Dataset Information

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

ABSTRACT:

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 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.

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 Ca(2+)-agonist carbachol in a dose-dependent fashion. A dose of 30 ?M 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 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.

SUBMITTER: Lexmond WS

PROVIDER: S-EPMC4583490 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Lexmond Willem S WS Rufo Paul A PA Fiebiger Edda E Lencer Wayne I WI

PLoS neglected tropical diseases 20150925 9

<h4>Background and aims</h4>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 direc ...[more]

PMID: 26405813

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Project description:BackgroundOral rehydration solution (ORS) is a form of oral rehydration therapy (ORT) for diarrhoea that has the potential to drastically reduce child mortality; yet, according to UNICEF estimates, less than half of children younger than 5 years with diarrhoea in low-income and middle-income countries (LMICs) received ORS in 2016. A variety of recommended home fluids (RHF) exist as alternative forms of ORT; however, it is unclear whether RHF prevent child mortality. Previous studies have shown considerable variation between countries in ORS and RHF use, but subnational variation is unknown. This study aims to produce high-resolution geospatial estimates of relative and absolute coverage of ORS, RHF, and ORT (use of either ORS or RHF) in LMICs.MethodsWe used a Bayesian geostatistical model including 15 spatial covariates and data from 385 household surveys across 94 LMICs to estimate annual proportions of children younger than 5 years of age with diarrhoea who received ORS or RHF (or both) on continuous continent-wide surfaces in 2000-17, and aggregated results to policy-relevant administrative units. Additionally, we analysed geographical inequality in coverage across administrative units and estimated the number of diarrhoeal deaths averted by increased coverage over the study period. Uncertainty in the mean coverage estimates was calculated by taking 250 draws from the posterior joint distribution of the model and creating uncertainty intervals (UIs) with the 2·5th and 97·5th percentiles of those 250 draws.FindingsWhile ORS use among children with diarrhoea increased in some countries from 2000 to 2017, coverage remained below 50% in the majority (62·6%; 12 417 of 19 823) of second administrative-level units and an estimated 6 519 000 children (95% UI 5 254 000-7 733 000) with diarrhoea were not treated with any form of ORT in 2017. Increases in ORS use corresponded with declines in RHF in many locations, resulting in relatively constant overall ORT coverage from 2000 to 2017. Although ORS was uniformly distributed subnationally in some countries, within-country geographical inequalities persisted in others; 11 countries had at least a 50% difference in one of their units compared with the country mean. Increases in ORS use over time were correlated with declines in RHF use and in diarrhoeal mortality in many locations, and an estimated 52 230 diarrhoeal deaths (36 910-68 860) were averted by scaling up of ORS coverage between 2000 and 2017. Finally, we identified key subnational areas in Colombia, Nigeria, and Sudan as examples of where diarrhoeal mortality remains higher than average, while ORS coverage remains lower than average.InterpretationTo our knowledge, this study is the first to produce and map subnational estimates of ORS, RHF, and ORT coverage and attributable child diarrhoeal deaths across LMICs from 2000 to 2017, allowing for tracking progress over time. Our novel results, combined with detailed subnational estimates of diarrhoeal morbidity and mortality, can support subnational needs assessments aimed at furthering policy makers' understanding of within-country disparities. Over 50 years after the discovery that led to this simple, cheap, and life-saving therapy, large gains in reducing mortality could still be made by reducing geographical inequalities in ORS coverage.FundingBill & Melinda Gates Foundation.

Project description:BackgroundOral rehydration therapy (ORT) is an effective and cheap treatment for diarrheal disease; globally, one of the leading causes of death in children under five. The World Health Organization launched a global campaign to improve ORT coverage in 1978, with activities such as educational campaigns, training health workers and the creation of designate programming. Despite these efforts, ORT coverage remains relatively low. The objective of this systematic review is to identify the barriers and facilitators to the implementation of oral rehydration therapy in low and middle-income countries.MethodsA comprehensive search strategy comprised of relevant subject headings and keywords was executed in 5 databases including OVID Medline, OVID Embase, OVID HealthStar, Web of Science and Scopus. Eligible studies underwent quality assessment, and a directed content analysis approach to data extraction was conducted and aligned to the Consolidated Framework for Implementation Research (CFIR) to facilitate narrative synthesis.ResultsThe search identified 1570 citations and following removal of duplicates as well as screening according to our inclusion/exclusion criteria, 55 articles were eligible for inclusion in the review. Twenty-three countries were represented in this review, with India, Bangladesh, Egypt, Nigeria, and South Africa having the most representation of available studies. Study dates ranged from 1981 to 2020. Overarching thematic areas spanning the barriers and facilitators that were identified included: availability and accessibility, knowledge, partnership engagement, and design and acceptability.ConclusionA systematic review of studies on implementation of ORT in low- and middle-income countries (LMICs) highlights key activities that facilitate the development of successful implementation that include: (1) availability and accessibility of ORT, (2) awareness and education among communities, (3) strong partnership engagement strategies, and (4) adaptable design to enhance acceptability. The barriers and facilitators identified under the CIFR domains can be used to build knowledge on how to adapt ORT to national and local settings and contribute to a better understanding on the implementation and use of ORT in LMICs. The prospects for scaling and sustaining ORT (after years of low use) will increase if implementation research informs local applications, and implementers engage appropriate stakeholders and test assumptions around localized theories of change from interventions to expected outcomes.RegistrationA protocol for this systematic review was developed and uploaded onto the PROSPERO international prospective register of systematic reviews database (Registration number: CRD420201695).

Dataset Information

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

Background and aims

Materials and methods

Results

Conclusion

Publications

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

Similar Datasets

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