Effects of fexofenadine hydrochloride in a guinea pig model of antigen-induced rhinitis.
Allergic rhinitis is an inflammatory disease of the nasal mucosa, induced by histamine, leukotrienes, and other substances released from mast cells. Fexofenadine hydrochloride, the active metabolite of terfenadine, is a novel, nonsedating antiallergic drug having H1 receptor antagonistic activity. Fexofenadine is effective for the treatment of allergic rhinitis. However, its mechanism of action in attenuating nasal congestion has not yet been elucidated. Therefore, we first examined the effects of fexofenadine on a guinea pig model of antigen-induced rhinitis. We also evaluated the effects of mepyramine, zafirlukast and ramatroban in this model; these drugs are an H1 receptor antagonist, a selective leukotriene antagonist and a selective thromboxane antagonist, respectively. Rhinitis was induced by ovalbumin (OVA) instillation into the nasal cavity of animals that had been sensitized by two earlier OVA injections (s.c. and i.p.). The nasal airway resistance was measured for 45 min after the challenge. Fexofenadine hydrochloride (20 mg/kg) and terfenadine (20 mg/kg) administered orally 70 min prior to the challenge significantly inhibited (fexofenadine, p < 0.001, terfenadine, p < 0.05) the increase in nasal airway resistance. Ramatroban (30 mg/kg) administered orally 60 min prior to the challenge also significantly inhibited (p < 0.05) the increase in nasal airway resistance. In contrast, mepyramine (3 mg/kg i.v.) and zafirlukast (3 mg/kg p.o.) failed to reduce the increase in nasal airway resistance. These results suggest that thromboxane may be involved in the increase in the nasal airway resistance in this model. Accordingly, fexofenadine may reduce the increase in nasal airway resistance by inhibiting the release of chemical mediators, including thromboxane, that are involved in the increase in nasal airway resistance in this model.
Sakairi
Takashi
T
Drug Safety Evaluation, Preclinical Development, Scientific Affairs, Sanofi-Aventis Group, Aventis Pharma Ltd., Kawagoe, Saitama, Japan. takashi.sakairi@sanofi-aventis.com
Suzuki
Katsuhisa
K
Makita
Shigeki
S
Wajima
Teruaki
T
Shakuto
Shuji
S
Yoshida
Yasushi
Y
Yaguchi
Masafumi
M
D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D019540:Area Under Curve; D002227:Carbazoles / Q000494:pharmacology; D004195:Disease Models, Animal; D006168:Guinea Pigs; D007211:Indoles; D015289:Leukotrienes / Q000502:physiology; D008297:Male; D010047:Ovalbumin / Q000276:immunology; D048448:Phenylcarbamates; D011738:Pyrilamine / Q000494:pharmacology; D012220:Rhinitis / Q000188:drug therapy*; D013449:Sulfonamides / Q000494:pharmacology; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013931:Thromboxanes / Q000502:physiology; D014105:Tosyl Compounds / Q000494:pharmacology
D018926:Anti-Allergic Agents; D002227:Carbazoles; D007211:Indoles; D015289:Leukotrienes; D048448:Phenylcarbamates; D013449:Sulfonamides; D013931:Thromboxanes; D014105:Tosyl Compounds; D016593:Terfenadine; D010047:Ovalbumin; C093230:fexofenadine; D011738:Pyrilamine; C063119:ramatroban; C062735:zafirlukast