INFLUENCE OF THE COMBINATION OF URSODEOXYCHOLIC ACID AND PENTOXYPHILLINE ON EXPERIMENTAL LIVER FIBROSIS

Hepatic fibrosis is a common result of different chronic liver diseases. Fibrosis is a dynamic process which can progress to complication, including cirrhosis, hepatocellular carcinoma, and liver failure. Considering the significance of problem, the search for a new effective substance with hepatoprotective and antifibrotic effects on liver fibrosis is an actual task.

The aim of the study was to investigate the influence of fixed-dose combination (FDC) containing ursodeoxycholic acid (UDCA) 350 mg and pentoxifylline (PTX) 150 mg on the development of carbon tetrachloride (CCL4 )-induced liver fibrosis in rats. The obtained results showed that FDC effectively reduced elevated serum markers enzyme activities, the hepatic hydroxyproline content, decreased levels of proinflammatory and profibrogenic cytokines. The histopathological analysis showed that FDC alleviated the severity of liver fibrosis induced by CCl4 . A high dose of FDC had the most positive effect.

Thus, the obtained results suggested that FDC has a sufficiently high therapeutic potential, demonstrating antifibrotic, antiinflammatory and hepatoprotective activities on experimental liver fibrosis. 

1. Bataller R., Brenner D. A. Liver fibrosis. Journal of Clinical Investigation, 2005, vol. 115, pp. 209–218. DOI: 10.1172/ JCI24282

2. Poynard T. A., Mathurin P., Lai C. L., Guyader D., Poupon R. A comparison of fibrosis progression in chronic liver diseases. Journal of Hepatology, 2003, vol. 38, pp. 257–265.

3. Mormone E., George J., Nieto N. Molecular pathogenesis of hepatic fibrosis and current therapeutic approaches. Chemico-Biological Interactions, 2011, vol. 193, no. 3, pp. 225–231. DOI: http://dx.doi.org/101155/2015/943497

4. Zatonsky W. A., Sulkovska U., Manczuk M. Liver cirrhosis mortality in Europe, with special attention to Central and Eastern Europe. European Addiction Research Journal, 2010, vol. 16, no. 4, pp. 193–201. DOI: 1159/000317248

5. Mortality in Repeblic of Belarus. An official statistics collection, 2014–2015. Minsk, Respublikanskaya meditsinskaya nauchnaya biblioteka [Republican Scientific Medical Library], 2016. 208 p. (in Russian).

6. Ivashkin V. Т., Maevskaja M. V. Treatment of liver cirrhosis complications. Мoscow, Litterra Publ., 2011, 64 p. (in Russian).

7. Parsons C. J., Takashima M., Rippe R. A. Molecular mechanisms of hepatic fibrogenesis. Journal of Gastroenterology and Hepatology, 2007, vol. 22, suppl. 1, pp. 79–84. DOI: 10.1111/j.1440–1746.2006.04659.x

8. Lemos Q. T., Andrade Z. A. Angiogenesis and experimental hepatic fibrosis. Memorias do Instituto Oswaldo Cruz, 2010, vol. 105, no. 5, pp. 611–614.

9. Tsochatzis E. A., Bosch J., Burroughs A. K. Liver cirrhosis. Lancet, 2014, vol. 383, pp. 1749–1761. DOI: 10.1016/ S0140–6736(14)60121–5

10. Bonis P. A., Friedman S. L., Kaplan M. M. Is liver fibrosis reversible? The New England Journal of Medicine, 2001, vol. 344, pp. 452–454. DOI: 10.1136/gut. 46.4.443

11. Liaw Y.F. Reversal of cirrhosis: an achievable goal of hepatitis B antiviral therapy. Journal of Hepatology, 2013, vol. 59, pp. 880–881. DOI: https://doi.org/10.3904/kjim.2016.268

12. Ellis E. L., Mann D. A. Clinical evidence for the regression of liver fibrosis. Journal of Hepatology, 2012, vol. 56, no. 5, pp. 1171–1180.

13. Kang Q., Chen A. Curcumin suppresses expression of low-density lipoprotein (LDL) receptor, leading to the ingibition of LDL-induced activation of hepatic stellate cells. British Journal of Pharmacology, 2009, vol. 157, no. 8, pp. 1354–1367. DOI: 10.1111/j.1476–5381.2009.00261.x

14. Hirschfield G. M., Invernizzi P. Progress in the genetics of primary biliary cirrhosis. Seminars in Liver Disease, 2011, vol. 31, no. 2, pp. 147–156.

15. Ishibashi H., Komori A., Shimoda S., Ambrosini Y. M., Gershwin M. E., Nakamura M. Risk factors and prediction of long-term outcome in primary biliary cirrhosis. Internal Medicine, 2011, vol. 50, no. 1, pp. 1–10.

16. Shirokova E. N., Kuznetcova Ye. L., Mayevskaya M. V. Effective of ursodeoxycholic acid acid in the treatment of patients with cholestatic form of alcoholic liver disease and primary biliary cirrhosis. Russian Journal of Gastroenterology, Hepatology, Coloproctology, 2007, no. 3, pp. 52–58 (in Russian).

17. Harnois D. M., Angulo P., Jorgensen R. A., Larusso N. F., Lindor K. D. High dose ursodeoxycholic acid as a therapy for patients with primary sclerosing cholangitis. American Journal of Gastroenterology, 2001, vol. 96, pp. 1558–1562.

18. Xiang Z., Chen Y. P., Ma K. F. The role of ursodeoxycholic acid in non-alcoholic steatohepatitis. BMC Gastroenterology, 2013, vol. 13, no. 1, p. 140. DOI: 10.1186/1471–230X-13–140

19. Sha M., Callahan C. The efficacy of pentoxifylline in the treatment of vascular dementia. Alzheimer Disease and Associated Disorders, 2003, vol. 17, no. 1, pp. 46–54. DOI: 10.1097/00002093–200301000–00006

20. Kamchatnov P. R., Radysh B., Glushkov K. S., B. Chugunov A. V. Chronic cerebrovascular disorders – modern approaches to treatment. Russkij medicinskij zhurnal [Russian Medical Journal], 2008, vol. 16, no. 6, pp. 358–361 (in Russian).

21. Ocunieff P., Augustine E., Hicks J., Cornelison T. L., Altemus R. M., Naydich B. G., Ding I., Huser A. K., Abraham E. H., Smith J. J., Coleman N., Gerber L. H. Pentoxifylline in the treatment of radiation-induced fibrosis. Journal of Clinical Oncology, 2004, vol. 22, no. 11, pp. 2207–2213.

22. O’Shea R. S., Dasarathy S., McCullough A. J. Alcoholic liver disease. Journal of Hepatology, 2010, vol. 51, no. 1, pp. 307–328. DOI: 10.1002/hep.23258

23. Satapathy S. K., Garg S., Chauhan R., Sakhuja P., Malhotra V., Sharma B. C. Beneficial effects of tumor necrosis factor-alpha inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis. American Journal of Gastroenterology, 2004, vol. 99, no. 10, pp. 1946–1952. DOI: 10.1111/j.1440–1746.2006.04756.x

24. Rokey D. C. Antifibrotic therapy in chronic liver desease. Clinical Gastroenterology and Hepatology, 2005, vol. 3, no. 2, pp. 95–107.

25. Avtandilov G. G. Introduction to quantitative pathological morphology. Мoscow, Меdicine, 1980. 216 p. (in Russian).

26. Cho J. J., Hocher B., Herbst H., Jia J. D., Ruehl M., Hahn E. G., Riecken E. O., Schuppan D. An oral endothelin-A receptor antagonist blocks collagen synthesis and deposition in advanced rat liver fibrosis. Journal of Gastroenterology, 2000, vol. 118, no. 6, pp. 1169–1178. DOI: http://dx.doi.org/10.1016/S0016–5085(00)70370–2

27. Buko V. U., Lukivskaya O. Y., Naruta E. E., Belonovskaya E. B., Tauschel H. D. Protective effects of norursodeoxycholic acid versus ursodeoxycholic acid on thioacetamide-induced rat liver fibrosis. Journal of Clinical and Experimental Hepatology, 2014, vol. 4, no. 4, pp. 293–301. DOI: 10.1016/j.jceh.2014.02.001

28. Mas N., Tasci I., Comert B., Ocal R., Mas M. R. Ursodeoxycholic acid treatment improves hepatocyte ultrastructure in rat liver fibrosis. World Journal of Gastroenterology, 2008, vol. 14, no. 7, pp. 1108–1111. DOI: 10.3748/wjg.14.1108

29. Buko V. U., Popov Y. V., Lis R. E., Zaks J., Schuppan D., Lukivskaya O. Y. Resolution of thioacetamide induced liver fibrosis in rats treated with pentoxifylline. Journal of Hepatology, 2007, vol. 46, suppl. 1, S80.

30. Raetsch C., Jia J. D., Boigk G., Bauer M., Hahn E. G., Riecken E. O., Schuppan D. Pentoxifylline downregulates profibrogenic cytokines and procollagen I expression in rat secondary billiary fibrosis. Gut, 2002, vol. 50, no. 2, pp. 241–247.