Pharmacological evaluation of selective α2c-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 α2c-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 α2c-adrenergic agonists. Acoustic rhinometry was used to determine nasal cavity dimensions following intranasal compound 48/80 (1%, 75 µl). 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 d-pseudoephedrine, compounds A and B did not alter systolic blood pressure. The plasma exposure of compound A to produce a robust decongestion (EC(80)) was 500 nM, which related well 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 α2c-adrenergic agonists behave as nasal decongestants without cardiovascular actions in animal models of upper airway congestion.
Departments of In Vivo Pharmacology (G.G.M., J.C.H., G.B.L., M.C., J.A.H., R.L.M.) and Immunology (Y.J.), Merck Research Laboratories, Boston, Massachusetts; Departments of Pharmacokinetics (J.R.P., H.M.) and Chemistry (C.W.B.), Merck Research Laboratories, Rahway, New Jersey; and Department of Cell Biology, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma (M.C.K., Y.Y.).
Yanlin
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Jia
Garfield G
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Mingo
John C
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Hunter
Gissela B
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Lieber
Jairam R
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Palamanda
Hong
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Mei
Christopher W
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Boyce
Michael C
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Koss
Yongxin
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Milenko
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Cicmil
John A
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Hey
Robbie L
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McLeod
D000281:Administration, Intranasal; D000284:Administration, Oral; D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D002415:Cats; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D014663:Nasal Decongestants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D009297:Nasal Mucosa / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D012223:Rhinitis, Vasomotor / Q000188:drug therapy* / Q000378:metabolism; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects
D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D014663:Nasal Decongestants; D018341:Receptors, Adrenergic, alpha-2