Electrophysiological Studies into the Safety of the Anti-diarrheal Drug Clotrimazole during Oral Rehydration Therapy

Abstract

Background and AimsMorbidity and mortality from acute diarrheal disease remains high, particularly in developing countries and in cases of natural or man-made disasters. Previous work has shown that the small molecule clotrimazole inhibits intestinal Cl- secretion by blocking both cyclic nucleotide- and Ca2+-gated K+ channels, implicating its use in the treatment of diarrhea of diverse etiologies. Clotrimazole, however, might also inhibit transporters that mediate the inwardly directed electrochemical potential for Na+-dependent solute absorption, which would undermine its clinical application. Here we test this possibility by examining the effects of clotrimazole on Na+-coupled glucose uptake.Materials and MethodsShort-circuit currents (Isc) following administration of glucose and secretagogues were studied in clotrimazole-treated jejunal sections of mouse intestine mounted in Ussing chambers.ResultsTreatment of small intestinal tissue with clotrimazole inhibited the Cl- secretory currents that resulted from challenge with the cAMP-agonist vasoactive intestinal peptide (VIP) or Ca2+-agonist carbachol in a dose-dependent fashion. A dose of 30 μM was effective in significantly reducing the Isc response to VIP and carbachol by 50% and 72%, respectively. At this dose, uptake of glucose was only marginally affected (decreased by 14%, p = 0.37). There was no measurable effect on SGLT1-mediated sugar transport, as uptake of SGLT1-restricted 3-O-methyl glucose was equivalent between clotrimazole-treated and untreated tissue (98% vs. 100%, p = 0.90).ConclusionTreatment of intestinal tissue with clotrimazole significantly reduced secretory responses caused by both cAMP- and Ca2+-dependent agonists as expected, but did not affect Na+-coupled glucose absorption. Clotrimazole could thus be used in conjunction with oral rehydration solution as a low-cost, auxiliary treatment of acute secretory diarrheas.

Dietary Genistein Rescues Reduced Basal Chloride Secretion in Diabetic Jejunum via Sex-Dependent Mechanisms

“…The concentrations of DIDS, clotrimazole, bumetanide and acetazolamide were as used previously [8,18]. The concentration of clotrimazole used is within the range of doses used in the literature (from 10 µM in colonic T84 cells [23], to 30 µM in human rectal tissue [24], to 150 µM in murine jejunum [25]. Glucose (10 mM, mucosal) was added at the end of each experiment to stimulate Na + -coupled glucose transport, as an assessment of tissue viability (denoted by > 10% increase in I sc ).…”

Congenital sodium diarrhoea caused by rare de novo activating guanylate cyclase mutation

“…Antifungal drug clotrimazole has been demonstrated to be a potent blocker of basolateral cAMP and Ca2+ gated K+ channels in enterocytes and therefore potentially has therapeutic efficacy for secretory diarrhoeas 14…”

The Cutting Edge of Gastroenteritis

“…NHE3 agonists have been shown to block secretion in cholera toxin mediated murine models (32). Clotrimazole has been shown to block cAMP mediated chloride channels and Ca 2+ mediated K + channels, demonstrating decreased secretion in murine models (33). Multiple other anti‐secretory agents have been identified in vitro or in animal studies, with further investigation pending.…”