Validating leads in mouse and rabbit models of cyanide Poisoning
The purpose of Project 3 is to receive promising drug candidates that have been identified in Project 1 and 2, and test them for efficacy in well-established mouse and rabbit models of cyanide poisoning. Project 3 will also supply serial blood samples (and tissue) for core metabolomics analysis during poisoning and response to determine basic mechanistic pathways and potential interventional targets. Drugs identified by screening in Project 1 will be modified in Project 2 to optimize their activity, safety, and solubility profile. They will then be passed on to Project 3A mouse model testing. If found to be efficacious and safe in mice, they progress to Project 3B for efficacy using highly monitored rabbit models of intravenous and oral exposure cyanide poisoning. In lethal and non-lethal rabbit models of cyanide poisoning, animals are monitored for oxy- and deoxy-Hb ratio changes, breathed gas exchange parameters, plasma lactate concentration, blood gas values, and blood pressure during cyanide treatment and reversal with the drugs identified. In addition, at the initial mammalian screening stage, the non-lethal rabbit model is used to determine initial possible efficacy with high dose intravenous injection of candidate agents. Rabbit blood and organ samples are also provided for metabolomic analysis and measuring drug concentrations.
Continuous wave near infrared spectroscopy of rabbit brain region oxy (red), deoxy (blue), and total (green) hemoglobin during cyanide infusion and reversal over time (a) control saline intravenous injection or (b) intravenous injection of cis-diaminechloro(dimethylsulfoxide)platinum(II). During cyanide poisoning, tissues are unable to utilize oxygen and extract oxygen from the blood. Therefore the oxyhemoglobin concentration of blood flowing through the tissues rises, and that of deoxyhemoglobin in the tissues falls. When cyanide infusion is stopped, the gradual return of the oxy and deoxyhemoglobin is seen (a – left sided figure). In contrast, when animals are given antidote (b – right figure) the compound causes immediate reversal of the effects of cyanide on oxy and deoxy-hemoglobin ratios as compared to control saline injection.