Serotonin synthesis inhibitors: a novel approach for managing gastrointestinal symptoms in carcinoid syndrome

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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 ENETSConcerence (2010)

Presenting Author: Brown P

Authors: Brown P, Jackson J, Frazier K, Turnage A, Clark E,

Keywords: carcinoid syndrome, TPH inhibitor, 5-HT, tryptophan hydroxylase, clinical trial, serotonin synthesis, serotonin synthesis inhibitor, LX1032, LX1031, Lexicon, IBS, irritable bowel syndrome, SSI,