Pharmacotherapy of the ion transport defect in cystic fibrosis

Kunzelmann, K. and Mall, M. (2001) Pharmacotherapy of the ion transport defect in cystic fibrosis. Clinical And Experimental Pharmacology And Physiology, 28 11: 857-867. doi:10.1046/j.1440-1681.2001.03541.x

Author Kunzelmann, K.
Mall, M.
Title Pharmacotherapy of the ion transport defect in cystic fibrosis
Journal name Clinical And Experimental Pharmacology And Physiology   Check publisher's open access policy
ISSN 0305-1870
Publication date 2001
Sub-type Critical review of research, literature review, critical commentary
DOI 10.1046/j.1440-1681.2001.03541.x
Volume 28
Issue 11
Start page 857
End page 867
Total pages 11
Place of publication Australia
Publisher Blackwell Science Asia
Collection year 2001
Language eng
Subject C1
270104 Membrane Biology
730110 Respiratory system and diseases (incl. asthma)
0606 Physiology
1115 Pharmacology and Pharmaceutical Sciences
Abstract 1. More than 1300 different mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF), a disease characterized by deficient epithelial Cl- secretion and enhanced Na+ absorption. The clinical course of the disease is determined by the progressive lung disease. Thus, novel approaches in pharmacotherapy are based primarily on correction of the ion transport defect in the airways. 2. The current therapeutic strategies try to counteract the deficiency in Cl- secretion and the enhanced Na+ absorption. A number of compounds have been identified, such as genistein and xanthine derivatives, which directly activate mutant CFTR. Other compounds may activate alternative Ca2+-activated Cl- channels or basolateral K+ channels, which supply the driving force for Cl- secretion. Apart from that, Na+ channel blockers, such as phenamil and benzamil, are being explored, which counteract the hyperabsorption of NaCl in CF airways. 3. Clinical trials are under way using purinergic compounds such as the P2Y(2) receptor agonist INS365. Activation of P2Y(2) receptors has been found to both activate Cl- secretion and inhibit Na+ absorption. 4. The ultimate goal is to recover Cl- channel activity of mutant CFTR by either enhancing synthesis and expression of the protein or by activating silent CFTR Cl- channels. Strategies combining these drugs with compounds facilitating Cl- secretion and inhibiting Na+ absorption in vivo may have the best chance to counteract the ion transport defect in cystic fibrosis.
Keyword Pharmacology & Pharmacy
Cystic Fibrosis
Cystic Fibrosis Transmembrane Conductance Regulator
Epithelial Na+ Channel
Transmembrane Conductance Regulator
Nasal Potential Difference
Human Bronchial Epithelia
Chloride Channel
Delta-f508 Cftr
Cl Secretion
Pharmacological Treatment
Uridine 5'-triphosphate
Mucociliary Clearance
Q-Index Code C1

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collection: School of Biomedical Sciences Publications
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Citation counts: TR Web of Science Citation Count  Cited 25 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 14 Aug 2007, 15:12:08 EST