Shahira F El MENSHAWE, Amira S. AHMED, Lamiaa N. ABDELATY, Mohamed A. ABOSEİF

Study of Hepatoprotective Effect of Silymarin and Ursodeoxycholic Acid in Chronic Hepatitis C Patients

Hepatitis C virus is a major public health problem causing significant morbidity and mortality. Until recently, the standard treatment with peginterferon and ribavirin was far from being perfect due to its cost, poor tolerability and low sustained virological rates (SVR) rates. Although, the novel direct-acting antiviral agents (DAAs) telaprevir, and boceprevir has dramatically improved SVR rates; issues such as adverse reactions, frequent dosing, and drug interactions still represent a challenge. Even overcoming these challenges with the new revolutionary development of sofosbuvir, its high cost still needs to be addressed. Therefore, the popularity of alternative medicines in chronic hepatitis C (CHC) treatment such as silymarin and ursodeoxycholic acid (UDCA) has increased. The multiple hepatoprotective effects of these drugs have made them attractive for evaluation in patients with different liver diseases. The aim of this study is to compare the hepatoprotective effect of silymarin, UDCA, and a combination therapy of both in chronic hepatitis C patients. Forty CHC patients (32 males and 8 females) were recruited from hepatology clinic at Beni-Suef University. Patients were divided randomly into four equal groups of tens A, B, C and D, who received 420 mg/day silymarin capsules, 500 mg/day UDCA capsules, combined therapy of both, and a placebo treatment, respectively. Serum liver parameters were measured at baseline and repeated 12 weeks after therapy.A statistically significant improvement in mean serum levels of ALT, AST, and bilirubin was obtained with UDCA therapy either when administered alone or combined with silymarin. However, silymarin treatment failed to significantly affect liver function tests.

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1. Tong MJ, El-Farra NS, Reikes AR. Clinical outcomes after transfusion-associated hepatitis C. N Engl J Med. 1995;332(22):1463-6.

2. Seeff LB, Buskell-Bales Z, Wright EC, Durako SJ, Alter HJ, Iber FL, Hollinger FB, Gitnick G, Knodell RG, Perrillo RP, et al. Long-term mortality after transfusion-associated non-A, non-B hepatitis. The National Heart, Lung, and Blood Institute Study Group. N Engl J Med. 1992;327(27):1906-11.

3. Fattovich G, Giustina G, Degos F, Tremolada F, Diodati G, Almasio P, Nevens F, Solinas A, Mura D, Brouwer JT, Thomas H, Njapoum C, Casarin C, Bonetti P, Fuschi P, Basho J, Tocco A, Bhalla A, Galassini R, Noventa F, Schalm SW, Realdi G. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology.1997; 112(2): 463-72.

4. Keating GM, Vaidya A, Sofosbuvir: first global approval. Drugs. 2014;74(2):273- 82.

5. Mohamoud YA, Mumtaz GR, Riome S, Miller D, Abu-Raddad LJ. The epidemiology of hepatitis C virus in Egypt: a systematic review and data synthesis. BMC Infect Dis. 2013;13: 288.

6. Stedman CA. Current prospects for interferon-free treatment of hepatitis C in 2012. J Gastroenterol Hepatol. 2013;28(1):38-45.

7. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, Poordad F, Goodman ZD, Sings HL, Boparai N, Burroughs M, Brass CA, Albrecht JK,

8. Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N, DiNubile MJ, Sniukiene V, Brass CA, Albrecht JK, Bronowicki JP; SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1195- 206.

9. Flamm SL, Commentary: sofosbuvir for treatment of hepatitis C virus genotype 2 or 3 infection in patients without treatment options. Gastroenterol Hepatol (NY). 2013;9(10):682-3.

10. Pockros PJ. Interferon-free hepatitis C therapy: how close are we? Drugs. 2012;72:1825-31.

11.Tanamly MD, Tadros F, Labeeb S, Makld H, Shehata M, Mikhail N, AbdelHamid M, Shehata M, Abu-Baki L, Medhat A, Magder LS, Afdhal NH, Strickland GT. Randomised double-blinded trial evaluating silymarin for chronic hepatitis C in an Egyptian village: study description and 12-month results. Dig Liver Dis. 2004;36(11):752-9.

12. Gentile I, Borgia F, Buonomo AR, Castaldo G, Borgia G. A novel promising therapeutic option against hepatitis C virus: an oral nucleotide NS5B polymerase inhibitor sofosbuvir. Curr Med Chem. 2013;20(30):3733-42.

13. Omar M. Chronic Hepatitis C: A Journey From INF to "INF Free, All Oral" Treatment. Journal of Rawalpindi Medical College (JRMC). 2013;17(1):161-2.

14. Kalantari H, Shahshahan Z, Hejazi SM, Ghafghazi T, Sebghatolahi V.Effects of silybum marianum on patients with chronic hepatitis C. J Res Med Sci. 2011;16(3):287-90.

15. Muriel P, Garciapiña T, Perez-Alvarez V, Mourelle M. Silymarin protects against paracetamol-induced lipid peroxidation and liver damage. J App Toxicol. 1992;12(6):439-42.

16.Ramellini G, Meldolesi J. Stabilization of isolated rat liver plasma membranes by treatment in vitro with silymarin. Arzneimittelforschung. 1974;24(5):806-8.

17.Láng I, Nékám K, Deák G, Müzes G, Gonzales-Cabello R, Gergely P, Csomós G, Fehér J. Immunomodulatory and hepatoprotective effects of in vivo treatment with free radical scavengers. Ital J Gastroenterol. 1990;22(5):283-7.

18. Leuschner U, Dienes H, Guldutuna S. Ursodeoxycholic acid influences immune parameters in patients with primary biliary cirrhosis. Hepatology. 1990;12:A957.

19. Meroni PL, Barcellini W, Borghi MO, Vismara A, Ferraro G, Ciani D, Zanussi C. Silybin inhibition of human T-lymphocyte activation. Int J Tissue React. 1988;10(3):177-81.

20.Boigk G, Stroedter L, Herbst H, Waldschmidt J, Riecken EO, Schuppan D. Silymarin retards collagen accumulation in early and advanced biliary fibrosis secondary to complete bile duct obliteration in rats. Hepatology, 1997;26(3):643- 9.

21. Fuchs EC, Gressne AM, Weyhenmayer R et al. Identification of the antifibrogenic properties of silibinin: effect on TGFb and matrix gene expression of hepatic stellate cells. Hepatology. 1995;22: 286A.

22.Wenzel S. Effects of silibinin and antioxidants on high glucose induced alterations of fibronectin turnover in human mesangial cell cultures. J Pharmacol Exp Ther. 1996;279(3):1520-6.

23. Marcellin P, Asselah T, Boyer N. Fibrosis and disease progression in hepatitis C. Hepatology. 2002;36(5 Suppl 1):S47-56.

24. Ghany MG, Kleiner DE, Alter H, Doo E, Khokar F, Promrat K, Herion D, Park Y, Liang TJ, Hoofnagle JH.Progression of fibrosis in chronic hepatitis C. Gastroenterology. 2003;124(1):97-104.

25. Angulo P. Use of ursodeoxycholic acid in patients with liver disease. Curr Gastroenterol Rep. 2002;4(1):37-44.

26.Ikegami T, Matsuzaki Y. Ursodeoxycholic acid: Mechanism of action and novel clinical applications. Hepatol Res. 2008;38(2):123-31.

27.Lirussi F, Beccarello A, Bortolato L, Morselli-Labate AM, Crovatto M, Ceselli S, Santini G, Crepaldi G. Long-term treatment of chronic hepatitis C with ursodeoxycholic acid: influence of HCV genotypes and severity of liver disease. Liver. 1999;19(5):381-8.

28. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60(8):646-9.

29. NIH/CTCAE. (2009). National Institute of Health; Common Terminology Criteria for Adverse Events v 4.0 http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010- 06-14_QuickReference_5x7.pdf. access date 13.06.2014

30.Wasley A, Alter MJ. Epidemiology of hepatitis C: geographic differences and temporal trends. Semin Liver Dis. 2000;20(1):1-16.

31. Yoshizawa H. Hepatocellular carcinoma associated with hepatitis C virus infection in Japan: projection to other countries in the foreseeable future. Oncology. 2000;62(Suppl 1):8-17.

32.El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med. 2003;139(10):817-23.

33. Mira L, Silva M, Manso CF. Scavenging of reactive oxygen species by silibinin dihemisuccinate. Biochem Pharmacol. 1994;48(4):753-9.

34.Wagoner J, Negash A, Kane OJ, Martinez LE, Nahmias Y, Bourne N, Owen DM, Grove J, Brimacombe C, McKeating JA, Pécheur EI, Graf TN, Oberlies NH, Lohmann V, Cao F, Tavis JE, Polyak SJ. Multiple effects of silymarin on the hepatitis C virus lifecycle. Hepatology. 2010;51(6):1912-21.

35. Nakagawa S, Makino I, Ishizaki T, Dohi I. Dissolution of cholesterol gallstones by ursodeoxycholic acid. Lancet. 1977;2(8034):367-9.

36.Bateson MC, Ross PE, Diffey BL. Ursodeoxycholic acid in primary biliary cirrhosis. Lancet. 1989;1(8643):898-9.

37. Poupon R, Poupon RE. Ursodeoxycholic acid therapy of chronic cholestatic conditions in adults and children. Pharmacol Ther. 1995;66(1):1-15.

38.Beuers U, Boyer JL, Paumgartner G. Ursodeoxycholic acid in cholestasis: Potential mechanisms of action and therapeutic applications. Hepatology. 1998;28(6):1449-53.

39. Heathcote EJ, Cauch-Dudek K, Walker V, Bailey RJ, Blendis LM, Ghent CN, Michieletti P, Minuk GY, Pappas SC, Scully LJ, et al. The Canadian multicenter double blind randomized controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology. 1994;19(5):1149-56.

40.Lindor KD, Dickson ER, Baldus WP, Jorgensen RA, Ludwig J, Murtaugh PA, Harrison JM, Wiesner RH, Anderson ML, Lange SM, et al. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology. 1994;106(5):1284- 90.

41.Lindor KD, Therneau TM, Jorgensen RA, Malinchoc M, Dickson ER. Effects of ursodeoxycholic acid on survival in patients with primary biliary cirrhosis. Gastroenterology. 1996;110(5):1515-8.

42. Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R, Heathcote EJ. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology. 1997;113(3):884-90.

43.Laurin J, Lindor KD, Crippin JS, Gossard A, Gores GJ, Ludwig J, Rakela J, McGill DB. Ursodeoxycholic acid or clo®brate in the treatment of non-alcoholinduced steatohepatitis: a pilot study. Hepatology 1996;23(6):1464-7.

44.Bellentani S, Podda M, Tiribelli C, Callea F, Marazzi M, Sodde M, Merlini R, Batezzati PM, Crosignani A, Zuin M, et al. Ursodiol in the long- term treatment of chronic hepatitis: a double-blind multi- center clinical trial. J Hepatol. 1993;19(3):459-64.

45. Gordon A, Hobbs DA, Bowden DS, Bailey MJ, Mitchell J, Francis AJ, Roberts SK. Effects of silybum marianum on serum hepatitis C virus RNA, alanine aminotransferase levels and well-being in patients with chronic hepatitis C. J Gastroenterol Hepatol. 2006;21(1 Pt 2):275-80.

46. Yoshizawa H. Hepatocellular carcinoma associated with hepatitis C virus infection in Japan: projection to other countries in the foreseeable future. Oncology. 2000;62(Suppl 1):8-17.

47. Omata M, Yoshida H, Toyota J, Tomita E, Nishiguchi S, Hayashi N, Iino S, Makino I, Okita K, Toda G, Tanikawa K, Kumada H; Japanese C-Viral Hepatitis Network. A large-scale, multicentre, double blind trial of ursodeoxycholic acid in patients with chronic hepatitis C. Gut. 2007;56(12):1747-53.

48.Liu J, Manheimer E, Tsutani K, Gluud C. Medicinal herbs for hepatitis C virus infection. Cochrane Database Systematic Rev. Am J Gastroenterol. 2003;98(3):538-44.

49.Takano S, Ito Y, Yokosuka O, Ohto M, Uchiumi K, Hirota K, Omata M. A multicenter randomized controlled dose study of ursodeoxycholic acid for chronic hepatitis C. Hepatology. 1994;20(3):558-64.

50. Mayer KE, Myers RP, Lee SS. Silymarin treatment of viral hepatitis: a systematic review. J Viral Hepat. 2005;12(6):559-67.

51. Nojiri S, Nakao H, Sugauchi F, Miyaki T, Senda K, Sasaki M, Kataoka H, Kamiya T, Nakazawa T, Ohara H, Orito E, Joh T. Effect of ursodeoxycholic acid on serum liver enzymes and bile acid metabolism in chronic active hepatitis C virus infection. Hepatol Res. 2009;39(1):21-30.

52. Marcellin P, Asselah T, Boyer N. Fibrosis and disease progression in hepatitis C. Hepatology. 2002;36(5 Suppl 1):S47-56.

53.Tarao K, Rino Y, Ohkawa S, Tamai S, Miyakawa K, Takakura H, Endo O, Yoshitsugu M, Watanabe N, Matsuzaki S. Close association between high serum alanine aminotransferase levels and multicentric hepatocarcinogenesis in patients with hepatitis C virus associated cirrhosis. Cancer. 2002;94(6):1787-95.

54. Schopen RD, Lange OK, Panne C, Kirnberger EJ. Searching for a new therapeutic principle. Experience with hepatic therapeutic agent Legalon. Med. Welt. 1969;20(15):888-93.

55. El-Kamary SS, Shardell MD, Abdel-Hamid M, Ismail S, El-Ateek M, Metwally M, Mikhail N, Hashem M, Mousa A, Aboul-Fotouh A, El-Kassas M, Esmat G, Strickland GT. A randomized controlled trial to assess the safety and efficacy of silymarin on symptoms, signs and biomarkers of acute hepatitis. Phytomedicine. 2009;16(5):391-400.