Reactive oxygen-derived free radical species have been implicated in the pathogenesis and pathophysiology of inflammatory lung diseases. In a guinea pig model of aerosolized endotoxin-induced bronchial hyperresponsiveness to substance P, a possible involvement of oxidative lung injury was assessed by measuring the changes in membrane-bound neutral endopeptidase activity in the airway tissues and the level of lipid peroxides in the plasma. Vehicle-treated animals developed a neutrophilic airway inflammation, bronchial hyperresponsiveness to substance P associated with neutral endopeptidase hypoactivity, and elevation of lipid peroxides at 18 to 24 h after an exposure to endotoxin (75 microgram/ml, 40 min). A nonselective phosphodiesterase inhibitor, aminophylline, and selective phosphodiesterase isoenzyme inhibitors, SDZ-ISQ-844 (type III/IV) and SDZ-MKS-492 (type III), attenuated the neutrophilic airway inflammation induced by endotoxin. Aminophylline, SDZ-MKS-492, and a superoxide anion-generating NADPH-oxidase inhibitor apocynin inhibited bronchial hyperresponsiveness to substance P with attenuation of neutral endopeptidase inactivation induced by endotoxin. SDZ-ISQ-844, SDZ-MKS-492, and apocynin attenuated the elevation of lipid peroxides. The generation of hypochlorite (OCl-) from whole blood leukocytes was attenuated by aminophylline, SDZ-ISQ-844, SDZ-MKS-492, and apocynin at 1 to 2 h after exposure. These results suggest that reactive oxygen-derived free radical species-mediated oxidative lung injury may play an important role in endotoxin-induced bronchial hyperresponsiveness to substance P, and that phosphodiesterase isoenzyme inhibitors may be potentially useful as anti-inflammatory drugs.

1997-05-01·Arerugi = [Allergy]

[Effects of SDZ ISQ 844, a cyclic nucleotide phosphodiesterase isozyme type III/IV inhibitor, on the release of histamine from human peripheral leukocytes].

Article

作者: Okamoto, M ; Adachi, M ; Idaira, K ; Horikoshi, S ; Sugeta, A ; Imai, T

We studied the effects of SDZ ISQ 844, a cyclic nucleotide phosphodiesterase (PDE) isozyme type III/IV inhibitor, and salbutamol on the release of histamine from activated human peripheral leukocytes. We stimulated the leukocyte suspensions with calcium ionophore A23187 (Ca-I, 10(-6 M) accompanied with SDZ ISQ 844 (10(-7) M, 10(-6) M, 10(-5) M), salbutamol (10(-7) M, 10(-6) M, 10(-5) M) and combination of SDZ ISQ 844 and salbutamol (10(-7) M, 10(-6) M, 10(-5) M), and measured the levels of histamine in the supernatant fluid and total cyclic AMP levels in the leukocyte suspensions. The increase of histamine levels induced by Ca-I was significantly inhibited by SDZ ISQ 844 (10(-6) M, 10(-5) M) in a dose-dependent manner (p < 0.05, p < 0.01). Salbutamol at the concentration until 10(-5) M did not inhibit the increase of histamine levels. Combination of SDZ ISQ 844 and salbutamol significantly inhibited the increase of histamine levels (10(-6) M, 10(-5) M) in a dose-dependent manner (p < 0.05, p < 0.01). The inhibition of the histamine release by SDZ ISQ 844 (10(-5) M was enhanced significantly by salbutamol (10(-5) M) (p < 0.05). Total cyclic AMP levels in the leukocytes suspensions increased significantly by SDZ ISQ 844 (10(-5) M) and combination of SDZ ISQ 844 and salbutamol (10(-6) M, 10(-5) M) in a dose-dependent manner (p < 0.05, p < 0.01). The increase of cyclic AMP levels by SDZ ISQ 844 (10(-5) M) was enhanced by salbutamol significantly (p < 0.01). These results suggest that selective inhibition of PDE isozyme type III/IV protects the release of histamine from human activated leukocytes in connection with intracellular cyclic AMP levels and the protection is enhanced by beta-agonist.

1994-04-01·Arerugi = [Allergy]

[Effects of inhaled SDZ ISQ 844, a cyclic nucleotide phosphodiesterase isoenzyme type III/IV inhibitor, on airway responsiveness in beagles].

Article

作者: Adachi, M ; Okamoto, M ; Idaira, K ; Horikoshi, S ; Imai, T

To evaluate the effects of inhaled SDZ ISQ 844, a selective cyclic nucleotide phosphodiesterase (PDE) isoenzyme type III/IV inhibitor and inhaled salbutamol on airway responsiveness, we studied the changes in airway responsiveness following inhalation of SDZ ISQ 844 and salbutamol in 7 beagles. Respiratory resistance and airway responsiveness to inhaled methacholine were determined by modified Astograph (7 Hz oscillation method), SDZ ISQ 844 solution (5 x 10(-4) M) and salbutamol solution (5 x 10(-5) M) were delivered as aerosols generated from a Bird nebulizer for ten minutes. After inhalation of salbutamol respiratory resistance showed a slight but significant decrease (p < 0.05). Inhaled SDZ ISQ 844 did not affect respiratory resistance. Airway responsiveness decreased significantly following inhalation of SDZ ISQ 844 and salbutamol (p < 0.02). There was no significant difference between the changes in airway responsiveness following the inhalation of SDZ ISQ 844 and salbutamol. These results indicate that inhalational administration of a selective PDE isoenzyme type III/IV inhibitor, SDZ ISQ 844 decreases airway responsiveness at dosage which does not affect the base-line respiratory resistance.

100 项与 SDZ-ISQ-844 相关的药物交易

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