Handley D A, Tomesch J C, Saunders R N
Thromb Haemost. 1986 Aug 20;56(1):40-4.
Systemic administration of synthetic PAF produces a number of dose-dependent circulatory effects in a variety of species. We have evaluated a novel PAF antagonist, SRI 63-441, for its ability to inhibit PAF-induced effects in the rat, guinea pig, dog and primate. In the rat, a 100 ng kg-1 i.v. PAF challenge produced a (mean +/- 1 S.D.) 39 +/- 5% decrease in carotid blood pressure. Prior injection of SRI 63-441 inhibited this hypotensive response in a dose-dependent manner, with an ED50 of 0.15 mg kg-1 i.v. In the guinea pig, PAF at 100 ng kg-1 elicited a 50 +/- 8% increase in hematocrit and a 50 +/- 11% elevation in bronchial resistance. The ED50 values for inhibition by SRI 63-441 of these two physiological parameters were 0.012 mg kg-1 and 0.035 mg kg-1 i.a., respectively. Dogs challenged with 1.5 micrograms kg-1 PAF i.v. exhibited 28.7 +/- 6.5% increase in hematocrit 10 min after injection. The ED50 value for SRI 63-441 inhibition of hemoconcentration in the dog was 0.18 mg kg-1 i.v. In the primate model of PAF-induced hemoconcentration, controls responded to 3.5 micrograms kg-1 i.v. PAF with a 30 +/- 6% increase in hematocrit. Using the primates in a cross-over design, the ED50 of SRI 63-441 was 0.11 mg kg-1 i.v. At this ED50 value, the ratio of nmol kg-1 PAF used versus nmol kg-1 antagonist is approximately 1:25. The effectiveness of SRI 63-441 in these models suggest potential clinical applications in disease states involving hyperpermeability and pulmonary dysfunction.
合成血小板活化因子（PAF）的全身给药在多种物种中会产生一系列剂量依赖性的循环效应。我们评估了一种新型PAF拮抗剂SRI 63 - 441抑制PAF在大鼠、豚鼠、狗和灵长类动物中诱导效应的能力。在大鼠中，静脉注射100 ng/kg的PAF激发后，颈动脉血压下降了（平均值±1标准差）39±5%。预先注射SRI 63 - 441以剂量依赖性方式抑制了这种降压反应，静脉注射的半数有效剂量（ED50）为0.15 mg/kg。在豚鼠中，100 ng/kg的PAF引起血细胞比容增加50±8%，支气管阻力升高50±11%。SRI 63 - 441抑制这两个生理参数的ED50值分别为腹腔注射0.012 mg/kg和0.035 mg/kg。静脉注射1.5 μg/kg的PAF激发的狗在注射后10分钟血细胞比容增加了28.7±6.5%。SRI 63 - 441抑制狗血液浓缩的ED50值为静脉注射0.18 mg/kg。在PAF诱导血液浓缩的灵长类动物模型中，对照组对静脉注射3.5 μg/kg的PAF反应为血细胞比容增加30±6%。采用交叉设计在灵长类动物中，SRI 63 - 441的ED50为静脉注射0.11 mg/kg。在此ED�0值下，所用PAF的nmol/kg与拮抗剂的nmol/kg之比约为1:25。SRI 63 - 441在这些模型中的有效性表明其在涉及通透性增加和肺功能障碍的疾病状态中具有潜在的临床应用价值。
