Development of the first thermolytic to suppress shivering and seizure

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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.