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

Background: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.Methods: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 μg of purified cholera toxin for 2 h prior to triple lumen perfusion with a plasma electrolyte solution containing []> 14C]‐polyethylene glycol as a non‐absorbable 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.Results: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.Conclusion: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.

Kynurenine pathway metabolism and the microbiota-gut-brain axis

“…Around 95% of the body's 5-HT is located within the GI tract, primarily synthesised by enterochromaffin cells, and 5% in the CNS (Camilleri, 2002;Gershon and Tack, 2007;Mayer et al, 2001). In healthy humans, other mammals and in disease states, 5-HT in the GI tract is involved in a range of largely reflexive functions including motility (Chial et al, 2003;Gorard et al, 1994), secretion and absorption (Bearcroft et al, 1997), intestinal transit (Wilmer et al, 1993) and colonic tone (Klatt et al, 1999;Talley et al, 1990). In addition, 5-HT mediates feelings of nausea and can induce vomiting by stimulating 5-HT3 receptors on vagal afferent pathways which signal to the nucleus tractus solitarii (Klatt et al, 1999;Talley et al, 1990).…”

New developments in the Understanding of cholera

“…The role of the BS component in providing protection is problematic because it appeared to afford protection in the Table 3. Antimicrobial and antisecretory drugs tested in cholera Study or studies Drug Efficacy [35,42] Ciprofloxacin Single dose of 1 g as effective as single dose of doxycycline, 300 mg orally, with similar stool volume; ciprofloxacin was better bacteriologically in eradicating bacteria after 2 days [36,43] Single daily dose of 250 mg for 3 days as effective as tetracycline, 500 mg x4/d for 3 days [44] Single dose of 250 mg as prophylaxis for household contacts was not effective in preventing disease [45] Norfloxacin 400 mg twice daily in adults or 7.5 mg/kg twice daily in children for 3 days as effective as tetracycline [37] Ampicillin, erythromycin Ampicillin or erythromycin or tetracycline given ever 6 hours for 3 days was significantly more effective than placebo in children for reducing stool volume and volume of ORS consumed [39,46,47] 5-Hydroxytryptamine (serotonin) receptor antagonists: granisetron, ketanserin, tropisetron,* ondansetron, and alosetron…”

Enterotoxins, enteric nerves, and intestinal secretion

“…Further evidence that a 5-HT-initiated neural secretory reflex is important in cholera is derived from pharmacologic inhibition studies in animal models [17][18][19], although the most profound inhibitory effects can only be achieved when the 5-HT antagonist is administered prior to exposure to cholera toxin. Some but not all studies of 5-HT 2 and 5-HT 3 antagonists in humans have provided further support of a role for 5-HT in cholera secretion [20][21][22].…”