Combination Therapy of All-Trans Retinoic Acid With Ursodeoxycholic Acid in Patients With Primary Sclerosing Cholangitis: A Human Pilot Study.
Combination Therapy of All-Trans Retinoic Acid With Ursodeoxycholic Acid in Patients With Primary Sclerosing Cholangitis: A Human Pilot Study.
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DOI：
10.1097/mcg.0000000000000591
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发表时间：
2017-02
影响因子：
2.9
通讯作者：
Boyer JL
中科院分区：
文献类型：
--
作者：
Assis DN;Abdelghany O;Cai SY;Gossard AA;Eaton JE;Keach JC;Deng Y;Setchell KD;Ciarleglio M;Lindor KD;Boyer JL
目的：进行全反式维甲酸(ATRA)联合熊去氧胆酸(UDCA)治疗原发性硬化性胆管炎(PSC)的探索性初步研究。PSC是一种进行性疾病，目前还没有公认的治疗方法。在人类肝细胞培养和胆汁淤积动物模型中的研究表明，全反式维甲酸可能对胆汁淤积疾病有有益的作用。ATRA(45 mg/m2/d，分次，每日2次)联合中剂量UDCA治疗对UDCA治疗无效的PSC患者。联合用药12周，然后进行为期12周的洗涤，患者返回UDCA单一疗法。分别于基线、12周和洗涤后测定碱性磷酸酶、丙氨酸氨基转移酶、胆红素、胆固醇、胆汁酸和胆汁酸中间体7-羟基-4-胆固酮-3-酮(7α-hyxy-4-cholesten-3-one，C4)。15名患者完成了12周的治疗。将全反式维甲酸加入UDCA后，血清ALP水平中位数降低(277±211至243±225U/L；P=0.09)，尽管这是主要终点，但并未达到显著水平。而血清ALT(76±55至46±32U/L；P=.001)和C4(9.8±19至7.9±11 ng/mL；P=0.03)水平显著降低。洗涤后ALP和C4水平无明显升高，ALT水平显著升高(46±32至74±74；p=0.0006)，恢复至基线水平。在这项人类先导性研究中，ATRA和UDCA的组合没有达到主要终点(ALP)，但它显著降低了ALT和胆汁酸中间体C4。全反式维甲酸似乎抑制胆汁酸的合成，减少炎症标志物，使其成为PSC进一步研究的潜在候选者。NCT01456468。
To perform an exploratory pilot study of all-trans retinoic acid (ATRA) combined with ursodeoxycholic acid (UDCA) in patients with primary sclerosing cholangitis (PSC). 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. ATRA (45 mg/m2/day, 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. 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=.09) although this, the primary endpoint, did not reach significance. In contrast, median serum ALT (76±55 to 46±32 U/L; P=.001) and C4 (9.8±19 to 7.9±11 ng/mL; P=.03) levels significantly decreased. After washout, ALP and C4 levels non-significantly increased while ALT levels significantly increased (46±32 to 74±74; p=0.0006), returning to baseline. 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. NCT01456468.