29 Trans Sodium Crocetinate: A Novel Kosmotropic Molecule that Enhances Oxygen Diffusion in the Treatment of Hypoxia-Driven Medical Emergencies

Abstract

Tissue-hypoxia directly contributes to underlying morbidity and mortality of the top 5 leading causes of death in the US which include heart disease, cancer, chronic lower respiratory diseases, accidents (unintentional injuries) and cerebrovascular accidents. These conditions frequently present as medical emergencies requiring urgent intervention which occurs either at home, site of an accident, in an ambulance or in the emergency department. Currently, aside from oxygen therapy, there are no effective therapies approved available to reverse hypoxia and its potentially catastrophic consequences. Trans sodium crocetinate (TSC) is a kosmotrope that was developed to treat oxygen deficits in emergency cases. TSC is based on a novel mechanism of action, that of increasing the diffusion of oxygen from the erythrocytes through the plasma to the vascular wall, thereby increasing the gradient for oxygen diffusion to hypoxic tissues. The increase in the diffusion rate is caused by the influence of the intermolecular forces of the TSC molecule on the water molecules: it increases the numbers of hydrogen bonds among them. The initial investigation of TSC was part of the Battlefield Casualty Program of the US Office of Naval Research and was further developed by Diffusion Pharmaceuticals Inc. To assess the effect of treating hypoxic emergency, TSC was evaluated preclinically in animal models of three common medical emergencies; namely hemorrhagic shock, myocardial infarction and stroke. The results are summarized below: Hemorrhagic shock resulting from severe blood loss. After inducing 60% loss in estimated blood volumes in rats, studies showed that treatment with TSC; a) increased whole body oxygen consumption, b) increased blood pressure, c) preserved organ function as reflected by liver enzymes and d) resulted in 100% survival at 24 hours compared to 15% in saline treated controls. Myocardial infarction. Studies of coronary artery ligation in a swine model showed that treatment with TSC conferred a 90% survival at 4 hours compared to 33% in controls. Stroke. Studies in both rats (3 vessel occlusion: two carotids and left middle cerebral arteries) and rabbits (injection of blood clots) showed improved neuronal preservation in animals treated with TSC compared to controls in ischemic stroke. Further, studies in rats injected with collagenase to induce hemorrhagic stroke showed an increase in live neurons and a reduction in cerebral edema in TSC treated animals compared to controls. To date, about 150 patients have received TSC in clinical trials without any serious side effects attributed to TSC. TSC is currently being developed to treat hypoxia in patients with cancer. TSC appears to be a safe and potentially beneficial treatment for hypoxia related conditions. Furthermore, compelling preclinical data call for urgent clinical investigation of TSC in hypoxia related medical emergencies.