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[Effect of AS-35 aerosol on bronchoconstriction induced by specific antigens in macacus rhesus monkeys]
H Takata1, G Tamura, A Shibasaki
1First Department of Internal Medicine, Tohoku University School of Medicine.
Abstract:
In a previous in vitro study, 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy) methyl]-3-(1H-tetrazol-5-yl)-4H- pyrido[1,2-a]pyrimidin-4-one (AS-35) was shown to have an inhibitory effect on antigen-induced mediator release and an antagonistic effect on leukotriene C4 and D4 receptors. In the present study, therefore, we investigated the effect of AS-35 aerosol on allergen-induced bronchoconstriction, using 6 female Macacus rhesus monkeys sensitized with DNP-Ascaris extracts (DNP-As). After treatment with an inactive placebo, inhalation challenge with DNP-As increased total lung resistance and decreased dynamic lung compliance dose-dependently 1 week after sensitization with DNP-As. Treatment with AS-35 aerosol, however, significantly inhibited allergen-induced bronchoconstriction dose-dependently 2 weeks after the sensitization. The inhibitory effect was about ten times more potent than that of DSCG. Because we confirmed that DNP-As evoked almost the same bronchoconstriction 1 and 2 weeks after sensitization and also that AS-35 did not inhibit histamine-induced bronchoconstriction at all, we inferred that AS-35 diminished allergen-induced bronchoconstriction by inhibiting allergen-induced mediator release from the cells in the airway.
Insights
AS-35 aerosol effectively inhibited allergen-induced bronchoconstriction in monkeys. This compound, a pyrido[1,2-a]pyrimidin-4-one derivative, works by blocking allergen-induced mediator release.
Area of Science:
- Pharmacology
- Respiratory Medicine
- Immunology
Context:
- Asthma and allergic respiratory diseases represent a significant global health burden.
- Current treatments aim to manage symptoms and underlying inflammatory processes.
- Novel therapeutic agents targeting specific pathways in allergic responses are continuously sought.
Purpose:
- To evaluate the efficacy of 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy) methyl]-3-(1H-tetrazol-5-yl)-4H- pyrido[1,2-a]pyrimidin-4-one (AS-35) aerosol in mitigating allergen-induced bronchoconstriction.
- To compare the potency of AS-35 with disodium cromoglycate (DSCG).
- To elucidate the mechanism of action of AS-35 in an in vivo model.
Summary:
- AS-35 aerosol demonstrated a significant dose-dependent inhibition of allergen-induced bronchoconstriction in DNP-Ascaris extract-sensitized rhesus monkeys.
- The inhibitory effect of AS-35 was approximately tenfold more potent than that of DSCG.
- AS-35 did not affect histamine-induced bronchoconstriction, suggesting its mechanism involves inhibiting allergen-induced mediator release rather than direct receptor antagonism.
Impact:
- These findings suggest AS-35 holds potential as a therapeutic agent for allergic airway diseases like asthma.
- The study provides in vivo evidence supporting the in vitro findings of AS-35's inhibitory effects on mediator release.
- Further research into AS-35 could lead to the development of more effective treatments for allergic respiratory conditions.