title: Combined use of ursodeoxycholic acid and bosentan prevents liver toxicity caused by endothelin receptor antagonist bosentan monotherapy: two case reports.
abstract: BACKGROUND
  Pulmonary arterial hypertension is a fatal disease characterized by progressive remodeling of the pulmonary arteries and an increase in pulmonary vascular resistance. Up to 50% of patients with systemic sclerosis have pulmonary arterial hypertension, which significantly affects the prognosis. The endothelin receptor antagonist bosentan is used for the treatment of pulmonary arterial hypertension and shows a great beneficial effect. However, the most frequent side effect of bosentan is liver toxicity, which often requires dose reduction and discontinuation.
  
  
  METHODS
  We report two cases (a 64-year-old Japanese woman and a 69-year old Japanese woman) of systemic sclerosis, both with severe Raynaud's phenomenon and pulmonary arterial hypertension. Both patients had initially received bosentan monotherapy, which caused liver toxicity as indicated by increased levels of alanine aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase. After dose reduction or discontinuation of bosentan, these liver function abnormalities were normalized and the patients subsequently received retreatment with a combination of bosentan and ursodeoxycholic acid. The results of liver function tests did not show any abnormalities after this combination therapy.
  
  
  CONCLUSIONS
  These reports suggest the usefulness of ursodeoxycholic acid for preventing liver toxicity caused by bosentan. Thus, the addition of ursodeoxycholic acid to the treatment protocol is expected to be useful when liver toxicity emerges as a side effect of bosentan.
authors.affiliation: First Department of Internal Medicine, Kansai Medical University, 2-5-1 Shin-machi, Hirakata City, Osaka 573-1010, Japan. itot@hirakata.kmu.ac.jp.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Ito
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ozaki
authors.forename: Yonsu
authors.initials: Y
authors.lastname: Son
authors.forename: Tohru
authors.initials: T
authors.lastname: Nishizawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Amuro
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tanaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tamaki
authors.forename: Shosaku
authors.initials: S
authors.lastname: Nomura
mesh_terms: D000368:Aged; D000077300:Bosentan; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000517:prevention & control*; D002756:Cholagogues and Choleretics / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D065128:Endothelin Receptor Antagonists / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D008111:Liver Function Tests; D008875:Middle Aged; D013449:Sulfonamides / Q000009:adverse effects* / Q000627:therapeutic use; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use*
chemical_list: D002756:Cholagogues and Choleretics; D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D014580:Ursodeoxycholic Acid; D000077300:Bosentan