Sutton T J, Luke J S, Jones H B
Department of Pathology and Toxicology, Smith Kline and French Research Ltd., Welwyn, Hertfordshire, UK.
Hum Toxicol. 1988 May;7(3):243-8. doi: 10.1177/096032718800700302.
SK&F 95018, a potential antihypertensive agent with the combined properties of vasodilation and beta-adrenoceptor antagonism, induced red urine when given intravenously to a dog. Further studies revealed that in the dog, SK&F 95018 treatment led to haemoglobinaemia, haemoglobinuria and a fall in the red blood cell count. The compound was therefore suspected of causing red cell haemolysis and this was confirmed using dog blood in an in vitro haemolysis test system. Oral administration of the compound to dogs gave no indication of haemolysis, but the animals lost large portions of their dose through vomiting and the lack of effect is therefore questionable. Rats, which have no vomit reflex, were treated orally and although no direct evidence of haemolysis was obtained (e.g. haemoglobinaemia), the presence of polychromasia suggested some loss of mature red blood cells had occurred. Rat blood was haemolysed in vitro by SK&F 95018. Human red cells were also used in the in vitro haemolysis test system and these, too, were lysed by the compound. The haemolysis was shown to be related to the structure of the compound itself rather than to its pharmacological effects and development of SK&F 95018 as an antihypertensive agent was abandoned. Electron microscopy indicated that SK&F 95018 induced alterations in the red cell membrane which led to shape change, characterized by discocyte to spherocyte transformation, and finally haemolysis. The mechanism of this effect remains under investigation.
SK&F 95018是一种具有血管舒张和β-肾上腺素能受体拮抗联合特性的潜在抗高血压药物，静脉注射给一只狗时会导致尿液变红。进一步研究表明，在狗身上，SK&F 95018治疗导致血红蛋白血症、血红蛋白尿和红细胞计数下降。因此怀疑该化合物导致红细胞溶血，这在体外溶血试验系统中使用狗血得到了证实。给狗口服该化合物未显示溶血迹象，但动物因呕吐损失了大部分剂量，因此其无效性值得怀疑。没有呕吐反射的大鼠接受口服治疗，尽管没有获得溶血的直接证据（如血红蛋白血症），但出现多染性提示发生了一些成熟红细胞的损失。SK&F 95018在体外使大鼠血液溶血。体外溶血试验系统中也使用了人红细胞，这些红细胞也被该化合物溶解。已表明溶血与化合物本身的结构有关，而与其药理作用无关，因此放弃了将SK&F 95018开发为抗高血压药物的计划。电子显微镜检查表明，SK&F 95018诱导红细胞膜发生改变，导致形状改变，其特征为盘状细胞向球形细胞转化，最终导致溶血。这种作用的机制仍在研究中。
