Evaluation of second generation amiloride analogs as therapy for cystic fibrosis lung disease

Andrew J. Hirsh, Juan R. Sabater, Andra Zamurs, Rick T. Smith, Anthony M. Paradiso, Sam Hopkins, William M. Abraham, Richard C. Boucher

Research output: Contribution to journalArticle

81 Citations (Scopus)

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, the maximal efficacy was benzamil = phenamil = amiloride, the recovery to baseline sodium transport was phenamil < benzamil ≪ amiloride, and the rate of drug absorption was phenamil > benzamil ≫ amiloride. Based on greater potency, benzamil was compared with amiloride in in vivo pharmacodynamic studies in sheep, including tracheal mucus velocity (TMV) and 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 equieffective with amiloride in vivo. More potent, less absorbable, third generation ENaC blockers will be required for an effective aerosol CF pharmacotherapy.

Original languageEnglish
Pages (from-to)929-938
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume311
Issue number3
DOIs
StatePublished - Dec 1 2004
Externally publishedYes

Fingerprint

Amiloride
Cystic Fibrosis
Lung Diseases
Mucus
Sheep
Therapeutics
Aerosols
Epithelial Sodium Channel Blockers
benzamil
Therapeutic Uses
Epithelium
Epithelial Cells
Sodium
phenylamil
Drug Therapy
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology

Cite this

Hirsh, A. J., Sabater, J. R., Zamurs, A., Smith, R. T., Paradiso, A. M., Hopkins, S., ... Boucher, R. C. (2004). Evaluation of second generation amiloride analogs as therapy for cystic fibrosis lung disease. Journal of Pharmacology and Experimental Therapeutics, 311(3), 929-938. https://doi.org/10.1124/jpet.104.071886

Evaluation of second generation amiloride analogs as therapy for cystic fibrosis lung disease. / Hirsh, Andrew J.; Sabater, Juan R.; Zamurs, Andra; Smith, Rick T.; Paradiso, Anthony M.; Hopkins, Sam; Abraham, William M.; Boucher, Richard C.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 311, No. 3, 01.12.2004, p. 929-938.

Research output: Contribution to journalArticle

Hirsh, AJ, Sabater, JR, Zamurs, A, Smith, RT, Paradiso, AM, Hopkins, S, Abraham, WM & Boucher, RC 2004, 'Evaluation of second generation amiloride analogs as therapy for cystic fibrosis lung disease', Journal of Pharmacology and Experimental Therapeutics, vol. 311, no. 3, pp. 929-938. https://doi.org/10.1124/jpet.104.071886
Hirsh, Andrew J. ; Sabater, Juan R. ; Zamurs, Andra ; Smith, Rick T. ; Paradiso, Anthony M. ; Hopkins, Sam ; Abraham, William M. ; Boucher, Richard C. / Evaluation of second generation amiloride analogs as therapy for cystic fibrosis lung disease. In: Journal of Pharmacology and Experimental Therapeutics. 2004 ; Vol. 311, No. 3. pp. 929-938.
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