TY - JOUR
T1 - Combination therapy of all-trans retinoic acid with ursodeoxycholic acid in patients with primary sclerosing cholangitis
T2 - A human pilot study
AU - Assis, David N.
AU - Abdelghany, Osama
AU - Cai, Shi Ying
AU - Gossard, Andrea A.
AU - Eaton, John E.
AU - Keach, Jill C.
AU - Deng, Yanhong
AU - Setchell, Kenneth D R
AU - Ciarleglio, Maria
AU - Lindor, Keith
AU - Boyer, James L.
N1 - Funding Information:
Supported by a CTSA grant (UL1 TR000142) from the National Center for Advancing Translational Science (NCATS), a grant from the PSC Partners Seeking a Cure Foundation, and the Yale Liver Center P30KD034989 grant.
Publisher Copyright:
© 2017 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2017
Y1 - 2017
N2 - Goals: 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. Study: ATRA (45mg/m2/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 7a-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±225U/L, P=0.09) although this, the primary endpoint, did not reach significance. In contrast, median serum ALT (76±55 to 46±32U/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).
AB - Goals: 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. Study: ATRA (45mg/m2/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 7a-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±225U/L, P=0.09) although this, the primary endpoint, did not reach significance. In contrast, median serum ALT (76±55 to 46±32U/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).
KW - All-trans retinoic acid
KW - Clinical trial
KW - FXR
KW - Primary sclerosing cholangitis
KW - RXR
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UR - http://www.scopus.com/inward/citedby.url?scp=84978734565&partnerID=8YFLogxK
U2 - 10.1097/MCG.0000000000000591
DO - 10.1097/MCG.0000000000000591
M3 - Article
C2 - 27428727
AN - SCOPUS:84978734565
SN - 0192-0790
VL - 51
SP - e11-e16
JO - Journal of Clinical Gastroenterology
JF - Journal of Clinical Gastroenterology
IS - 2
ER -