SaNOtize has developed a nitric oxide releasing solution (NORSTM) for early treatment and prevention of

COVID-19 infection. NORS been shown to inactivate more than 99.9% of SARS-CoV-2 (to below limit
of detection), within 2 minutes. NORS can be delivered as a nasal spray and is easily self-administered by
patients in a variety of settings (office, airplane, etc.). This can act as “the hand sanitizer for your nose”
Nitric Oxide
Nitric oxide (NO), a natural molecule produced in our body, is shown to possess a wide variety of
biochemical characteristics like regulating blood flow.1 Consequently, nitric oxide was shown to be a
selective pulmonary vasodilator and was subsequently approved as a prescription drug 20 years ago, to be
delivered as inhalational gas for treatment of blue baby syndrome in full term infants.2
Nitric oxide (NO), has been shown to be a promising efficient broad spectrum anti-infective agent. It has
been reported to have antimicrobial activity against bacteria, fungi, viruses and even drug resistant
microbes both in-vitro and in animal studies.3-8 NO rapidly kills pathogens as it is a lipophilic small
molecule that readily crosses cell membranes to target essential organelles within the microbe.9 NO kills by
nitrosylating multiple targets like DNA, RNA and essential proteins and lipids.10 However, NO is safe
because human cells easily detoxify NO.11 Almost every cell in our body produces NO. NO possesses
simple pharmacokinetics and has an extremely short half-life (seconds). Excess NO will be inactivated by
binding to hemoglobin to create methemoglobin within minutes. Methemoglobin is further reduced to
nitrites and nitrates then excreted in the urine within hours.12
Recent publication at Redox Biology13 has demonstrated, using an NO donor, a dose dependent effect on
the level of inhibition of the SARS-CoV-2 viral replication. The author of the article was quoted saying
“To our knowledge, nitric oxide is the only substance shown so far to have a direct effect on SARS-
CoV-2”
NO delivery problem
To date, nitric oxide used in a therapeutic setting is provided in large high pressurized cylinders. These
cylinders are cumbersome, expensive and potentially dangerous when moved around. There have been
previous attempts to harness nitric oxide’s antimicrobial properties for therapeutic use for infectious dermal
and wound applications but to date there have been no commercial successes. There are a number of
challenges in developing nitric oxide as a drug to treat infections. The biggest barriers are how to deliver
nitric oxide topically at the effective high antimicrobial dose without the use of large and expensive gas
cylinders and how to patent a new technology for a naturally occurring molecule.
SaNOtize has developed and patented a way to deliver nitric oxide as a liquid at a dose that is
sufficient to act as a powerful and rapid acting antimicrobial. Imagine carbonated water but the
bubbles are nitric oxide gas. This is NORS (Nitric Oxide Releasing solution).
NORS and COVID-19
Recent laboratory tests conducted by the Institute for Antiviral Research at Utah State University confirm
SaNOtize’s NORS inactivated more than 99.9% of SARS-CoV-2 (to below limit of detection), within two
minutes. The unique formulation of NORS allows for intranasal delivery of a short, local, high dose of NO
that is lethal to microbes but safe to humans. NORS has the advantage of allowing NO to be administered
by the patient, easily and safely, outside of the hospital. SaNOtize is currently in the middle of a phase 2
clinical trial (N=210) for COVID in Canada and has all the safety data to support it.
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We hypothesize that NORS, with its NO releasing capability, will act as an antiviral and virucidal agent by
nitrosylating key proteins on the surface of the virion (viricidal effect) and by inhibiting angiotensin
converting enzyme 2 (ACE2) receptors which prevents the ability for the virion to fuse onto the host cell
wall. In addition, NO passes readily into the host cell where it interferes with mRNA transcription and
replication of the virus. A recent Nature14 publication said that “…given that nasal carriage is likely to be a
key feature of transmission, drugs/vaccines administered intranasally could be highly effective in
limiting spread”. SaNOtize has a nasal spray that can be referred to as the “hand sanitizer for the nose”
We anticipate that these mechanisms of action provided by NORS and the knowledge gained to date on the
progression of the disease will result in an improved clinical outcome for COVID-19 patients.
Safety of NORS
NORS, delivered as nasal spray, is producing nitric oxide at a lower level than what is approved for
treating “blue babies”. The compounds that are used to create the nasal spray are compounds that are food
grade materials and are used in a daily concentration that is under the Average Daily Intake guidelines.
Over 1,600 nasal spray treatment were already delivered in the current COVID clinical trial and did not
result in any adverse events.

References
1. Gustafsson, L. E., Leone, A. M., Persson, M. G., Wiklund, N. P., & Moncada, S. (1991). Endogenous nitric oxide
is present in the exhaled air of rabbits, guinea pigs and humans. Biochem Biophys Res Commun, 181(2), 852-857.
2. FDA. (2013). INOmax Full Prescribing Information Reference ID: 3270345.
3. Ghaffari, A., Jalili, R., Li, Y., Miller, C. C., & Ghahary, A. (2006). Antimicrobial safety and efficacy of gaseous
nitric oxide on bacterial and human skin cells. Wound Rep Reg.
4. Ghaffari, A., Neil, D. H., Ardakani, A., Road, J., Ghahary, A., & Miller, C. C. (2005). A direct nitric oxide gas
delivery system for bacterial and mammalian cell cultures. Nitric Oxide, 12(3), 129-140.
5. Regev-Shoshani, G., Ko, M., Miller, C., & Av-Gay, Y. (2010). Slow release of nitric oxide from charged catheters
and its effect on biofilm formation by Escherichia coli. Antimicrob Agents Chemother, 54(1), 273-279.
6. Regev-Shoshani, G., Vimalanathan, S., McMullin, B., Road, J., Av-Gay, Y., & Miller, C. (2013). Gaseous nitric
oxide reduces influenza infectivity in vitro. Nitric Oxide, 31, 48-53.
7. Rimmelzwaan, G. F., Baars, M. M., de Lijster, P., Fouchier, R. A., & Osterhaus, A. D. (1999). Inhibition of
influenza virus replication by nitric oxide. J Virol, 73(10), 8880-8883.
8. Regev-Shoshani G., Vimalanathan S., Prema D., Church J.S., Reudink M.W., Nation N., Miller C.C. 2014. Safety,
bioavailability and mechanism of action of nitric oxide to control Bovine Respiratory Disease Complex in calves
entering a feedlot. Res Vet Sci, 96(2), 328-337.
9. Fang, F. C. (1997) Perspectives series: host/pathogen interactions. Mechanisms of nitric oxide-related
antimicrobial activity. J Clin Invest 99, 2818-2825, doi:10.1172/JCI119473.
10. Schairer, D. O., Chouake, J. S., Nosanchuk, J. D. & Friedman, A. J. (2012) The potential of nitric oxide releasing
therapies as antimicrobial agents. Virulence 3, 271-279, doi:10.4161/viru.20328.
11. Miller, C. C., Rawat, M., Johnson, T., & Av-Gay, Y. (2007). Innate protection of Mycobacterium smegmatis
against the antimicrobial activity of nitric oxide is provided by mycothiol. Antimicrob Agents Chemother, 51(9),
3364-3366.
12. Wennmalm, A., Benthin, G., Edlund, A., Jungersten, L., Kieler-Jensen, N., Lundin, S., et al. (1993). Metabolism
and excretion of nitric oxide in humans. An experimental and clinical study. Circ Res, 73(6), 1121-1127.
13. Akaberi D, et al. (2020). Mitigation of the replication of SARS-CoV-2 by nitric oxide in vitro. Redox Biology 37.

14. Sungnak, W. et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate
immune genes. Nat Med 26, 681-687, doi:10.1038/s41591-020-0868-6 (2020).

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