| Talniflumate increases survival in a cystic fibrosis mouse model of distal intestinal obstructive syndrome. | |
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MedLine Citation:
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PMID: 16354791 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Intestinal disease in cystic fibrosis (CF) mice closely mirrors aspects of obstructive syndromes in CF patients. The pathogenesis involves accumulation of mucoid debris in the crypts that fuse with intestinal content to form obstructing mucofeculant impactions. Treatment involves modalities that increase the fluidity of the luminal content, such as osmotic laxatives and liquid diets. We investigated the effects of talniflumate (Lomucin, Genaera Corporation, Plymouth Meeting, PA), a compound that may be beneficial to treatment of CF intestinal disease based on three mechanisms of action: mucus synthesis inhibition by blockade of the murine calcium-activated chloride channel 3 (mCLCA3), nonsteroidal anti-inflammatory effects, and inhibition of Cl(-)/HCO (-)(3) exchanger(s) involved in intestinal NaCl absorption. Cohorts of CF mice were fed control diet or diets containing either talniflumate (0.4 mg/g chow) or ibuprofen (0.4 mg/g chow) for 21 days to assess survival. Talniflumate significantly increased CF mouse survival from 26 to 77%, whereas ibuprofen had no effect (22% survival). Oral talniflumate did not alter crypt goblet cell numbers or change intestinal expression of mCLCA3 but tended to decrease crypt mucoid impaction. Ussing chamber studies indicated that talniflumate slightly increased the basal short-circuit current of CF intestine, but the change was not sensitive to secretagogue stimulation or bumetanide inhibition. In contrast, intracellular pH measurements of intact intestinal villous epithelium indicated that talniflumate significantly inhibited apical membrane Cl(-)/HCO (-)(3) exchange by >50%. We conclude that oral talniflumate increases the survival of CF mice, possibly by the beneficial effects of decreasing small intestinal NaCl absorption through the inhibition of apical membrane Cl(-)/HCO (-)(3) exchanger(s). |
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Authors:
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Nancy M Walker; Janet E Simpson; Roy C Levitt; Kathryn T Boyle; Lane L Clarke |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2005-12-14 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 317 ISSN: 0022-3565 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2006 Apr |
Date Detail:
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Created Date: 2006-03-22 Completed Date: 2006-05-25 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 275-83 Citation Subset: IM |
Affiliation:
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Dalton Cardiovascular Research Center, University of Missouri, Columbia, 65211, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anti-Inflammatory Agents, Non-Steroidal / therapeutic use* Benzofurans / therapeutic use* Cell Count Chloride Channels / biosynthesis Cystic Fibrosis / complications*, genetics Cystic Fibrosis Transmembrane Conductance Regulator / genetics Disease Models, Animal Hydrogen-Ion Concentration Intestinal Mucosa / cytology, drug effects, metabolism Intestinal Obstruction / drug therapy*, etiology, metabolism Intestine, Small / cytology, drug effects, metabolism Ion Transport / drug effects Mice Mucins / biosynthesis Mucoproteins / biosynthesis Mutation Pyridines / therapeutic use* |
| Grant Support | |
ID/Acronym/Agency:
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DK44816/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Anti-Inflammatory Agents, Non-Steroidal; 0/Benzofurans; 0/Chloride Channels; 0/Clca3 protein, mouse; 0/Mucins; 0/Mucoproteins; 0/Pyridines; 0/talniflumate; 126880-72-6/Cystic Fibrosis Transmembrane Conductance Regulator |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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