Niemegeers C J, Awouters F, de Nollin S, Janssen P A
Arch Int Pharmacodyn Ther. 1978 Jul;234(1):164-76.
The dose of 0.5 mg/kg i.v. of compound 48/80 was lethal in 97.2% of the injected rats. Observations before death and at autopsy were in accordance with the basic effect of compound 48/80 in rats i.e. the sustained release of mast cell mediators, whose action on the cardiovascular system leads to circulatory collapse. The administration of drugs with various pharmacological effects before the intravenous challenge with compound 48/80 allowed us to conclude that the following effects are not sufficient to prevent the lethal shock: inhibition of prostaglandin biosynthesis; H2-histamine antagonism; cholinergic, alpha- or beta-adrenergic blockade; beta-adrenergic stimulation; CNS-effects of antidepressants, hypnotics, sedatives, neuroleptics or narcotic analgesics; ganglion blockade; glucocorticoid or cromoglycate-like activity. Dose-dependent protection from the lethal reaction was obtained with compounds known to exert a single or several actions of the following types: oxatomide-like inhibition of mast cell mediator release; h1-histamine antagonism; serotonin antagonism. Quantitatively, however, when measured in in vitro systems these effects are poorly related to the protection from lethal compound 48/80 challenge. The new test offers the advantage of a simple, comprehensive measure of the potency of a compound to prevent mast cell-mediated shock.
静脉注射剂量为0.5mg/kg的化合物48/80可导致97.2%的受试大鼠死亡。死亡前及尸检时的观察结果与化合物48/80对大鼠的基本作用一致，即肥大细胞介质的持续释放，其对心血管系统的作用导致循环衰竭。在静脉注射化合物48/80之前给予具有各种药理作用的药物，使我们得出以下结论：以下作用不足以预防致死性休克：抑制前列腺素生物合成；H2组胺拮抗作用；胆碱能、α或β肾上腺素能阻断；β肾上腺素能刺激；抗抑郁药、催眠药、镇静剂、抗精神病药或麻醉性镇痛药的中枢神经系统作用；神经节阻断；糖皮质激素或色甘酸样活性。已知具有以下一种或几种作用的化合物可获得对致死反应的剂量依赖性保护：类似奥沙米特的抑制肥大细胞介质释放；H1组胺拮抗作用；5-羟色胺拮抗作用。然而，从数量上看，在体外系统中进行测量时，这些作用与预防致死性化合物48/80攻击的保护作用之间的相关性较差。这项新测试具有简单、全面地衡量化合物预防肥大细胞介导休克效力的优点。
