Development of a novel aIIbB3 receptor antagonist for pre-hospital myocardial infarction therapy

与到达医院后治疗的显著进步相比，院前治疗的改善相对较小。在ST段抬高心肌梗死(STEMI)患者的院前治疗中，在标准口服阿司匹林的基础上增加一种有效的aIIbB3拮抗剂，有可能降低早期死亡率和未来6-12个月内充血性心力衰竭的发展。这一假说是基于证据表明，在症状出现后立即使用其他aIIbB3拮抗剂(连同阿司匹林)可以中止血栓性心肌缺血发展为不可逆转的心脏损害，并降低死亡率。此外，我们预计会有良好的安全性，因为患者在院前设置时既不会进行抗凝治疗，也不会接受动脉介入治疗，而且这种影响将在2-4小时内消失。目前的aIIbB3拮抗剂都必须静脉给药，这是院前治疗的主要缺点。我们目前正在收集所需的研究新药(IND)-使数据能够推动新型aIIbB3拮抗剂RUC-4进入人体研究。基于aIIbB3的晶体结构研究，RUC-4被设计为针对aIIbB3，具有独特的作用机制，不仅可以防止配体结合，还可以防止当前根据R(K)gD序列模式的aIIbB3拮抗剂引起的3个亚基的构象变化，这些拮抗剂与导致血小板减少和矛盾受体激活有关。RUC-4还具有高溶解度(80毫克/毫升)，因此可能的人体剂量(1毫克/公斤)可以通过自动注射器在1毫升内注射。基于对老鼠和非人类灵长类动物的研究，RUC-4在肌肉注射后很快就会被吸收。非人灵长类动物肌注0.27ml1.93 mg/kg后15分钟内即可消除血小板聚集，4.5小时后部分恢复聚集。小剂量(0.47ml；1 mg/kg)在15min时部分抑制聚集，30min时完全抑制，2小时后部分恢复聚集。因此，RUC4目前的情况符合ST段抬高心肌梗死(STEMI)患者院前治疗的预期需求。

There has been relatively little improvement in pre-hospital therapy compared to the dramatic advances in therapy after arriving to the hospital. The addition of a potent aIIbB3 antagonist administered alongside standard oral aspirin in the pre-hospital therapy of patients with ST segment-elevated myocardial infarction (STEMI) has the potential to decrease early mortality and the development of congestive heart failure during the next 6-12 months. This hypothesis is based on evidence showing that therapy with other aIIbB3 antagonists (along with aspirin) soon after symptom onset can abort the progression of thrombotic myocardial ischemia to irreversible cardiac damage and decrease mortality. Moreover, we expect a favorable safety profile since patients will neither be anticoagulated nor undergo arterial access in the pre-hospital setting, and the effects will wear off within 2-4 hours. The current aIIbB3 antagonists all must be administered intravenously, a major disadvantage for pre-hospital therapy. We currently are gathering the needed Investigational New Drug (IND)-enabling data to advance RUC-4, a novel aIIbB3 antagonist, to human studies. Based on crystallographic structural studies of aIIbB3, RUC-4 was designed to be specific for aIIbB3 and to have a unique mechanism of action that not only prevents ligand binding, but also prevents the conformational changes in the 3 subunit induced by current aIIbB3 antagonists patterned on the R(K)GD sequence that have been implicated in causing thrombocytopenia and paradoxical receptor activation. RUC-4 was also designed to have high solubility (80 mg/ml) so that the likely human dose (1 mg/kg) can be administered in 1 ml by autoinjector. Based on studies in mice and non-human primates, RUC-4 is rapidly absorbed after intramuscular injection. In non-human primates, platelet aggregation was eliminated within 15 minutes after a 0.27 ml IM dose of 1.93 mg/kg with partial return of platelet aggregation after 4.5 hours. A lower dose (0.47 ml; 1 mg/kg) produced partial inhibition of aggregation at 15 minutes, complete inhibition at 30 minutes, and partial return of aggregation at 2 hours. Thus, the current profile for RUC4 matches the anticipated needs for a pre-hospital therapy of patients with ST segment-elevated myocardial infarction (STEMI).