key: cord-0699216-7p3gcr9w
authors: Tang, Chuan-Feng; Ding, Hong; Jiao, Rui-Qing; Wu, Xing-Xin; Kong, Ling-Dong
title: Possibility of magnesium supplementation for supportive treatment in patients with COVID-19
date: 2020-09-12
journal: Eur J Pharmacol
DOI: 10.1016/j.ejphar.2020.173546
sha: b004af9d1dda80da12947b4cd94357f14c7c5ba8
doc_id: 699216
cord_uid: 7p3gcr9w

Magnesium as an enzymatic activator is essential for various physiological functions such as cell cycle, metabolic regulation, muscle contraction, and vasomotor tone. A growing body of evidence supports that magnesium supplementation (mainly magnesium sulfate and magnesium oxide) prevents or treats various types of disorders or diseases related to respiratory system, reproductive system, nervous system, digestive system, and cardiovascular system as well as kidney injury, diabetes and cancer. The ongoing pandemic coronavirus disease 19 (COVID-19) characterized by respiratory tract symptoms with different degrees of important organ and tissue damages has attracted global attention. Particularly, effective drugs are still lacking in the COVID-19 therapy. In this review, we find and summarize the effectiveness of magnesium supplementation on the disorders or diseases, and provide a reference to the possibility of magnesium supplementation for supportive treatment in patients with COVID-19.

muscle contraction, as well as airway structure change. Exacerbation of asthma may be life-threatening and bring a heavy burden on medical service. More evidences from meta-analyses and comprehensive reviews of randomized clinical trials have demonstrated the beneficial effects of magnesium supplementation on lung diseases, such as asthma and pneumonia (Blitz et al., 2005; Kew et al., 2014; Knightly et al., 2017; Powell et al., 2012; Rowe et al., 2000; Shan et al., 2013; Villeneuve and Zed, 2006) .

For the children with acute severe asthma hospitalized in the emergency department, intravenous magnesium sulfate infusion, at a dose of 25 mg/kg (maximum 2 g) with an infusion time of 20 min within the first hour of hospitalization, can significantly reduce the proportion of children requiring mechanical ventilation support (Torres et al., 2012) . Intravenous injection and nebulized inhalation of magnesium sulfate show positive clinical effects in children with asthma (Irazuzta and Chiriboga, 2017; Liu et al., 2016; Powell et al., 2013) . This injection, a short infusion of 25-75 mg/kg over 20 min (maximum 2-2.5 g/dose) or other optimized dosing regimens, can significantly improve the respiratory function and reduce the hospitalization rate of children with moderate to severe asthma exacerbation (Liu et al., 2016) . Timely administration of the appropriate dose (50-75 mg/kg) of intravenous magnesium sulfate prevents hospitalization of patients with acute asthma (Irazuzta and Chiriboga, therapy of aerosolized ipratropium bromide/fenoterol, there is no statistically significant change and difference in PRAM score assessment without severe side effect (Wongwaree and Daengsuwan, 2019) .

For acute asthmatic adults, a single infusion of 1.2 or 2 g of magnesium sulfate intravenously within 15 to 30 min is reported to reduce the hospitalization rate and improve lung function of the patients who have not responded sufficiently to oxygen, nebulised short-acting β2-agonist and intravenous corticosteroids (Kew et al., 2014) . A survey of Turkish doctors' attitudes towards the use of magnesium sulfate to treat exacerbation of acute asthma is also conducted (Baççıoğlu et al., 2016) .

Oral 340 mg magnesium supplement for 6.5 months improves both objective outcome measures of bronchial response to peak expiratory flow rate and methacholine, and subjective measures of asthma control and quality of life in adults (Kazaks et al., 2010) . The two major reasons for using magnesium sulfate are to reduce days of hospital stay (94.7%) and prevent access to the intensive care unit (80.3%).

Despite the well-known role of magnesium sulfate in acute severe asthma, of the 456 respondents, only 42.3% dealing with asthma patients have used magnesium sulfate in their practices, and 48.7 % agree to include magnesium sulfate in asthma guidelines (Baççıoğlu et al., 2016) . Therefore, the education and encouragement for magnesium sulfate use are necessary for the treatment of acute asthma in patients.

Meanwhile, a systematic analysis of adult patients with acute asthma shows that intravenous magnesium sulfate is more effective than placebo in improving lung function in terms of peak expiratory flow and forced expiratory volume in 1 second. Intravenous magnesium sulfate has a modest effect in decreasing hospital admissions in acute asthmatic adults who do not have positive responses to standard therapy (Green, 2016) . In adults with community acquired pneumonia, abnormal magnesium levels on admission are associated with the increased 30-day mortality rate, compared with the normal value (Nasser et al., 2018) . Magnesium sulfate (a single dose of 1.5 g intravenously within 20 min) enhances the bronchodilation effect of inhaled long-acting β2-agonist in patients with chronic obstructive pulmonary disease (Abreu González et al., 2006) . In a clinical trial with a total of 2907 randomized patients, atomized magnesium sulfate, combined with inhaled β2-agonist and ipratropium bromide, have modest additional benefits in terms of pulmonary function and hospitalization (Knightly et al., 2017) . Additionally, intraoperative administration of magnesium sulfate (50 mg/kg intravenously for 10 min, followed by continuous infusion of 15 mg/kg/h during the operation) improves lung J o u r n a l P r e -p r o o f function in patients receiving video-assisted thoracoscopic surgery, and reduces the doses of rocuronium and postoperative analgesics (Sohn et al., 2017) . Furthermore, magnesium sulfate (100 mg/kg, intravenously) is found to mitigate lung injury score, inflammation response, and oxidative stress induced by bilateral lower limb ischemia-reperfusion in rats (Kao et al., 2011) . Magnesium sulfate inhibits inflammatory molecules including chemokine (macrophage inflammatory protein-2), cytokine (Interleukin-6, IL-6), prostaglandin E2, and cyclooxygenase-2 in lung tissue possibly by inhibiting L-type calcium channels (Kao et al., 2011) . In a model of acute lung injury, magnesium sulfate (150 mg/kg, intraperitoneally) ameliorates hydrochloric acid-induced lung histopathology including peribronchial inflammatory cell infiltration, alveolar septal infiltration, alveolar edema, and alveolar exudation (Güzel et al., 2019) . It also significantly restores oxidative stress and inflammatory response in lipopolysaccharides-induced acute lung injury of mice . These observations demonstrate that magnesium has the antioxidant and anti-inflammatory effects on lung injury. Magnesium sulfate also inhibits airway smooth muscle contraction by blocking the voltage-dependent calcium channels, which is another mechanism of magnesium for the treatment of asthma (Gourgoulianis et al., 2001) . However, more detailed molecular mechanisms are still lacking. We summarized representative papers (Table 1) and provided existing possible mechanisms by which magnesium supplementation ameliorates lung symptoms and diseases with anti-inflammation, anti-oxidation and bronchial smooth muscle relaxation (Fig. 1) .

Magnesium sulfate has been widely used in the obstetric environment for several decades (Matsuda et al., 2000; Pritchard, 1955) . Magnesium can inhibit the release of acetylcholine from motor nerve endings, block nerve-muscle conduction, and relax skeletal muscle. Therefore, it effectively controls and prevents preterm labor, gestational hypertension, preeclampsia, and eclampsia with few side effects on the fetus (Alexander et al., 2006; Kreepala et al., 2018; Magee and von Dadelszen, 2011) . Recent research has further proven that oral magnesium supplementation (800 mg magnesium oxide daily) prevents the postoperative complications of cardiac surgery, including nausea, vomiting and constipation in patients from the admission to discharge from hospital (Moradian et al., 2017) . The data from a clinical trial including a total of 259 patients with gallbladder cancer, 701 patients with gallstones, and 851 population-based controls in Shanghai, China, have demonstrated that serum magnesium level is inversely related to gallbladder disease (Lee et al., 2020) . Aquamin is a natural product rich in magnesium and calcium. Aquamin can reduce total bile acid levels and increase short-chain fatty acid acetate levels in stool samples from healthy subjects, however, calcium or placebo treatment shows no change in bile acids or short-chain fatty acids (Aslam et al., 2020) .

Magnesium sulfate is also used as an adjuvant analgesic drug for stomach surgery. Before sedation, intravenous magnesium sulfate at 50 mg/kg decreases analgesic requirements both during and after endoscopic submucosal dissection for gastric neoplasm without adverse effects in patients (Kim et al., 2015) . These observations suggest that magnesium supplementation may play a major role in digestive system diseases.

Experimentally, magnesium sulfate at 100 or 200 mg/kg prevents a massive bridging fibrosis around the portal and central vein induced by bile duct ligation in rats (Eshraghi et al., 2015) . It remarkably decreases serum alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamyltransferase (GGT) levels, increases liver superoxide dismutase (SOD) and catalase in this animal model. Subsequently, magnesium sulfate ameliorates bile duct ligation-induced liver fibrosis, bile duct hyperplasia, hepatocyte necrosis and inflammation in rats (Eshraghi et al., 2015) .

It has long been known that magnesium deficiency causes an increased incidence of cardiovascular diseases, including hypertension and atherosclerosis (Saris et al., 2000; Seelig, 1994) .

As mentioned above, magnesium has a good effect on hypertension during pregnancy (Alexander et al., 2006; Kreepala et al., 2018) . Oral magnesium supplementation (300 mg/kg magnesium oxide daily) for 1 month effectively decreases systolic, diastolic and mean arterial blood pressure in patients with essential hypertension at home (Banjanin and Belojevic, 2018) . Magnesium chelate supplementation (600 mg/kg) daily for 6 months, is associated with better blood pressure control. It improves cardiovascular endothelial function and ameliorates subclinical atherosclerosis in thiazide-treated J o u r n a l P r e -p r o o f hypertensive women (Cunha et al., 2017) . A strategy with the magnesium therapy (10 mM, a total of 2.47 g magnesium sulfate infused daily for 3 days) after cardiac surgery is effective in reducing the risk of atrial fibrillation (Osawa et al., 2018) , which is also demonstrated by corresponding systematic review and meta-analysis (Gu et al., 2012; Shepherd et al., 2008) . A possible explanation might be that magnesium regulates cardiac enzymatic and metabolic pathways, and stabilizes cellular membranes (Romani and Scarpa, 1990) . Of note, the strategy of magnesium supplementation in clinical practice cannot be unified. In patients who have cardiothoracic surgery, the strategy of a 10 mmol bolus of magnesium sulfate followed by a continuous infusion of 3 mmol/h over 12 h delivers a sustained and moderately elevated magnesium concentration, with greater time-weighted magnesium plasma level than a single 20 mmol bolus (Osawa et al., 2018) . In the protection of heart, further research is needed to assess whether extending the duration of the continuous infusion can continue to provide high but stable magnesium level, maintaining safety.

Magnesium supplementation can lower blood pressure, inhibit smooth muscle contraction and prevent cardiovascular diseases (Eshraghi et al., 2015; Kim et al., 2015) mainly through the following molecular mechanisms. Magnesium has similar property as calcium antagonist, and is considered a physiological calcium blocker (Altura et al., 1987) . It is known that the concentration of calcium is a major determinant of vascular smooth muscle cell contractile activity and vascular tone. The main action of magnesium on vascular smooth muscle is to decrease intracellular calcium by the inhibition of calcium influx as well as the blockage of calcium release from the sarcoplasmic reticulum, resulting in the inactivation of calmodulin-dependent myosin light chain kinase activity and the reduction of NO level in serum, playing an important cause of vascular smooth muscle cells relaxation and blood pressure reduction especially in patients with gestational hypertension, but the specific mechanism is still unclear (Teragawa et al., 2002; Wang et al., 2019) .

Magnesium shows the preventive effect on cisplatin-induced acute kidney injury in patients (Hamroun et al., 2019; Solanki et al., 2014; Solanki et al., 2015) . A retrospective analysis of 3,828 patients has demonstrated that magnesium sulfate supplement, as a co-adjuvant drug during the period of major laparoscopic abdominal surgery, reduces a risk of postoperative acute kidney injury (Oh et al., 2019) . Magnesium deficient diet for 2 weeks before cisplatin-induced acute kidney injury, significantly increases renal damage characterized by high plasma levels of urea nitrogen and creatinine in female mice, with the enhanced oxidative stress and increased expression of inflammatory factors IL-6, TNF-α and IL-1β in kidney (Solanki et al., 2014) .

In fact, magnesium deficiency is a common problem in diabetic patients (Kachhawa et al., 2019; Kumar et al., 2019; Mather and Levin, 1979) . Magnesium deficiency increases the risk of poor glycemic control and diabetic retinopathy in a cross-sectional study including 250 diabetics in North India (Kumar et al., 2019) . A continuous infusion of magnesium sulfate at 15 mg/kg/h produces a better-controlled effect on blood glucose level in patients with diabetes mellitus undergoing cardiac surgery (Soliman and Nofal, 2019) . Oral magnesium supplementation (jamieson magnesium tablet, containing 250 mg elemental magnesium) daily for 3 months reduces insulin resistance and improves glycemic control indicators among type 2 diabetes patients (Elderawi et al., 2018) .

Recent study suggests that increasing intake of magnesium-containing foods may help reduce the incidence and mortality of primary liver cancer (Zhong et al., 2020) . One case report shows that the subcutaneous administration of magnesium in a syringe pump can reduce repeated hospital admissions for patients with recurrent symptomatic hypomagnesaemia like the patients with advanced ovarian cancer (Fenning et al., 2018) . Higher magnesium intake in the diet is associated with a lower risk of colorectal tumors (Wark et al., 2012) . Prior research has demonstrated that high dietary magnesium intake may reduce the prevalence of chemotherapy-induced peripheral neuropathy and severity in J o u r n a l P r e -p r o o f patients with colorectal cancer (Wesselink et al., 2018) . Thus, eating magnesium-rich foods may be a new strategy for cancer prevention. Table 2 summarizes the treatment of magnesium supplementation for the various diseases in recent basic researches and clinical trials.

COVID-19 has spread globally with severe epidemics (Table 3) . SARS-CoV-2 gene sequence has a very high similarity to severe acute respiratory syndrome coronaviruses (SARS-CoV) broke out in 2003, and the Middle East respiratory syndrome coronavirus (MERS-CoV) epidemic in 2012 (Wu et al., 2020a; Wu et al., 2020c) . SARS-CoVs-2, a previously unknown beta-coronavirus, is listed as the 7th member of the coronaviruses family that infects humans (Zhu et al., 2020) . In addition to respiratory damage, clinical evidences show that a relatively high proportion of patients with COVID-19 has different damage degrees of important organ and tissue such as liver, kidney, and heart (Escalera-Antezana et al., 2020; Guan et al., 2020; Yang et al., 2020) . Moreover, patients with ARDS may be accompanied by cytokine storm, which increases multiple organ damage and makes the treatment of COVID-19 more difficult (Guo et al., 2020; Mehta et al., 2020) .

Most COVID-19 patients develop pneumonia accompanied with respiratory tract symptoms, including cough, sore throat, sputum production, hemoptysis, nasal congestion, dyspnea and shortness of breath (Escalera-Antezana et al., 2020; Guan et al., 2020; Wang et al., 2020a; Young et al., 2020; Zhang et al., 2020) . COVID-19 patients admitted to intensive care unit have more severe respiratory symptoms. Among 1300 patients with available respiratory support data, 1287 (99%) require respiratory support, and a large part of patients need positive end-expiratory pressure. But there is still a high mortality rate of 26% in intensive care unit (Grasselli et al., 2020) . The pathological features of COVID-19 show bilateral diffuse alveolar injury with cellular fbromyxoid exudates. Right lung sample displays obvious desquamation of pneumocytes and hyaline membrane formation, indicating ARDS, whereas, the left shows pulmonary oedema with hyaline membrane formation. And the bilateral lung tissue exhibits obvious inflammatory infiltration in COVID-19 patients (Grasselli et al., 2020) . The elderly and people with underlying diseases are susceptible to infection and prone to serious outcomes J o u r n a l P r e -p r o o f even death, which may be associated with ARDS. ARDS can induce inflammatory response and cytokine storm following heavily release of proinflammatory cytokines IFN-γ, TNF-α, interleukin and chemokines, which increase organ damage and accelerate the deterioration of the disease status (Guo et al., 2020; Mehta et al., 2020) . Magnesium sulfate as a calcium antagonist is commonly used to inhibit bronchial smooth muscle contraction and promote bronchodilation (Hirota et al., 1999; Landon and Young, 1993; Torres et al., 2012) . It also decreases inflammatory response and oxidative stress, as well as improves lung inflammation possibly by inhibiting IL-6 pathway, NF-κB pathway, and L-type calcium channels (Güzel et al., 2019; Kao et al., 2011) . Therefore, magnesium sulfate has a good application prospect in controlling pulmonary symptoms.

As the epidemic spreads, the number of infected pregnant women is also increased. Human populations during COVID-19 outbreak, which will cause newborns to be more prone to complications such as fetal distress, premature delivery, respiratory distress and thrombocytopenia (Dashraath et al., 2020; Liu et al., 2020) . Pregnant women are at increased risk for more severe clinical symptoms and complications especially in respiratory system due to high metabolic level and high oxygen consumption (Karimi-Zarchi et al., 2020) . Unfortunately, there is little experience with SARS-Cov-2 infections at current stage. Many drugs are restricted during pregnancy according to pregnancy drug category of Food and Drug Administration (FDA). Commonly used antiviral drugs ganciclovir, lamivudine, and compound of lopinavir/ritonavir, belong to C category according to the FDA risk classification, which largely limits the use and also makes the treatment of pregnant women more difficult. But magnesium sulfate belonging to B category formulated by FDA, is safe and non-teratogenic. Magnesium sulfate is a commonly used drug in obstetrics, for its effective prevention and control of preterm labor, gestational hypertension, preeclampsia, and eclampsia with few side effects (Alexander et al., 2006; Damron, 2007; Kreepala et al., 2018; Magee and von Dadelszen, 2018) .

Besides, magnesium sulfate is utilized for fetal neuroprotection in preterm birth, its maternal administration prior to anticipated preterm delivery decreases cerebral palsy in survivors possibly by the anti-inflammatory action (Bachnas et al., 2019; Kao et al., 2011; Ozen et al., 2020; Rouse et al., 2008) . In view of the beneficial effects of magnesium sulfate on pregnancy-induced hypertension, preeclampsia, and eclampsia, we strongly recommend that magnesium sulfate with fetal neuroprotection can be the treatment of choice for pregnant women infected with SARS-CoV-2 timely.

Coronary heart disease and hypertension are common coexisting disorders in COVID-19 patients.

In China, a total of 1099 COVID-19 patients, 27 (2.5%) coexist coronary heart disease and 164 (14.9%) coexist hypertension (Guan et al., 2020) . In Italy, of 1591 COVID-19 patients admitted to intensive care unit, the number of patients coexisting with hypertension or cardiovascular disease are 509 (49%) and 223 (23%), respectively (Grasselli et al., 2020) . A report of 72314 cases from the China shows that mortality rate is elevated among those with coexisting disorders -10.5% for cardiovascular disease, 6.0% for hypertension, compared with overall case-fatality rate of 2.3% (Wu and McGoogan, 2020) .

Besides, COVID-19 outbreak leads to severe ventricular dysfunction, even without obvious symptoms and signs of interstitial pneumonia (Escalera-Antezana et al., 2020). Magnesium inhibits smooth muscle contraction and decreases systolic, diastolic and mean arterial blood pressure (Banjanin and Belojevic, 2018; Shimosawa et al., 2004) , possibly by the inhibition of calcium release from the sarcoplasmic reticulum, as well as the promotion of the outflow of calcium ion via activating potassium channel (Altura et al., 1987; Ko et al., 2008; Shimosawa et al., 2004; Zhang et al., 1993 ), or increasing endothelium-derived NO level (Teragawa et al., 2002 and blocking N-type calcium channel to inhibit norepinephrine release (Shimosawa et al., 2004) . Magnesium supplementation therapy can lower blood pressure, reduce the risk of atrial fibrillation, ameliorate subclinical atherosclerosis and prevent other various cardiovascular diseases (Banjanin and Belojevic, 2018; Osawa et al., 2018; Shimosawa et al., 2004) . These results indicate that while controlling respiratory symptoms, magnesium also takes the control of cardiovascular symptoms in a large number of patients with cardiac complications or comorbidities.

What cannot be ignored is coexisting disorders in COVID-19 patients, mainly including nervous system disease, cardiovascular and cerebrovascular disease, kidney diseases, diabetes, and cancer, J o u r n a l P r e -p r o o f corresponding ratio in representative research are summarized in Table 4 . Hypertension and diabetes mellitus are the most common diseases in COVID-19 patients Wu et al., 2020b; Zhang et al., 2020; Zhou et al., 2020) . Of note, case-fatality rate is increased among COVID-19 patients with preexisting comorbid conditions such as acute kidney injury, diabetes, hypertension, and cancer (Cheng et al., 2020; Wu and McGoogan, 2020) . Of 701 COVID-19 patients, 43.9% patients with proteinuria, 26.7% patients with hematuria, and 5.1% patients with acute kidney injury have a significantly higher risk of death in hospital (Cheng et al., 2020) . Diabetes is suggested to a risk factor for mortality in patients infected with SARS and MERS-CoV (Alanazi et al., 2020; Yang et al., 2006) .

Patients with diabetes have an increased risk of developing infection with SARS-CoV-2 (Gupta et al., 2020; Muniyappa and Gubbi, 2020). The mortality rate of COVID-19 patients with diabetes is 7.3%, which is significantly higher than the total mortality rate of 2.3% (Wu and McGoogan, 2020) .

Magnesium deficiency is found in patients with chronic medical illnesses, including kidney disease, and diabetes (Gröber et al., 2015; Kachhawa et al., 2019; Mather and Levin, 1979; Mauskop and Varughese, 2012) . Thus, magnesium deficiency may be one of the reasons for the further deterioration of COVID-19 patient's condition. Magnesium supplementation plays a beneficial role in improving acute kidney injury (Barbosa et al., 2016; Hamroun et al., 2019; Solanki et al., 2015) , controlling blood glucose in diabetic patients (Soliman and Nofal, 2019) . Therefore, we recommend that serum magnesium level in COVID-19 patients with other coexisting disorders should be monitored.

Magnesium supplementation should be given in a timely manner for COVID-19 patients to prevent from worsening and ensure the patients to have good prognosis.

The drugs recommended for COVID-19 therapy are mainly antiviral drugs, such as lopinavir/ritonavir, ribavirin, and chloroquine phosphate, but no specific antiviral drugs have been approved for the treatment of COVID-2019 due to lack of definite clinical evidence (Du and Chen, 2020). Remdesivir as antiviral drug can incorporate into nascent viral RNA chain to inhibit RNA polymerase and stop viral replication eventually (Warren et al., 2016) . Recently, a COVID-19 patient in the United States recovers after intravenous injection remdesivir (Holshue et al., 2020) . Remdesivir, as compassionate-use currently, is a lack of further evidence to prove the safety and effectiveness. The treatment with lopinavir-ritonavir (400 and 100 mg, respectively) in 99 COVID-19 patients fail to show a significant difference in the time to clinical improvement, compared to standard care comprised J o u r n a l P r e -p r o o f supplemental oxygen, noninvasive and invasive ventilation, renal-replacement therapy, antibiotic agents, vasopressor support, or extracorporeal membrane oxygenation as necessary. In the process of treatment, lopinavir and ritonavir are used to treat COVID-19, because of having inhibitory activity against SARS-CoV and MERS-CoV in vitro (Chu et al., 2004) . However, these antiviral drugs may cause organ damage and other harmful effects (such as dyslipidemia, hepatotoxicity and elevated transaminases) (Benson et al., 2002; Meraviglia et al., 2004; Patel et al., 2018) . Magnesium supplements can decrease serum levels of ALP, ALT, AST and GGT, ameliorate liver fibrosis and injury (Eshraghi et al., 2015) . Moreover, magnesium supplementation (magnesium gluconate) enhances antioxidant enzyme activity, reduces blood levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol, and improves dyslipidemia in high-fat diet-fed rats (Zhang et al., 2018) . Therefore, reasonable magnesium supplementation may alleviate hepatotoxicity and dyslipidemia induced by lopinavir-ritonavir. The malaria medication chloroquine (or its chemical cousin hydroxychloroquine) is also suggested to treat COVID-19 for reducing viral load in nasal swabs (Gautret et al., 2020), but it might actually do more harm than good due to its cardiac toxicity (Chatre These observations indicate that magnesium supplement may alleviate chloroquine-induced cardiac toxicity or neuromyotoxicity.

Taken together, the available clinical data of the above drugs to treat COVID-19 are limited. Their various side effects cannot be ignored, which would accelerate the progression of turning from mild to severe illness, and easily lead to poor clinical outcome, such as organ failure and death. In the special period, all efforts of approved drugs in drug design and clinical trials for COVID-19 therapy are creditable and worthy. As mentioned in this paper, magnesium sulfate can relieve lung symptoms, protect nervous system, improve cardiovascular function, ameliorate liver and kidney injury, and 

Generally, magnesium is a necessary cation in the body. Its serum concentration range in healthy adults is approximately 0.75 ~ 0.96 mmol/L (Arnaud, 2008) . Magnesium sulfate is a cheap, safe and readily available medication in the treatment of several diseases, and its safety window is large enough. However, its megadose therapy is debatable. The most common symptoms of excess magnesium are nausea, vomiting, and diarrhea, the others include hypotension, confusion, slowed heart and respiratory rates, coma, cardiac arrhythmia, deficiency of other minerals, as well as death from cardiac arrest (McGuire et al., 2000; Kontani et al., 2005; Kutsal et al., 2007; Ajib and Childress, 2020) .

The first warning of imminent toxicity is the loss of knee tendon reflex when magnesium concentration is between 3.5 and 5 mmol/L (Sibai, 1990) . Respiratory paralysis occurs between 5 and 6.5 mmol/L (Winkler et al., 1942) . Cardiac conduction change occurs above 7.5 mmol/L, and cardiac arrest can be expected when magnesium concentration exceeds 12.5 mmol/L (McCubbin et al., 1981) . Clinically, the use of magnesium sulfate is relatively mature. On the other hand, chronically low serum magnesium levels are associated with metabolic syndrome, fasciculation, diabetic and hypertension, etc (Nadler et al. 1995) . Therefore, under the premise of monitoring blood pressure, knee tendon reflex, magnesium, other cofactors and modulators, magnesium can be used as an adjuvant drug to treat COVID-19 patients, who occur adverse reactions or have no improvement of conditions after the recommended treatment.

Of note, except magnesium, other metal ions (sodium, potassium, calcium, etc) and anions (phosphate, chloride etc.) are fundamental constitutive cofactors and modulators of endless physiological functions. This includes numerous cellular enzymes, ion channels, transport, motor function, signal transduction, transmission, activation, synthesis and more. A standard physiological concentration level of each cofactor is essential in maintaining normal homeostasis. Any long term imbalance in extracellular, intracellular and/or serum levels of any of these cofactors due to lack of external supply, diseases modulator and/or drug-induced loss or accumulation often is detrimental both in diseases associated and even in normal healthy subjects. Thus, in any critically ill surgical or diseases patients, it is crucial to address and stabilize cofactor imbalance, and is a prerequisite even before any therapeutic intervention.

Under pathological conditions, more than one electrolyte disorder often occurs. Increasing epidemiological studies have shown that insufficient or excessive electrolyte is closely related to the development of diseases such as hypertension, diabetes, chronic kidney disease, coronary heart disease, and stroke, etc (Adrogué and Madias, 2007; Hill Gallant and Spiegel, 2017; S. C. Palmer et al., 2011) .

Magnesium deficiency (serum magnesium less than 0.5 mmol/L) can result in multiple symptoms including tremor, poor coordination, muscle spasms, loss of appetite, personality change, and nystagmus (William C. Shiel Jr.) . Of note, magnesium ion transport critically depends on the extracellular sodium concentration. High intracellular sodium concentration normally inhibits this ion transport (Tashiro et al, 2005) . In fact, low magnesium (hypomagnesemia) is often associated with hypocalcemia and hypokalemia (Krämer and Endemann, 2000; William C. Shiel Jr.) . In patients undergoing peritoneal dialysis, 29% of patients with hypokalemia are accompanied by hypomagnesemia (Hamad et al., 2019) . Thiazide diuretic therapy is the first-line treatment of hypertension, which often causes hypokalemia, and 40% of patients are accompanied by hypomagnesemia (Krämer and Endemann, 2000) . And when hypomagnesemia coexists, it is usually difficult to compensate for hypokalemia (Whang et al, 1992) . A study shows that 93% of severe and critically ill COVID-19 patients have hypokalemia, which may be due to continuous renal potassium loss caused by ACE2 degradation, however, the change in magnesium concentration was not monitored in this study . Thus, hypocalcemia or hypokalemia occurs, clinicians should be alert for the occurrence of hypomagnesemia. When magnesium deficiency is detected, it should be supplemented according to the actual clinical situation to prevent serious incidents. We estimate that, in patients with moderate and severe COVID-19, most of them accompany hypomagnesemia.

Recent studies have suggested that serum magnesium level of critically ill patients deserves attention (Bani et al., 2020; Browne et al., 2020; Iotti et al, 2020) ]. Hypomagnesemia is common in all hospitalized patients, especially in critically ill patients with coexisting electrolyte abnormalities (Hansen and Bruserud, 2018) . In a study on the clinical management of Ebola virus disease in the United States and Europe, 90% of patients had hypomagnesemia before admission, and almost all patients received electrolyte supplementation therapy (Uyeki et al., 2016) . A clinical trial of allogeneic human dental pulp stem cells for the treatment of patients with severe COVID-19 included magnesium concentration in the indicators of liver and kidney function tests (Ye et al., 2020) . Moreover, some studies have mentioned that trace elements including magnesium, vitamins and other nutrients play an J o u r n a l P r e -p r o o f important and complementary role in supporting the immune system and combating COVID-19 (Calder et al, 2020; Wallace, 2020) .

Together all, we gave our clinical recommendations on the administration method of magnesium supplementation. According to the 2015-2020 Edition of the Dietary Guidelines for Americans, we recommend daily oral magnesium supplementation 310-320 mg or 400-420 mg for COVID-19 adult women or men patients with mild symptoms, respectively, especially in patients with mild magnesium deficiency (serum magnesium concentration range from 0.5 to 0.75 mmol/L). For children, oral magnesium supplement needs to be reduced referring to the guide for details (Ayuk and Gittoes, 2014;  Institute of Medicine Committee to Review Dietary Reference Intakes for Vitamin & Calcium, 2011). Magnesium has a wide range of effects, and supplementation effectively prevents the development of the disorders or diseases within the safe blood concentration range. Accordingly, we believe that, J o u r n a l P r e -p r o o f under the premise of reasonable use and detection of serum magnesium concentration as well as control of fundamental constitutive cofactors and modulators, timely supplementation of magnesium will benefit COVID-19 patients, with few side effects occurrences. Of course, in the special period of COVID-19 outbreak, more clinical evidences are needed in the future research whether magnesium sulfate combined with other recommended treatment drugs is more beneficial to the COVID-19 patient's condition.

The COVID-19 epidemic with a relatively high mortality rate is still spreading quickly, and has brought great challenge to the world. It is very important to implement effective treatment programs actively. Magnesium supplementation protects organs and tissues from damage through multiple mechanisms including anti-inflammation, anti-oxidation, immune-regulation. It is worth noting that magnesium sulfate can be a drug of choice in supportive treatment of COVID-19 especially critically ill patients with promising crucial beneficial medical effects (Bani et al., 2020) . The evidence from this review preliminarily supports the expected efficacy of magnesium supplementation in the prevention and treatment of COVID-19 patients, especially pregnant women, as well as subjects with hypertension and diabetes. Therefore, magnesium supplementation is expected to play an active role in clinical practice in the prevention and treatment of COVID-19. However, more clinical studies are necessary to provide true representation of beneficial role of magnesium in light of other essential physiologically linked cofactors in COVID-19 and non-COVID-19 state. Note: [a] No country is mentioned in the paper.

J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f 

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Prehospital use of magnesium sulfate as neuroprotection in acute stroke

Involvement of serotonergic and opioidergic systems in the antinociceptive effect of ketamine-magnesium sulphate combination in formalin test in rats

An Analysis of 38 Pregnant Women with COVID-19, Their newborn infants, and maternal-fetal transmission of SARS-CoV-2: Maternal coronavirus infections and pregnancy outcomes

Consequences of magnesium-deficiency on the enhancement of stress reactions-preventive and therapeutic implications -a review

Magnesium in depression

Intravenous and nebulized magnesium sulfate for treating acute asthma in adults and children: a systematic review and meta-analysis

Intravenous magnesium sulphate and sotalol for prevention of atrial fibrillation after coronary artery bypass surgery: a systematic review and economic evaluation

Magnesium inhibits norepinephrine release by blocking N-type calcium channels at peripheral sympathetic nerve endings

Magnesium sulfate is the ideal anticonvulsant in preeclampsia-eclampsia

Magnesium-deficient diet alters depression-and anxiety-related behavior in mice -influence of desipramine and Hypericum J o u r n a l P r e -p r o o f perforatum extract

Effects of magnesium and related divalent metal ions in topoisomerase structure and function

Magnesium sulphate improves pulmonary function after video-assisted thoracoscopic surgery: a randomised double-blind placebo-controlled study

Magnesium protects against cisplatin-induced acute kidney injury by regulating platinum accumulation

Magnesium protects against cisplatin-induced acute kidney injury without compromising cisplatin-mediated killing of an ovarian tumor xenograft in mice

The effect of perioperative magnesium sulfate on blood sugar in patients with diabetes mellitus undergoing cardiac surgery: a double-blinded randomized study

Hydroxychloroquine neuromyotoxicity

Effectiveness of magnesium sulfate as initial treatment of acute severe asthma in children

Effects of nebulised magnesium sulphate on inflammation and function of the guinea-pig airway

Clinical management of Ebola virus disease in the United States and Europe

Nebulized magnesium sulfate in the management of acute exacerbations of asthma

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan

Combating COVID-19 and Building Immune Resilience: A Potential Role for Magnesium Nutrition?

Efficacy of combined medication of nifedipine and magnesium sulfate on gestational hypertension and the effect on PAPP-A, VEGF, NO, Hcy and vWF

Clinical features of 69 cases with coronavirus disease 2019 in Wuhan, China

Magnesium intake and colorectal tumor risk: a case-control study and meta-analysis

Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys

A proportional but slower NMDA potentiation follows AMPA potentiation in LTP

Dietary intake of magnesium or calcium and chemotherapy-induced peripheral neuropathy in colorectal cancer patients

Refractory potassium repletion. A consequence of magnesium deficiency

Medical definition of magnesium deficiency

Intravenous magnesium sulphate in the treatment of nephritic convulsions in adults

Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome

Comparison efficacy of randomized nebulized magnesium sulfate and ipratropium bromide/fenoterol in children with moderate to severe asthma exacerbation

Coronavirus disease (COVID-2019) situation reports. Updated

Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China

Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan

Specific requirement of NMDA receptors for long-term memory consolidation in drosophila ellipsoid body

A new coronavirus associated with human respiratory disease in China

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the chinese center for disease control and prevention

Experiences of an outpatient infusion center with intravenous magnesium therapy for status migrainosus

Preventive effect of continuous cisternal irrigation with magnesium sulfate solution on angiographic cerebral vasospasms associated with aneurysmal subarachnoid hemorrhages: a randomized controlled trial

Plasma glucose levels and diabetes are morbidity in patients with SARS

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Safety and efficacy assessment of allogeneic human dental pulp stem cells to treat patients with severe COVID-19: structured summary of a study protocol for a randomized controlled trial (Phase I / II)

Hydroxychloroquine-induced cardiomyopathy: case report, pathophysiology, diagnosis, and treatment. The Canadian journal of cardiology

Epidemiologic features and clinical course of patients

Maternal and perinatal outcomes with COVID-19: a systematic review of 108 pregnancies

Mg 2+ and caffeine-induced intracellular Ca 2+ release in human vascular endothelial cells

Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan

Effect of magnesium gluconate administration on lipid metabolism, antioxidative status, and related gene expression in rats fed a high-fat diet

Magnesium intake and primary liver cancer incidence and mortality in the prostate, lung, colorectal and ovarian cancer screening trial

Clinical course and risk factors for mortality of adult in patients with COVID-19 in Wuhan, China: a retrospective cohort study

A novel coronavirus from patients with pneumonia in China

Saudi Arabia