Development of the first thermolytic to suppress shivering and seizure

开发出第一种抑制颤抖和癫痫发作的热解药物

• 批准号: 9407549
• 负责人: KELLY L DREW
• 金额: $ 29.89万
• 依托单位: BE COOL PHARMACEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9407549
• 关键词: Adenosine; Adenosine A1 Receptor; Adverse effects; Affect; Agonist; Alaska Native; American Indians; Anesthesia procedures; Animals; Area; Attenuated; Automobile Driving; Body Temperature; Bradycardia; Brain; Brain Injuries; Buspirone; Cardiovascular system; Cessation of life; Critical Illness; Data; Death Rate; Development; Drug Controls; Drug usage; Emergency Medicine; Formulation; Growth; Heart Arrest; Hibernation; Hospitals; Hypotension; Investigational New Drug Application; Label; Laboratories; Licensing; Life; Meperidine; Methods; Neurological outcome; Outcome; Patients; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacology Study; Pharmacy (field); Phase; Physicians; Population; Postoperative Period; Prophylactic treatment; Publishing; Purinergic P1 Receptors; Rattus; Recovery; Rodent Model; Rural; Rural Population; Safety; Savings; Seizures; Shivering; Surface; Technology; Temperature; Theophylline; Time; Underserved Population; Work; base; commercialization; cost; disability; drug development; experience; experimental study; improved; improved outcome; meetings; natural hypothermia; novel; pre-clinical; receptor; remote location; survival outcome; trial comparing

Summary The temperature management market is expected to reach $2.6 billion by 2020, yet no pharmaceutical has yet been developed specifically for this market. A1 adenosine (A1AR) agonists are well known to attenuate seizure and protect the brain from injury, but development of these drugs has been limited by side-effects including hypothermia, bradycardia and hypotension. Inspired by our discoveries that 6N cyclohexyl adenosine (CHA) lowers body temperature and induces hibernation and that cardiovascular side-effects of CHA can be reversed with a peripherally acting adenosine receptor antagonist 8-(p-Sulfophenyl)theophylline (8-SPT) without affecting body temperature, the present proposal aims to meet three milestones that will define the market to target for commercialization. Aim 1 is to meet our first milestone which is to demonstrate that CHA/ 8-SPT attenuates shivering better than state-of-the-art meperidine/buspirone in rats cooled to 33°C. Aim 2 is to meet our second milestone which is to demonstrate CHA/ 8-SPTattenuates seizure better than meperidine/buspirone and Aim 3 is to meet our third milestone to demonstrate neuroprotective efficacy of CHA/8-SPT at target temperatures of 33°C and 36°C while showing that CHA/8-SPT controls shivering and seizure at both target temperatures. When completed we will have necessary preliminary data to define the thermolytic, antiseizure and neuroprotective efficacy and side effects of CHA/8-SPT relative to the state-of-the-art antishivering medication. These outcomes will be accomplished through standard methods currently used in the PI's laboratory. The results will significantly contribute to proving the scientific and technical feasibility of developing CHA combined with 8-SPT as a novel thermolytic and antiseizure medication that will make targeted temperature management accessible to underserved populations and meet market demand to treat post-operative shivering. The proposed work is necessary to justify additional support in Phase II.

概括 预计到2020年温度管理市场将达到26亿美元，但没有 药品尚未专门为该市场开发。 A1腺苷（A1AR） 众所周知，激动剂会减弱癫痫发作并保护大脑免受伤害，但发育 这些药物在包括体温过低，心动过缓和 低血压。受到我们发现6N环己基腺苷（CHA）降低身体的启发 温度并诱导冬眠，CHA的心血管副作用可以是 用外周作用的腺苷受体拮抗剂逆转8-（p-磺苯基）phylline （8-SPT）没有影响体温，目前的建议旨在达到三个里程碑 这将定义市场的目标。目标1是达到我们的第一个里程碑 这表明CHA/ 8-SPT比最新的 大鼠中的近端/丁螺酮冷却至33°C。目标2是达到我们的第二个里程碑 表现出比Meperidine/ buspirone更好的癫痫发作，AIM 3是 达到我们的第三个里程碑，以在目标处证明CHA/8-SPT的神经保护效率 33°C和36°C的温度表明CHA/8-SPT控制在颤抖和癫痫发作 两个目标温度。 完成后，我们将有必要的初步数据来定义热解，恒定 以及CHA/8-SPT相对于最新的神经保护效果和副作用 抗药药。这些结果将通过标准方法实现 目前在PI的实验室中使用。结果将极大地促进科学证明 以及开发CHA的技术可行性与8-SPT一起作为一种新型的热液和 将靶向温度管理访问 服务不足的人口并满足市场需求，以治疗术后发抖。这 提出的工作对于证明第二阶段的额外支持是必要的。