Animal Modeling, Photonics, and Antidote Efficacy Core

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Animal Modeling, Photonics, and Efficacy Evaluation Core (AEC) Abstract The Animal Modeling, Photonics and Efficacy Evaluation Core consists of two core photonics based diagnostic technologies and 2 non-rodent species of established CN poisoning: highly monitored mid-size animal (rabbit) (UC Irvine) and large animal (pig) models (University of Colorado Denver). The core provides the capabilities for advanced in-vivo animal candidate antidote diagnostics, efficacy testing, and capabilities for real time quantitative determination of chemical induced injury development, extent, and response to therapy. The Core supports advanced mammalian testing of the promising antidote candidates identified in projects 1, 2, and 3. This integrated core has the capability to rapidly advance testing of such candidate agents in pre-clinical evaluation, as well as to provide feedback iteration to the earlier phase projects and to the Pharmaceutical Sciences Core for drug design enhancement, and to provide samples to the Metabolic Phenotyping and Pharmacokinetics Core (MPPC) to promote our mechanistic understanding of the consequences of CN poisoning. The Core photonics based technologies include diffuse optical spectroscopy and continuous wave near infrared spectroscopy for assessment of effects of the metabolic poison cyanide, and monitoring of tissue oxygenation and cytochrome C oxidase redox states in the rabbit and swine models, and real-time micro-sensors for continuous tissue lactate monitoring in animals with metabolic poison exposures. The core will also provide a state-of-the-art rabbit testing facility and established lethal and sub-lethal models for cyanide antidote development supporting all projects. Advanced technology capabilities will be extended to the U. of Colorado as part of the Core deliverables, and will function there in the large animal (pig) model in addition to their ongoing availability in the rabbit testing facility and animal operating rooms at UC Irvine Beckman Laser Institute. As shown in our prior chemical defense research, these core technologies enable more accurate, precise, and noninvasive determination of injury and treatment effectiveness, dramatically accelerating antidote development and reducing animal numbers required for definitive results and successful translation of antidote compounds to therapeutic use.