Evaluation of second generation amiloride analogs as therapy for cystic fibrosis lung disease
| Autor: | Anthony M. Paradiso, Sam Hopkins, Andrew J. Hirsh, Richard C. Boucher, Juan R. Sabater, Andra Zamurs, Rick T. Smith, William M. Abraham |
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| Rok vydání: | 2004 |
| Předmět: |
Epithelial sodium channel
Lung Diseases medicine.medical_specialty Cystic Fibrosis Bronchi Pharmacology In Vitro Techniques Cystic fibrosis Epithelium Sodium Channels Absorption Amiloride chemistry.chemical_compound In vivo Internal medicine Benzamil medicine Potency Animals Humans Mannitol Epithelial Sodium Channels Microscopy Confocal Sheep business.industry Viscosity Sodium Epithelial Cells respiratory system medicine.disease In vitro Electrophysiology Mucus Endocrinology chemistry Pharmacodynamics Molecular Medicine Female business medicine.drug Muscle Contraction Sodium Channel Blockers |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 311(3) |
| ISSN: | 0022-3565 |
| Popis: | 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 benzamilphenamilamiloride, the maximal efficacy was benzamil = phenamil = amiloride, the recovery to baseline sodium transport was phenamilbenzamilamiloride, and the rate of drug absorption was phenamilbenzamilamiloride. 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. |
| Databáze: | OpenAIRE |
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