Comparison of Diazeniumdiolated Dialkylhexanediamines as Nitric Oxide Release Agents on Nonthrombogenicity in an Extracorporeal Circulation Model,ACS Applied Bio Materials

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Comparison of Diazeniumdiolated Dialkylhexanediamines as Nitric Oxide Release Agents on Nonthrombogenicity in an Extracorporeal Circulation Model
ACS Applied Bio Materials ( IF 4.6 ) Pub Date : 2020-01-08 , DOI: 10.1021/acsabm.9b00924
Mark M Jeakle ₁ , Terry C Major ₁ , Mark E Meyerhoff ₂ , Robert H Bartlett ₁

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When blood from a patient is circulated through extracorporeal circuits (ECCs), such as in cardiopulmonary bypass or extracorporeal life support, platelets in the blood are activated and form a thrombus. This is prevented clinically with a range of different systemic anticoagulation agents (e.g., heparin); however, this increases a patient’s risk of hemorrhage. Previous work with nitric oxide (NO) releasing materials using the combined diazeniumdiolated diamine, N–N-di-N′-butyl-1,6-hexanediamine (DBHD), and a polymer-linked thrombin inhibitor, argatroban (AG), showed significant nonthrombogenicity in ECCs using a 4 h rabbit model. Herein, we evaluated if diazeniumdiolated N–N-di-N′-propyl-1,6-hexanediamine (DPHDN₂O₂), which has a slightly lower degree of lipophilicity compared to DBHDN₂O₂, would provide similar nonthrombogenicity as the AG/DBHDN₂O₂-polymer-coated circuits. While DPHDN₂O₂ releases NO at a higher flux rate than DBHDN₂O₂ when coated (within CarboSil polymer) on the inner wall of polyvinyl chloride tubing, neither coated circuit significantly affected animal hemodynamics. Both diazeniumdiolated diamines, in combination with immobilized AG or alone, significantly reduced thrombus formation similarly in the 4 h rabbit model (vs uncoated control): AG/DBHDN₂O₂: 0.12 ± 0.03 cm²; DBHDN₂O₂: 2.57 ± 0.82 cm²; AG/DPHDN₂O₂: 0.68 ± 0.22 cm²; DPHDN₂O₂: 1.87 + 1.26 cm²; uncoated control: 6.95 ± 0.82 cm². AG/DPHDN₂O₂ was no different than AG/DBHDN₂O in preserving platelet count and function. In addition, AG did not leach into the systemic circulation as the total clotting times were insignificantly different from the baseline values (AG/DPHDN₂O₂: 12.7 + 0.5 s (n = 3); AG/DBHDN₂O₂: 12.3 + 0.7 s (n = 3); baseline: 13.9 + 0.3 s (n = 13)). Based on these results, both DPHDN₂O₂ and DPHDN₂O₂ are good candidates as NO donor molecules for creating nonthrombogenic polymer coatings for ECCs.

中文翻译：

在体外循环模型中二氮烯鎓二醇化二烷基己二胺作为一氧化氮释放剂对非血栓形成性的比较

当来自患者的血液通过体外回路 (ECC) 循环时，例如在体外循环或体外生命支持中，血液中的血小板被激活并形成血栓。这在临床上可以通过一系列不同的全身性抗凝剂（例如肝素）来预防；然而，这会增加患者出血的风险。先前使用二氮烯鎓二醇化二胺、 N - N-二-N'-丁基-1,6-己二胺 (DBHD) 和聚合物连接的凝血酶抑制剂阿加曲班 (AG)的组合释放一氧化氮 (NO) 材料的研究表明使用 4 小时兔模型在 ECC 中具有显着的非血栓形成性。在此，我们评估了二氮烯鎓二醇化N – N -di- N'-丙基-1,6-己二胺 (DPHDN ₂ O _{2 ) 与 DBHDN}₂ O ₂相比具有稍低的亲脂性，可提供与 AG/DBHDN ₂ O ₂聚合物涂层电路类似的非血栓形成性。而 DPHDN ₂ O _{2以比 DBHDN}₂ O ₂更高的通量率释放 NO当在聚氯乙烯管的内壁上（在 CarboSil 聚合物内）涂层时，涂层电路都不会显着影响动物的血流动力学。在 4 小时兔模型（与未涂层对照相比）中，与固定化 AG 组合或单独使用两种二氮烯鎓二醇二胺均显着减少血栓形成：AG/DBHDN ₂ O ₂：0.12 ± 0.03 cm ²；DBHDN ₂ O ₂：2.57±0.82 cm ²；AG/DPHDN ₂ O ₂：0.68 ± 0.22 cm ²；DPHDN ₂ O ₂：1.87 + 1.26 cm ²；无涂层对照：6.95 ± 0.82 cm ²。AG/DPHDN ₂O ₂在保持血小板计数和功能方面与 AG/DBHDN _{2 O 没有区别。}此外，AG 没有渗入体循环，因为总凝血时间与基线值差异不大（AG/DPHDN ₂ O ₂ : 12.7 + 0.5 s ( n = 3); AG/DBHDN ₂ O ₂ : 12.3 + 0.7 秒（n = 3）；基线：13.9 + 0.3 秒（n = 13））。基于这些结果，DPHDN ₂ O ₂和 DPHDN ₂ O ₂都是作为 NO 供体分子的良好候选者，可用于为 ECC 创建非血栓形成聚合物涂层。

更新日期：2020-01-08

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