Prophylactic P-selectin inhibition with PSI-421 promotes resolution of venous thrombosis without anticoagulation
Prophylactic P-selectin inhibition with PSI-421 promotes resolution of venous thrombosis without anticoagulation
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DOI：
10.1160/th07-10-0608
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发表时间：
2008-02-01
影响因子：
6.7
通讯作者：
Wakefield, Thomas W.
中科院分区：
文献类型：
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作者：
Meier, Thomas R.;Myers, Daniel D., Jr.;Wakefield, Thomas W.
p选择素抑制已被评价为预防和治疗静脉血栓形成的一种治疗方法。在这项研究中，一种新的口服小分子p选择素抑制剂PSI-421在狒狒停滞诱导的深静脉血栓形成（DVT）模型中进行了评估。实验组包括：(1)灵长类动物在血栓形成前2天单次口服1 mg/kg PSI-421，并在血栓形成后6天继续口服（n=3）；Ii)灵长类动物在血栓形成前2天每日皮下注射0.57 mg/kg依诺肝素钠，并在血栓形成后6天继续注射（n=3）；iii)未接受治疗的灵长类动物（n=3）。与依诺肝素和对照组相比，PSI-421治疗的灵长类动物在第6天静脉重开率更高，静脉壁炎症更少。在血栓形成后立即接受PSI-421治疗的动物（第0天T+6小时），微粒组织因子活性（MPTFA）显著降低，表明这些动物的血栓形成潜力较低。与对照组相比，PSI-421在第0天、第2天和第6天的T+6小时也降低了可溶性p选择素的水平。各组实验动物对凝血均无不良影响。这项研究首次证明，在狒狒DVT模型中，口服p -选择素抑制可减少MPTFA与静脉重新开放和静脉炎症的关系。
P-selectin inhibition has been evaluated as a therapeutic for prevention and treatment of venous thrombosis. In this study, a novel oral small-molecule inhibitor of P-selectin, PSI-421, was evaluated in a baboon model of stasis induced deep vein thrombosis (DVT). Experimental groups included i) primates receiving a single oral dose of 1 mg/kg PSI-421 two days prior and continued six days after thrombosis (n=3); ii) primates receiving a single daily subcutaneous dose of 0.57 mg/kg enoxaparin sodium two days prior and continued six days post thrombosis (n=3); and iii) primates receiving no treatment (n=3). PSI-421 treated primates had greater percent vein reopening and less vein wall inflammation than the enoxaparin and controls at day 6. Microparticle tissue factor activity (MPTFA) was significantly lower in the animals receiving PSI-421 immediately after thrombosis (T+6 hours day 0) suggesting lower potential for thrombogenesis in these animals. PSI-421 also reduced soluble P-selectin levels versus controls at T+6 hours day 0, day 2 and 6. Experimental animals in any group showed no adverse effects on coagulation. This study is the first to demonstrate a reduction in MPTFA associated with vein reopening and reduced vein inflammation due to oral P-selectin inhibition in a baboon model of DVT.