Adjunctive Use of Apyrase to Fibrinolytic Therapy

腺苷三磷酸双磷酸酶辅助纤溶治疗

• 批准号: 8520381
• 负责人: RIDONG CHEN
• 金额: $ 57.78万
• 依托单位: APT THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-07 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8520381
• 关键词: Accounting; Acute; Acute myocardial infarction; Adenosine; Adverse event; Aftercare; Alteplase; Amino Acid Substitution; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Apyrase; Aspirin; Attenuated; Award; Bleeding time procedure; Blood Platelets; Blood Vessels; Blood flow; Canis familiaris; Cardiac; Cause of Death; Cell Line; Chinese Hamster Ovary Cell; Clinical; Coronary; Data; Developed Countries; Disease; Dose; Endotoxins; Enzymes; Event; Exhibits; Fibrinolysis; Fibrinolytic Agents; Goals; Hemorrhage; Hemostatic function; Heparin; Homeostasis; Hour; Human; Hypoxia; Incidence; Infarction; Injury; Investigational New Drug Application; Left Ventricular Function; Licensing; Maintenance; Marketing; Modeling; Morbidity - disease rate; Myocardial Infarction; Myocardial Reperfusion; Myocardial perfusion; Oryctolagus cuniculus; Outcome; Patients; Perfusion; Phase; Platelet Activation; Preparation; Procedures; Proteins; Recurrence; Regimen; Reperfusion Injury; Reporting; Risk; Safety; Site; Small Business Innovation Research Grant; Therapeutic; Thrombolytic Therapy; Thrombosis; Tissues; Toxic effect; adverse outcome; attenuation; clinically relevant; clopidogrel; commercial application; cost effective; desensitization; drug development; experience; extracellular; follow-up; immunogenicity; improved; mortality; myocardial infarct sizing; prevent; programs; research clinical testing; thrombolysis; vascular inflammation

DESCRIPTION (provided by applicant): Acute myocardial infarction is the leading cause of death in most industrialized nations. The estimated annual incidence in the US is 865,000 events, with ST-segment elevation myocardial infarction (STEMI, severe AMI) comprising an estimated 500,000 events per year. Fibrinolytic therapy is widely utilized to restore coronary blood flow due to its widespread availability to the broad cross-section of patients. The current regimen, including tissue plasminogen activator, aspirin, clopidogrel and heparin, still induces inadequate coronary reperfusion in 30-40% of patients and early thrombotic reocclusion in 5-10% patients. Moreover, successful recanalization causes detrimental reperfusion injury that accounts for up to 50% of the final size of a myocardial infarct. Net clinical adverse outcomes remain 10-12% at 30 days after treatment and 16-17% STEMI patients die during 1-year follow-up. Moreover, both morbidity and mortality are dramatically increased in patients experiencing peri-procedure bleeding. Importantly, most of the recurrent MI and major bleeding events occur in the first hours and days after treatment. Consequently, the search for more efficacious and safer acute antithrombotic agents with effective attenuation of reperfusion injury remains the "holy grail' of drug development. APT102 is an optimized human apyrase with two amino acid substitution that has significantly higher activity than the wild-type apyrases. This enzyme inhibits platelet activation and limits vascular inflammation by enzymatically hydrolyzing extracellular ADP and ATP. Adenosine is further generated by CD73 which prevents tissue damage during hypoxia and in the setting of cardiac reperfusion injury. In addition, APT102 prevents platelet desensitization and maintains homeostasis. With the Phase I award, we demonstrated that in the r-tPA induced fibrinolysis model in dogs, treatment of APT102 completely prevented re-occlusion, maintained normal blood flow, and profoundly reduced infarct size of hearts by 80% compared with clopidogrel. Meanwhile, APT102 did not prolong bleeding time, as did clopidogrel. The goal of this Phase II SBIR grant application is to rigorously determine whether in the coronary fibrinolysis model in dogs, APT102 promotes improved myocardial perfusion and left ventricular function with minimal bleeding compared with clopidogrel. The long-term goal is to develop APT102 as a highly effective antithrombotic and anti-inflammatory therapy with minimal bleeding risk that will profoundly improve efficacy and safety of acute treatment for AMI and other thrombotic patients.

描述（由申请人提供）：急性心肌梗死是大多数工业化国家的主要死亡原因。美国的估计年发病率为865，000起事件，其中ST段抬高型心肌梗死（STEMI，重度AMI）估计每年发生500，000起事件。纤溶治疗被广泛用于恢复冠状动脉血流，因为它广泛适用于广泛的患者。目前的治疗方案，包括组织纤溶酶原激活剂、阿司匹林、氯吡格雷和肝素，仍然在30-40%的患者中诱导冠状动脉再灌注不足，在5-10%的患者中诱导早期血栓性再闭塞。此外，成功的再通导致有害的再灌注损伤，其占心肌梗死最终大小的高达50%。治疗后30天的净临床不良结局仍为10-12%，16-17%的STEMI患者在1年随访期间死亡。此外，发生围手术期出血的患者的发病率和死亡率都会显着增加。重要的是，大多数复发性MI和大出血事件发生在治疗后的最初几小时和几天内。因此，寻找更有效和更安全的急性抗血栓药物，有效衰减再灌注损伤仍然是药物开发的“圣杯”。 APT 102是具有两个氨基酸取代的优化的人腺苷三磷酸双磷酸酶，其具有比野生型腺苷三磷酸双磷酸酶显著更高的活性。这种酶通过酶促水解细胞外ADP和ATP抑制血小板活化并限制血管炎症。CD 73进一步产生腺苷，可防止缺氧期间和心脏再灌注损伤时的组织损伤。此外，APT 102可防止血小板脱敏并维持体内平衡。在I期研究中，我们证明了在犬r-tPA诱导的纤维蛋白溶解模型中，与氯吡格雷相比，APT 102治疗完全防止了再闭塞，维持了正常血流，并将心脏梗死面积大幅减少了80%。同时，APT 102没有延长出血时间，如氯吡格雷。这项SBIR II期资助申请的目的是严格确定在犬冠状动脉纤溶模型中，与氯吡格雷相比，APT 102是否能促进心肌灌注和左心室功能的改善，同时出血量最少。长期目标是将APT 102开发为具有最小出血风险的高效抗血栓和抗炎治疗，这将大大提高AMI和其他血栓性患者急性治疗的疗效和安全性。

项目成果

A non-contrast CMR index for assessing myocardial fibrosis.

用于评估心肌纤维化的非对比度CMR指数。

• DOI: 10.1016/j.mri.2017.04.012
• 发表时间: 2017-10
• 期刊: Magnetic resonance imaging
• 影响因子: 2.5
• 作者: Yin Q;Abendschein D;Muccigrosso D;O'Connor R;Goldstein T;Chen R;Zheng J
• 通讯作者: Zheng J

Body fat distribution, menopausal hormone therapy and incident type 2 diabetes in postmenopausal women of the MESA study.

MESA 研究中绝经后女性的身体脂肪分布、绝经期激素治疗和 2 型糖尿病发生情况。

• DOI: 10.1016/j.maturitas.2016.06.020
• 发表时间: 2016
• 期刊: Maturitas
• 影响因子: 4.9
• 作者: Ebong,ImoA;Watson,KarolE;Hairston,KristenG;Carnethon,MercedesR;Ouyang,Pamela;Szklo,Moyses;Bertoni,AlainG
• 通讯作者: Bertoni,AlainG

Higher HDL cholesterol levels are associated with increased markers of interstitial myocardial fibrosis in the MultiEthnic Study of Atherosclerosis (MESA).

• DOI: 10.1038/s41598-023-46811-8
• 发表时间: 2023-11-17
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Chehab, Omar;Akl, Elie;Abdollahi, Ashkan;Zeitoun, Ralph;Ambale-Venkatesh, Bharath;Wu, Colin;Tracy, Russell;Blumenthal, Roger S.;Post, Wendy S.;Lima, Joao A. C.;Rodriguez, Annabelle
• 通讯作者: Rodriguez, Annabelle