AbstractThe effects of NZ-107 on some airway inflammation models and the generation of superoxide anion (O2−) were studied in guinea-pigs. Airway inflammation was caused by intra-tracheal injection of murine recombinant interleukin-5 (mrIL-5, 15 μg/animal), inhalation of platelet-activating factor (PAF, 0·003%) and intra-tracheal injection of leukotriene B4 (LTB4, 10 μg/animal). NZ-107 (4-bromo-5-(3-ethoxy-4-methoxybenzylamino)-3(2H)-pyridazinone) at a dose of 50 mg kg−1, intraperitoneally reduced mrIL-5- and PAF-induced eosinophilia. This compound at a dose of 25 and 50 mg kg−1 also suppressed LTB4-induced eosinophilia and neutrophilia in bronchoalveolar lavage fluid (BALF). On the other hand, prednisolone at a dose of 20 mg kg−1, i.p., prevented the increased number of macrophages, eosinophils and neutrophils induced by mrIL-5, the increased number of eosinophils induced by PAF and the increased number of eosinophils and neutrophils induced by LTB4 in BALF. Furthermore, both drugs reduced mrIL-5- or PAF-induced increase in the number of airway epithelial cells in BALF. The generation of O2− was measured by the method of cytochrome C reduction. NZ-107 (10–100 μg mL−1) attenuated PAF- and FMLP-induced O2− production from macrophages and reduced PAF-induced O2− generation by eosinophils but had no effect on that from neutrophils. These results indicate that NZ-107 prevents the increased number of pulmonary eosinophils and airway epithelial cells and the activation of macrophages and eosinophils, suggesting that NZ-107 may be useful as a remedy for airway inflammatory diseases such as bronchial asthma.

01 Sep 1992·Prostaglandins, Leukotrienes and Essential Fatty AcidsQ3 · MEDICINE

Effects of a newly synthesized leukotriene antagonist, NZ-107, on immediate-type hypersensitivity reaction in rats and guinea-pigs

Q3 · MEDICINE

Article

Author: Toru Miura ; Akihide Koda ; Hiroshi Suda ; Takehisa Iwama ; Hiroichi Nagai

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.

01 Jan 1992·International Archives of Allergy and ImmunologyQ3 · MEDICINE

Inhibitory Effect of NZ-107 on Anaphylactic Bronchoconstriction in Guinea Pigs and Rats

Q3 · MEDICINE

Article

Author: Yamamoto, Akiko ; Iwama, Takehisa ; Sakashita, Mitsuaki ; Hibi, Morihide ; Tanaka, Sakuya ; Shikada, Kenichi

We studied the effect of NZ-107 in a number of animal models of anaphylactic bronchoconstriction. In conscious guinea pigs, pretreated with indomethacin, pyrilamine and propranolol, passively sensitized with heterologous anti serum, NZ-107 in doses of 10-30 mg/kg per os inhibited the aerosolized antigen-induced cough and collapse. NZ-107 in a high dose of 100 mg/kg per os significantly prevented aerosolized antigen-induced anaphylactic collapse, but not cough in actively or passively sensitized conscious guinea pigs and also significantly protected aerosolized histamine-induced collapse, but not cough in conscious guinea pigs. This compound had little inhibitory effect on aerosolized acetylcholine-induced cough and collapse. In anesthetized animals, the effect of NZ-107 on bronchoconstriction induced by intravenous administration of antigen and various agonists was examined by the method of Konzett and Rössler. In doses of 10-50 mg/kg per os, NZ-107 inhibited antigen-induced bronchoconstriction in anesthetized guinea pigs. NZ-107 when intravenously administered to the anesthetized guinea pigs inhibited not only leukotriene D4-induced bronchoconstriction, but also thromboxane A2 mimetic U-46619-, platelet-activating factor- and histamine-induced bronchoconstriction. In anesthetized rats, NZ-107 in a dose of 300 mg/kg per os tended to inhibit the antigen-induced bronchoconstriction, but this effect was not significant. These results indicate that NZ-107 acts as a spasmolytic agent which inhibits bronchial responses to antigens or various other bronchoconstrictors in animal models, suggesting that NZ-107 may be potentially beneficial in the treatment of bronchial asthma.

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 1	-	Zeria Pharmaceutical Co., Ltd.	-
Asthma	Phase 1	-	Nissan Chemical Corp.	-
Asthma	Phase 1	JP	-	-

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