Inhibitory effect of aerosol administration of a sulfidopeptide leukotriene antagonist on bronchoconstriction induced by antigen inhalation in guinea pigs.
The effects of inhalation of the sulfidopeptide leukotriene antagonist AS-35 (9-[(4-Acetyl-3-hydroxy-2-n-propyl-phenoxy)methyl]-3-(1H- tetrazol-5-yl)-4H-pyrido [1,2-a]pyrimidin-4-one, CAS 108427-72-1) on bronchoconstriction induced by aerosol antigen, histamine, and leukotriene C4, D4 (LTC4, D4) were investigated in anesthetized and artificially ventilated guinea pigs. The increase in pressure at the airway opening (P(ao)) was measured as an index representing the grade of bronchial response. The bronchoconstriction induced by aerosol antigen was suppressed dose-dependently by pretreatment with inhaled AS-35 (0.1 mg and 1 mg) through a pressurized meter-dosed inhaler in the passively sensitized animals pretreated with diphenhydramine hydrochloride. But the histamine-induced bronchoconstriction was not altered by the pretreatment with AS-35 inhalation. On the other hand, LTC4- and LTD4-induced bronchoconstriction was inhibited by the pretreatment with aerosol AS-35 in a dose-dependent manner. The deposited dose of inhaled AS-35 in the peripheral airways was 3.5 micrograms and 6.5 micrograms when 0.1 mg and 1 mg of the drug was inhaled, respectively. These results suggest that sulfidopeptide leukotrienes (s-LTs) play an important role in the allergic bronchoconstriction in guinea pigs pretreated with antihistamine, and AS-35 inhalation may be beneficial in the treatment of asthma.
Bando
T
T
Third Department of Internal Medicine, Kanazawa University School of Medicine, Japan.
Fujimura
M
M
Shintani
H
H
Saito
M
M
Kurashima
K
K
Nishi
K
K
Matsuda
T
T
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology*; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000494:pharmacology; D020024:Leukotriene Antagonists; D017997:Leukotriene C4 / Q000037:antagonists & inhibitors; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors; D008297:Male; D010047:Ovalbumin / Q000276:immunology; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D012130:Respiratory Hypersensitivity / Q000503:physiopathology; D013777:Tetrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D000336:Aerosols; D000941:Antigens; D001993:Bronchodilator Agents; D006633:Histamine Antagonists; D020024:Leukotriene Antagonists; D011725:Pyridines; D011744:Pyrimidinones; D013777:Tetrazoles; C073308:AS 35; D017997:Leukotriene C4; D017998:Leukotriene D4; D010047:Ovalbumin