A novel, rapid method to compare the therapeutic windows of oral anticoagulants using the Hill coefficient
A novel, rapid method to compare the therapeutic windows of oral anticoagulants using the Hill coefficient
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DOI：
10.1038/srep29387
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发表时间：
2016-07-21
影响因子：
4.6
通讯作者：
Tatonetti, Nicholas P.
中科院分区：
文献类型：
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作者：
Chang, Jeremy B.;Quinnies, Kayla M.;Tatonetti, Nicholas P.
设计和施用有效抗凝剂的核心挑战是为每个患者实现适当的治疗窗口和剂量。希尔系数n（H）可测量剂量-反应关系的陡度，可能是该治疗窗的有用度量。我们试图测量现有抗凝剂的希尔系数，以了解其治疗窗。我们使用了一个简单的荧光体外测定法，以确定血小板贫乏血浆暴露于不同浓度的抗凝剂后的凝血活性。阿加曲班的希尔系数最低，为1.7 +/- 0.2（95%置信区间，CI），磺达肝素的希尔系数最高，为4.5 +/- 1.3（95% CI）。因此，磺达肝癸钠的剂量从其IC 50加倍将使凝血活性降低近一半，而阿加曲班的剂量从其IC 50加倍将仅使凝血活性降低四分之一。这些结果显示希尔系数之间存在显著变化，表明我们的测定中抗凝剂之间的治疗窗存在类似变化。
A central challenge in designing and administering effective anticoagulants is achieving the proper therapeutic window and dosage for each patient. The Hill coefficient, n(H), which measures the steepness of a dose-response relationship, may be a useful gauge of this therapeutic window. We sought to measure the Hill coefficient of available anticoagulants to gain insight into their therapeutic windows. We used a simple fluorometric in vitro assay to determine clotting activity in platelet poor plasma after exposure to various concentrations of anticoagulants. The Hill coefficient for argatroban was the lowest, at 1.7 +/- 0.2 (95% confidence interval, CI), and the Hill coefficient for fondaparinux was the highest, at 4.5 +/- 1.3 (95% CI). Thus, doubling the dose of fondaparinux from its IC50 would decrease coagulation activity by nearly a half, whereas doubling the dose of argatroban from its IC50 would decrease coagulation activity by merely one quarter. These results show a significant variation among the Hill coefficients, suggesting a similar variation in therapeutic windows among anticoagulants in our assay.