Electrophysiological Studies into the Safety of the Anti-diarrheal Drug Clotrimazole during Oral Rehydration Therapy.
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 Ca(2+)-gated K...
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ftdoajarticles:oai:doaj.org/article:3d1b4a164ef8496e9cad9c6aab861c20 2023-05-15T15:13:06+02:00 Electrophysiological Studies into the Safety of the Anti-diarrheal Drug Clotrimazole during Oral Rehydration Therapy. Willem S Lexmond Paul A Rufo Edda Fiebiger Wayne I Lencer 2015-09-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0004098 https://doaj.org/article/3d1b4a164ef8496e9cad9c6aab861c20 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC4583490?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004098 https://doaj.org/article/3d1b4a164ef8496e9cad9c6aab861c20 PLoS Neglected Tropical Diseases, Vol 9, Iss 9, p e0004098 (2015) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2015 ftdoajarticles https://doi.org/10.1371/journal.pntd.0004098 2022-12-31T12:31:34Z 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 Ca(2+)-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.Short-circuit currents (Isc) following administration of glucose and secretagogues were studied in clotrimazole-treated jejunal sections of mouse intestine mounted in Ussing chambers.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 Ca(2+)-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).Treatment of intestinal tissue with clotrimazole significantly reduced secretory responses caused by both cAMP- and Ca(2+)-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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 9 9 e0004098 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Willem S Lexmond Paul A Rufo Edda Fiebiger Wayne I Lencer Electrophysiological Studies into the Safety of the Anti-diarrheal Drug Clotrimazole during Oral Rehydration Therapy. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
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 Ca(2+)-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.Short-circuit currents (Isc) following administration of glucose and secretagogues were studied in clotrimazole-treated jejunal sections of mouse intestine mounted in Ussing chambers.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 Ca(2+)-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).Treatment of intestinal tissue with clotrimazole significantly reduced secretory responses caused by both cAMP- and Ca(2+)-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. |
format |
Article in Journal/Newspaper |
author |
Willem S Lexmond Paul A Rufo Edda Fiebiger Wayne I Lencer |
author_facet |
Willem S Lexmond Paul A Rufo Edda Fiebiger Wayne I Lencer |
author_sort |
Willem S Lexmond |
title |
Electrophysiological Studies into the Safety of the Anti-diarrheal Drug Clotrimazole during Oral Rehydration Therapy. |
title_short |
Electrophysiological Studies into the Safety of the Anti-diarrheal Drug Clotrimazole during Oral Rehydration Therapy. |
title_full |
Electrophysiological Studies into the Safety of the Anti-diarrheal Drug Clotrimazole during Oral Rehydration Therapy. |
title_fullStr |
Electrophysiological Studies into the Safety of the Anti-diarrheal Drug Clotrimazole during Oral Rehydration Therapy. |
title_full_unstemmed |
Electrophysiological Studies into the Safety of the Anti-diarrheal Drug Clotrimazole during Oral Rehydration Therapy. |
title_sort |
electrophysiological studies into the safety of the anti-diarrheal drug clotrimazole during oral rehydration therapy. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2015 |
url |
https://doi.org/10.1371/journal.pntd.0004098 https://doaj.org/article/3d1b4a164ef8496e9cad9c6aab861c20 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 9, Iss 9, p e0004098 (2015) |
op_relation |
http://europepmc.org/articles/PMC4583490?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004098 https://doaj.org/article/3d1b4a164ef8496e9cad9c6aab861c20 |
op_doi |
https://doi.org/10.1371/journal.pntd.0004098 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
9 |
container_issue |
9 |
container_start_page |
e0004098 |
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1766343695050735616 |