Neonatal and Pediatric Platelet Function and Pharmacology

新生儿和儿童血小板功能和药理学

• 批准号: 9759659
• 负责人: SCOTT L DIAMOND
• 金额: $ 51.04万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759659
• 关键词: Address; Adhesions; Adult; Age; Agonist; Animal Model; Antiplatelet Drugs; Arterial Injury; Aspirin; Biochemical; Biological; Biological Assay; Blood; Blood Platelets; Blood Vessels; Cardiac; Caring; Child; Childhood; Clinical Trials; Complex; Congenital Heart Defects; Critical Illness; Deposition; Development; Diagnostic tests; Diamond; Disease; Dose; Drug Monitoring; Drug effect disorder; Enrollment; Epidemic; Event; FDA approved; Fibrinolytic Agents; Future; Heart; Human; In Vitro; Infant; Intravenous; Knowledge; Lesion; Life; Light; Limb structure; Measures; Mediating; Microfluidic Microchips; Microfluidics; Mission; Monitor; Neonatal; Operative Surgical Procedures; Oral; Pain; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Physiological; Population; Prevention; Production; Public Health; Pulmonary artery structure; Repair Complex; Research; Risk; Savings; Scanning; Second Messenger Systems; Shunt Device; Signal Pathway; Signal Transduction; Site; Stimulus; Surface; System; Techniques; Technology; Therapeutic; Thrombosis; Thrombus; Translations; Transplanted tissue; Work; age group; age related; base; clinically relevant; clopidogrel; cohort; congenital heart disorder; design; drug development; drug efficacy; falls; high throughput screening; in vitro Assay; in vivo; individualized medicine; inhibitor/antagonist; injured; microfluidic technology; neonate; novel; palliative; patient population; pediatric patients; platelet function; prevent; public health relevance; release of sequestered calcium ion into cytoplasm; response; tertiary care; thrombogenesis

 DESCRIPTION (provided by applicant): Arterial thromboembolic disease is rapidly becoming the new epidemic of pediatric tertiary care centers due to an increase in invasive monitoring, life saving technologies such as ECMO, and new surgical techniques and graft materials used to repair complex congenital heart lesions. Yet, therapeutic options for preventing or treating this life and limb threatening disorder are limited. Major obstacles to drug development include: (i) A deficiency in knowledge of the extent to which platelets from neonates, infants, and children can form thrombi in injured blood vessels, (ii) limited information on the ability of various agents to curtail pediatric platelet- mediated adhesion and activation under physiologically relevant conditions, and (iii) a lack of sophisticated technologies that permit rapid assessment of pediatric platelet responses to agonists and antagonists in a high-throughput manner using a minimum quantity of blood. To address these clinically relevant issues, low volume microfluidic devices and high throughput screens (HTS) will be used to predict platelet responses to multiple combinations of agonists as well as antagonists, while a novel biological platform will be used for the in vivo assessment of drug efficacy in the prevention of pediatric platelet-mediated thrombosis. Critical questions to be addressed include: Can sophisticated technologies be developed that permit rapid assessment of pediatric platelet responses to agonists and antagonists in a high- throughput manner using a minimum quantity of blood? Can novel agents be identified for future development or use? Are there age related differences in function that would preclude the use of specific anti-platelet agents in certain subsets of pediatric patients? Can a small animal model be developed to better assess pediatric platelet responses to anti-thrombotic agents? Can in vitro assays be predictive of drug efficacy in vivo? Ultimately, we believe the work outlined in this proposal will lead to a better understanding of the appropriate class of anti-platelet agent to use for at risk pediatric patients. Moreover, it may be possible to define the feasibility and enrollment criteria for future clinical trials to test the diagnostic utlity of our in vitro approaches. The proposed work is also relevant to the mission of the agency, which is to encourage translational and collaborative research to advance our knowledge of underlying mechanisms of drug action and response in children at various developmental stages.

 描述（由申请人提供）：由于侵入性监测的增加，动脉血栓栓塞性疾病正在迅速成为儿科三级护理中心的新流行病， 节省技术，如ECMO，以及用于修复复杂先天性心脏病病变的新手术技术和移植材料。然而，用于预防或治疗这种威胁生命和肢体的疾病的治疗选择是有限的。药物开发的主要障碍包括：（i）缺乏对新生儿、婴儿和儿童血小板在受损血管中形成血栓的程度的了解，（ii）关于各种药物在受损血管中形成血栓的能力的信息有限， 在生理相关条件下减少儿科血小板介导的粘附和活化，和（iii）缺乏允许使用最少量血液以高通量方式快速评估儿科血小板对激动剂和拮抗剂的应答的复杂技术。为了解决这些临床相关问题，低容量微流体装置和高通量筛选（HTS）将用于预测血小板对多种激动剂和拮抗剂组合的反应，而一种新的生物平台将用于预防儿科血小板介导的血栓形成的药物疗效的体内评估。需要解决的关键问题包括：能否开发出先进的技术，以高通量的方式使用最少量的血液快速评估儿科血小板对激动剂和拮抗剂的反应？能否识别出新的药剂以供未来开发或使用？在某些儿科患者亚群中，是否存在与年龄相关的功能差异，从而妨碍使用特异性抗血小板药物？能否开发一种小动物模型来更好地评估儿科血小板对抗血栓药物的反应？体外试验能否预测体内药物疗效？最终，我们相信，这项提案中概述的工作将有助于更好地了解用于高危儿科患者的适当抗血小板药物。此外，还可以 确定未来临床试验的可行性和入选标准，以测试我们体外方法的诊断效用。拟议的工作也与该机构的使命有关，即鼓励转化和合作研究，以增进我们对处于不同发育阶段的儿童的药物作用和反应的基本机制的了解。

项目成果

Recommendations to Enhance Pediatric Cardiovascular Drug Development: Report of a Multi-Stakeholder Think Tank.

• DOI: 10.1161/jaha.117.007283
• 发表时间: 2018-02-10
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: Torok RD;Li JS;Kannankeril PJ;Atz AM;Bishai R;Bolotin E;Breitenstein S;Chen C;Diacovo T;Feltes T;Furlong P;Hanna M;Graham EM;Hsu D;Ivy DD;Murphy D;Kammerman LA;Kearns G;Lawrence J;Lebeaut B;Li D;Male C;McCrindle B;Mugnier P;Newburger JW;Pearson GD;Peiris V;Percival L;Pina M;Portman R;Shaddy R;Stockbridge NL;Temple R;Hill KD
• 通讯作者: Hill KD

P2Y12 Receptor Function and Response to Cangrelor in Neonates With Cyanotic Congenital Heart Disease.

紫绀型先天性心脏病新生儿 P2Y12 受体功能和对坎格雷洛的反应。

• DOI: 10.1016/j.jacbts.2017.04.002
• 发表时间: 2017
• 期刊: JACC. Basic to translational science
• 作者: Kaza,ElisabethA;Egalka,MatthewC;Zhou,Hairu;Chen,Jianchun;Evans,Denise;Prats,Jayne;Li,Ruizhi;Diamond,ScottL;Vincent,JulieA;Bacha,EmileA;Diacovo,ThomasG
• 通讯作者: Diacovo,ThomasG