Trans sodium crocetinate
|Trans sodium crocetinate|
|Molar mass||788.20 g mol−1|
|Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)|
Trans sodium crocetinate (TSC) is a synthetic drug that increases the movement of oxygen from red blood cells into hypoxic (oxygen-starved) tissues. TSC belongs to a group of substances known as bipolar trans carotenoid salts, which constitute a subclass of oxygen diffusion-enhancing compounds. One of the first such compounds discovered was the naturally occurring substance crocetin, the trans isomer of which forms the backbone structure of TSC. 
Invention and investigation
TSC was invented by American chemical engineer John L. Gainer, who reacted saffron with sodium hydroxide, and extracted the salt of the trans crocetin isomer from the solution. Gainer and colleagues subsequently investigated the effects of TSC in animal models.  They discovered that the drug could reverse the potentially fatal decrease in blood pressure produced by the loss of large volumes of blood in severe hemorrhage, and thereby improve survival.
Early investigations of TSC suggested that it had potential applications in battlefield medicine, specifically in treatment of the many combat casualties with hemorrhagic shock. Additional studies, carried out in animal models and in clinical trials in humans, indicated that TSC might prove beneficial in the treatment of a variety of conditions associated with hypoxia and ischemia (a lack of oxygen reaching the tissues, usually due to a disruption in the circulatory system), including cancer, myocardial infarction (heart attack), and stroke.    
TSC has shown promise of effectiveness in restoring tissue oxygen levels and improving the ability to walk in a clinical trial of patients with peripheral artery disease(PAD) in which reduced delivery of oxygen-rich blood to tissues can cause severe leg pain and impair mobility. The drug has also been under investigation in a clinical trial sponsored by drug developer Diffusion Pharmaceuticals for potential use as a radiosensitizer, increasing the susceptibility of hypoxic cancer cells to radiation therapy, in patients with a form of brain cancer known as glioblastoma.
Mechanism of action
Similar to other oxygen diffusion-enhancing compounds, TSC appears to improve oxygenation in hypoxic tissues by exerting hydrophobic effects on water molecules in blood plasma and thereby increasing the hydrogen bonding between the water molecules. This in turn causes the overall organization of water molecules in plasma to become more structured, which facilitates the diffusion of oxygen through plasma and promotes the movement of oxygen into tissues. 
- Gainer, J (2008). "Trans-sodium crocetinate for treating hypoxia/ischemia". Expert Opinion in Investigational Drugs 17 (6): 917–924. doi:10.1517/13543718.104.22.1687.
- US patent 8,206,751, Gainer J, "New Class of Therapeutics that Enhance Small Molecule Diffusion", issued 2009-04-30
- US patent 6,060,511, Gainer J, "Trans-sodium crocetinate, methods of making and methods of use thereof", issued 2000-05-09
- Giassi L, et al (2001). "Trans-Sodium Crocetinate Restores Blood Pressure, Heart Rate, and Plasma Lactate after Hemorrhagic Shock". Journal of Trauma-Injury Infection & Critical Care 55 (5): 932–938. doi:10.1097/00005373-200111000-00018. PMID 11706343.
- Lapchak P, (2010). "Efficacy and safety profile of the carotenoid trans sodium crocetinate administered to rabbits following multiple infarct ischemic strokes: A combination therapy study with tissue plasminogen activator". Brain Research 1309: 136–145. doi:10.1016/j.brainres.2009.10.067. PMID 19891959.
- Mohler E, et al (2010). "Evaluation of trans sodium crocetinate on safety and exercise performance in patients with peripheral artery disease and intermittent claudication". Vascular Medicine 16 (5): 346–352. doi:10.1177/1358863X11422742. PMID 22003000.
- "Safety and Efficacy Study of Trans Sodium Crocetinate (TSC) With Concomitant Radiation Therapy and Temozolomide in Newly Diagnosed Glioblastoma (GBM)". ClinicalTrials.gov. November 2011. Retrieved 18 September 2012.
- Stennett a, et al (2006). "Trans sodium crocetinate and diffusion enhancement". Physical Chemistry B 110: 18078–18080. doi:10.1021/jp064308.
- Laidig, K.E., J.L. Gainer, V. Daggett (1998). "Altering Diffusivity in Biological Solutions through Modification of Solution Structure and Dynamics". Journal of the American Chemical Society 120 (36): 9394–9395. doi:10.1021/ja981656j.
- Manabe H, et al. (2010). "Protection against focal ischemic injury to the brain by trans-sodium crocetinate". Journal of Neurosurgery 113 (4): 802–809. doi:10.3171/2009.10.JNS09562. PMC 3380430. PMID 19961314.