Oxygen diffusion-enhancing compound

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An oxygen diffusion-enhancing compound is any substance that increases the availability of oxygen in body tissues by influencing the molecular structure of water in blood plasma and thereby promoting the movement (diffusion) of oxygen through plasma. [1] Oxygen diffusion-enhancing compounds have shown promise in the treatment of conditions associated with hypoxia (a lack of oxygen in tissues) and ischemia (a lack of oxygen in the circulating blood supply). [1] [2] Such conditions include hemorrhagic shock, myocardial infarction (heart attack), and stroke. [2]

Contents

Types

One of the first substances that was reported to produce an oxygen diffusion-enhancing effect was crocetin, [3] a carotenoid that occurs naturally in plants such as crocus sativus , and is related to another carotenoid, saffron. Saffron has been used culturally (e.g., as a dye) and medicinally since ancient times. [4]

Trans sodium crocetinate (TSC), a synthetic drug containing the carotenoid structure of trans crocetin has been extensively investigated in animal disease models and in human clinical trials. [2] [5] [6] Clinical trials of TSC have focused on testing the compound's effectiveness in sensitizing hypoxic cancer cells to radiation therapy in patients with glioblastoma, an aggressive form of brain cancer. [6]

TSC, which is being developed by Diffusion Pharmaceuticals, has been shown to enhance the oxygenation of hypoxic tumor tissue [7] and belongs to a subclass of oxygen diffusion-enhancing compounds known as bipolar trans carotenoid salts. [1] Diffusion Pharmaceuticals is currently investigating the use of trans sodium crocetinate in the treatment of COVID-19, acute stroke, and solid cancerous tumors. [8]

Mechanism of action

Oxygen diffusion-enhancing compounds are thought to act by exerting hydrophobic forces that interact with water molecules. [9] These interactions result in greater hydrogen bonding among water molecules, which constitute the majority of the blood plasma medium. [9] [10] As hydrogen bonding increases, the overall molecular structure of water in the plasma becomes more lattice-like, a phenomenon known as structure building. [11] [12] Structure building reduces resistance to the movement of oxygen through plasma via diffusion. [11] Since blood plasma offers the major barrier for oxygen to move from the red blood cells and into the tissues, [2] the more structured character of water imparted by the oxygen diffusion-enhancing compound will enhance movement into tissues. [9] [13]

Computer simulations have shown that TSC specifically can increase the transport of oxygen through water by as much as 30 percent. [10]

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Diffusion Pharmaceuticals Inc (NASDAQ:DFFN) is a publicly traded biotechnology and drug development company based in Charlottesville, Virginia, U.S. It was co-founded in 2001 by American life sciences entrepreneur David Kalergis and University of Virginia Chemical Engineering Professor John L. Gainer. Gainer is the inventor of the company's platform technology of oxygen diffusion-enhancing compounds and its lead drug, trans sodium crocetinate (TSC). TSC acts to increase the rate at which oxygen moves through blood plasma by the process of diffusion, a phenomenon that forms the basis for the company's name. On January 8, 2016, the formerly privately held company merged with Restorgenex Corporation to become a publicly traded NASDAQ-listed company with the trading symbol DFFN. TSC and other oxygen diffusion-enhancing compounds, including bipolar trans carotenoid salts, have been investigated by Diffusion Pharmaceuticals for treatment of conditions associated with reduced oxygen availability in tissues (hypoxia). Most recently, Diffusion has begun the initiation of clinical trials in the U.S. and Eastern Europe for the use of trans sodium crocetinate in the treatment of COVID-19 patients with respiratory distress-related oxygen deficiency and the risk of multiple organ failure.

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John L. Gainer is an American chemical engineer and co-founder and former chief scientific officer of Diffusion Pharmaceuticals, a biotechnology and pharmaceutical company based in Charlottesville, Virginia, U.S. Professor Gainer retired from his position as Chief Science Officer of Diffusion Pharmaceuticals in March, 2020. Gainer pioneered investigation into the mechanism of action underlying oxygen diffusion-enhancing compounds (ODECs) and invented the subclass of ODECs known as bipolar trans carotenoid salts. The lead compound of this class is trans sodium crocetinate (TSC) which Gainer invented while a professor of chemical engineering at the University of Virginia.

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References

  1. 1 2 3 USpatent 8206751,Gainer J,"New Class of Therapeutics that Enhance Small Molecule Diffusion",issued 2009-04-30
  2. 1 2 3 4 Gainer, J (2008). "Trans-sodium crocetinate for treating hypoxia/ischemia". Expert Opinion on Investigational Drugs. 17 (6): 917–924. doi:10.1517/13543784.17.6.917. PMID   18491992. S2CID   71663644.
  3. ↑ Gainer J; G.M. Chisolm III (1974). "Oxygen diffusion and atherosclerosis". Atherosclerosis. 19 (1): 135–138. doi:10.1016/0021-9150(74)90049-5. PMID   4810465.
  4. ↑ Abdullaev F, Espinosa-Aguirre J (2004). "Biomedical properties of saffron and its potential use in cancer therapy and chemoprevention trials". Cancer Detection and Prevention. 28 (6): 426–432. doi:10.1016/j.cdp.2004.09.002. PMID   15582266.
  5. ↑ 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. S2CID   25369069.
  6. 1 2 "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.
  7. ↑ Sheehan, Jason; et al. (2008). "Use of trans sodium crocetinate for sensitizing glioblastoma multiforme to radiation". Journal of Neurosurgery. 108 (5): 972–978. doi:10.3171/JNS/2008/108/5/0972. PMID   18447715.
  8. ↑ "Diffusion Pharmaceuticals Announces FDA Accelerated Review of TSC Clinical Development Plan to Treat COVID-19 Patients with ARDS". Diffusion Pharmaceuticals. May 5, 2020. Retrieved May 25, 2020.
  9. 1 2 3 USpatent 7919527,Gainer J&Grabiak R,"Bipolar trans carotenoid salts and their uses",issued 2011-04-05
  10. 1 2 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. 1 2 Cannon, Joseph G (1999). Pharmacology for Chemists. New York: Oxford University Press. ISBN   978-0841235243.
  12. ↑ 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.
  13. ↑ Starr, Cecie; McMillan, Beverly (2012). Human Biology (9th ed.). Cengage Learning. ISBN   978-0840061669.
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