More

Abstract: Exposure to cyanide occurs more commonly in everyday life than many would believe, although most exposure is rather innocuous. However, the main concern is the misuse of cyanide in mass casualty events. Misuse of cyanide as a poison has been documented since before World War II.1 The potential for malicious use still pervades in our society. Current scavenging treatments center on cobalt ions to bind cyanide in the blood. 2,3 Unfortunately, these treatments require high doses of cobalt that can be associated with some significant toxic side effects when used in higher doses, possibly resulting in a dose limiting toxicity.4–6 When administered shortly after cyanide exposure, cobalt-based scavengers only improves survival by 50-70%, thus adding concern over the therapeutic options.6–10 In addition, the delivery of the FDA approved scavenger, hydroxocobalamin requires intravenous infusion over several minutes, adding delays to treatment time. Slow delivery has been demonstrated to reduce the chance of survival in patients suffering from cyanide exposure.5 Therefore, there is an ever-pressing need for the rapid delivery of an effective scavenger to mitigate the morbidity and mortality associated with high levels of exposure. Chapter 1 is a literature review for topics related to cyanide poisoning, current scavengers, and emerging solutions in development for treating cyanide in. Previous work with platinum demonstrated the capacity to mitigate cyanide-associated toxicity in both zebrafish and mice when exposed to lethal levels.11 The resulting Pt-sulfide complexes might have been acting as a cis or trans-directing ligand that was later hypothesized to have contributed to the efficacious response. Mechanistically, Pt-S interactions may activate platinum, improving the rate of cyanide substitution onto the platinum center.12–15 A possible advantage of platinum complexes over cobalt lies in the fact that little evidence supports strong interactions between sulfur and cobalt, which would limit the usefulness of the trans effect in these complexes. Interactions of cobalt with amino acids would occur primarily through carboxylate and amines, which have stronger bonds and would limit cyanide reactivity.16,17 Chapter 2 focuses on identifying suitable Pt-sulfide complexes using a combination of in vitro and in vivo testing. The overall project aims to identify suitable formulation conditions which maintain efficacy by intramuscular injection. Associative properties of ligands (e.g. amine and hydroxide) on platinum might be influenced by hydrogen ion concentration (pH) in solution.18,19 Regarding the trans effect, a conversion to related isomers may change the reactivity between platinum and cyanide. Chapter 3 begins identifying the relationship between formulation pH, cyanide scavenging, and efficacy. One of the leading adverse reactions with platinum drugs is acute kidney injury (AKI), which leads to renal disfunction.20 Sulfides have been found to modulate renal injury in vivo, suggesting sulfide complexed to platinum might reduce nephrotoxicity from platinum.21 One such example, thioethers (e.g. methionine) co-administered with cisplatin almost completely removed symptoms of renal injury in rats.22,23 Chapter 3 also describes our investigation of the risk of AKI and lingering renal injury for the most efficacious platinum complexes identified in chapter 2. Furthermore, we highlight a potential strategy to mitigate AKI with the complexes. In summary, platinum complexes based on naturally occurring metabolites of platinum have demonstrated promise as a new class of cyanide countermeasures. Centered on the chemistry of methionine and analogs of methionine, we investigate the scavenging activity, formulation stability, and toxicity in this work. We hypothesize thioethers enhance cyanide scavenging rates showing improved increased efficacy, while also offering nephrotoxic protection that can be attenuated.