Rapid translation of novel cyanide treatment drugs to clinical practice using DOS

总体目标:

Overall goal: This is an integrated collaborative project with the overall goal: To provide and implement new methods for rapid translation of novel cyanide antidote drugs to clinical stages using a unique rabbit cyanide toxicity model and noninvasive broadband diffuse optical spectroscopy assessment of pathophysiologic events of cyanide poisoning and therapeutic response. RFA Objectives and relevance to program priorities: This proposal directly addresses all of the following RFA-NS-08-003 and RFA-NS-08-004 objectives for "metabolic/cellular poisons such as cyanide": 1) Enhancing diagnostic and treatment response capabilities during an emergency 2) The rapid advancement of new diagnostic techniques 3) The development and use of animal models to identify lead compounds as well as advance preclinical studies 4) Development of better diagnostic tools and techniques 5) Efficacy of screening of therapeutic/diagnostics using new and validated animal models This research proposal involves the following RFA-NS-06-005 suggested components: 1) Therapies based on toxicity and chemical threat agents, 2) therapies based on cyanide sulfur donors 3) alternative routes of administration for new and improved therapies that would be safe, effective and easy to administer during a mass casualty scenario, and 4) improved rapid diagnostic techniques/technologies for the purpose of differential diagnosis, triage, detection of subclinical exposures, prognosis, and prediction of tissue damage. Proposal Core Foundation: We have 1) developed a reliable, reproducible rabbit model of cyanide toxicity, and 2) demonstrated the ability of diffuse optical spectroscopy (DOS) technologies recently developed at Beckman Laser Institute to noninvasively assess the pathophysiologic events occurring during cyanide toxicity and reversal with standard agents (hydroxocobalamin, and nitrite induced met hemoglobin induction). We propose to utilize this animal model and new optical technology assessment methodology in collaborative studies to rapidly translate potential novel cyanide treatment drugs to clinical testing stages. Purpose: To assess and optimize the capabilities of 1) cobinamide, 2) Mercaptopyruvate Dithiane sodium salt (3-MPDT), and 3) combination therapies of cobinamide and 3-MPDT to reverse cyanide toxicity in a rabbit model compared to currently available treatments and controls. Specific aims: For each drug (and drug combination), the following specific aims will be investigated: 1. What is the dose response relationship of these drugs in cyanide toxicity treatment? 2. What are the rates and extent of cyanide toxicity reversal and how well does noninvasive DOS correlate with cyanide levels and physiologic measurements during these drug treatments? 3. What drug administration modes can be utilized for effective delivery of these drugs and what are the optimal parameters for each of the following administration modes: a. Intravenous b. Intramuscular c. Aerosol (Nebulized, Direct tracheal instillation, Dry power) With the proposed animal models and broadband noninvasive DOS optical detection and monitoring capabilities, addressing these fundamental drug translation questions will be considerably accelerated, potential risks will be minimized, and drug development costs may be reduced. In the future, DOS technologies can be readily miniaturized and made available for cyanide toxicity detection and monitoring on a level needed for mass casualty screening and care. On a broader level, DOS is enabling technology for a wide range of toxicologic and other clinical needs.