NZ-107

The effects of 4-bromo-5-(3-ethoxy-4-methoxybenzylamino)-3(2H)-pyridazinone (NZ-107) on immediate type hypersensitivity reactions in rats and guinea-pigs were studied. 1. When NZ-107, at a dose of 50 mg/kg (i.p.) or 100 mg/kg (orally), was administered to rats, 48-h homologous passive cutaneous anaphylaxis (PCA) reaction and histamine-, leukotriene C4 (LTC4)- and leukotriene D4 (LTD4)-induced skin reactions were suppressed by the agent. 2. NZ-107 (10(-6) g/ml) inhibited both LTC4- and LTD4-induced contractions of isolated rat stomach smooth muscle. 3. NZ-107 inhibited antigen-induced histamine release from rat peritoneal mast cells by 26% at a concentration of 10(-4) g/ml. 4. NZ-107, at doses of 25 and 50 mg/kg (orally), significantly inhibited guinea-pig 3-h heterologous PCA reaction. 5. NZ-107 inhibited antigen-induced histamine release from guinea-pig lung tissue by 17% and 48% at concentrations of 5 x 10(-5) and 10(-4) g/ml, respectively. 6. NZ-107, at doses of 25 and 50 mg/kg (i.p.), inhibited antigen-induced bronchoconstriction and eosinophil accumulation in the bronchoalveolar lavage fluid (BALF) of guinea-pigs. These results suggest that NZ-107 has anti-allergic action including inhibition of eosinophil accumulation in an antigen-challenged airway lesion in rats and guinea-pigs. The anti-allergic action of this agent is thought to be due to its action as a histamine and LT antagonist and its consequent inhibition of antigen-induced histamine release.

The effect of 4-bromo-5-(3-ethoxy-4-methoxybenzylamino)-3(2H)-pyridazinone (NZ-107) on bronchoconstriction in guinea pigs was studied (1). The antigen-induced bronchoconstriction was studied in guinea pigs which had been passively sensitized by intravenous injection of antiserum containing anti-benzylpenicilloyl bovine-gamma-globulin IgE antibody. The sensitized guinea pigs were divided into two groups; one group was pretreated with metyrapone (11 beta-hydroxylase inhibitor in glucocorticoid metabolism) and the other with saline. The antigen-induced bronchoconstriction in the metyrapone-treated animals was more severe than that in the saline-treated animals. The asthmatic respiratory changes, in terms of prolongation of the ratio between expiration and inspiration, was also dramatically increased. NZ-107 at doses of 25 and 50 mg/kg significantly inhibited antigen-induced bronchoconstriction in both the saline-and metyrapone-treated animals. NZ-107 showed a tendency to inhibit accelerated severe asthmatic respiration more strongly in metyrapone-treated animals than in those treated with saline. Salbutamol inhibited antigen-induced bronchoconstriction in saline-treated animals, but its efficacy decreased in metyrapone-treated animals. Unlike salbutamol, prednisolone and hydrocortisone showed the reverse effect, inhibiting bronchoconstriction in metyrapone-but not in saline-treated animals. Sodium cromoglycate inhibited antigen-induced bronchoconstriction in both saline- and metyrapone-treated animals (2). When a subthreshold dose of platelet-activating factor was injected into guinea pigs, airway responsiveness against histamine was clearly increased. NZ-107 at a dose of 0.2 mg/kg i.v. inhibited PAF-induced airway hyperreactivity.(ABSTRACT TRUNCATED AT 250 WORDS)