In vivo effects of the 5-HT3 antagonist alosetron on basal and cholera toxin-induced secretion in the human jejunum: a segmental perfusion study.

Abstract

5-hydroxytryptamine type 3 receptor antagonists have been shown to reduce fluid and electrolyte secretion or promote absorption in experimental models of small intestinal secretion. The aim of this study was to compare the effects of a single dose (4 mg) of the 5-hydroxytryptamine type 3 receptor antagonist alosetron and placebo on jejunal fluid and electrolyte movement in humans under basal conditions (n = 7) and following cholera toxin-induced secretion (n = 5) in a randomized, double-blind, crossover design over two separate study periods. One hour after oral alosetron or placebo, jejunal intubation was performed. A 30 cm segment of jejunum, isolated by two occluding balloons, was exposed to 15 microg of purified cholera toxin for 2 h prior to triple lumen perfusion with a plasma electrolyte solution containing [14C]-polyethylene glycol as a nonabsorbable volume marker. In the basal study, intestinal perfusion was performed without exposure to cholera toxin. Collection and analysis of the effluent from the jejunal segment allowed fluid and electrolyte movement to be calculated. Alosetron treatment increased basal jejunal fluid absorption (median 5.1 mL/cm/h [interquartile range 4.2 to 7.1] compared with placebo (3.8 [3.6 to 4.3] P = 0.028, two sided Wilcoxon matched pairs signed rank test)). However, following establishment of a secretory state by cholera toxin, alosetron failed to significantly promote absorption or reduce secretion (0.3 [-1.2 to 1.2] compared to placebo (-4.3 [-7.7 to -1.3] P = 0.14)). Adverse events during the study, which included anorexia, nausea, dizziness and loose bowel movements, were not considered to be clinically important. There were no clinically significant changes in laboratory parameters. The 5-hydroxytyptamine type 3 receptor antagonist, alosetron, increased basal fluid absorption in normal human small intestine but failed to have a beneficial effect in cholera toxin-induced secretion.