Nitric oxide in the treatment of coronavirus disease (COVID-19)

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Inhaled nitric oxide dilates or widens arteries to allow more blood to flow through the lungs. It also relaxes the trachea and bronchioles, allowing more air to come in” (Louis Ignarro, Ph.D. Nobel laurate for discovery of NO)

A number of published earlier findings from the year 2004’ SARS-CoV infection suggest the potential role of inhaled nitric oxide (iNO) as a supportive measure for treating infection in patients with pulmonary complications. Treatment with iNO was found to reverse pulmonary hypertension, improved severe hypoxia, and shortened the length of ventilatory support compared with matched control patients with SARS. Nitric oxide gas inhalation has long been used in the U.S. for the treatment of term and near-term neonates with hypoxic respiratory failure associated with pulmonary hypertension. Such device in therapy is the INOmax® product marketed by Mallinckrodt (Fig. 1A). iNO works by widening blood vessels in the lungs that become constricted as a result of inflammation and formation of clots and cannot provide the body with enough oxygen. [2]

Fig. 1A) INOmax DSIR,, B) INOpulse® device by Bellerophon Therapeutics ®, C) GenoSyl® the first and only tankless nitric oxide delivery system (VERO Biotech) (sources: https://www.inomax.com/inomax-delivery-systems/device-innovation, https://bellerophon.com/pipeline/inopulse-technology/, https://www.vero-biotech.com/genosyl-ds/

Current clinical trials against COVID-19 using inhaled nitric oxide

In March, the US FDA gave a handful of pharmaceutical companies emergency clearance to allow use of their nitric oxide providing devices to treat these patients, including Bellerophon Therapeutics (Fig. 1B) and Vero Biotech companies (Fig. 1C). Currently scientists across the USA are actively recruiting subjects for studies to confirm that this inhaled gas can have therapeutic benefits in COVID-19 patients by preventing further damage to the vessels inside the lungs.

Conclusion of INOpulse® treatment: three COVID-19 patients that completed improved oxygenation that allowed them to avoid the need for mechanical ventilation and two of the patients have already been discharged from the Hospital (source: Hunter Gillies, MD, chief medical officer at Bellerophon Therapeutics [3])

Studies of the collaboration between George Washington University and Albert Einstein College of Medicine demonstrated that nitric oxide treatment can be really pivotal in the world’s fight against SARS-CoV-2. Their findings were published in the journal Nitric Oxide. [4]

The authors highlight the potential for inhaled nitric oxide contributing to better clinical outcomes and alleviating the rapidly rising strain on health care capacity due to COVID-19. Authors also reviewed the benefits of use of nitric oxide in a broad range of medical indications covering clinical experiences of about two decades, and together are now developing nitric oxide-based therapeutics for COVID-19. The INOpulse® platform is an extension of the technology that is used in hospitals to deliver continuous-flow inhaled nitric oxide. The INOpulse® technology utilizes targeted pulsatile delivery of inhaled nitric oxide, allowing it to be extended into chronic use applications.

Another nitric oxide delivery device is Genosyl DS® by Vero Biotech Co. It is a tankless system (Fig. 1C) that produces on-demand nitric oxide via a chemical reaction. To ensure safety, sensors continuously monitor nitric oxide, NO2 and O2 levels. “Application of Vero’s tankless inhaled nitric oxide system at home under physician supervision is particularly critical during a time of crisis when hospital beds and ventilators are in short supply,” said Brent Furse, president and CEO of Vero Biotech, in a statement [5]. According to the company, Genosyl® is indicated to improve oxygenation and reduce the need for extracorporeal membrane oxygenation in neonates with hypoxic respiratory failure associated with pulmonary hypertension. Now, it may also benefit home-based use of inhaled nitric oxide to treat COVID-19 patients in need.

In a human study, investigators utilized iNO in the treatment of six patients infected with SARS-CoV. This study compared the outcomes of the six patients treated with iNO to eight controls. Improvements in blood oxygenation, a reduction in supplemental oxygen and a reduction in the amount of ventilator support were achieved and published. [6]

Nitric oxide shows direct antiviral effect besides its beneficial pulmonary action

While nitric oxide has not been specifically studied or used to treat COVID-19, it has demonstrated remarkable in vitro inhibitory effect on the replication cycle of severe acute respiratory syndrome-related coronavirus. [7] An earlier paper by Colsanti et al reported on antiviral effect of NO and even on the molecular mechanisms of the effect: the nitric oxide-based nitrosylation process of coronavirus proteins. [8] Another paper also discussed the molecular mechanism of this antiviral effect, and found that the S-nitrosylation of thiol groups of cystein amino acid of virus proteins stands actually behind the antiviral effect. [9]

Nitric oxide was found to increase survival rate of mammalian cell culture infected with SARS-CoV coronavirus. The in vitro study using NO-donor, S-nitroso- N-acetylpenicilliamine, greatly improved the survival rate of infected cells and inactivated SARS-CoV virus. [10]

This last example suggest that not only the inhaled nitric oxide gas but also the NO-releasing compounds can be beneficial. Several NO-releasing cyclodextrin complexes and derivatives have been developed, some of them presented on our blog

 (https://cyclodextrinnews.com/2019/12/04/cyclodextrin-related-papers-in-recent-issues-of-acs-applied-nano-materials/
https://cyclodextrinnews.com/2019/06/07/no-delivering-fluorescent-beta-cyclodextrin-polymer/
https://cyclodextrinnews.com/2018/11/29/no-releasing-cyclodextrins/). Their effect in Covid-19 is waiting to be explored.

References

[1] Roberts, J.D. et al Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group. New Engl. J Med. 1997, 336 (9), 605-610. 10.1056/NEJM199702273360902

[2] Zapol, W. Nitric oxide story. Anesthesiology 3 2019, 130, 435-440. https://doi.org/10.1097/ALN.0000000000002579

[3] http://investors.bellerophon.com/news-releases/news-release-details/bellerophon-therapeutics-submits-investigational-new-drug

[4] Adusumilli, N.C., et al.(2020) Harnessing nitric oxide for preventing, limiting and treating the severe pulmonary consequences of COVID-19. Nitric Oxide. https://doi.org/10.1016/j.niox.2020.07.003.)

[5] https://www.vero-biotech.com/home-use-of-genosyl-delivery-system-ds-to-administer-genosyl-nitric-oxide-gas-for-inhalation-for-the-treatment-of-pulmonary-hypertension-complicated-by-covid-19-infection-published-in/

[6] Chen L. at al. Inhalation of nitric oxide in the treatment of acute respiratory syndrome: a rescue trial in Beijing. Clinical Infectious Diseases 2004; 39(10):1531-1535. https://doi.org/10.1086/425357

[7] Akerstrom S et. Al. Nitric oxide inhibits the Replication Cycle of Severe Acute Respiratory Syndrome Coronavirus. J Virol 2005, 79(3), 1966–1969. https://doi.org/10.1128/JVI.79.3.1966-1969.2005

[8] M. Colasanti et al, S-Nitrosylation of viral proteins: molecular bases for antiviral effect of nitric oxide. IUBMB Life, 1999, 48, 25-31, https://doi.org/10.1080/713803459

[9] N. Shahani and Sawa, A. Protein S-nitrosylation: role for nitric oxide signaling in neuronal death, Biochim. Biophys. Acta, 2012 ., 1820, 736–742. https://doi.org/10.1016/j.bbagen.2011.07.010

[10] Keyaerts, E. et al Inhibition of SARS coronavirus infection in vitro by S-nitroso-N-acetyl penicillamine, a nitric oxide donor compound Int. J. Infect. Disease, 2004, 8, 223-226. https://doi.org/10.1016/j.ijid.2004.04.012

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