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

Background and aims: morbidity 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 methods: short-circuit currents (isc) following administration of glucose and secretagogues were studied in clotrimazole-treated jejunal sections of mouse intestine mounted in ussing chambers. results: treatment 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). conclusion: treatment 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. © 2015 lexmond et al.