Albert D H, Luo G, Magoc T J, Tapang P, Holms J H, Davidsen S K, Summers J B, Carter G W
Immunoscience Research Area, Abbott Laboratories, Illinois 60064-3500, USA.
Shock. 1996 Aug;6(2):112-7. doi: 10.1097/00024382-199608000-00006.
ABT-299, a highly potent and selective platelet activating factor (PAF) antagonist, was found to be effective in rat models of endotoxic shock. ABT-299 inhibited and reversed LPS-induced hypotension (ED50 of .008 mg/kg, intraarterially). When given prior to LPS challenge, ABT-299 (.1 mg/kg, intravenously) completely inhibited LPS-induced intestinal damage for as long as 8 h after the administration of the antagonist. Pretreatment of rats with ABT-299 (5 mg/kg, intravenously over 4 h) prevented by 85-95% symptoms of disseminated intravascular coagulation (DIC) induced by LPS, including thrombocytopenia, prolongation of prothrombin and partial thromboplastin time, decreased serum fibrinogen, and elevation of serum fibrinogen/fibrin degradation products. A .1 mg/kg dose of ABT-299 administered orally or intravenously improved long-term survival to 80% and 90%, respectively, following a lethal dose (LD65) of LPS. ABT-299 (.1 mg/kg) was also effective in preventing hypotension and gastrointestinal damage induced by lipoteichoic acid (LTA), a putative causative agent of shock in Gram-positive infections. These results illustrate the impressive potency and duration of action of ABT-299 and support the putative role of PAF in acute models of endotoxic shock.
ABT - 299是一种高效且具选择性的血小板活化因子（PAF）拮抗剂，在内毒素休克大鼠模型中显示出有效性。ABT - 299可抑制并逆转脂多糖（LPS）诱导的低血压（动脉内给药的半数有效剂量[ED50]为0.008 mg/kg）。在LPS攻击前给予ABT - 299（0.1 mg/kg，静脉注射），可在给予拮抗剂后的长达8小时内完全抑制LPS诱导的肠道损伤。用ABT - 299（5 mg/kg，静脉注射，持续4小时）预处理大鼠，可使LPS诱导的弥散性血管内凝血（DIC）症状减少85% - 95%，这些症状包括血小板减少、凝血酶原时间和部分凝血活酶时间延长、血清纤维蛋白原降低以及血清纤维蛋白原/纤维蛋白降解产物升高。在给予致死剂量（LD65）的LPS后，口服或静脉注射0.1 mg/kg剂量的ABT - 299可分别使长期存活率提高至80%和90%。ABT - 299（0.1 mg/kg）在预防由脂磷壁酸（LTA）（革兰氏阳性感染中休克的一种假定致病因子）诱导的低血压和胃肠道损伤方面也有效。这些结果说明了ABT - 299令人印象深刻的效力和作用持续时间，并支持了PAF在内毒素休克急性模型中的假定作用。
