Pharmacological Evaluation of Selective a2c-Adrenergic Agonists in Experimental Animal Models of Nasal Congestion

Nasal congestion is one of the most troublesome symptoms of many upper airways diseases. We characterized the effect of selective a2c-adrenergic agonists in animal models of nasal congestion. In porcine mucosa tissue, compound A and compound B contracted nasal veins with only modest effects on arteries. In in vivo experiments, we examined the nasal decongestant dose-response characteristics, pharmacokinetic/ pharmacodynamic relationship, duration of action, potential development of tolerance, and topical efficacy of a2c-adrenergic agonists. Acoustic rhinometry was used to determine nasal cavity dimensions following intranasal compound 48/80 (1%, 75 ml). In feline experiments, compound 48/80 decreased nasal cavity volume and minimum cross-sectional areas by 77% and 40%, respectively. Oral administration of compound A (0.1–3.0 mg/kg), compound B (0.3–5.0 mg/kg), and d-pseudoephedrine (0.3 and 1.0 mg/kg) produced dose-dependent decongestion. Unlike dpseudoephedrine, compounds A and B did not alter systolic blood pressure. The plasma exposure of compound A to produce a robust decongestion (EC80) was 500 nM, which relatedwell to the duration of action of approximately 4.0 hours. No tolerance to the decongestant effect of compound A (1.0 mg/kg p.o.) was observed. To study the topical efficacies of compounds A and B, the drugs were given topically 30 minutes after compound 48/80 (a therapeutic paradigm) where both agents reversed nasal congestion. Finally, nasal-decongestive activity was confirmed in the dog. We demonstrate that a2c-adrenergic agonists behave as nasal decongestants without cardiovascular actions in animal models of upper airway congestion.