title: Combination Therapy of All-Trans Retinoic Acid With Ursodeoxycholic Acid in Patients With Primary Sclerosing Cholangitis: A Human Pilot Study.
abstract: OBJECTIVE
  To perform an exploratory pilot study of all-trans retinoic acid (ATRA) combined with ursodeoxycholic acid (UDCA) in patients with primary sclerosing cholangitis (PSC).
  
  
  BACKGROUND
  PSC is a progressive disorder for which there is no accepted therapy. Studies in human hepatocyte cultures and in animal models of cholestasis indicate that ATRA might have beneficial effects in cholestatic disorders.
  
  
  METHODS
  ATRA (45 mg/m/d, divided and given twice daily) was combined with moderate-dose UDCA in patients with PSC who had incomplete response to UDCA monotherapy. The combination was administered for 12 weeks, followed by a 12-week washout in which patients returned to UDCA monotherapy. We measured alkaline phosphatase (ALP), alanine aminotransferase (ALT), bilirubin, cholesterol, bile acids, and the bile acid intermediate 7α-hydroxy-4-cholesten-3-one (C4) at baseline, week 12, and after washout.
  
  
  RESULTS
  Fifteen patients completed 12 weeks of therapy. The addition of ATRA to UDCA reduced the median serum ALP levels (277±211 to 243±225 U/L, P=0.09) although this, the primary endpoint, did not reach significance. In contrast, median serum ALT (76±55 to 46±32 U/L, P=0.001) and C4 (9.8±19 to 7.9±11 ng/mL, P=0.03) levels significantly decreased. After washout, ALP and C4 levels nonsignificantly increased, whereas ALT levels significantly increased (46±32 to 74±74, P=0.0006), returning to baseline.
  
  
  CONCLUSIONS
  In this human pilot study, the combination of ATRA and UDCA did not achieve the primary endpoint (ALP); however, it significantly reduced ALT and the bile acid intermediate C4. ATRA appears to inhibit bile acid synthesis and reduce markers of inflammation, making it a potential candidate for further study in PSC (NCT 01456468).
authors.affiliation: *Department of Medicine, Section of Digestive Diseases, Yale University School of Medicine †Research Pharmacy, Yale-New Haven Hospital §Yale University School of Public Health, New Haven, CT ‡Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN ∥Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center ¶Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH #College of Health Solutions, Arizona State University, Tempe, AZ.
authors.forename: David N
authors.initials: DN
authors.lastname: Assis
authors.forename: Osama
authors.initials: O
authors.lastname: Abdelghany
authors.forename: Shi-Ying
authors.initials: SY
authors.lastname: Cai
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Gossard
authors.forename: John E
authors.initials: JE
authors.lastname: Eaton
authors.forename: Jill C
authors.initials: JC
authors.lastname: Keach
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Deng
authors.forename: Kenneth D R
authors.initials: KD
authors.lastname: Setchell
authors.forename: Maria
authors.initials: M
authors.lastname: Ciarleglio
authors.forename: Keith D
authors.initials: KD
authors.lastname: Lindor
authors.forename: James L
authors.initials: JL
authors.lastname: Boyer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D001647:Bile Acids and Salts / Q000096:biosynthesis; D002756:Cholagogues and Choleretics / Q000008:administration & dosage*; D015209:Cholangitis, Sclerosing / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D002783:Cholestenones / Q000097:blood; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008099:Liver / Q000503:physiopathology; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D016896:Treatment Outcome; D014212:Tretinoin / Q000008:administration & dosage*; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D002783:Cholestenones; C002656:7 alpha-hydroxy-4-cholesten-3-one; D014212:Tretinoin; D014580:Ursodeoxycholic Acid; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase