Advanced Nitric Oxide Generating Nanomedicine for Therapeutic Applications.

Nitric oxide (NO), a gaseous transmitter extensively present in the human body, regulates vascular relaxation, immune response, inflammation, neurotransmission, and other crucial functions. Nitrite donors have been used clinically to treat angina, heart failure, pulmonary hypertension, and erectile dysfunction. Based on NO's vast biological functions, it further can treat tumors, bacteria/biofilms and other infections, wound healing, eye diseases, and osteoporosis. However, delivering NO is challenging due to uncontrolled blood circulation release and a half-life of under five seconds. With advanced biotechnology and the development of nanomedicine, NO donors packaged with multifunctional nanocarriers by physically embedding or chemically conjugating have been reported to show improved therapeutic efficacy and reduced side effects. Herein, we review and discuss recent applications of NO nanomedicines, their therapeutic mechanisms, and the challenges of NO nanomedicines for future scientific studies and clinical applications. As NO enables the inhibition of the replication of DNA and RNA in infectious microbes, including COVID-19 coronaviruses and malaria parasites, we highlight the potential of NO nanomedicines for antipandemic efforts. This review aims to provide deep insights and practical hints into design strategies and applications of NO nanomedicines.

Inhaled Nitric Oxide in Acute Severe Pulmonary Hypertension and Severe Acute Respiratory Distress Syndrome Secondary to COVID-19 Pneumonia: A Case Report.

BACKGROUND Inhaled nitric oxide (iNO) is used as a treatment for pulmonary arterial hypertension (PAH). Severe hypoxia with hypoxic vasoconstriction caused by severe acute respiratory distress syndrome (ARDS) can induce pulmonary hypertension with hemodynamic implications, mainly secondary to right ventricle (RV) systolic function impairment. We report the case of the use of iNO in a critically ill patient with bilateral SARS-CoV-2 pneumonia and severe ARDS and hypoxemia leading to acute severe PAH, causing a ventilation/perfusion mismatch, RV pressure overload, and RV systolic dysfunction. CASE REPORT A 36-year-old woman was admitted to the Intensive Care Unit with a severe ARDS associated with SARS-CoV-2 pneumonia requiring invasive mechanical ventilation. Severe hypoxia and hypoxic vasoconstriction developed, leading to an acute increase in pulmonary vascular resistance, severe to moderate tricuspid regurgitation, RV pressure overload, RV systolic function impairment, and RV dilatation. Following 24 h of treatment with iNO at 15 ppm, significant oxygenation and hemodynamic improvement were noted, allowing vasopressors to be stopped. After 24 h of iNO treatment, echocardiography showed very mild tricuspid regurgitation, a non-dilated RV, no impairment of transverse free wall contractility, and no paradoxical septal motion. iNO was maintained for 7 days. The dose of iNO was progressively decreased with no adverse effects and maintaining an improvement of oxygenation and hemodynamic status, allowing respiratory weaning. CONCLUSIONS Sustained acute hypoxia in ARDS secondary to SARS-CoV-2 pneumonia can lead to PAH, causing a ventilation/perfusion mismatch and RV systolic impairment. iNO can be considered in patients with significant PAH causing hypoxemia and RV dysfunction.

Inhaled Nitric Oxide for Clinical Management of COVID-19: A Systematic Review and Meta-Analysis.

BACKGROUND: Severe COVID-19 is associated with hypoxemia and acute respiratory distress syndrome (ARDS), which may predispose multiorgan failure and death. Inhaled nitric oxide (iNO) is a clinical vasodilator used in the management of acute respiratory distress syndrome (ARDS). This study evaluated the response rate to iNO in patients with COVID-19-ARDS. METHOD: We searched Medline and Embase databases in May 2022, and data on the use of iNO in the treatment of ARDS in COVID-19 patients were synthesized from studies that satisfied predefined inclusion criteria. A systematic synthesis of data was performed followed by meta-analysis. We performed the funnel plot and leave-one-out sensitivity test on the included studies to assess publication bias and possible exaggerated effect size. We compared the effect size of the studies from the Unites States with those from other countries and performed meta-regression to assess the effect of age, year of publication, and concomitant vasodilator use on the effect size. RESULTS: A total of 17 studies (including 712 COVID-19 patients) were included in this systematic review of which 8 studies (involving 265 COVID-19 patients) were subjected to meta-analysis. The overall response rate was 66% (95% CI, 47-84%) with significantly high between-studies heterogeneity (I2 = 94%, p < 0.001). The funnel plot showed publication bias, although the sensitivity test using leave-one-out analysis showed that removing any of the study does not remove the significance of the result. The response rate was higher in the Unites States, and meta-regression showed that age, year of publication, and use of concomitant vasodilators did not influence the response rate to iNO. CONCLUSION: iNO therapy is valuable in the treatment of hypoxemia in COVID-19 patients and may improve systemic oxygenation in patients with COVID-19-ARDS. Future studies should investigate the mechanism of the activity of iNO in COVID-19 patients to provide insight into the unexplored potential of iNO in general ARDS.

Utility of NO and H2S donating platforms in managing COVID-19: Rationale and promise.

Viral infections are a continuing global burden on the human population, underscored by the ramifications of the COVID-19 pandemic. Current treatment options and supportive therapies for many viral infections are relatively limited, indicating a need for alternative therapeutic approaches. Virus-induced damage occurs through direct infection of host cells and inflammation-related changes. Severe cases of certain viral infections, including COVID-19, can lead to a hyperinflammatory response termed cytokine storm, resulting in extensive endothelial damage, thrombosis, respiratory failure, and death. Therapies targeting these complications are crucial in addition to antiviral therapies. Nitric oxide and hydrogen sulfide are two endogenous gasotransmitters that have emerged as key signaling molecules with a broad range of antiviral actions in addition to having anti-inflammatory properties and protective functions in the vasculature and respiratory system. The enhancement of endogenous nitric oxide and hydrogen sulfide levels thus holds promise for managing both early-stage and later-stage viral infections, including SARS-CoV-2. Using SARS-CoV-2 as a model for similar viral infections, here we explore the current evidence regarding nitric oxide and hydrogen sulfide's use to limit viral infection, resolve inflammation, and reduce vascular and pulmonary damage.

Inhaled nitric oxide as temporary respiratory stabilization in patients with COVID-19 related respiratory failure (INOCOV): Study protocol for a randomized controlled trial.

BACKGROUND: In March 2020, WHO announced the COVID-19 a pandemic and a major global public health emergency. Mortality from COVID-19 is rapidly increasing globally, with acute respiratory failure as the predominant cause of death. Many patients experience severe hypoxia and life-threatening respiratory failure often requiring mechanical ventilation. To increase safety margins during emergency anaesthesia and rapid sequence intubation (RSI), patients are preoxygenated with a closed facemask with high-flow oxygen and positive end-expiratory pressure (PEEP). Due to the high shunt fraction of deoxygenated blood through the lungs frequently described in COVID-19 however, these measures may be insufficient to avoid harmful hypoxemia. Preoxygenation with inhaled nitric oxide (iNO) potentially reduces the shunt fraction and may thus allow for the necessary margins of safety during RSI. METHODS AND DESIGN: The INOCOV protocol describes a phase II pharmacological trial of inhaled nitric oxide (iNO) as an adjunct to standard of care with medical oxygen in initial airway and ventilation management of patients with known or suspected COVID-19 in acute respiratory failure. The trial is parallel two-arm, randomized, controlled, blinded trial. The primary outcome measure is the change in oxygen saturation (SpO2), and the null hypothesis is that there is no difference in the change in SpO2 following initiation of iNO. TRIAL REGISTRATION: EudraCT number 2020-001656-18; WHO UTN: U1111-1250-1698. Protocol version: 2.0 (June 25th, 2021).

Nitric oxide versus epoprostenol for refractory hypoxemia in Covid-19.

OBJECTIVE: To compare the efficacy and outcomes with inhaled nitric oxide (iNO) and inhaled epoprostenol (iEPO) in patients with refractory hypoxemia due to COVID-19. DESIGN: Retrospective Cohort Study. SETTING: Single health system multicenter academic teaching hospitals. PATIENTS OR SUBJECTS: Age group of 18-80 years admitted to the medical ICU. INTERVENTIONS: Mechanically ventilated patients with COVID-19 infection, who received either iNO or iEPO between March 1st, 2020, and June 30th, 2020. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the change in the PaO2/FiO2 (P/F) ratio 1 hour after initiation of pulmonary vasodilator therapy. Secondary outcomes include P/F ratios on days 1-3 after initiation, positive response in P/F ratio (increase of at least 20% in PaO2), total days of treatment, rebound hypoxemia (if there was a drop in oxygen saturation after treatment was stopped), ventilator free days (if any patient was extubated), days in ICU, days to extubation, days to tracheostomy, mortality days after intubation, 30-day survival and mortality. 183 patients were excluded, as they received both iNO and iEPO. Of the remaining 103 patients, 62 received iEPO and 41 received iNO. The severity of ARDS was similar in both groups. Change in P/F ratio at one hour was 116 (70.3) with iNO and 107 (57.6) with iEPO (Mean/SD). Twenty-two (53.7%) patients in the iNO group and 25 (40.3%) in the iEPO group were responders to pulmonary vasodilators n(%)(p = 0.152) (more than 20% increase in partial pressure of oxygen, Pao2), and 18 (43.9%) and 31 (50%) patients in the iNO and iEPO group (p = 0.685), respectively, had rebound hypoxemia. Only 7 patients in the cohort achieved ventilator free days (3 in the iEPO group and 4 in iNO group). CONCLUSIONS: We found no significant difference between iNO and iEPO in terms of change in P/F ratio, duration of mechanical ventilation, ICU, in-hospital mortality in this cohort of mechanically ventilated patients with COVID-19. Larger, prospective studies are necessary to validate these results.

Safety and practicality of high dose inhaled nitric oxide in emergency department COVID-19 patients.

BACKGROUND: Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator and mild bronchodilator that has been shown to improve systemic oxygenation, but has rarely been administered in the Emergency Department (ED). In addition to its favorable pulmonary vascular effects, in-vitro studies report that NO donors can inhibit replication of viruses, including SARS Coronavirus 2 (SARS-CoV-2). This study evaluated the administration of high-dose iNO by mask in spontaneously breathing emergency department (ED) patients with respiratory symptoms attributed to Coronavirus disease 2019 (COVID-19). METHODS: We designed a randomized clinical trial to determine whether 30 min of high dose iNO (250 ppm) could be safely and practically administered by emergency physicians in the ED to spontaneously-breathing patients with respiratory symptoms attributed to COVID-19. Our secondary goal was to learn if iNO could prevent the progression of mild COVID-19 to a more severe state. FINDINGS: We enrolled 47 ED patients with acute respiratory symptoms most likely due to COVID-19: 25 of 47 (53%) were randomized to the iNO treatment group; 22 of 47 (46%) to the control group (supportive care only). All patients tolerated the administration of high-dose iNO in the ED without significant complications or symptoms. Five patients receiving iNO (16%) experienced asymptomatic methemoglobinemia (MetHb) > 5%. Thirty-four of 47 (72%) subjects tested positive for SARS-CoV-2: 19 of 34 were randomized to the iNO treatment group and 15 of 34 subjects to the control group. Seven of 19 (38%) iNO patients returned to the ED, while 4 of 15 (27%) control patients did. One patient in each study arm was hospitalized: 5% in iNO treatment and 7% in controls. One patient was intubated in the iNO group. No patients in either group died. The differences between these groups were not significant. CONCLUSION: A single dose of iNO at 250 ppm was practical and not associated with any significant adverse effects when administered in the ED by emergency physicians. Local disease control led to early study closure and prevented complete testing of COVID-19 safety and treatment outcomes measures.

Initiation of Inhaled Nitric Oxide by an Air Transport Team in Adult Coronavirus Disease 2019 Respiratory Failure.

The coronavirus disease 2019 (COVID-19) pandemic has caused a significant increase in the volume of critical care flight transports between outlying referral hospitals and tertiary care facilities. Because of the tropism of severe acute respiratory syndrome coronavirus 2, flight crews are often asked to transport mechanically ventilated patients in refractory hypoxemic respiratory failure. The authors present a case series of 5 patients with COVID-19 acute respiratory distress syndrome (ARDS) who were initiated on inhaled nitric oxide (iNO) by the transport team before rotor wing transport and survived the journey in stable or improved condition upon arrival. Previously, no case reports have described adults with COVID-19 ARDS transported after iNO initiation by the transport team. This case series shows the feasibility of iNO initiation by trained air medical transport teams and suggests a short-term stabilizing effect of iNO in patients with ARDS from COVID-19.

Compassionate use of Pulmonary Vasodilators in Acute Severe Hypoxic Respiratory Failure due to COVID-19.

BACKGROUND: There have been over 200 million cases and 4.4 million deaths from COVID-19 worldwide. Despite the lack of robust evidence one potential treatment for COVID-19 associated severe hypoxaemia is inhaled pulmonary vasodilator (IPVD) therapy, using either nitric oxide (iNO) or prostaglandins. We describe the implementation of, and outcomes from, a protocol using IPVDs in a cohort of patients with severe COVID-19 associated respiratory failure receiving maximal conventional support. METHODS: Prospectively collected data from adult patients with SARS-CoV-2 admitted to the intensive care unit (ICU) at a large teaching hospital were analysed for the period 14th March 2020 - 11th February 2021. An IPVD was considered if the PaO2/FiO2 (PF) ratio was less than 13.3kPa despite maximal conventional therapy. Nitric oxide was commenced at 20ppm and titrated to response. If oxygenation improved Iloprost nebulisers were commenced and iNO weaned. The primary outcome was percentage changes in PF ratio and Alveolar-arterial (A-a) gradient. RESULTS: Fifty-nine patients received IPVD therapy during the study period. The median PF ratio before IPVD therapy was commenced was 11.33kPa (9.93-12.91). Patients receiving an IPVD had a lower PF ratio (14.37 vs. 16.37kPa, p = 0.002) and higher APACHE-II score (17 vs. 13, p = 0.028) at ICU admission. At 72 hours after initiating an IPVD the median improvement in PF ratio was 33.9% (-4.3-84.1). At 72 hours changes in PF ratio (70.8 vs. -4.1%, p < 0.001) and reduction in A-a gradient (44.7 vs. 14.8%, p < 0.001) differed significantly between survivors (n = 33) and non-survivors (n = 26). CONCLUSIONS: The response to IPVDs in patients with COVID-19 associated acute hypoxic respiratory failure differed significantly between survivors and non-survivors. Both iNO and prostaglandins may offer therapeutic options for patients with severe refractory hypoxaemia due to COVID-19. The use of inhaled prostaglandins, and iNO where feasible, should be studied in adequately powered prospective randomised trials.

Nitric Oxide Inhalation Therapy Attenuates Postoperative Hypoxemia in Obese Patients with Acute Type A Aortic Dissection.

Objective: To investigate the differences between inhaled nitric oxide (iNO) treatment and conventional therapy in the treatment of postoperative hypoxemia in obese patients with acute type A aortic dissection (ATAAD). Methods: ATAAD patients diagnosed and treated with emergency surgery in our hospital from June 2017 to December 2019 were retrospectively analyzed. Patients with postoperative hypoxemia were divided into the iNO group and control group. Propensity score matching was used to analyze clinical characteristics and results of the two groups. Results: A total of 218 ATAAD patients with BMI ≥ 25 were treated with surgery. Among them, 115 patients developed refractory hypoxemia (64 in the control group and 51 in the iNO group). Patients in the iNO group had significantly shorter invasive mechanical ventilation time, intensive care unit (ICU) stay, and hospital stay. After 6 h of iNO treatment, the PaO2/FiO2 ratio in the iNO group increased significantly, and this ratio was higher than that in the control group at 6, 12, 24, 48, and 72 h after treatment. Conclusion: Low-dose iNO could improve oxygenation and shorten mechanical ventilation and ICU stay in patients with hypoxemia after ATAAD surgery, but without significant side effects or increase in postoperative mortality or morbidity. These findings provide a basis for a randomized multicenter controlled trial to assess the efficacy of iNO in the treatment of hypoxemia after ATAAD surgery.

Current status of potential therapeutic candidates for the COVID-19 crisis.

As of April 15, 2020, the ongoing coronavirus disease 2019 (COVID-2019) pandemic has swept through 213 countries and infected more than 1,870,000 individuals, posing an unprecedented threat to international health and the economy. There is currently no specific treatment available for patients with COVID-19 infection. The lessons learned from past management of respiratory viral infections have provided insights into treating COVID-19. Numerous potential therapies, including supportive intervention, immunomodulatory agents, antiviral therapy, and convalescent plasma transfusion, have been tentatively applied in clinical settings. A number of these therapies have provided substantially curative benefits in treating patients with COVID-19 infection. Furthermore, intensive research and clinical trials are underway to assess the efficacy of existing drugs and identify potential therapeutic targets to develop new drugs for treating COVID-19. Herein, we summarize the current potential therapeutic approaches for diseases related to COVID-19 infection and introduce their mechanisms of action, safety, and effectiveness.

Nitric oxide: Clinical applications in critically ill patients.

Inhaled nitric oxide (iNO) acts as a selective pulmonary vasodilator and it is currently approved by the FDA for the treatment of persistent pulmonary hypertension of the newborn. iNO has been demonstrated to effectively decrease pulmonary artery pressure and improve oxygenation, while decreasing extracorporeal life support use in hypoxic newborns affected by persistent pulmonary hypertension. Also, iNO seems a safe treatment with limited side effects. Despite the promising beneficial effects of NO in the preclinical literature, there is still a lack of high quality evidence for the use of iNO in clinical settings. A variety of clinical applications have been suggested in and out of the critical care environment, aiming to use iNO in respiratory failure and pulmonary hypertension of adults or as a preventative measure of hemolysis-induced vasoconstriction, ischemia/reperfusion injury and as a potential treatment of renal failure associated with cardiopulmonary bypass. In this narrative review we aim to present a comprehensive summary of the potential use of iNO in several clinical conditions with its suggested benefits, including its recent application in the scenario of the COVID-19 pandemic. Randomized controlled trials, meta-analyses, guidelines, observational studies and case-series were reported and the main findings summarized. Furthermore, we will describe the toxicity profile of NO and discuss an innovative proposed strategy to produce iNO. Overall, iNO exhibits a wide range of potential clinical benefits, that certainly warrants further efforts with randomized clinical trials to determine specific therapeutic roles of iNO.

Delivery of Nitric Oxide in the Cardiovascular System: Implications for Clinical Diagnosis and Therapy.

Nitric oxide (NO) is a key molecule in cardiovascular homeostasis and its abnormal delivery is highly associated with the occurrence and development of cardiovascular disease (CVD). The assessment and manipulation of NO delivery is crucial to the diagnosis and therapy of CVD, such as endothelial dysfunction, atherosclerotic progression, pulmonary hypertension, and cardiovascular manifestations of coronavirus (COVID-19). However, due to the low concentration and fast reaction characteristics of NO in the cardiovascular system, clinical applications centered on NO delivery are challenging. In this tutorial review, we first summarized the methods to estimate the in vivo NO delivery process, based on computational modeling and flow-mediated dilation, to assess endothelial function and vulnerability of atherosclerotic plaque. Then, emerging bioimaging technologies that have the potential to experimentally measure arterial NO concentration were discussed, including Raman spectroscopy and electrochemical sensors. In addition to diagnostic methods, therapies aimed at controlling NO delivery to regulate CVD were reviewed, including the NO release platform to treat endothelial dysfunction and atherosclerosis and inhaled NO therapy to treat pulmonary hypertension and COVID-19. Two potential methods to improve the effectiveness of existing NO therapy were also discussed, including the combination of NO release platform and computational modeling, and stem cell therapy, which currently remains at the laboratory stage but has clinical potential for the treatment of CVD.

Inhaled high dose nitric oxide is a safe and effective respiratory treatment in spontaneous breathing hospitalized patients with COVID-19 pneumonia.

BACKGROUND: Inhaled nitric oxide (NO) is a selective pulmonary vasodilator. In-vitro studies report that NO donors can inhibit replication of SARS-CoV-2. This multicenter study evaluated the feasibility and effects of high-dose inhaled NO in non-intubated spontaneously breathing patients with Coronavirus disease-2019 (COVID-19). METHODS: This is an interventional study to determine whether NO at 160 parts-per-million (ppm) inhaled for 30 min twice daily might be beneficial and safe in non-intubated COVID-19 patients. RESULTS: Twenty-nine COVID-19 patients received a total of 217 intermittent inhaled NO treatments for 30 min at 160 ppm between March and June 2020. Breathing NO acutely decreased the respiratory rate of tachypneic patients and improved oxygenation in hypoxemic patients. The maximum level of nitrogen dioxide delivered was 1.5 ppm. The maximum level of methemoglobin (MetHb) during the treatments was 4.7%. MetHb decreased in all patients 5 min after discontinuing NO administration. No adverse events during treatment, such as hypoxemia, hypotension, or acute kidney injury during hospitalization occurred. In our NO treated patients, one patient of 29 underwent intubation and mechanical ventilation, and none died. The median hospital length of stay was 6 days [interquartile range 4-8]. No discharged patients required hospital readmission nor developed COVID-19 related long-term sequelae within 28 days of follow-up. CONCLUSIONS: In spontaneous breathing patients with COVID-19, the administration of inhaled NO at 160 ppm for 30 min twice daily promptly improved the respiratory rate of tachypneic patients and systemic oxygenation of hypoxemic patients. No adverse events were observed. None of the subjects was readmitted or had long-term COVID-19 sequelae.

A Novel Inhalation Mask System to Deliver High Concentrations of Nitric Oxide Gas in Spontaneously Breathing Subjects.

Nitric Oxide (NO) is administered as gas for inhalation to induce selective pulmonary vasodilation. It is a safe therapy, with few potential risks even if administered at high concentration. Inhaled NO gas is routinely used to increase systemic oxygenation in different disease conditions. The administration of high concentrations of NO also exerts a virucidal effect in vitro. Owing to its favorable pharmacodynamic and safety profiles, the familiarity in its use by critical care providers, and the potential for a direct virucidal effect, NO is clinically used in patients with coronavirus disease-2019 (COVID-19). Nevertheless, no device is currently available to easily administer inhaled NO at concentrations higher than 80 parts per million (ppm) at various inspired oxygen fractions, without the need for dedicated, heavy, and costly equipment. The development of a reliable, safe, inexpensive, lightweight, and ventilator-free solution is crucial, particularly for the early treatment of non-intubated patients outside of the intensive care unit (ICU) and in a limited-resource scenario. To overcome such a barrier, a simple system for the non-invasive NO gas administration up to 250 ppm was developed using standard consumables and a scavenging chamber. The method has been proven safe and reliable in delivering a specified NO concentration while limiting nitrogen dioxide levels. This paper aims to provide clinicians and researchers with the necessary information on how to assemble or adapt such a system for research purposes or clinical use in COVID-19 or other diseases in which NO administration might be beneficial.

Nitric Oxide to Fight Viral Infections.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that has quickly and deeply affected the world, with over 60 million confirmed cases. There has been a great effort worldwide to contain the virus and to search for an effective treatment for patients who become critically ill with COVID-19. A promising therapeutic compound currently undergoing clinical trials for COVID-19 is nitric oxide (NO), which is a free radical that has been previously reported to inhibit the replication of several DNA and RNA viruses, including coronaviruses. Although NO has potent antiviral activity, it has a complex role in the immunological host responses to viral infections, i.e., it can be essential for pathogen control or detrimental for the host, depending on its concentration and the type of virus. In this Essay, the antiviral role of NO against SARS-CoV, SARS-CoV-2, and other human viruses is highlighted, current development of NO-based therapies used in the clinic is summarized, existing challenges are discussed and possible further developments of NO to fight viral infections are suggested.

Coronavirus Disease 2019 (COVID-19): Research, Clinical Knowledge, and Preventive Measures.

In early December 2019, a novel coronavirus disease 2019 (COVID-19), the global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) commenced in Wuhan, China, and WHO declared the outbreak a pandemic and Public Health Emergency of International Concern. An ample number of clinical trials with multiple drugs is underway to overcome the current perilous condition. Still, the situation is alarming with no therapeutic measure in our hand at present. Keeping the present scenario in mind, this review comprises the research, clinical knowledge, and repurposed herbals with regard to COVID-19. Preventive measures such as yoga, nasal breathing, and herbal administration could also provide protection and beneficial effects against coronavirus. Innumerable clinical trials are ongoing to manage COVID-19 and the drugs were selected on the basis of life cycle of coronavirus. The selection of herbals was done on the basis of the previous reported pharmacological activities and docking study. The results concluded that garlic, liquorice, and Ashwagandha have a potential against SARS-CoV-2, which was further proved via a docking study and their reported biological functions. The very well-known fact "prevention is always better than cure" is applied to overcome with coronavirus infection. It is expected that following the preventive measures could impede or lessen the adverse effect of SARS-CoV-2.

The role of NO in COVID-19 and potential therapeutic strategies.

Nitric oxide (NO) is a free radical playing an important pathophysiological role in cardiovascular and immune systems. Recent studies reported that NO levels were significantly lower in patients with COVID-19, which was suggested to be closely related to vascular dysfunction and immune inflammation among them. In this review, we examine the potential role of NO during SARS-CoV-2 infection from the perspective of the unique physical, chemical and biological properties and potential mechanisms of NO in COVID-19, as well as possible therapeutic strategies using inhaled NO. We also discuss the limits of NO treatment, and the future application of this approach in prevention and therapy of COVID-19.