Efficacy and safety of glycyrrhizic acid combined to essential phospholipids (Phosphogliv) at non-alcoholic fatty liver disease: results of multicenter double blind randomized placebo-controlled post-registration clinical study (IV phase) «Gepard» (PHG-M2/P02-12)

Aim of investigation. To estimate efficacy and safety of two pharmacological forms of «Phosphogliv» (lyophilizate for intravenous administration and capsules) for the treatment of fatty liver degeneration of non-alcoholic etiology. Material and methods. Original study included overall 180 patients with nonalcoholic fatty liver disease that were randomized to the basic and control groups in the ratio of 2:1. The basic group patients received Phosphogliv 5 mg/day as intravenous bolus injection for 2 weeks, followed by oral intake of 2 capsules t.i.d. for 10 weeks (the total treatment duration was 12 weeks), control group patients received placebo in the same mode. Serum levels of inflammatory marker adiponectin, NAFLD fibrosis score, treatment effect on quality of life and safety of patients were monitored. Results. In 12 wks in patients with more significant cytolysis (threefold and higher serum alanine transaminase activity) and the rate of adiponectin level improvement on the background of Phosphogliv was 57.9% versus only 10.0% (p=0.019) in the placebo group. The mean NAFLD fibrosis score in the basic group remained almost unchanged, while in the control group negative dynamics was revealed, that resulted in statistically significant differences between groups (2.5±1.2 units versus 2.0±1.3 units respectively; р=0.009). At Phosphogliv injection already during the first 2 wks more pronounced improvement of subjective perception of dyspeptic symptoms was observed (mean score was 5.6±1.3 versus 5.1±1.4; р=0.021). When the treatment course was completed the basic group patients had higher mean score by «level of energy» scale (5.9±1.0 versus 5.6±1.0; р=0.034). Only sporadic adverse effects were found to the background of treatment, no statistically significant differences in their rate in were recorded. Dynamics of the basic physical parameters and laboratory tests was comparable as well. Conclusions. Treatment of non-alcoholic fatty liver disease that includes Phosphogliv provides reduction of steatohepatitis activity, retardation of fibrosis progression, improvement of overall disease prognosis and high satisfaction of patients at a favorable safety profile.

Фосфоглив, гепатопротектор, неалкогольная жировая болезнь печени, воспаление, фиброз, качество жизни

1. Younossi Z.M., Koenig A.B., Abdelatif D. et al. Global Epidemiology of Non-Alcoholic Fatty Liver DiseaseMeta-Analytic Assessment of Prevalence, Incidence and Outcomes. Hepatology 2015. doi: 10.1002/hep.28431.

2. Ивашкин В.Т., Драпкина О.М., Маев И.В. и др. Распространенность неалкогольной жировой болезни печени у пациентов амбулаторно-поликлинической практики в Российской Федерации: результаты исследования DIREG 2. Рос журн гастроэнтерол гепатол колопроктол 2015; 6:31-41.

3. Buzzetti E., Pinzani M., Tsochatzis E.A. The multiplehit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 2016. doi.org/10.1016/j. metabol.2015.12.012.

4. Sun Xiao-peng, Shi Ran-ran, Yuan Xue-qiang. Effect of glycyrrhizin on expression of TNF-a, IL-1 and IL-6 in adjuvant arthritis rat. Heilongjiang Med Pharm 2011: http://en.cnki.com.cn/Article_en/CJFDTOTAL- KXJY201101015.htm.

5. Asl M.N., Hosseinzadeh H. Review of pharmacological effects of Glycyrrhiza sp. And its bioactive compounds. Phytother Res 2008 Jun; 22(6):709-24.

6. Moro T., Shimoyama Y., Kushida M., Hong Y.Y., Nakao S., Higashiyama R. et al. Glycyrrhizin and its metabolite inhibit Smad3-mediated type I collagen gene transcription and suppress experimental murine liver fibrosis. Life Sci 2008 Oct 10;83(15-16):531-9.

7. Ивашкин В.Т., Маевская М.В., Павлов Ч.С. 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; 2:24-42.

8. 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):1621-30.

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

10. Гейвандова Н.И., Белова Н.Г., Фалеева О.В. и др. Клинико-патогенетическое значение некоторых показателей воспаления и возможности их фармакологической коррекции у больных неалкогольной жировой болезнью печени. Мед вестн Северного Кавказа 2009; 2:25-30.

11. Вьючнова Е.С., Маев И.В., Бабина С.М. Эффективность эссенциальных фосфолипидов в лечении больных с неалкогольным стеатогепатитом. Клин перспект гастроэнтерол гепатол 2010; 3:3-11.

12. Недогода С.В., Санина Т.Н., Почепцов Д.А. Алгоритм выбора терапии при неалкогольном гепатите на фоне метаболического синдрома. Вестн ВолгГМУ 2013; 2(46):92-5.

13. Мойсеенко В.А., Манжалий Э.Г. Возможности применения препарата «Фосфоглив» в лечении стеатогепатита с сопутствующим хроническим колитом. Сучасна гастроентерологiя 2014; 2(76):107-14.

14. Недогода С.В., Чумачек Е.В., Санина М.С. и др. Препарат «Фосфоглив®» в терапии неалкогольной жировой болезни печени: предварительные результаты многоцентрового рандомизированного двойного слепого плацебоконтролируемого исследования «Гепард» (PHGM2/P02-12). Клин перспект гастроэнтерол гепатол 2015; 5:16-22.

15. Browning J.D., Szczepaniak L.S., Dobbins R. et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 6(40):1387-95.

16. Torres D.M., Harrison S.A. Diagnosis and therapy of nonalcoholic steatohepatitis. Gastroenterology 2008; 6(134):1682-98.

17. Mofrad P., Contos M.J., Haque M. et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 2003; 6(37): 1286-292.

18. Fracanzani A.L., Valenti L., Bugianesi E. et al. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes. Hepatology 2008; 3(48): 792-8.

19. Buechler C., Wanninger J., Neumeier M. Adiponectin, a key adipokine in obesity related liver diseases. World J Gastroenterol 2011.21; 17(23):2801-11. doi: 10.3748/wjg. v17.i23.2801.

20. Jarrar M.H., Baranova A., Collantes R. et al. Adipokines and cytokines in non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2008;27:412-21. doi: 10.1111/j.13652036.2007.03586.x.

21. Argentou M., Tiniakos D.G., Karanikolas M. et al. Adipokine serum levels are related to liver histology in severely obese patients undergoing bariatric surgery. Obes Surg 2009:9(19):1313-23.

22. Angulo P., Hui J.M., Marchesini G. et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007; 45:846-54. Doi: 10.1002/hep.21496.

23. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64:1388-402. DOI: http://dx.doi.org/10.1016/j. jhep.2015.11.004.

24. Treeprasertsuk S., Björnsson E., Enders F. et al. NAFLD fbrosis score: A prognostic predictor for mortality and liver complications among NAFLD patients. World J Gastroenterol 2013; 19(8):1219-29. doi:10.3748/wjg.v19. i8.1219.

25. Younossi Z.M., Guyatt G., Kiwi M. et al. Development of a disease specific questionnaire to measure health related quality of life in patients with chronic liver disease. Gut 1999; 45:295-300.

26. Winston D., Maimes S. Adaptogens herbs for strength, stamina and stress relief. Vermont: Healing Arts Press. Rochester; 2007.