BIOMARKERS FOR IDENTIFYING EFFICACY OF TEGASEROD IN PATIENTS WITH CHRONIC CONSTIPATION.

摘要

Pharmacogenetics was used to evaluate the effect of polymorphisms in select candidate genes on the response of patients with chronic constipation to tegaserod (Zelmac??/Zelnorm??). The analysis identified twelve single nucleotide polymorphisms (SNPs) in six genes (HTR4, HTR3B, MLN, AQP3, SLC12A2, SCNN1A) that were associated with at least a 60% response rate to tegaserod and an odds ratios of 5 or greater (compared to placebo) after 4 weeks of treatment. The identified genes display a wide range of different functions, including serotonin signaling, secretion and motility, all of which are important in maintaining the normal function of the gastrointestinal tract. Thus, these data imply that chronic constipation may result from a variety of pathophysiological mechanisms related to variants in the above identified genes, all of which respond well to treatment with tegaserod. Patients without these variants do not respond to treatment significantly more than they do to placebo, which could indicate that their chronic constipation is not due to pathophysiological mechanisms but rather to environmental or possibly psychological factors. Patients with these variants are also less likely to respond to placebo, again implying that these variants are associated with a true pathophysiology.