Hidetsugu Takagaki

Inhibitory effect of a novel quinolinone derivative, TA-270, on asthmatic inflammatory responses in sensitized guinea pigs

TA-270 (4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)- quinolinone), a novel quinolinone derivative, was designed as an antioxidant to scavenge reactive oxygen species. Here, we investigated the effects of TA-270, in comparison with several antiasthmatic drugs, on asthmatic responses as induced by ovalbumin in sensitized guinea pigs. When orally administered 1 h before and 3 h after the antigen challenge, TA-270 at 10 mg/kg and higher doses significantly inhibited both immediate and late responses in airway resistance induced by the antigen. The inhibitory effects were comparable to or superior, at least under the present experimental conditions, to those of several clinically used antiasthmatic drugs. Furthermore, TA-270, in a dose-dependent manner, reduced accumulation of pulmonary inflammatory cells, especially eosinophils, and significantly reversed the airway hyperresponsiveness to acetylcholine 24 h after the antigen challenge. These results suggest that TA-270 may be of therapeutic use for bronchial asthma.

Effect of TA-270, a novel quinolinone derivative, on antigen-induced nasal blockage in a guinea pig model of allergic rhinitis.

TA-270 (4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone) is a novel quinolinone derivative that has been demonstrated to possess an anti-oxidative activity against peroxynitrite, a potent oxidant, that is generated by the reaction of nitric oxide with superoxide anions. The current study describes the inhibitory effect of TA-270 on the biphasic nasal blockage induced by repeated antigen challenge in an allergic rhinitis guinea pig model. In the present in vitro study, TA-270 potently inhibited the oxidative reaction induced by peroxynitrite (IC(50)=79 nM). In addition, TA-270 (0.3-30 mg/kg, p.o.) dose-dependently inhibited peroxynitrite (3 mM, 10 mul/nostril)-induced nasal blockage in guinea pigs. In the antigen-induced allergic rhinitis model, TA-270 (0.3, 3, and 30 mg/kg, p.o.) given 1 h before the antigen challenge suppressed early phase nasal blockage by 36%, 42%, and 63%, respectively. Furthermore, TA-270 (0.3, 3, and 30 mg/kg, p.o.) showed a relatively strong suppression of late phase nasal blockage (39%, 62%, and 72%, respectively). The late phase nasal blockage was significantly inhibited (61%) even when TA-270 (30 mg/kg, p.o.) was administered 18 h before the antigen challenge. In conclusion, TA-270 improved antigen-induced nasal blockage, probably through its peroxynitrite scavenging action, and the effect was sustained for at least 18 h. Thus, TA-270 would be expected to relieve nasal blockage in allergic rhinitis patients.

Radical Scavenging Properties of Novel Benzopyran Derivatives, TA248 and TA276, and Effects of the Compounds on Ischemic/Reperfused Myocardium in Dogs

Characteristics of novel benzopyran derivatives, TA248 and TA276, and their effects on myocardial contraction in ischemic/reperfused hearts in dogs were examined. TA248 and TA276 inhibited NADPH-dependent lipid peroxidation induced by Fe(3+) in the rat brain homogenate. Both compounds reduced *O(2-) produced by xanthine-xanthine oxidase system in a dose-dependent manner. TA276 scavenged.OH generated by Fenton reaction in a dose-dependent manner. TA248 also inhibited the.OH production, but the effect was neither complete nor dose dependent. Myocardial contraction was assessed as segment shortening of the left ventricular wall in pentobarbital-anesthetized open-chest dogs. The segment shortening was decreased by the left anterior descending coronary artery ligation (ischemia) and returned by release of the ligated artery (reperfusion). The segment shortening did not recover fully during reperfusion. Either TA248 or TA276 injected 10 min before ischemia improved the recovery of myocardial contraction during reperfusion. Both compounds preserved the level of ATP in the 60-min reperfused myocardium. However, the level of lipid peroxides was not changed by TA248 and TA276. TA248 and TA276 may protect myocardium against ischemic/reperfusion insult, partly because of their free radical scavenging activity, but no significant change in myocardial lipid peroxide level was observed.