipopolysaccharide/D-galactosamineinduced acute hepatitis in albino rats: a histological and immunohistochemical study. Egypt J Histol 2011; 34(3):518-27.

17. Crance J. M., Lévêque F., Biziagos E. et al. Studies on mechanism of action of glycyrrhizin against hepatitis A virus replication in vitro. Antiviral Res 1994; 23(1):63-76.

18. Van Rossum T. G., Vulto A. G., de Man R. A. et al. Review article: glycyrrhizin as a potential treatment for chronic hepatitis C. Aliment Pharmacol Ther 1998; 12(3):199-205.

19. Honda H., Nagai Y., Matsunaga T. et al. Glycyrrhizin and isoliquiritigenin suppress the LPS sensor Toll-like receptor 4/MD-2 complex signaling in a different manner. J Leukocyte Biol 2012; 91(6): 967-76.

20. Gao H.­X., Shao S.­H., Wang G.­Q. Research progress of Radix Glycyrrhizae. J Jinggangshan Med Coll 2004; 11(5):8-11.

21. Ивашкин В. Т., Маевская М. В., Павлов Ч. С., Тихонов И. Н., Широкова Е. Н. и др. Клинические рекомендации по диагностике и лечению неалкогольной жировой болезни печени Российского общества по изучению печени и Российской гастроэнтерологической ассоциации. Рос журн гастроэнтерол гепатол колопроктол. 2016;26(2):24-42.

22. Jingze Zhang, Wenyuan Gao, Shufang Bai et al. Glycyrrhizic Acid-Phospholipid Complex: Preparation Process Optimization and Therapeutic and Pharmacokinetic Evaluation in Rats. Lat Am J Pharm 2011; 30(8): 162130.

23. Воскресенская А. А., Медведева Н. В., Прозоров­ ский В. Н. Особенности всасывания глицирризиновой кислоты в составе лекарственного препарата «Фосфоглив». Биомед химия 2012; 58(5):564-72.

24. Никитин И. Г., Байкова И. Е., Волынкина В. М. и др. Опыт использования глицирризиновой кислоты в лечении пациентов с алкогольной болезнью печени. Рос журн гастроэнтерол гепатол колопроктол 2009; 19(1): 53-8

25. Никитин И. Г., Байкова И. Е., Кисляков В. А. и др. Динамика провоспалительных цитокинов у пациентов с алкогольной болезнью печени на фоне лечения Фосфогливом. Леч дело 2009; 3:66-74 [

26. Тихоновская Е. Ю. Оптимизация терапии неотложных состояний, ассоциированных с приемом этанола, у соматических больных в многопрофильном стационаре: Автореф. дис. … канд. мед. наук: 14.01.04. М.; 2010. 24 с.

27. Мехтиев С. Н. Перспективы комплексной терапии больных алкогольной болезнью печени с выраженными стадиями фиброза. Эффект фармакотер. Гастроэнтерология 2011; 2:15-22

28. Мараховский Ю. Х., Уласевич Д. Н., Саевич Н. И. Оценка эффективности лечения алкогольного гепатита инфузионной формой препарата «Фосфоглив®». Здравоохранение (Минск) 2015; 5:47-52.

29. Винникова М. А., Усманова Н. Н., Ненастьева А. Ю. и др. Эффективность и безопасность препарата «Фосфоглив®» при алкогольной болезни печени: предварительные результаты многоцентрового рандомизированного двойного слепого плацебоконтролируемого исследования «Ягуар» (PHG-M2/P03-12). Клин перспект гастроэнтерол гепатол 2015; 4:23-8.

30. Двойрин В.В., Клименков А.А. Методика контролируемых клинических испытаний. М.: Медицина; 1985.

31. Friedman L. M., Furberg C. D., DeMets D. L. Fundamentals of Clinical Trials. 4th ed. Springer; 2010.

32. Bell H., Tallaksen C. M., Try K., Haug E. Carbohydratedeficient transferrin and other markers of high alcohol consumption: a study of 502 patients admitted consecutively to a medical department. Alcohol Clin Exp Res 1994; 18: 1103-8.

33. Nalpas B., Vassault A., Charpin S. et al. Serum mitochondrial aspartate aminotransferase as a marker of chronic alcoholism: diagnostic value and interpretation in a liver unit. Hepatology 1986; 6: 608-14.

34. Naveau S., Gaude G., Asnacios A. et al. Diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with alcoholic liver disease. Hepatology 2009;49:97-105.

35. Hind I. Fallatah. Noninvasive Biomarkers of Liver Fibrosis: An Overview. Adv Hepatol 2014. Article ID357287. http://dx.doi.org/10.1155/2014/357287

36. Monika Gudowska, Ewa Wojtowicz, Bogdan Cylwik. The Distribution of Liver Steatosis, Fibrosis, Steatohepatitis and Inflammation Activity in Alcoholics According to FibroMax Test. Adv Clin Exp Med 2015; 24(5): 823-7. DOI: 10.17219/acem/28485.

37. Zhai D., Zhao Y., Chen X. et al. Protective effect of glycyrrhizin, glycyrrhetic acid and matrine on acute cholestasis induced by α-naphthyl isothiocyanate in rats. Planta Med 2007 Feb; 73(2): 128-33.

38. Wang Y. G., Zhou J. M., Ma Z. C. et al. Pregnane X receptor mediated-transcription regulation of CYP3A by glycyrrhizin: a possible mechanism for its hepatoprotective property against lithocholic acid-induced injury. Chem Biol Interact 2012; 200(1):11-20. doi: 10.1016/j. cbi.2012.08.023.

39. Winston D., Maimes S. Adaptogens: herbs for strength, stamina and stress relief. Rochester. Vermont: Inner Traditions/Bear & Co; 2007.

40. Rouse J. Herbal Support for Adrenal Function. Clin Nutr Insights 1998; 6(9): 1-2.