ArticleThe Journal of general physiology2013
Convective washout reduces the antidiarrheal efficacy of enterocyte surface-targeted antisecretory drugs.
Article in The Journal of general physiology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
18 citing papers in PubMed, 25 citations in OpenAlex.
- A Phase 2a randomized, single-center, double-blind, placebo-controlled study to evaluate the safety and preliminary efficacy of oral iOWH032 against cholera diarrhea in a controlled human infection model.PLoS neglected tropical diseases · 2021Trial
- Model of ocular surface ion and water transport predicts efficacy of dry eye therapeutics.The Journal of general physiology · 2026Article
- Epithelial plasma membrane transporters as drug targets.Physiological reviews · 2026Review
- Krisanaklan Reduces Intestinal Anion and Fluid Secretion Through Inhibition of NaAnnals of the New York Academy of Sciences · 2026Article
- Anti-Cryptosporidial Drug-Discovery Challenges and Existing Therapeutic Avenues: A "One-Health" Concern.Life (Basel, Switzerland) · 2024Review
- Article
- Chloride transport modulators as drug candidates.American journal of physiology. Cell physiology · 2021Review
- Optimization of the Urea Linker of Triazolopyridazine MMV665917 Results in a New Anticryptosporidial Lead with Improved Potency and Predicted hERG Safety Margin.Journal of medicinal chemistry · 2021Article
- Strategies for cystic fibrosis transmembrane conductance regulator inhibition: from molecular mechanisms to treatment for secretory diarrhoeas.FEBS letters · 2020Review
- Benzopyrimido-pyrrolo-oxazine-dione CFTR inhibitor (R)-BPO-27 for antisecretory therapy of diarrheas caused by bacterial enterotoxins.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2017Article
- Calcium-sensing receptor: A new target for therapy of diarrhea.World journal of gastroenterology · 2016Review
- Secretory diarrhoea: mechanisms and emerging therapies.Nature reviews. Gastroenterology & hepatology · 2015Review
- Antidiarrheal efficacy and cellular mechanisms of a Thai herbal remedy.PLoS neglected tropical diseases · 2014Article
- Discovery and development of antisecretory drugs for treating diarrheal diseases.Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association · 2014Review
- Chloride channel-targeted therapy for secretory diarrheas.Current opinion in pharmacology · 2013Review
- Diffusion against convection.The Journal of general physiology · 2013Article
- Response to "Diffusion versus convection".The Journal of general physiology · 2013Article
- CFTR inhibitors.Current pharmaceutical design · 2013Review
Corrections and comments
- Commented on by
- Commented on by
Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Secretory diarrheas such as cholera are a major cause of morbidity and mortality in developing countries. We previously introduced the concept of antisecretory therapy for diarrhea using chloride channel inhibitors targeting the cystic fibrosis transmembrane conductance regulator channel pore on the extracellular surface of enterocytes. However, a concern with this strategy is that rapid fluid secretion could cause convective drug washout that would limit the efficacy of extracellularly targeted inhibitors. Here, we developed a convection-diffusion model of washout in an anatomically accurate three-dimensional model of human intestine comprising cylindrical crypts and villi secreting fluid into a central lumen. Input parameters included initial lumen flow and inhibitor concentration, inhibitor dissociation constant (K(d)), crypt/villus secretion, and inhibitor diffusion. We modeled both membrane-impermeant and permeable inhibitors. The model predicted greatly reduced inhibitor efficacy for high crypt fluid secretion as occurs in cholera. We conclude that the antisecretory efficacy of an orally administered membrane-impermeant, surface-targeted inhibitor requires both (a) high inhibitor affinity (low nanomolar K(d)) to obtain sufficiently high luminal inhibitor concentration (>100-fold K(d)), and (b) sustained high luminal inhibitor concentration or slow inhibitor dissociation compared with oral administration frequency. Efficacy of a surface-targeted permeable inhibitor delivered from the blood requires high inhibitor permeability and blood concentration (relative to K(d)).
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.