Ishikawa J, Saitoh C, Masaki K, Asano M
Infectious Disease & Immunology Research Laboratory, Yamanouchi Pharmaceutical Co. Ltd., Ibaraki, Japan.
J Pharm Pharmacol. 1996 Oct;48(10):1034-40. doi: 10.1111/j.2042-7158.1996.tb05896.x.
YM934 is a novel synthetic potassium-channel opener. We have investigated its anti-asthma effect after intravenous (i.v.) and oral (p.o.) administration in various experimental asthma models in the guinea-pig, and compared the results with those for lemakalim, theophylline and salbutamol. In an ovalbumin-active sensitization anaphylaxis asthma model, YM934, lemakalim, theophylline and salbutamol dose-dependently prolonged the time before the occurrence of asthma attacks and reduced the mortality rate. The respective ED50 values (dose required to prolong by 50% the time before the occurrence of attacks) of the anti-asthma effects of YM934, lemakalim, theophylline and salbutamol were 6, 340, 30000, and 45 micrograms kg-1 (i.v.); the efficacy ratios were YM934 (1) > salbutamol (1/9) > lemakalim (1/57) > > theophylline (1/5000). YM934 also prolonged the period before the occurrence of attacks in the anti-BSA (bovine serum albumin) serum-passive sensitization anaphylaxis, histamine-induced and methacho-line-induced asthma models, with respective ED50 values for these models of 15, 22 and 20 micrograms kg-1 (i.v.). Among these models a reduction in mortality rate was seen in the histamine- and methacholine-induced asthma models. After oral administration, YM934 showed an anti-asthma effect in the ovalbumin-active sensitization anaphylaxis, histamine-induced and methacholine-induced asthma models, with respective ED50 values of 38, 44 and 193 micrograms kg-1. YM934 was 5-6 times more potent than salbutamol. These results indicate that YM934 has potent anti-asthma activity, and that this activity is mainly attributable to bronchodilation, most likely mediated through its potassium-channel opening activity.
YM934是一种新型合成钾通道开放剂。我们在豚鼠的多种实验性哮喘模型中研究了其静脉注射（i.v.）和口服（p.o.）给药后的抗哮喘作用，并将结果与雷马卡林、茶碱和沙丁胺醇的结果进行了比较。在卵清蛋白主动致敏过敏哮喘模型中，YM934、雷马卡林、茶碱和沙丁胺醇剂量依赖性地延长了哮喘发作前的时间并降低了死亡率。YM934、雷马卡林、茶碱和沙丁胺醇抗哮喘作用的各自ED50值（使发作前时间延长50%所需的剂量）静脉注射分别为6、340、30000和45微克·千克⁻¹；效价比为YM934（1）>沙丁胺醇（1/9）>雷马卡林（1/57）>>茶碱（1/5000）。YM934在抗牛血清白蛋白（BSA）血清被动致敏过敏、组胺诱导和乙酰甲胆碱诱导的哮喘模型中也延长了发作前的时间，这些模型的静脉注射ED50值分别为15、22和20微克·千克⁻¹。在这些模型中，组胺和乙酰甲胆碱诱导的哮喘模型中观察到死亡率降低。口服给药后，YM934在卵清蛋白主动致敏过敏、组胺诱导和乙酰甲胆碱诱导的哮喘模型中显示出抗哮喘作用，各自的ED50值分别为38、44和193微克·千克⁻¹。YM934的效力比沙丁胺醇高5至6倍。这些结果表明YM934具有强大的抗哮喘活性，并且这种活性主要归因于支气管扩张，很可能是通过其钾通道开放活性介导的。
