Camilleri Michael
Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Charlton 8-110, 200 First St SW, Rochester, MN 55905, USA.
IDrugs. 2010 Dec;13(12):921-8.
LX-1031, being developed by Lexicon Pharmaceuticals, is an oral, small-molecule tryptophan 5-hydroxylase (TPH) inhibitor that reduces 5-HT synthesis peripherally. LX-1031 is being developed for the potential treatment of diarrhea-predominant irritable bowel syndrome (IBS-D), which is characterized by excess 5-HT. In preclinical studies, LX-1031 dose-dependently reduced expression of 5-HT in the duodenum, jejunum and ileum, but had no effect on brain 5-HT levels. In ascending single-dose and multiple-dose (14 day) phase I clinical trials in healthy volunteers, LX-1031 significantly reduced urinary 5-hydroxyindoleacetic acid (5-HIAA; a marker of 5-HT metabolism) levels, starting by day 5 and persisting over the duration of exposure. In a phase II clinical trial in patients with IBS-D, a 1000-mg qid dose of LX-1031 was associated with improved weekly global scores and stool consistency, and lower urinary 5-HIAA levels over a 28-day treatment period. LX-1031 was well tolerated in trials to date. In conclusion, LX-1031 appears promising for IBS-D. Optimal doses, efficacy in IBS clinical trials and safety need to be fully elucidated.
莱克斯康制药公司正在研发的LX-1031是一种口服小分子色氨酸5-羟化酶（TPH）抑制剂，可在外周减少5-羟色胺（5-HT）的合成。LX-1031正被开发用于潜在治疗以5-HT过量为特征的腹泻型肠易激综合征（IBS-D）。在临床前研究中，LX-1031剂量依赖性地降低十二指肠、空肠和回肠中5-HT的表达，但对脑内5-HT水平无影响。在健康志愿者进行的单剂量递增和多剂量（14天）I期临床试验中，LX-1031从第5天开始显著降低尿5-羟吲哚乙酸（5-HIAA；5-HT代谢标志物）水平，并在整个暴露期间持续存在。在一项针对IBS-D患者的II期临床试验中，每日四次、每次1000毫克剂量的LX-1031在28天的治疗期内与每周总体评分和大便稠度改善以及较低的尿5-HIAA水平相关。到目前为止，LX-1031在试验中耐受性良好。总之，LX-1031对IBS-D似乎有前景。最佳剂量、在IBS临床试验中的疗效和安全性有待充分阐明。
