Development of the first thermolytic to suppress shivering and seizure

总结 到2020年，温度管理市场预计将达到26亿美元， 目前，制药业还没有专门针对这一市场开发。A1腺苷（A1 AR） 众所周知，激动剂可减弱癫痫发作并保护大脑免受损伤，但 这些药物的副作用，包括体温过低，心动过缓， 低血压受我们发现的6 N环己基腺苷（CHA）降低身体的启发， 温度和诱导冬眠，CHA心血管副作用可以 用外周作用腺苷受体拮抗剂8-（对磺基苯基）茶碱逆转 （8-SPT）在不影响体温的情况下，本提案旨在实现三个里程碑 这将确定商业化的目标市场。目标1是实现我们的第一个里程碑 这是为了证明CHA/ 8-SPT比现有技术更好地减轻颤抖 哌替啶/丁螺环酮在冷却至33°C的大鼠中的作用。目标二是达到第二个里程碑， 证明CHA/ 8-SPT比哌替啶/丁螺环酮更好地减弱癫痫发作，目的3是 达到我们的第三个里程碑，以证明CHA/8-SPT在靶点的神经保护功效 同时显示CHA/8-SPT在33°C和36°C的温度下控制颤抖和癫痫发作， 都是目标温度。 完成后，我们将有必要的初步数据，以确定治疗，抗癫痫 CHA/8-SPT相对于最新技术水平的神经保护功效和副作用 抗寒战药这些结果将通过标准方法实现 目前在PI实验室使用。这些结果将大大有助于证明科学 探讨了CHA与8-SPT联用作为新型治疗药物的技术可行性， 抗癫痫药物，这将使有针对性的温度管理， 满足市场需求，以治疗手术后颤抖。的 建议的工作是必要的，以证明在第二阶段的额外支持。

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.