sch-37224 and Hypersensitivity

Sulfidopeptide leukotrienes (LTs) C4, D4 and E4 are important mediators in the pathophysiology of bronchial asthma. Sch 37224, 1-(1,2-dihydro-4-hydroxy-2-oxo-1-phenyl-1,8-naphthyridin-3-yl) pyrrolidinium, hydroxide inner salt, has been found to inhibit the formation of these autocoids. Although Sch 37224 did not inhibit 5-lipoxygenase, cyclooxygenase or phospholipase A2, it inhibited LTD4 and thromboxane B2 release by anaphylactic guinea pig lung (IC40 = 3.9 and 1.9 microM, respectively). At 5 microM Sch 37224 also inhibited superoxide anion radical generation from activated human polymorphonuclear neutrophilic leukocytes. When administered p.o. to guinea pigs, Sch 37224 decreased a LT-mediated allergic bronchospasm (ED40 = 1.1 mg/kg) for 6 hr and did not exhibit tolerance. In addition to its activities in allergen-induced bronchospasm in guinea pigs, Sch 37224 also inhibited hyperventilation-induced bronchospasm in guinea pigs at 0.5 to 5 mg/kg and anaphylactic bronchospasm in rats at 0.1 to 10 mg/kg. Sch 37224 was weak or ineffective as an antagonist of histamine, methacholine, serotonin, LTC4 or platelet activating factor induced bronchospasms in guinea pigs. Also, Sch 37224 was not a bronchodilator or calcium influx blocker and had only weak relaxant activity on guinea pig trachea in vitro (IC40 = 51 microM). Sch 37224 is, therefore, a potential antiallergic agent that inhibits LT release. It is p.o. effective in animal models of allergic and nonallergic-mediated bronchospasms.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Bronchi; Bronchial Spasm; Guinea Pigs; Histamine H1 Antagonists; Histamine Release; Hypersensitivity; In Vitro Techniques; Leukotriene Antagonists; Leukotrienes; Male; Naphthyridines; Rats; Thromboxane B2

Peptide leukotrienes and thromboxane A2 are putative mediators of allergen-induced late responses and allergen-induced airway hyperresponsiveness (AHR), respectively. Sch 37224 blocks antigen-induced leukotriene D4 and thromboxane B2 release in guinea pig lung fragments. It also inhibits leukotriene-mediated allergic guinea pig bronchospasm. Sch 37224 was, therefore, tested in allergic sheep (n = 6) with documented immediate and late airway responses and AHR to inhaled Ascaris suum antigen. For these studies, base-line airway dose-response curves to histamine and carbachol were determined on the same day. The sheep were challenged 1 to 2 days later with Ascaris suum antigen, once after placebo treatment and once after 10 mg/kg of Sch 37224, administered orally 18 and 2 hr before challenge (total dose, 20 mg/kg). Airway dose-response curves were subsequently performed 24 hr after antigen challenge. In the placebo trial, antigen challenge caused significant peak immediate and peak late increases over base line in specific lung resistance (SRL) of 286 +/- 51 and 196 +/- 29%, respectively. SRL returned to baseline values 24 hr later, but the sheep had AHR to both histamine and carbachol as indicated by 2.6- and 3.1-fold increases in the slopes of the dose-response curves (P less than .05). Sch 37224 treatment reduced the peak immediate and peak late increases in SRL to 128 +/- 32 and 43 +/- 17%, respectively (both P less than .05 vs. placebo). Furthermore, 24 hr later, the antigen-induced AHR to both histamine and carbachol was blocked (P less than .05 vs. placebo).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antigens; Bronchi; Carbachol; Dose-Response Relationship, Drug; Histamine; Hypersensitivity; Leukotriene Antagonists; Naphthyridines; Sheep; Thromboxanes