Development of the first thermolytic to suppress shivering and seizure

摘要 到2020年，温度管理市场预计将达到26亿美元，但没有 目前还没有专门为这个市场开发的药物。A1腺苷(A1 AR) 众所周知，激动剂可以减轻癫痫发作并保护大脑免受伤害，但 这些药物中有一些受到副作用的限制，包括体温过低、心动过缓和 低血压。受我们发现6N环己基腺苷(CHA)降低身体的启发 体温和诱导冬眠以及CHA心血管副作用可能是 外周作用的腺苷受体拮抗剂8-(对磺苯基)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 这将定义商业化的目标市场。目标1是达到我们的第一个里程碑 这是为了证明CHA/8-SPT比最先进的技术更好地减弱颤抖 在冷却到33℃的大鼠中使用度冷丁/丁螺环酮。目标2是达到我们的第二个里程碑，即 证明CHA/8-SPT比度冷丁/丁螺环酮更有效地抑制癫痫发作，目标3是 达到我们的第三个里程碑，展示CHA/8-SPT的神经保护效果 33°C和36°C的温度，同时显示CHA/8-SPT控制颤抖和癫痫 两者都是目标温度。 当完成后，我们将有必要的初步数据来确定热分解，抗癫痫 CHA/8-SPT的神经保护效果和副作用 抗寒战药物。这些结果将通过标准方法实现。 目前在PI的实验室中使用。这一结果将极大地有助于证明 开发与8-SPT联用的CHA作为一种新型热分解剂的技术可行性 抗癫痫药物将使有针对性的体温管理变得 服务不足的人群，并满足治疗术后寒战的市场需求。这个 拟议的工作是必要的，以证明在第二阶段提供额外支助是合理的。

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.