Introduction: Carcinoid syndrome (CS) occurs when metastatic carcinoid tumors secrete large amounts of serotonin (5-HT) and other bioactive substances into systemic circulation, causing a variety of symptoms, including GI symptoms such as profound diarrhea. Reduction in 5-HT production by the tumor would be expected to improve symptoms in patients with CS.
Aim(s): To examine the utility of inhibiting tryptophan hydroxylase (TPH), the enzyme that catalyzes the rate-limiting step in the synthesis of 5-HT, as a strategy to reduce 5-HT production in vivo with the goal of developing a new therapeutic approach to CS. The ability of LX1031 and LX1032, two novel TPH inhibitors, to reduce 5-HT production was determined in clinical trials.
Materials and methods: Single and multiple ascending dose studies with LX1031 and LX1032 were conducted in normal volunteers. In addition, a 28-day study was conducted with the locally acting TPH inhibitor LX1031 in patients with non-constipating IBS. In the IBS study, multiple measures of GI symptoms were recorded daily, along with a weekly global assessment. In all studies, blood and urine were collected for measurement of 5-HT and 5-HIAA, biomarkers of 5-HT production.
Conference: 7th Annual ENETS Conference (2010)
Presenting Author: Jay L Mitchell
, TPH inhibitor
, tryptophan hydroxylase
, clinical trial
, serotonin synthesis inhibitor
, irritable bowel syndrome
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