Hemodynamic Evaluation of Recombinant Human Tumor Necrosis Factor (TNF)-α, TNF‐SAM2 and Liposomal TNF‐SAM2 in an Anesthetized Dog Model
Hemodynamic Evaluation of Recombinant Human Tumor Necrosis Factor (TNF)-α, TNF‐SAM2 and Liposomal TNF‐SAM2 in an Anesthetized Dog Model
复制标题
麻醉犬模型中重组人肿瘤坏死因子 (TNF)-α、TNF-SAM2 和脂质体 TNF-SAM2 的血流动力学评估
DOI：
10.1097/00002371-199501000-00003
复制
发表时间：
1995
期刊：
影响因子：
--
通讯作者：
J. Klostergaard
中科院分区：
文献类型：
--
作者：
R. Lodato;B. Feig;K. Akimaru;G. Soma;J. Klostergaard
我们在麻醉的杂种犬模型中评价了全身给予重组人肿瘤坏死因子（TNF）-α、TNF-SAM 2和脂质体结合TNF-SAM 2的血流动力学效应。在外周静脉中注射10 μ g TNF蛋白/kg剂量的每种制剂，并测量平均全身动脉压（SAP）、心率（HR）和心输出量（CO）。TNF-α在所有3只犬中诱导SAP显著下降（平均下降= 59.3 ± 5.2 mm Hg;至基线的61.5%; p = 0.008）;而TNF-SAM 2在4只犬中引起SAP较小且短暂的下降（平均下降= 25.5 ± 10.1 mm Hg;至基线的81.2%; p = 0.086）。在三只给予脂质体结合的TNF-SAM 2（其保留体内抗肿瘤活性）的犬中，出现了净轻微高血压期和持续升高的CO，随后恢复到基本正常的血压状态（基线SAP的101.0%）。该模型表明TNF的主要急性全身毒性，即，低血压，可以通过第二代TNF的脂质体制剂显著减弱。
Summary We have evaluated the hemodynamic effects of systemically administered recombinant human tumor necrosis factor (TNF)-α, TNF-SAM2 and liposome-bound TNF-SAM2 in an anesthetized mongrel dog model. A dose of 10 μg TNF protein/kg of each formulation was injected in a peripheral vein and mean systemic arterial pressure (SAP), heart rate (HR) and cardiac output (CO) were measured. TNF-α induced a marked drop in SAP in all three dogs (mean decrease = 59.3 ± 5.2 mm Hg; to 61.5% of baseline; p = 0.008); whereas TNF-SAM2 caused a smaller and transient drop in SAP in four dogs (mean decrease = 25.5 ± 10.1 mm Hg; to 81.2% of baseline; p = 0.086). In three dogs administered liposome-bound TNF-SAM2, which retains antitumor activity in vivo, a net slight hypertensive phase and sustained elevated CO occurred, followed by a return to an essentially normotensive state (101.0% of baseline SAP). This model demonstrates that the principal acute systemic toxicity of TNF, i.e., hypotension, can be markedly attenuated by liposomal formulation of a second-generation TNF.