Protocol for a randomized controlled trial testing inhaled nitric oxide therapy in spontaneously breathing patients with COVID-19

Abstract

Introduction: the current worldwide outbreak of Coronavirus disease 2019 due to a novel coronavirus (SARS-CoV-2) is seriously threatening the public health. The number of infected patients is continuously increasing and the need for Intensive Care Unit admission ranges from 5 to 26%. The mortality is reported to be around 3.4% with higher values for the elderly and in patients with comorbidities. Moreover, this condition is challenging the healthcare system where the outbreak reached its highest value. To date there is still no available treatment for SARS-CoV-2. Clinical and preclinical evidence suggests that nitric oxide (NO) has a beneficial effect on the coronavirusmediated acute respiratory syndrome, and this can be related to its viricidal effect. The Trial registration. Clinicaltrials.gov. NCT submitted . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

Nitric oxide (NO) and nanoparticles – Potential small tools for the war against COVID-19 and other human coronavirus infections

“…NO inhaled treatment against COVID has already been proposed in 2020 in two different countries, China and United States of America ( Berra et al, 2020 ; Gianni et al, 2020a ; Lei et al, 2020 ). The motivation comes from the historical use of NO-based treatment against SARS-CoV, and also against other respiratory diseases caused by viruses.…”

“…Three different strategies were proposed to comprehend the treatment under different conditions, using a randomized experiment evolving 2 centers: Boston and Xi’an ( Berra et al, 2020 ; Gianni et al, 2020a ; Lei et al, 2020 ). Firstly, NO application in severely ill patients is proposed in two different conditions: (i) high doses of gaseous NO, up to 180 ppm, during short periods of time (20-30 min), and (ii) low doses of gaseous NO, up to 80 ppm, during 48 h-treatment ( Berra et al, 2020 ; Lei et al, 2020 ). Interestingly, a second protocol proposed inhaled NO to prevent COVID-19 in healthcare providers who are in direct contact with patients infected with SARS-CoV-2 ( Gianni et al, 2020a ).…”

Pharmacological treatments of COVID-19

“…It has been shown in vitro and clinical studies that iNO has anti-viral activity against other strains of coronavirus [271]. The increased survival rate of infected eukaryotic cells by SARS-CoV1 using S-nitroso-N-acetylpenicillamine, as a NO donor, has shown the antiviral potential of NO [276]. Moreover, the use of iNO in patients with SARS-CoV1 who had severe symptoms could improve the severe hypoxemia and pulmonary hypertension, and shortened the time of ventilation support [276].…”

The Natural-Mineral-Based Novel Nanomaterial IFMC Increases Intravascular Nitric Oxide without Its Intake: Implications for COVID-19 and beyond

“…Previous studies treating SARS-CoV-infected patients with inhaled NO have shown pharmacological and antiviral effects of NO [ 41 , 42 , 43 ], suggesting that NO inhalation might be effective for COVID-19 patients [ 37 , 44 ]. Indeed, two clinical trials of inhaled NO are being conducted in COVID-19 patients [ 45 , 46 ]. Meanwhile, balneotherapy (hot spring therapy), sauna therapy and thermal therapy (hyperthermia) also reportedly increase endothelial NO synthase (eNOS), thus inducing vascular endothelial NO production [ 47 , 48 , 49 , 50 , 51 , 52 ].…”