The tryptophan hydroxylase inhibitor LX1031 shows clinical benefit in patients with nonconstipating irritable bowel syndrome.
The tryptophan hydroxylase inhibitor LX1031 shows clinical benefit in patients with nonconstipating irritable bowel syndrome.
复制标题
DOI：
10.1053/j.gastro.2011.05.005
复制
发表时间：
2011-08
期刊：
影响因子：
29.4
通讯作者：
Gershon MD
中科院分区：
文献类型：
--
作者：
Brown PM;Drossman DA;Wood AJ;Cline GA;Frazier KS;Jackson JI;Bronner J;Freiman J;Zambrowicz B;Sands A;Gershon MD
5-羟色胺（5-HT）在胃肠道功能中具有重要作用。LX 1031是一种口服、局部作用的色氨酸羟化酶（TPH）小分子抑制剂。在胃肠道局部抑制TPH可能会减少5-羟色胺（5-HT）的粘膜产生，并用于治疗非便秘型肠易激综合征（IBS）患者。我们在一项为期28天、多中心、随机、双盲、安慰剂对照研究中对155例非便秘型IBS患者进行了2种剂量水平的LX 1031（250 mg或1000 mg，每日4次给药）评价。5-在基线（LX 1031给药后24小时）以及第4周和第6周（n = 76），在尿样中测量了药效学活性生物标志物--羟基吲哚乙酸（5-HIAA）。每种剂量的LX 1031均安全且耐受性良好。主要疗效终点，IBS疼痛和不适的缓解，在第1周给予1000 mg LX 1031的患者（25.5%）与给予安慰剂的患者相比显著改善（P = 0.018）;在第2、3和4周无显著改善（分别为17.9%、16.3%和11.6%）。从基线到第4周，症状改善与5-HIAA（TPH抑制的标志物）的剂量依赖性降低相关。这表明LX 1031的功效与5-HT生物合成的抑制程度有关。与安慰剂组相比，在第1、4周（P <0.01）和第2周（P <0.001），粪便硬度显著改善。在一项II期研究中，LX 1031耐受性良好，可缓解非便秘型IBS患者的症状并增加粪便粘稠度。症状缓解与尿样中5-HIAA水平降低相关。该标记物可用于识别对5-HT合成抑制剂有反应的非便秘型IBS患者。
Serotonin (5-hydroxytryptamine [5-HT]) has an important role in gastrointestinal function. LX1031 is an oral, locally acting, small molecule inhibitor of tryptophan hydroxylase (TPH). Local inhibition of TPH in the gastrointestinal tract might reduce mucosal production of serotonin (5-HT) and be used to treat patients with nonconstipating irritable bowel syndrome (IBS). We evaluated 2 dose levels of LX1031 (250 mg or 1000 mg, given 4 times/day) in a 28-day, multicenter, randomized, double-blind, placebo-controlled study of 155 patients with nonconstipating IBS. 5-hydroxyindoleacetic acid (5-HIAA), a biomarker of pharmacodynamic activity, was measured in urine samples at baseline (24 hours after LX1031 administration), and at weeks 4 and 6 (n = 76). Each dose of LX1031 was safe and well-tolerated. The primary efficacy end point, relief of IBS pain and discomfort, improved significantly in patients given 1000 mg LX1031 (25.5%), compared with those given placebo, at week 1 (P = .018); with nonsignificant improvements at weeks 2, 3, and 4 (17.9%, 16.3%, and 11.6%, respectively). Symptom improvement correlated with a dose-dependent reduction in 5-HIAA, a marker for TPH inhibition, from baseline until week 4. This suggests the efficacy of LX1031 is related to the extent of inhibition of 5-HT biosynthesis. Stool consistency significantly improved, compared with the group given placebo, at weeks 1 and 4 (P < .01) and at week 2 (P < .001). In a phase 2 study, LX1031 was well tolerated, relieving symptoms and increasing stool consistency in patients with nonconstipating IBS. Symptom relief was associated with reduced levels of 5-HIAA in urine samples. This marker might be used to identify patients with nonconstipating IBS who respond to inhibitors of 5-HT synthesis.