key: cord-0807726-5xlyqy7q authors: Badhe, Ravindra V.; Nipate, Sonali S. title: The use of negative oxygen ion clusters [O(2)(−)(H(2)O)(n)] and bicarbonate ions [HCO(3)(-)] as the supportive treatment of COVID-19 infections: a possibility date: 2021-08-05 journal: Med Hypotheses DOI: 10.1016/j.mehy.2021.110658 sha: f4bba0efc8af58c7b5facf95b6f6fbf20dd88e1f doc_id: 807726 cord_uid: 5xlyqy7q The COVID-19 or novel coronavirus SARS-CoV-2 pandemic is challenging worldwide healthcare system and severely affecting global economy. Furious efforts to end the pandemic including prevention of spread of SARS-CoV-2, use of antiviral drugs, symptomatic treatments and vaccination are underway. But there are no effective treatments available to save the dying patient in stage 2 (pulmonary) and stage 3 (hyperinflammation) of the infection. The detailed genetic and phenotypical analysis of SARS-CoV-2 revealed that the spike protein (S1) has increased positive charges (compared to SARS-CoV) on them and are responsible for attachment to human angiotensin-converting enzyme 2 (ACE2) receptor and infection by the virus. In addition, it was also reported that the inflammation in the tissue rendered the lung environment more acidic supporting the fusion of SARS-CoV-2 with the cells. We hypothesize that the intermittent use of the oxygen ionizer generating negative oxygen ion clusters [O(2)(−)(H(2)O)(n)] and sodium bicarbonate nebulizer (generating HCO(-)); when connected to ventilator inlet or oxygen concentrator will neutralize the spike protein of the virus in respiratory tract and lungs and change the lung environment to neutral/alkaline condition respectively facilitating improved oxygen pressure in blood. These physical changes can effectively reduce the viral burden and help the patient recover from the infection faster. Till date around 185 million infections and 4 million deaths were reported globally due to coronavirus disease . This virus is also known as SARS-CoV-2 and mainly attacks the respiratory system and lungs in humans, ultimately leading to pneumonia like condition and death. This viral infection was originated in Wuhan, China and spread through out the world in first quarter of the year 2020 [1] . Initially in first wave, this virus mainly infected elderly patients (above the age of 50) and proved deadly for the patients with preexisting medical conditions (diabetes, blood pressure, lung diseases etc.) [2] . In second wave of infection all adult aged population has suffered, specifically in countries like Brazil, and India. Now at the brink of the third wave, more lethal mutated strains of virus are threatening the world. It is observed that the new viral strain is infecting younger population too [3] . This is the alarming situation for the whole world as the vaccination program is still in its intermediate stage and there is no medication available for the treatment of the COVID-19 infections. The questions are also raised against the effectiveness of the available vaccine against the newly mutated viral strains. The coronavirus disease (COVID-19) progress mainly in 3 stages, Mild stage [with non or mild pneumonia conditions, most commonly occurring (almost 80%) cases], Severe / pulmonary stage [dyspnea, increased respiratory frequency and reduced blood oxygen level fluctuating from 60-90% occurring in almost 15% of cases] and Critical / hyperinflammation stage [characterized with respiratory failure, multiple organ dysfunction / failure (MOD / MOF) and septic shock occurring in 5% of cases] [4] . The symptoms observed in the Mild stage of the infection are fever, dry cough, tiredness, loss of taste or smell, aches and pains, sore throat, headache, a rash on skin and diarrhoea. The more serious symptoms indicating Severe / pulmonary stage are difficulty breathing / shortness of breath, chest pain and loss of speech or movement. The Critical / hyperinflammation stage is marked with sever shortness of breath, sever chest pain, dangerously low oxygen levels in body and complete loss of lung movements requiring intervention of life support instrument like ventilators to assist breathing and maintaining oxygen in blood. Generally, the Mild stage symptoms are misunderstood as Flu or Influenza symptoms and the COVID-19 patients become carrier of the virus and can infect other people There are no proven antiviral treatments available against COVID-19 virus however use of antiviral Ramdisavier, chloroquine and corticosteroid Dexamethasone if used in proper stage of infection can help to reduce supportive oxygen and ventilation time in Severe / pulmonary stage and Critical / hyperinflammation stage [6] . As preventive measures, use of N95 masks, social distancing, frequent hand washing, sanitization of the places, lockdowns and vaccination were employed and were found effective controlling the spread of infection [7, 8] . The SARS-CoV-2 spike (S) protein is a transmembrane glycoprotein (180-200 kDa) with 1273 amino acids and has two subunits (S1 and S2) playing multifaceted role in COVID infections. The S1 subunit (14-685 residues) is responsible for host cell receptor binding and S2 subunit (686-1273 residues) is responsible for fusion of the viral and cellular membranes. The S1 is a signal peptide containing N-terminal domain with 14-305 residues and receptorbinding domain (RBD) with 319-541 residues. S2 has the fusion peptide (FP) with 788-806 residues, heptapeptide repeat sequence 1 (HR1) with 912-984 residues, HR2 with 1163-1213 residues, trans membrane (TM) domain with 1213-1237 residues, and cytoplasm domain with 1237-1273 residues. The S1 subunit with receptor-binding domain (RBD) has ten more positively charged amino acid residues (Arg346, Arg357, Arg403, Lys417, Lys444, Lys458, Lys462, His519, Lys529 and Lys537) compared to SARS-CoV S RBD that increased the overall positive charge of the S1 RBD in COVID-19 virus [9] [10] [11] . The S glycoprotein has 22 predicted N-linked glycosylation and three O-glycosylation sites. The mutations of the virus regularly modify the glycan in the S glycoprotein and fool the host immune system and increase the infections many folds. Thus the combination of increased positive charges on the S glycoprotein and complex glycosylation enhanced the SARS-CoV-2 -ACE2 receptor binding by10 to 20 fold higher compared to SARS-CoV [12] [13] [14] . The genetic mapping studies of COVID-19 or novel coronavirus SARS-CoV-2 reveled that though SARS CoV-2 is a betacoronavirus closely linked to the SARS-CoV (77% identical sequence); the spike protein charges differ largely in both. The SARS-CoV-2 spike glycoprotein bares ten more positively charged amino acid residues that have increased the affinity of the spike glycoprotein to negatively charged binding regions of ACE2 receptors rendering the SARS-CoV-2 virus more infectious compared to other SARS strains [15] [16] [17] [18] [19] ( Figure 1a) . Thus, one of prime site of viral infection i.e. SARS-CoV-2 virus -ACE2 receptors binding, suggested an important role of electrostatic bonding and alterations in glycolylation. These binding forces also form the basis for successful (good antigenicity) vaccine development [20, 21] and virus-cell fusion inhibitor (lipopeptides, aptamer and carbon nanoparticles) development [22] [23] [24] . It is reported that the pH of the bronchoalveolar fluids of a COVID-19 patient is acidic (resulting in respiratory acidosis with pH <7.30) [25] [26] [27] . It was reported that the acidic pH favors the binding of the S -protein with ACE2 receptors and ultimately fusion of the viral protein coat resulting in lungs as well as systemic infection [28] [29] [30] [31] (Figure 1b) . The respiratory acidosis begins with COVID-19 infection of lungs ultimately resulting in pneumonia conditions and little or no gaseous exchange through lungs. This leads to increase in CO 2 concentrations in blood causing systemic acidosis. As the infection conditions worsen, the pH further decreases resulting in acute shortage of the oxygen (average pCO 2 > 40 mmHg and average pO 2 < 35 mmHg) [32] . Thus, more the lung infection more is the respiratory acidosis, more the acidosis more is the pCO 2 levels and less pO 2 levels in blood; as the O 2 is very less in body, many organs slowly stop functioning normally [33, 34] . In addition to acidic pH, COVID-19 infections also result in airway inflammation leading to cytokine storm, mucus hypersecretion and build-up. The formation of mucus plugs cause airway obstruction and respiratory failure. Deaths due to mucoid tracheitis and acute respiratory distress syndrome (ARDS) were observed in 33 % of COVID-19 patients [35] . In addition to this, ARDS also enhanced secretory phospholipase A2 (sPLA2) activity degrading the phospholipids in the lungs which are the major component of surfactants present in respiratory system. These surfactants reduce the surface tension of the mucus and help to reduce fluid infiltration into the alveoli. Dysfunctioning of surfactant also changes alveolar capillary shape and also alters the pulmonary blood flow to exacerbate hypoxemia. Thus it is necessary to provide the supportive treatment which can help in the maintenance of the surface tension of the mucus to improve the recovery of the COVID-19 patient [36] . The health advantages of ionized air were explored and exploited for last few decades. The ionized air effectively prevented the airborne transmission of influenza virus [37] . Specifically, in recent years, the health benefits of negative air ions (NAIs) are being studied. NAIs were also reported to show beneficiary effects on cardiovascular and respiratory system as well as on mental health [38] . These NAIs are very effective (97% viral deactivation in 45 min) against aerosolized viruses [39] (Figure 2a ). The NAIs, specifically negative oxygen ions are very effective in reacting with lipids, proteins, glycoproteins, carbohydrates, and nucleic acids of the viruses and neutralizing them in spite of mutations [40] . The in-vitro effectiveness of NAIs on air-born, aerosolized and suspended virus inactivation and other health benefits were already proven. Thus, negative oxygen ions cluster is expected to effectively neutralize multiple existing and newly emerging SARS-CoV-2 variants as proposed in the hypothesis. The studies were conducted to analyze the SARS-CoV-2 virus binding and fusion inhibition to the ACE2 receptors and ultimately to the bronchoalveolar cells in the presence of raised pH of the bronchoalveolar fluids. It was clearly observed that with the change (increased) in pH of the bronchoalveolar fluid, the viscosity of the fluid and mucus was reduced and can be easily taken out (Figure 2b) [41, 42] . NSB is will also support in the maintainse of the pH in respiratory system by improving the surfactant activity. Thus reduced surface tension of the mucus helps in easy expulsion of the mucus from the lungs. The pH change and mucus clearance will also improve pulmonary blood flow ultimately leading to faster recovery of the COVID-19 patient [43, 44] . The NSB therapy will enhance the pH of the lung, disturbing the ecology of the infecting virus as well as reestablishing surfactant actions helping in reduction of viscosity and easy expelling of the mucus. In addition, NSB will also facilitate the gas exchange in the lungs reducing systemic acidosis and maintaining pO 2 . In the case of stage 3, where the damage to the lung tissue is severe, the negative oxygen ion clusters can help to reduce the viral burden in the bronchial fluids and provide pure oxygen. At the same time the NSB therapy will help to change the pH and reduce the viscosity of bronchial fluid and mucus, so that it can be easily taken out of lungs. But, the response and recovery of the patient due the treatment of the negative oxygen ion clusters and NSB will be limited. The limitations will be due to systemic (multi organ) infection of the virus, major loss in the breathing/lung capacity and severe decrease in blood pO 2 . It is also proposed that, all the benefits of negative oxygen ion cluster In the middle of the second wave of the COVID-19 pandemic the death rate was very high, specifically in countries like India and Brazil. All healthcare systems in these countries and around the world are struggling to control and minimize these death rates. There are no fixed medications and treatments available to completely cure COVID-19 infections. The stage 2 and 3 patients only has ventilated oxygen as a desperate supportive treatment. In this hypothesis, a modified oxygen supportive therapy along with nebulized sodium bicarbonate (NSB) therapy is proposed. This modified supportive therapy will combine the advantages of The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Funding statement: This work was not supported by any funding agency but authors thank SidIra Labs and Modern college of pharmacy for providing library facility to do the full text reference search to write the article. 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