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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 23, 2004; DOI: 10.1124/jpet.104.071886

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Received for publication May 28, 2004.
Revised July 21, 2004.
Accepted for publication July 22, 2004.

EVALUATION OF SECOND GENERATION AMILORIDE ANALOGUES AS THERAPY FOR CF LUNG DISEASE

Andrew J Hirsh 1*, Juan R Sabater 2, Andra Zamurs 3, Rick Smith 3, Anthony Paradiso 4, Sam Hopkins 3, William M Abraham 2, Richard C Boucher 4

1 Parion Sciences and University of North Carolina at Chapel Hill, CF Center 2 University of Miami at Mount Sinai Medical Center 3 Parion Sciences 4 University of North Carolina at Chapel Hill, CF Center

* Address correspondence to: E-mail: ajhirsh{at}parion.com

Abstract

Epithelial sodium channel (ENaC) blockers have been proposed as a therapy to restore mucus clearance (MC) in cystic fibrosis (CF) airways. The therapeutic effects of the first generation ENaC blocker, amiloride, in CF patients, however, were minimal. Because the failure of amiloride reflected both its low potency and short duration of action on airway surfaces, we investigated whether the increased potency of benzamil and phenamil would produce more favorable pharmacodynamic properties. In vitro potency, maximal efficacy, rate of recovery from maximal block of ENaC, and rate of drug absorption were compared for amiloride, benzamil and phenamil in cultured human and ovine bronchial epithelial cells. In both human and ovine bronchial epithelia, the rank order of potency was benzamil > phenamil >> amiloride; 2) the maximal efficacy was benzamil = phenamil = amiloride; 3) the recovery to baseline sodium transport was phenamil < benzamil << amiloride; and 4) the rate of drug absorption was phenamil > benzamil >> amiloride. Based on greater potency, benzamil was compared to amiloride in vivo pharmacodynamic studies in sheep, including tracheal mucus velocity (TMV) and mucus clearance (MC). Benzamil enhanced MC and TMV, but acute potency or duration of effect did not exceed that of amiloride. In conclusion, our data support the hypothesis that ENaC blocker aerosol therapy increases MC. However, rapid absorption of benzamil from the mucosal surface offset its greater potency, making it equi-effective with amiloride in vivo. More potent, less absorbable, third generation ENaC blockers will be required for an effective aerosol CF pharmacotherapy.


Key words: Benzamil, Epithelial sodium channels, airway surface liquid, cystic fibrosis, mucociliary clearance, sodium channel blockers


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