Promising new fixed combination for the treatment of diseases of the hepatobiliar system: Substantiation of pharmacotherapeutic properties and pharmaceutical quality profile

Keywords: ursodeoxycholic acid; artichoke; taurine; Angelica sinensis; clinical trials; pharmaceutical quality


In this review article an analysis of literature data on the pharmacological and clinical study of a fixed combination of medicinal substances (artichoke leaf extract, ursodeoxycholic acid, taurine, and Angelica sinensis roots extract), as well a scientific substantiation of the pharmaceutical quality profile of the corresponding finished solid dosage form has been conducted. Chronic diseases of the hepatobiliary system are some of the most common human diseases and inferior only to atherosclerosis . The fact that cholecystectomy is the most common surgical operation in the abdominal organs is evidenced by the widespread distribution of the pathology of the biliary system. The fact that there is an increasing number of diagnoses of cholelithiasis in children and infants is a cause for concern. Diseases of the biliary system are closely related to violations of the functional state of the liver. Synthesis of cholesterol supplemented bile with reduced bile acid content significantly increases the risk of gallstones, as well as gallbladder cholesterol. We have substantiated that the developed preparation is a fixed combination of medicinal substances with well-researched medical applications in the treatment of dyspeptic disorders with functional disorders of the biliary system, biliary dyskinesia of the hypokinetic type, and gastritis with reflux of bile. Each of the components of the fixed combination has an important influence on the human hepatobiliary system. The effect of ursodeoxycholic acid is due to the relative replacement of lipophilic toxic bile acids, improving the secretory capacity of hepatocytes and immunoregulatory processes, which is especially important in liver and cholestatic diseases. Taurine is a synergist of ursodeoxycholic acid, since it forms biliary conjugates in the liver. The artichoke extract has choleretic, hepatoprotective and diuretic effects, while the A. sinensis roots extract demonstrates moderate spasmolytic and anti-inflammatory properties. We conducted a general description of active pharmaceutical ingredients and a review of biopharmaceutical tests, analyzed relevant pharmacokinetic and pharmacodynamic studies, and summarized the results of clinical efficacy and safety trials. Particular attention is paid to the results of clinical studies of the developed fixed combination. It should be noted that artichoke leaf extract, ursodeoxycholic acid, and taurine are widely used throughout the world in official medicine, at the same time, A. sinensis roots extract is more widely used in traditional Chinese medicine. The fixed combination has a favorable safety profile, is investigated in clinical conditions in vivo both in the form of individual components and in the form of a single drug. A fixed combination pharmaceutical profile is based on the general requirements for solid dosage forms, as well as experimentally substantiated specific indicators and research methods.


Abebe, W. (2002). Herbal medication: Potential for adverse interactions with analgesic drugs. Journal of Clinical Pharmacy and Therapeutics, 27, 391–401.

Aerts, L., & Van Assche, F. A. (2002). Taurine and taurine-deficiency in the perinatal period. The Journal of Perinatal Medicine, 30(4), 281–286.

Alberts, D. S., Martínez, M. E., Hess, L. M., Einspahr, J. G., Green, S. B., Bhattacharyya, A. K., Guillen, J., Krutzsch, M., Batta, A. K., Salen, G., Fales, L., Koonce, K., Parish, D., Clouser, M., Roe, D., & Lance, P. (2005). Phase III trial of ursodeoxycholic acid to prevent colorectal adenoma recurrence. Journal of the National Cancer Institute, 97(11), 846–853.

Amaral, J. D., Viana, R. J. S., Ramalho, R. M., Steer, C. J., & Rodrigues, C. M. P. (2009). Bile acids: Regulation of apoptosis by ursodeoxycholic acid. Journal of Lipid Research, 50(9), 1721–1734.

Angulo, P., Dickson, E. R., Therneau, T. M., Jorgensen, R. A., Smith, C., DeSotel, C. K., Lange, S. M., Anderson, M. L., Mahoney, D. W., & Lindor, K. D. (1999). Comparison of three doses of ursodeoxycholic acid in the treatment of primary biliary cirrhosis: A randomized trial. Journal of Hepatology, 30(5), 830–835.

Anokhina, G. A., Kharchenko, V. V., Opanasiuk, N. D., Lopukh, I. Y., & Yakubovska, I. O. (2014). Some aspects of the use of preparations of ursodeoxycholic acid, combined with plant extracts, in the treatment of the diseases of the hepatobiliary system. Modern Gastroenterology, 1, 49–54 (in Russian).

Azuma, K., Ippoushi, K., Nakayama, M., Ito, H., Higashio, H., & Terao, J. (2000). Absorption of chlorogenic acid and caffeic acid in rats after oral administration. Journal of Agricultural and Food Chemistry, 48, 5496–5500.

Babak, O. Y., Frolov, V. M., & Fadeenko, U. D. (2006). Influence of the combination of articholes and vitamin E on the state of lipid peroxidation in patients with non-alcoholic steatohepatitis, combined with chronic noncalculous cholecystitis, against secondary immunodeficiency states. Problems of Ecological and Medical Genetics and Clinical Immunology, 6(75), 111–118 (in Ukrainian).

Barrat, E., Zaïr, Y., Sirvent, P., Chauveau, P., Maudet, C., Housez, B., Derbord, E., Lescuyer, J. F., Bard, J. M., Cazaubiel, M., & Peltier, S. L. (2013). Effect on LDL-cholesterol of a large dose of a dietary supplement with plant extracts in subjects with untreated moderate hypercholesterolaemia: A randomised, double-blind, placebo-controlled study. European Journal of Nutrition, 52(8), 1843–1852.

Battezzati, P. M., Podda, M., Bianchi, F. B., Naccarato, R., Orlandi, F., Surrenti, C., Pagliaro, L., & Manenti, F. (1993). Ursodeoxycholic acid for symptomatic primary biliary cirrhosis. Preliminary analysis of a double-blind multicenter trial. Italian Multicenter Group for the Study of UDCA in PBC. Journal of Hepatology, 17(3), 332–338.

Ben Salem, M., Ben Abdallah Kolsi, R., Dhouibi, R., Ksouda, K., Charfi, S., Yaich, M., Hammami, S., Sahnoun, Z., Mounir Zeghal, K., Jamoussi, K., & Affes, H. (2017). Protective effects of Cynara scolymus leaves extract on metabolic disorders and oxidative stress in alloxan-diabetic rats. BMC Complementary and Alternative Medicine, 17, 328.

Betancor-Fernández, A., Pérez-Gálvez, A., Sies, H., & Stahl, W. (2003). Screening pharmaceutical preparations containing extracts of turmeric rhizome, artichoke leaf, devil’s claw root and garlic or salmon oil for antioxidant capacity. Journal of Pharmacy and Pharmacology, 55(7), 981–986.

Beuers, U., Trauner, M., Jansen, P., & Poupon, R. (2015). New paradigms in the treatment of hepatic cholestasis: From UDCA to FXR, PXR and beyond. Journal of Hepatology, 62(1), S25–S37.

Blikhar, V. I., Chumak, V. T., Maltsev, V. I., Morozov, A. M., Parii, V. D., Stepanenko, A. V., & Dumenko, T. M. (2012). State form of medicines. 4th ed. State Expert Center of Ukraine.

Borum, M., & Fromm, D. H. (1990). Expression of HLA molecules on hepatocytes: Does ursodeoxycholic acid prevent immunologic injurY? Gastroenterology, 99(2), 561–562.

Buko, V. U., Lukivskaya, O. Y., Naruta, E. E., & Belonovskaya, E. B. (2014). Horst-dietmar tauschel, protective effects of norursodeoxycholic acid versus ursodeoxycholic acid on thioacetamide-induced rat liver fibrosis. Journal of Clinical and Experimental Hepatology, 4(4), 293–301.

Bundy, R., Walker, A. F., Middleton, R. W., Marakis, G., & Booth, J. C. (2004). Artichoke leaf extract reduces symptoms of irritable bowel syndrome and improves quality of life in otherwise healthy volunteers suffering from concomitant dyspepsia: A subset analysis. Journal of Alternative and Complementary Medicine, 10(4), 667–669.

Chan, W. K., Ida, N. H., Cheah, P. L., & Goh, K. L. (2014). Progression of liver disease in non-alcoholic fatty liver disease: A prospective clinicopathological follow-up study. Journal of Digestive Diseases, 15, 545–552.

Chen, W., & Gluud, C. (2003). Bile acids for primary sclerosing cholangitis. Cochrane database of systematic reviews, 2, CD003626.

Chen, X. D., Zhao, S. M., Hua, X. Y., & Yu, H. (2010). Angelica effects on proliferation and differentiation of neural stem cells from neonatal rats with intrauterin hypoxia. Journal of Clinical Rehabilitative Tissue Engineering Research, 14(27), 5050–5053.

Cheng, K., Ashby, D., & Smyth, R. L. (2012). Ursodeoxycholic acid for cystic fibrosis-related liver disease. Cochrane Database Systematic Reviews, 10, CD000222.

Chernobrovy, V. M. (2013). Bile reflux gastritis and esophagitis: The urgent questions of treatment with Ukrliv – ursodeoxycholic acid (future trends in diagnosis using 24-hour multichannel intraluminal impedance-pH-monitoring). Modern Gastroenterology, 2, 47–53 (in Ukrainian).

Chesney, R. W. (1985). Taurine: Its biological role and clinical implications. Advances in Pediatrics, 32, 1–42.

Chhabra, S. K., Ahmed, Z., Massey, A., Agarwal, S., Vij, V., Agarwal, B., Vij, V., Agarwal, B., Kankaria, J., & Jenaw, R. K. (2016). Laparoscopic cholecystectomy in a 2 year old male child with choleilithiasis and recurrent right hypochondrial pain: Case report and review of literature. International Journal of Surgery Case Reports, 26, 142–145.

Coats, M., & Shimi, S. M. (2015). Cholecystectomy and the risk of alimentary tract cancers: A systematic review. World Journal of Gastroenterology, 21(12), 3679–3693.

Colombo, C., Battezzati, P. M., Podda, M., Bettinardi, N., & Giunta, A. (1996). Ursodeoxycholic acid for liver disease associated with cystic fibrosis: A double-blind multicenter trial. The Italian Group for the Study of Ursodeoxycholic Acid in Cystic Fibrosis. Hepatology, 23(6), 1484–1490.

Cong, W. M., Dong, H., Tan, L., Sun, X. X., & Wu, M. C. (2011). Surgicopathological classification of hepatic space-occupying lesions: A single-center experience with literature review. World Journal of Gastroenterology: WJG, 17(19), 2372–2378.

Crosignani, A., Battezzati, P. M., Setchell, K. D., Invernizzi, P., Covini, G., Zuin, M., Podda, M. (1996). Tauroursodeoxycholic acid for treatment of primary biliary cirrhosis. A dose-response study. Digestive Diseases and Sciences, 41(4), 809–815.

De la Puerta, C., Arrieta, F. J., Balsa, J. A., Botella-Carretero, J. I., Zamarrón, I., & Vázquez, C. (2010). Taurine and glucose metabolism: A review. Nutrición Hospitalaria, 25(6), 910–919.

De Luca, A., Pierno, S., & Camerino, D. C. (2015). Taurine: The appeal of a safe amino acid for skeletal muscle disorders. Journal of Translational Medicine, 13, 243.

Dhami, N., Dev Mishra, A. (2015). Phytochemical variation: How to resolve the quality controversies of herbal medicinal products? Journal of Herbal Medicine, 5(2), 118–127.

Dilger, K., Hohenester, S., Winkler-Budenhofer, U., Bastiaansen, B. A., Schaap, F. G., Rust, C., & Beuers, U. (2012). Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and health. Journal of Hepatology, 57(1), 133–140.

Dong, W. G., Liu, S. P., Zhu, H. H., Luo, H. S., & Yu, J. P. (2004). Abnormal function of platelets and role of angelica sinensis in patients with ulcerative colitis. World Journal of Gastroenterology, 10(4), 606–609.

Dymowski, W. (2013). Assessment report on Angelica sinensis (Oliv.) Diels, radix. EMA/HMPC/614586/2012. Committee on Herbal Medicinal Products, European Medicines Agency, United Kingdom, London.

Englisch, W., Beckers, C., Unkauf, M., Ruepp, M., & Zinserling, V. (2000). Efficacy of artichoke dry extract in patients with hyperlipoproteinemia. Arzneimittelforschung, 50(3), 260–265.

Fang, C., Filipp, F. V., & Smith, J. W. (2012). Unusual binding of ursodeoxycholic acid to ileal bile acid binding protein: role in activation of FXRα. Journal of Lipid Research, 53(4), 664–673.

Fang, L., Xiao, X., Liu, C., & He, X. (2012). Recent advance in studies on Angelica sinensis. Chinese Herbal Medicines, 4(1), 12–25.

Ferracane, R., Pellegrini, N., Visconti, A., Graziani, G., Chiavaro, E., Miglio, C., & Fogliano, V. (2008). Effects of different cooking methods on antioxidant profile, antioxidant capacity, and physical characteristics of artichoke. Journal of Agricultural and Food Chemistry, 56(18), 8601–8608.

Frolov, V. M., Garnik, T. P., & Peresadin, M. O. (2009). Effect of phyto-preparations from artichokes of barbed on lipo peroxidation indices in patients with non-alcoholic steatohepatitis, combined with chronic noncalculous cholecystitis and obesity. Ukrainian Medical Almanac, 12(4), 185–191 (in Ukrainian).

Galkin, A. Y., & Kotov, A. G. (2011). Development of quality control methods and analysis of herbal preparation for treatment and prevention of alopecia. Ukrainian Journal of Clinical and Laboratory Medicine, 6(2), 115–119 (in Ukrainian).

Galkin, A. Y., Solovjova, V. F., & Dugan, A. M. (2013). Anti-inflammatory and immunomodulating properties of the herbal preparation indicated for prevention and treatment of alopecia. Botanics: Targets and Therapy, 3, 49–55.

Gan, T., Liu, Y. D., Wang, Y., & Yang, J. (2010). Traditional chinese medicine herbs for stopping bleeding from haemorrhoids. Cochrane Database of Systematic Reviews, 10, CD006791.

Gebara, E., Udry, F., Sultan, S., & Toni, N. (2015). Taurine increases hippocampal neurogenesis in aging mice. Stem Cell Research, 14(3), 369–379.

Gérard, P. (2014). Metabolism of cholesterol and bile acids by the gut microbiota. Pathogens, 3(1), 14–24.

Ghandforoush-Sattari, M., Mashayekhi, S., Krishna, C. V., Thompson, J. P., & Routledge, P. A. (2010). Pharmacokinetics of oral taurine in healthy volunteers. Journal of Amino Acids, 2010, ID 346237.

Giacosa, A., Guido, D., Grassi, M., Riva, A., Morazzoni, P., Bombardelli, E., Perna, S., Faliva, M. A., & Rondanelli, M. (2015). The effect of ginger (Zingiber officinalis) and artichoke (Cynara cardunculus). Extract supplementation on functional dyspepsia: A randomised, double-blind, and placebo-controlled clinical trial. Evidence-Based Complementary and Alternative Medicine, 915087.

Gontova, T., Ilyinska, N., Golembiovska, O., & Mashtaler, V. (2016). A study of the component composition of phenolic compounds obtained from Dahlia varieties. Der Pharma Chemica, 8(18), 455–459.

Gorchakova, N. A., Bondarenko, L. B., & Galkin, A. J. (2017). Grounds of ursodeoxycholic acid, taurine and extractum folii artishoke combine use safety in the hepatobiliar system diseases. Phytotherapy, 2, 10–14 (in Ukrainian).

Grohmann, M. (1987). The activity of the neuronal and extra neuronal catecholamine-metabolizing enzymes of the perfused rat heart. Naunyn-Schmiedeberg’s Archives of Pharmacology, 336, 139–147.

Gu, Y., Zhao, Y., Qian, K., & Sun, M. (2015). Taurine attenuates hippocampal and corpus callosum damage, and enhances neurological recovery after closed head injury in rats. Neuroscience, 291, 331–340.

Guarino, M. P. L., Cocca, S., Altomare, A., Emerenziani, S., & Cicala, M. (2013). Ursodeoxycholic acid therapy in gallbladder disease, a story not yet completed. World Journal of Gastroenterology, 19(31), 5029–5034.

Guarino, M. P. L., Cong, P., Cicala, M., Alloni, R., Carotti, S., & Behar, J. (2007). Ursodeoxycholic acid improves muscle contractility and inflammation in symptomatic gallbladders with cholesterol gallstones. Gut, 56(6), 815–820.

Guarrera, P. M., Salerno, G., & Caneva, G. (2005). Folk phytotherapeutical plants from Maratea area (Basilicata, Italy). Journal of Ethnopharmacology, 99(3), 367–378.

Gubska, O. Y. (2013). The role and place of ursodeoxycholic acid drugs in treatment of chronic liver disease and pathology of hepatobiliary system. Liky Ukrayiny, 2, 10–13 (in Russian).

Harnois, D. M., Angulo, P., Jorgensen, R. A., Larusso, N. F., & Lindor, K. D. (2001). High-dose ursodeoxycholic acid as a therapy for patients with primary sclerosing cholangitis. The American Journal of Gastroenterology, 96(5), 1558–1562.

Hess, L. M., Krutzsch, M. F., Guillen, J., Chow, H. H., Einspahr, J., Batta, A. K., Salen, G., Reid, M. E., Earnest, D. L., & Alberts, D. S. (2004). Results of a phase I multiple-dose clinical study of ursodeoxycholic acid. Cancer Epidemiology, Biomarkers and Prevention, 13(5), 861–867.

Heubi, J. E., Wiechmann, D. A., Creutzinger, V., Setchell, K. D., Squires, R., Jr., Couser, R., & Rhodes, P. (2002). Tauroursodeoxycholic acid (TUDCA) in the prevention of total parenteral nutrition-associated liver disease. The Journal of Pediatrics, 141(2), 237–242.

Hirata, J. D., Swiersz, L. M., Zell, B., Small, R., & Ettinger, B. (1997). Does dong quai have estrogenic effects in postmenopausal women? A double-blind, placebo-controlled trial. Fertility and Sterility, 68(6), 981–986.

Hohlacheva, N. A., Sergeeva, N. N., & Vahrushev, Y. M. (2016). Age and gender peculiarities of development of gallstone disease. Archive of Internal Medicine, 6(1), 34–39 (in Russian).

Hopf, C., Grieshaber, R., Hartmann, H., Hinrichsen, H., Eisold, M., Cordes, H. J., Greinwald, R., & Rust, C. (2013). Therapeutic equivalence of ursodeoxycholic acid tablets and ursodeoxycholic acid capsules for the treatment of primary biliary cirrhosis. Clinical Pharmacology in Drug Development, 2, 231–236.

Hua, Y., Xue, W., Zhang, M., Wei, Y., & Ji, P. (2014). Metabonomics study on the hepatoprotective effect of polysaccharides from different preparations of Angelica sinensis. Journal of Ethnopharmacology, 151(3), 1090–1099.

Huo, X., Juergens, S., Zhang, X., Rezaei, D., Yu, C., Strauch, E. D., Wang, J. Y., Cheng, E., Meyer, F., Wang, D. H., Zhang, Q., Spechler, S. J., & Souza, R. F. (2011). Deoxycholic acid causes DNA damage while inducing apoptotic resistance through NF-κB activation in benign Barrett’s epithelial cells. American Journal of Physiology – Gastrointestinal and Liver Physiology, 301(2), G278–G286.

Hwang, S. J., Chan, C. Y., Lee, S. D., Wu, J. C., Tsay, S. H., & Lo, K. J. (1993). Ursodeoxycholic acid in the treatment of primary biliary cirrhosis: A short-term, randomized, double-blind controlled, cross-over study with long-term follow up. Journal of Gastroenterology and Hepatology, 8, 217–223.

Jacobsen, J. G., & Smith, L. H. (1968). Biochemistry and physiology of taurine and taurine derivatives. Physiological Reviews, 48(2), 424–511.

Jin, Y., Tang, Y. P., Zhu, Z. H., Shang, E. X., Pang, H. Q., Shi, X. Q., Chen, Y. Y., Wang, J., Chang, X., Kang, A., Zhou, G. S., Shi, Y. J., Sun, J., Tang, Z. S., Li, S. P., & Duan, J. A. (2017). Pharmacokinetic comparison of seven major bio-active components in normal and blood stasis rats after oral administration of herb pair danggui-honghua by UPLC-TQ/MS. Molecules, 22, 1746.

Jin, Y., Wu, L., Tang, Y. P., Cao, Y. J., Li, S. J., Shen, J., Yue, S. J., Qu, C., Shan, C. X., Cui, X. B., Zhang, L., & Duan, J. A. (2016). UFLC-Q-TOF/MS based screening and identification of the metabolites in plasma, bile, urine and feces of normal and blood stasis rats after oral administration of hydroxysafflor yellow A. Journal of Chromatography B, 1012–1013, 124–129.

Keiding, S., Høckerstedt, K., Bjøro, K., Bondesen, S., Hjortrup, A., Isoniemi, H., Erichsen, C., Söderdahl, G., & Ericzon, B. G. (1997). The nordic multicenter double-blind randomized controlled trial of prophylactic ursodeoxycholic acid in liver transplant patients. Transplantation, 63(11), 1591–1594.

Kim, H., Lee, K., Lee, K. W., Yi, N. J., Lee, H. W., Hong, G., Choi, Y., You, T., Suh, S. W., Jang, J. J., & Suh, K. S. (2014). Histologically proven non-alcoholic fatty liver disease and clinically related factors in recipients after liver transplantation. Clinical Transplantation, 28(5), 521–529.

Kirchhoff, R., Beckers, C., Kirchhoff, G. M., Trinczek-Gärtner, H., Petrowicz, O., & Reimann, H. J. (1994). Increase in choleresis by means of artichoke extract. Phytomedicine, 1(2), 107–115.

Ko, W. C. (1980). A newly isolated antispasmodic – butylidenephthalide. The Japanese Journal of Pharmacology, 30(1), 85–91.

Kotb, M. A. (2012). Molecular mechanisms of ursodeoxycholic acid toxicity and side effects: Ursodeoxycholic acid freezes regeneration and induces hibernation mode. International Journal of Molecular Sciences, 13(7), 8882–8914.

Kraft, K. (1997). Artichoke leaf extract – Recent findings reflecting effects on lipid metabolism, liver and gastrointestinal tracts. Phytomedicine, 4(4), 369–378.

Lafay, S., Morand, C., Manach, C., Besson, C., & Scalbert, A. (2006). Absorption and metabolism of caffeic acid and chlorogenic acid in the small intestine of rats. British Journal of Nutrition, 96, 39–46.

Lafay, S., Morand, C., Manach, C., Besson, C., & Scalbert, A. (2006). Absorption and metabolism of caffeic acid and chlorogenic acid in the small intestine of rats. British Journal of Nutrition, 96(1), 39–46.

Lammert, F., Neubrand, M. W., Bittner, R., Feussner, H., Greiner, L., Hagenmüller, F., Kiehne, K. H., Ludwig, K., Neuhaus, H., Paumgartner, G., Riemann, J. F., & Sauerbruch, T. (2007). S-3 guidelines for diagnosis and treatment of gallstones. German Society for Digestive and Metabolic Diseases and German Society for Surgery of the Alimentary Tract. Zeitschrift Fur Gastroenterologie, 45(9), 971–1001.

Larghi, A., Crosignani, A., Battezzati, P. M., De Valle, G., Allocca, M., Invernizzi, P., Zuin, M., & Podda, M. (1997). Ursodeoxycholic and tauro-ursodeoxycholic acids for the treatment of primary biliary cirrhosis: A pilot crossover study. Alimentary Pharmacology and Therapeutics, 11, 409–414.

Lazaridis, K. N., Gores, G. J., & Lindor, K. D. (2001). Ursodeoxycholic acid mechanisms of action and clinical use in hepatobiliary disorders. Journal of Hepatology, 35(1), 134–146.

Li, W., Guo, J., Tang, Y., Wang, H., Huang, M., Qian, D., & Duan, J. A. (2012). Pharmacokinetic comparison of ferulic acid in normal and blood deficiency rats after oral administration of Angelica sinensis, Ligusticum chuanxiong and their combination. International Journal of Molecular Sciences, 13(3), 3583–3597.

Lo, A. C. T., Chan, K., Yeung, J. H. K., & Woo, K. S. (1995). Danggui (Angelica sinensis) affects the pharmacodynamics but not the pharmacokinetics of warfarin in rabbits. European Journal of Drug Metabolism and Pharmacokinetics, 20(1), 55–60.

Loseva, N. V., & Moiseenko, E. E. (2010). Experience in the use of Dibicor in the complex therapy of non-alcoholic fatty liver disease. Pharmateca, 13, 63–67 (in Russian).

Luo, H., Xiao, F., & Gu, F. (2003). Study on pharmacokinetic of ferulic acid and peoniflorin in Angelic-Paeonia root powder. Zhong yao cai Journal of Chinese Medicinal Materials, 23, 189–192 (in Chinese).

Lupattelli, G., Marchesi, S., Lombardini, R., Roscini, A. R., Trinca, F., Gemelli, F., Vaudo, G., & Mannarino, E. (2004). Artichoke juice improves endothelial function in hyperlipemia. Life Sciences, 76(7), 775–782.

Lutsenko, T. N., Kovalenko, M. V., & Galkin, O. Y. (2017). Validation of biological activity testing procedure of recombinant human interleukin-7. Ukrainian Biochemical Journal, 89(1), 82–89.

Ma, J. P., Guo, Z. B., Jin, L., & Li, Y. D. (2015). Phytochemical progress made in investigations of Angelica sinensis (Oliv.) Diels. Chinese Journal of Natural Medicines, 13(4), 241–249.

Marcinkiewicz, J., & Kontny, E. (2014). Taurine and inflammatory diseases. Amino Acids, 46(1), 7–20.

May, G. R., Sutherland, L. R., & Shaffer, E. A. (1993). Efficacy of bile acid therapy for gallstone dissolution: A meta-analysis of randomized trials. Alimentary Pharmacology and Therapeutics, 7, 139–148.

Mayev, I. V., Kucheryavy, Y. A., Morozov, S. V., Stukova, N. Y. (2010). Effect of ursodeoxycholic acid drugs on blood biochemical parameters and results of liver elastography in patients with alcohol-induced liver cirrhosis. Clinical Perspectives in Gastroenterology and Hepatology, 4, 43–48 (in Russian).

Miyazaki, T., & Matsuzaki, Y. (2014). Taurine and liver diseases: A focus on the heterogeneous protective properties of taurine. Journal of Amino Acids, 46(1), 101–110.

Mizushima, S., Nara, Y., Sawamura, M., Yamori, Y. (1996). Effects of oral taurine supplementation on lipids and sympathetic nerve tone. In: Huxtable, R. J., Azuma, J., Kuriyama, K., Nakagawa, M., & Baba, A. (Eds.). Taurine 2. Advances in Experimental Medicine and Biology, Vol. 403. Springer, Boston.

Mootoosamy, A., & Fawzi Mahomoodally, M. (2014). Ethnomedicinal application of native remedies used against diabetes and related complications in Mauritius. Journal of Ethnopharmacology, 151(1), 413–444.

Moridani, M. Y., Scobie, H., Jamshidzadeh, A., Salehi, P., & O’Brien, P. J. (2001). Caffeic acid, chlorogenic acid, and dihydrocaffeic acid metabolism: Glutathione conjugate formation. Drug Metabolism and Disposition, 29(11), 1432–1439.

Naismith, D. J., Rana, S. K., & Emery, P. W. (1987). Metabolism of taurine during reproduction in women. Human Nutrition. Clinical Nutrition, 41(1), 37–45.

Özkardeş, A. B., Tokaç, M., Dumlu, E. G., Bozkurt, B., Çiftçi, A. B., Yetişir, F., & Kılıç, M. (2014). Early versus delayed laparoscopic cholecystectomy for acute cholecystitis: A prospective, randomized Study. International Surgery, 99(1), 56–61.

Pallayova, M., & Taheri, S. (2014). Non-alcoholic fatty liver disease in obese adults: Clinical aspects and current management strategies. Clinical Obesity, 4, 243–253.

Pei, K., Ou, J., Huang, J., & Ou, S. (2016). p-Coumaric acid and its conjugates: Dietary sources, pharmacokinetic properties and biological activities. Journal of the Science of Food and Agriculture, 96, 2952–2962.

Pelletier, G., Roulot, D., Davion, T., Masliah, C., Causse, X., Oberti, F., Raabe, J. J., Van Lemmens, C., Labadie, H., & Serfaty, L. (2003). A randomized controlled trial of ursodeoxycholic acid in patients with alcohol-induced cirrhosis and jaundice. Hepatology, 37, 887–892.

Podda, M., Ghezzi, C., Battezzati, P. M., Bertolini, E., Crosignani, A., Petroni, M. L., & Zuin, M. (1989). Effect of different doses of ursodeoxycholic acid in chronic liver disease. Digestive Diseases and Sciences, 34(12), 59S–65S.

Portincasa, P., Ciaula, A. D., Bonfrate, L., & Wang, D. Q. (2012). Therapy of gallstone disease: What it was, what it is, what it will be. World Journal of Gastrointestinal Pharmacology and Therapeutics, 3(2), 7–20.

Ramaekers, J. G. (2017). Drugs and driving research in medicinal drug development. Trends in Pharmacological Sciences, 38(4), 319–321.

Raphael, B. P., & Duggan, C. (2012). Prevention and treatment of intestinal failure-associated liver disease in children. Seminars Liver Disease, 32(4), 341–347.

Roma, M. G., Toledo, F. D., Boaglio, A. C., Basiglio, C. L., Crocenzi, F. A., & Sánchez Pozzi, E. J. (2011). Ursodeoxycholic acid in cholestasis: Linking action mechanisms to therapeutic applications. Clinical Science (Lond), 121(12), 523–544.

Rost, D., Rudolph, G., Kloeters-Plachky, P., & Stiehl, A. (2004). Effect of high-dose ursodeoxycholic acid on its biliary enrichment in primary sclerosing cholangitis. Hepatology, 40, 693–698.

Ru, Y., Ge, L., Ko, N. L., & Tam, Y. K. (2007). Low oral bioavailability and pharmacokinetics of senkyunolide A, a major bioactive component in Rhizoma Chuanxiong in the rat. Therapeutic Drug Monitoring, 29, 49–56.

Rudic, J. S., Poropat, G., Krstic, M. N., Bjelakovic, G., & Gluud, C. (2012). Ursodeoxycholic acid for primary biliary cirrhosis. Cochrane Database of Systematic Reviews, 12, CD000551.

Sagara, M., Murakami, S., Mizushima, S., Liu, L., Mori, M., Ikeda, K., & Yamori, Y. (2015). Taurine in 24-h urine samples is inversely related to cardiovascular risks of middle aged subjects in 50 populations of the world. Advances in Experimental Medicine and Biology, 803, 623–636.

Sahebkar, A., Pirro, M., Banach, M., Mikhailidis, D. P., Atkin, S. L., & Cicero, A. F. G. (2017). Lipid-lowering activity of artichoke extracts: A systematic review and meta-analysis. Critical Reviews in Food Science and Nutrition, 1–8.

Sannia, A. (2010). Phytotherapy with a mixture of dry extracts with hepato-protective effects containing artichoke leaves in the management of functional dyspepsia symptoms. Minerva Gastroenterologica e Dietologica, 56(2), 93–99 (in Italian).

Santoveña, A., Sánchez-Negrín, E., Charola, L., Llabrés, M., & Fariña, J. B. (2014). Study of quality and stability of ursodeoxycholic acid formulations for oral pediatric administration. International Journal of Pharmaceutics, 477(1–2), 32–38.

Sheybak, V. M., & Sheybak, L. N. (2005). The biological role of taurine in mammals. Medical News, 10, 1–8 (in Russian).

Simoni, P., Cerrè, C., Cipolla, A., Polimeni, C., Pistillo, A., Ceschel, G., Roda, E., & Roda, A. (1995). Bioavailability study of a new, sinking, enteric-coated ursodeoxycholic acid formulation. Pharmacological Research, 31(2), 115–119.

Sital, R. R., Kusters, J. G., De Rooij, F. W., Kuipers, E. J., & Siersema, P. D. (2006). Bile acids and Barrett’s oesophagus: A sine qua non or coincidence? Scandinavian Journal of Gastroenterology. Supplement, 243, 11–17.

Sturman, J. A., Hepner, G. W., Hofmann, A. F., & Thomas, P. J. (1975). Metabolism of [35S]taurine in man. Journal of Nutrition, 105(9), 1206–1214.

Su, Y. W., Chiou, W. F., Chao, S. H., Lee, M. H., Chen, C. C., & Tsai, Y. C. (2011). Ligustilide prevents LPS-induced iNOS expression in RAW 264.7 macrophages by preventing ROS production and down-regulating the MAPK, NF-κB and AP-1 signaling pathways. International Immunopharmacology, 11(9), 1166–1172.

Sumizu, K. (1962). Oxidation of hypotaurine in rat liver. Biochimica et Biophysica Acta, 63, 210–212.

Thao, T. D., Ryu, H. C., Yoo, S. H., & Rhee, D. K. (2008). Antibacterial and antiatrophic effects of a highly soluble, acid stable UDCA formula in Helicobacter pylori-induced gastritis. Biochemical Pharmacology, 75(11), 2135–2146.

Tian, Y., Yang, Z. F., Li, Y., Qiao, Y., Yang, J., Jia, Y. Y., & Wen, A. D. (2010). Pharmacokinetic comparisons of hydroxysafflower yellow A in normal and blood stasis syndrome rats. Journal of Ethnopharmacology, 129, 1–4.

Tiedemann, F., & Gmelin, L. (1827). Einige neue Bestandtheile der Galle des Ochsen. Annalen der Physik, 85(2), 326–337.

Tomeno, W., Kawashima, K., Yoneda, M., Saito, S., Ogawa, Y., Honda, Y., Kessoku, T., Imajo, K., Mawatari, H., Fujita, K., Saito, S., Hirayasu, Y., & Nakajima, A. (2015). Non-alcoholic fatty liver disease comorbid with major depressive disorder: The pathological features and poor therapeutic efficacy. Journal of Gastroenterology and Hepatology, 30, 1009–1014.

Tomida, S., Abei, M., Yamaguchi, T., Matsuzaki, Y., Shoda, J., Tanaka, N., & Osuga, T. (1999). Long-term ursodeoxycholic acid therapy is associated with reduced risk of biliary pain and acute cholecystitis in patients with gallbladder stones: A cohort analysis. Hepatology, 30, 6–13.

Toyoda, A., Koike, H., Nishihata, K., Iio, W., & Goto, T. (2015). Effects of chronic taurine administration on gene expression, protein translation and phosphorylation in the rat hippocampus. Advances in Experimental Medicine and Biology, 803, 473–480.

Triantos, C. K., Koukias, N. M., Nikolopoulou, V. N., & Burroughs, A. K. (2011). Meta-analysis: Ursodeoxycholic acid for primary sclerosing cholangitis. Alimentary Pharmacology and Therapeutics, 34, 901–910.

Tsai, M. C., Chen, C. H., Lee, H. C., Lin, H. C., & Lee, C. Z. (2015). Increased risk of depressive disorder following cholecystectomy for gallstones. PLoS ONE, 10(6), e0129962.

Uvarova, K. G., Saprykina, M. M., Ahmed, M. A., Oyebamire, I. B., Makienko, N. V., Maltseva, M. S., Kamenskaya, E. P., & Yabluchanskiy, M. I. (2014). Polymorbidity in clinical practice. The Journal of V. N. Karazin Kharkiv National University. Series: Medicine, 1141(28), 48–51.

van Stijn, M. F., Vermeulen, M. A., Siroen, M. P., Wong, L. N., van den Tol, M. P., Ligthart-Melis, G. C., Houdijk, A. P., & van Leeuwen, P. A. (2012). Human taurine metabolism: Fluxes and fractional extraction rates of the gut, liver, and kidneys. Metabolism, 61(7), 1036–1040.

Venneman, N. G., Besselink, M. G. H., Keulemans, Y. C. A., van Berge-Henegouwen, G. P., Boermeester, M. A., Broeders, I. A. M. J., Go, P. M. N. Y. H., & van Erpecum, K. J. (2006). Ursodeoxycholic acid exerts no beneficial effect in patients with symptomatic gallstones awaiting cholecystectomy. Hepatology, 43, 1276–1283.

Vettorazzi, J. F., Kurauti, M. A., Soares, G. M., Borck, P. C., Ferreira, S. M., Branco, R. C. S., de Souza Lima Michelone, L., Boschero, A. C., Costa Junior, J. V., & Carneiro, E. M. (2017). Bile acid TUDCA improves insulin clearance by increasing the expression of insulin-degrading enzyme in the liver of obese mice. Scientific Reports, 7, 14876.

Wang, D. Q. H., Cohen, D. E., & Carey, M. C. (2009). Biliary lipids and cholesterol gallstone disease. Journal of Lipid Research, 50(Suppl), S406–S411.

Wang, J., Du, J. R., Wang, Y., Kuang, X., & Wang, C. Y. (2010). Z-ligustilide attenuates lipopolysaccharide-induced proinflammatory response via inhibiting NF-κB pathway in primary rat microglia. Acta Pharmacologica Sinica, 31(7), 791–797.

Wei, W. L., Zeng, R., Gu, C. M., Qu, Y., & Huang, L. F. (2016). Angelica sinensis in China-A review of botanical profile, ethnopharmacology, phytochemistry and chemical analysis. Journal of Ethnopharmacology, 190, 116–141.

Wider, B., Pittler, M. H., Thompson-Coon, J., & Ernst, E. (2009). Artichoke leaf extract for treating hypercholesterolaemia. Cochrane Database of Systematic Reviews, 4, CD003335.

Wisher, D. (2012). Martindale: The complete drug reference. 37th ed. Journal of the Medical Library Association, 100(1), 75–76.

Wittemer, S. M., Ploch, M., Windeck, T., Müller, S. C., Drewelow, B., Derendorf, H., & Veit, M. (2005). Bioavailability and pharmacokinetics of caffeoylquinic acids and flavonoids after oral administration of Artichoke leaf extracts in humans. Phytomedicine, 12(1–2), 28–38.

Wu, S. D., Li, L., & Wang, J. Y. (2012). Ursodeoxycholic acid for nonalcoholic steatohepatitis. European Journal of Gastroenterology and Hepatology, 24(11), 1247–1253.

Wu, X., Qian, Z., Zhu, L., Du, F., Yung, W., Gong, Q., & Ke, Y. (2011). Neuroprotective effect of ligustilide against ischaemia-reperfusion injury via up-regulation of erythropoietin and down-regulation of RTP801. British Journal of Pharmacology, 164(2), 332–343.

Wu, Y. C., & Hsieh, C. L. (2011). Pharmacological effects of radix Angelica sinensis (Danggui) on cerebral infarction. Chinese Medicine, 6, 32.

Yan, R., Ko, N. L., Li, S. L., Tam, Y. K., & Lin, G. (2007). Pharmacokinetics and metabolism of ligustilide, a major bioactive component in Rhizoma Chuanxiong, in the rat. Drug Metabolism and Disposition, 36(2), 400–408.

Zaretskiy, M. M., Chernikova, N. M., & Lobachevskaya, T. V. (2011). Possibilities of using ursodeoxycholic acid in the treatment of cholelithiasis. Modern Gastroenterology, 2, 136–140 (in Russian).

Zeng, H. T., Xue, P., Su, S. L., Huang, X. C., Shang, E. X., Guo, J. M., Qian, D. W., Tang, Y. P., & Duan, J. A. (2016). Comparative pharmacokinetics of three major bioactive components in rats after oral administration of Typhae Pollen-Trogopterus Feces drug pair before and after compatibility. DARU Journal of Pharmaceutical Sciences, 20, 2.

Zhang, M., Bi, L. F., Fang, J. H., Su, X. L., Da, G. L., Kuwamori, T., & Kagamimori, S. (2004). Beneficial effects of taurine on serum lipids in overweight or obese non-diabetic subjects. Amino Acids, 26(3), 267–271.

Zhao, Z., & Moghadasian, M. H. (2010). Bioavailability of hydroxycinnamates: A brief review of in vivo and in vitro studies. Phytochemistry Reviews, 9(1), 133–145.

Zvyagintseva, T. D., & Gridnyova, S. V. (2014). The mechanisms of development and approaches to the treatment of sphincter of oddi dysfunction after cholecystectomy. Gastroenterology, 2, 77–81 (in Russian).


How to Cite
Bondarenko, L. B., Gorchakova, N. O., Golembiovska, O. I., & Galkin, O. Y. (2018). Promising new fixed combination for the treatment of diseases of the hepatobiliar system: Substantiation of pharmacotherapeutic properties and pharmaceutical quality profile. Regulatory Mechanisms in Biosystems, 9(1), 23-40.