Pharmacological treatment of COVID-19: an update

Pharmacological treatment of COVID-19: an update Oyiyechukwu A Onwudiwe 1 , Homayemem Weli 2 , Toluwanimi A Shaanu 3 , Nkechi M Akata 4 , Imoh L Ebong 5 1 College of Medicine, University of Lagos, Lagos, Nigeria, 2 Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA, 3 College of Medicine, Lagos State University, Lagos, Nigeria, 4 College of Medicine, University of Nigeria Nsukka, Nigeria, 5 School of Medicine and Dentistry, University of Ghana, Accra, Ghana


INTRODUCTION
In the past century, the world has gone through pandemics such as the 1918 H1N1 influenza pandemic, the 1957 H2N2, and 1968 H3N2 pandemics which have brought about advances in science and led to the development of new medications and vaccines. The world has been significantly impacted by the coronavirus-19 (COVID-19) outbreak caused by the novel coronavirus-2 (SARS-CoV-2) and the race is on to find a vaccine. In the interim, various medications are being used. SARS-CoV-2 is a single-stranded RNA beta-coronavirus whose genome encodes structural proteins, non-structural proteins, and accessory proteins. 1 It appeared for the first time in Wuhan, China, at the end of 2019 and is presently being transmitted by human to human transmission. 2,3 Affected individuals demonstrate a wide range of clinical manifestations from asymptomatic, mildly symptomatic, to severe viral pneumonia with respiratory failure, multiorgan and systemic dysfunctions in terms of sepsis and septic shock, and death. 4,5 By the 7th of September 2020, there were over 27 million confirmed cases of COVID-19 and 881,464 deaths worldwide, reported to World Health Organization (WHO) with the highest cases in the United States of America, India, and Brazil. 6 Various medications have been proposed and applied to control COVID-19 based on prior experiences with other viral infections such as Ebola, Human Immunodeficiency Virus (HIV), 2003 Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), and the 2012 Middle East Respiratory Syndrome coronavirus (MERS-CoV)). 7,8 However, some of these medications have been shown to lack efficacy against this virus or have been associated with serious adverse effects as in the case of chloroquine and hydroxychloroquine. 9,10 Coronaviruses are a group of large, enveloped, positivesense single-stranded RNA viruses found in humans, birds, and other mammals. They cause respiratory tract infections in humans and birds which can range from mild to fatal. They also cause gastrointestinal and neurologic disease in other mammals. SARS-CoV-2 is the third coronavirus that has caused severe disease in humans and spread globally in the past 2 decades. 11 Through genetic recombination and variation, coronaviruses can adapt to new hosts and infect them. The pathophysiology of this virus has been studied and extensively discussed. [11][12][13][14][15] A thorough review of the repurposed medications used since the outbreak and experimental medications in clinical trials is presented.

METHODS
A literature search was conducted to cover the period of January-September 2020. PubMed, LitCOVID, Google Scholar, Science Direct, and clinicaltrials.gov were the databases used. "Medications", "treatment", "therapeutics", "pharmacological management", "COVID-19", "SARS-CoV-2" were the keywords used in the search engines without considering any restriction of language to identify potential published studies. EndNote X 7.0 software was used to exclude duplicates from searched data. Missing studies were identified by checking the reference list of the selected articles. Information on ongoing clinical trials was obtained from clinicaltrials.gov. Extra information was obtained from case series, case reports, review articles, and randomized clinical trials describing the outcomes of medications used for SARS-CoV-2 treatment, as well as the rationale behind their use. Studies with only abstracts and those without results were excluded from this review.

CORTICOSTEROIDS
Corticosteroids include dexamethasone, prednisone, methylprednisolone, and hydrocortisone. Corticosteroids exert their anti-inflammatory effect by inhibiting pro-inflammatory transcription factors. They have been used in a wide range of inflammatory conditions. There is concern about inhibiting the immune system and decreased viral clearance with the use of corticosteroids in COVID-19 patients. This is because the use of corticosteroids in other coronavirus outbreaks did not improve mortality but rather was associated with decreased viral clearance and high rate of complications. 16,17 A study that was done early in the pandemic showed no difference in mortality with the use of corticosteroids in COVID-19 patients. 18 Dexamethasone has been studied for use in the treatment of or prevention of organ dysfunction and lung injury from SARS-CoV-2-induced inflammation. The RECOVERY trial (NCT04381936) arm of dexamethasone showed that the use of this medication in patients hospitalized with COVID-19 resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone but not among those receiving no respiratory support. 19 It is not yet known if this may make a positive impact on COVID-19 treatment. However, it is important to note that corticosteroids are the first and so far, only medications to significantly improve survival in hospitalized COVID-19 patients. Moreover, these medications have been around for a while, are cheap, widely available, and have been extensively studied and used. In the REMCAP clinical trial (NCT02735707) of patients with severe COVID-19, hydrocortisone treatment resulted in a 93% probability of superiority with regard to improve odds in organ support free days within 21 days compared to 80% probability in the no hydrocortisone group. 20 Although this trial was stopped early due to results of the RECOVERY trial which showed positive results with the use of corticosteroids, it suggests a beneficial use of steroids in severely ill COVID-19 patients. A recent study of methylprednisolone showed an improvement in oxygenation and no deaths in 15 critically ill COVID-19 patients with no negative impact on virus removal. 21 It is unclear whether or not dexamethasone and other corticosteroids have deleterious effects on viral clearance when used for less severe COVID-19 cases. Further clinical trials would be useful in clarifying this. Although there are numerous side effects of corticosteroid use, the most important of which may be prolonged shedding of the virus; the benefits of low dose steroids in critically ill patients who require oxygen may likely outweigh the risks.

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used drugs because they have a wide range of use like anti-inflammation, anti-pyrexia. At the beginning of the COVID-19 outbreak, the French Minister of Health made a recommendation to alert healthcare workers to avoid the use of anti-inflammatory medications like ibuprofen or cortisone, claiming it could aggravate infections and make it worse. 22 This was because a study done suggested that the SARS-CoV-2 virus has an increased affinity for the Angiotensin-Converting Enzyme-2 (ACE2) receptor and Ibuprofen, an NSAID has been known to increase the production of ACE2 and increase the expression of the ACE receptors. 23,24 This was later refuted by the World health organization, who stated that there was no evidence that NSAIDs like ibuprofen could worsen the outcome of the disease. A cohort study done on COVID-19 patients showed that there was no difference in outcome between Ibuprofen users and acetaminophen users. 25 Indomethacin is another NSAID that has exhibited potent antiviral activity against canine coronavirus, by dramatically inhibiting virus replication and protecting the host cell from virus-induced damage. This activity was also observed Pharmacological treatment of COVID-19: an update Journal of Global Health Reports in vivo and against human SARS-CoV. 26 Indomethacin does not affect coronavirus binding or entry into host cells, but acts by blocking viral RNA synthesis at cytoprotective doses. 26 This may be of possible benefit in patients affected by SARS-CoV-2. The effects of another NSAID naproxen in patients with COVID-19 is also yet to be established. Noting that a major side effect of NSAIDs is bleeding from gastrointestinal ulcers and that severe COVID-19 patients end up with disseminated intravascular coagulopathy (DIC) and bleeding, more research is needed to ascertain the dose at which these medications are safe to use in COVID-19 patients and if they are of any benefit. COLCHICINE Colchicine is a medication used in gout and familial Mediterranean fever. It functions by disrupting cytoskeletal functions through inhibition of beta-tubulin polymerization into microtubules, which prevents activation, degranulation, and migration of neutrophils thereby showing antiinflammatory properties. Colchicine also acts as an anti-oxidative and anti-fibrotic agent. In an animal model of bronchopulmonary dysplasia, treatment with colchicine showed a reduction in inflammatory markers [Interleukin-6(IL-6) and Tumor Necrosis Factor-alpha (TNF-α)]. 27 Colchicine may therefore help mitigate the cytokine storm associated with COVID-19 infection as high levels of IL-6 have been seen in these patients. A case report of a patient with moderate COVID-19 treated with colchicine showed an improvement in symptoms and a reduction in levels of IL-6. 28 A cohort study of 9 patients with moderate COVID-19 treated with colchicine showed an improvement in symptoms within 72 hours. 29 This study also postulated that treatment with colchicine early in the disease process may be more beneficial before the onset of ARDS. However, the true efficacy of this medication in COVID-19 patients is still unknown. There are several ongoing clinical trials to confirm the benefit and utility of this medication in COVID-19 patients.

ANTIVIRALS
There is presently no approved antiviral therapy for COVID 19, however, clinical trials are presently ongoing to assess for the efficacy of antivirals as monotherapy or as a combination with other drug classes. A study done early on in the pandemic suggested that antiviral drugs if administered shortly after symptom onset can reduce infectiousness to others by reducing viral shedding in the respiratory secretions of patients as it has been shown that SARS-CoV-2 viral load in sputum peaks at around 5-6 days after symptom onset and lasts up to 14 days. 30 Antivirals that have been used in COVID-19 patients include remdesivir, favipiravir, umifenovir, lopinavir/ritonavir, sofosbuvir, daclatasvir, and ribavirin.

FAVIPIRAVIR AND UMIFENOVIR
Favipiravir and umifenovir (Arbidol) were originally used in Influenza patients. Favipiravir works by inhibiting RNA-dependent RNA polymerase thereby inhibiting viral replica-tion in the host cell. Umifenovir works by direct viricidal activity and interaction with viral proteins and lipids. A randomized controlled clinical trial comparing the use of favipiravir to umifenovir showed a shorter recovery time of mild to moderate COVID-19 patients with cough and fever in the favipiravir group compared to the umifenovir group. 31 There was no difference in outcome for patients with severe COVID-19 who were on oxygen therapy or required ventilation. A study done comparing treatment with umifenovir to lopinavir/ritonavir in COVID-19 patients showed no viral load in the umifenovir group compared to 44% in the treatment group thereby concluding that umifenovir monotherapy may be superior to lopinavir/ritonavir. 32 However, another study done showed that umifenovir use in COVID-19 patients did not accelerate SARS-CoV-2 clearance and was associated with a longer hospital stay. 33 These medications are presently under multiple clinical trials, but available data have not shown significant efficacy as a therapy for COVID 19.

REMDESIVIR
Remdesivir is an antiviral medication that works by binding to viral RNA-dependent RNA polymerase thereby inhibiting viral replication. Remdesivir was previously manufactured for use in Ebola patients however it lacked efficacy against the virus. A National Institute of Health (NIH)-sponsored, multinational, randomized, double-blind placebo-controlled trial in hospitalized adults with COVID-19 showed that remdesivir reduced time to recovery especially in patients who required supplemental oxygen. 34 However, this study did not show any benefit in patients with mild to moderate COVID-19. In another study, a cohort of patients hospitalized for severe COVID-19 who were treated with remdesivir for compassionate use, clinical improvement was observed in 68% of these patients. 35 A multinational randomized clinical trial of remdesivir in patients with moderate COVID-19 showed an improvement in clinical status on day 11 in those who were on a 5-day course of remdesivir compared to standard care. 36 However, there was no difference in the 10-day course compared to the standard of care. There are also no clinical trials in patients with mild COVID-19 to determine if this medication would be more efficacious early in the disease process. Limitations to its use include cost and availability. The true efficacy and benefit of this medication are unknown and more clinical trials in all age groups and stages of the disease are needed.

LOPINAVIR/RITONAVIR
Lopinavir and ritonavir are protease inhibitors used in treating HIV infection. Lopinavir has shown an antiviral effect against the SARS-CoV-2 virus in Vitro. 37 A study of 44 patients with mild/moderate COVID-19 in which 21 patients were assigned to receive lopinavir/ritonavir compared to 16 receiving umifenovir and 7 controls showed that were was no difference in the improvement of symptoms among all 3 groups. 38 Another study of a total of 199 patients with laboratory-confirmed SARS-CoV-2 infection, treatment with lopinavir/ritonavir was not associated with a difference from standard care in the time to clinical im-Pharmacological treatment of COVID-19: an update Journal of Global Health Reports provement. 39 A meta-analysis of COVID-19 patients treated with lopinavir/ritonavir showed a slight reduction in the risk of requiring invasive mechanical ventilation, developing respiratory failure, or acute respiratory distress syndrome. However, it did not lead to any difference in the duration of hospitalization. 40 The available evidence does not show the true benefit of this medication. However, evidence from ongoing clinical trials should be available soon to inform physicians on the efficacy of this medication combination in COVID-19 patients. RIBAVIRIN Ribavirin is an antiviral medication used to treat hepatitis C, respiratory syncytial virus, and some viral hemorrhagic fevers such as Lassa fever. It is a nucleoside inhibitor and interferes with RNA metabolism required for viral replication. Studies have shown that ribavirin did not inhibit previous coronaviruses and did not improve survival in other outbreaks. 41-43 However, due to the lack of any medications for this present coronavirus outbreak, ribavirin was still applied. A retrospective cohort study done on critically ill COVID-19 patients showed that ribavirin therapy was not associated with improved negative conversion time for the SARS-CoV-2 test or an improved mortality rate compared to controls. 44 In a prospective, open-label, randomized, phase 2 trial in adults with COVID-19 ribavirin was used in combination with Interferon β-1b and lopinavir/ritonavir as triple therapy. 45 The triple therapy group had a significantly shorter median time from the start of study treatment to negative nasopharyngeal swab (7 days) than the control group (12 days); hazard ratio 4·37 [95% CI 1·86-10·24], P=0·0010). It is unclear if this was due to ribavirin or the other medications that were also used. With the currently available research, there is no evidence for the use of ribavirin in COVID-19 patients.

SOFOSBUVIR AND DACLATASVIR
Sofosbuvir and daclatasvir are direct-acting antivirals (DAAs) that work by binding to hepatitis C virus (HCV) NS5B and NS5A RNA dependent polymerases respectively thereby inhibiting viral replication. They are used in combination with ribavirin and interferon to treat hepatitis C infection. They have been applied for use in COVID-19 patients as in-vitro studies have demonstrated some antiviral effects against SARS-CoV-2. 46 Studies done have shown promise in the treatment of COVID-19 patients by shortening clinical recovery and duration of hospitalization. [47][48][49] Limitations to these studies are the small sample sizes, as well as all studies being from one region. Therefore, more research is needed to evaluate their true benefits. Several clinical trials are ongoing to determine if they are of benefit in SARS-CoV-2 infection. Interleukin-1(IL-1) family is a group of 11 cytokines, which induces a complex network of proinflammatory cytokines and via expression of integrins on leukocytes and endothelial cells, regulates and initiates inflammatory responses. 50 IL-1 α and IL-1 β are the strongest pro-inflammatory cytokines. Interleukin 1 (IL-1) is a potential target of therapy in COVID-19 patients during the cytokine storm phase when pulmonary macrophages are hyperactivated, releasing IL-1 and other cytokines. IL-1 inhibitors include anakinra, canakinumab, rilonacept. There are currently no randomized clinical trials that assess the utility or safety of IL-1 inhibitors in severe COVID-19 patients. Preliminary evidence from a retrospective study on COVID-19 patients treated with high dose anakinra showed an improvement in respiratory function in 72% of patients compared to 56% in the standard treatment group and a 90% survival rate compared to 56% in the standard treatment group. 51 Another cohort study done showed that anakinra reduced both the need for invasive mechanical ventilation in the ICU and mortality among patients with severe forms of COVID-19. 52 Randomized clinical trials are needed to assess the efficacy, dosing, and adverse effects of these medications in patients with severe COVID-19. There are ongoing clinical trials to determine the benefits of these medications in patients with COVID-19. Patients with severe COVID-19 exhibit high serum levels of IL-6 as well as other pro-inflammatory cytokines. 53 Elevated levels of IL-6 were associated with a worse prognosis. 54 It, therefore, follows that inhibiting these cytokines may lead to improved outcomes in these patients. Tocilizumab is the only IL-6 inhibitor that has been used in severe COVID-19 patients and has shown an improvement in outcome. It is originally approved by the FDA for rheumatoid arthritis, giant cell arteritis, and cytokine release syndrome. Studies done on COVID-19 patients with tocilizumab showed a reduction of fever and IL-6 levels, reduced need for oxygen therapy and mechanical ventilation, and improved radiologic lung findings. [55][56][57] A large retrospective multicenter cohort study also showed a reduced risk of mechanical ventilation and death with the use of tocilizumab irrespective of the route of administration. 58 Clinical trials are ongoing to study the effect of tocilizumab on COVID-19 patients. Preliminary results from the COVIDOSE trial showed that low-dose tocilizumab was associated with rapid improvement in clinical and laboratory measures of hyper inflammation in hospitalized patients with COVID-19. 59 Ongoing clinical trials to determine the safety and efficacy of tocilizumab, as well as other IL-6 inhibitors, would shed more light on the use of this class of drugs in COVID-19 patients.
pro-inflammatory cytokines simultaneously) and anti-viral effects (impeding cellular viral endocytosis) thereby being superior to other immunomodulators. 60 There are several ongoing, randomized controlled trials evaluating the therapeutic potential of Janus Kinase inhibitors (JAKi) in severe COVID-19. JAKi is FDA approved for use in the treatment of adults with rheumatoid arthritis, myelofibrosis, polycythemia vera, and steroid-refractory acute graft versus host disease. They are proposed for use in severe COVID-19 because they inhibit the JAK-STAT signaling pathway involved in immune regulation. An open-label trial in Italy showed a significant reduction in fever, breathlessness, cough as well as improvement in pulmonary function test and lower C-reactive protein levels in patients treated with baricitinib compared to controls. 61 A meta-analysis of patients treated with JAKi showed that recipients had significantly reduced odds of mortality (OR, 0.12; 95%CI, 0.03-0.39, P=0.0005) and ICU admission (OR, 0.05; 95%CI, 0.01-0.26, P=0.0005), and had significantly increased odds of hospital discharge (OR, 22.76; 95%CI, 10.68-48.54, P<0.00001), when compared to standard treatment group. 62 Limitations to the use of JAKi include the risk of venous thromboembolism which is already a complication of severe COVID-19. This is a potential side effect of baricitinib but not ruxolitinib. As a class, however, it is important to keep this adverse effect in mind when attempting to use JAKi for severe COVID-19 patients due to their already prothrombotic state brought on by the SARS-CoV-2. Several clinical trials are still ongoing to weigh the risk-benefit of this treatment in COVID-19 patients.
TNF is a cytokine involved in systemic inflammation. It induces fever, apoptosis, cachexia, inflammation, and inhibits tumorigenesis and viral replication. Its primary function is immune regulation and it responds to sepsis via IL-1 and IL-6 producing cells. It has been reported that the binding of SARS-CoV-2 to angiotensin-converting enzyme (ACE)-2 induces TNFα-converting enzyme (TACE)-dependent shedding of the ACE2 ectodomain, which facilitates viral entry and causes tissue damage through TNFα production. 63 TNF inhibitors are FDA approved for several autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, Crohn's disease, ankylosing spondylitis. The anti-inflammatory properties of TNF inhibitors suggest that they may be helpful with the inflammation associated with COVID-19. Side effects of superimposed bacterial and fungal infection should be kept in mind when using these medications in COVID-19 patients given their risk of overwhelming sepsis. There are no studies that have demonstrated their benefits in COVID-19 patients however two clinical trials investigating infliximab are underway. More clinical trials are needed for this class of medications considering their already established safety profile.

FACTOR (GM-CSF) INHIBITORS
Most of the lung damage seen in severe COVID-19 patients is driven by a surge in inflammatory cytokines [interleukin-6, interferon-γ, and granulocyte-monocyte colonystimulating factor (GM-CSF)]. GM-CSF is a pro-inflammatory cytokine. It also stimulates epithelial repair and barrier restoration through direct interaction with the alveolar epithelial cells, thereby providing a lung-protective effect. 64 GM-CSF can have a dual role as a pro-inflammatory and regulatory cytokine, depending on the dose and presence of other relevant cytokines. 65 Levels of GM-CSF have been shown to be higher in patients with COVID-19 compared to healthy controls. 18 This means that there are 2 targets for GM-CSF in COVID-19 patients. GM-CSF can be used as a barrier to protect the lung tissues or it can be inhibited to prevent its pro-inflammatory effect with other cytokines. Sargramostim and molgramostim were investigated in clinical trials of patients with acute lung injury and severe sepsis with respiratory dysfunction respectively. 66,67 There was no improvement in survival in both groups however, there was an improvement in gas exchange and functional activation of pulmonary macrophages in the molgramostim group compared to placebo. To this end, recombinant human GM-CSF is being investigated in clinical trials for use in COVID-19 patients. On the other hand, as GM-CSF is increased in patients with severe COVID-19; inhibition may improve the lung injury associated with cytokine release. A single-center prospective cohort study examined the use of mavrilimumab, a monoclonal antibody GM-CSF inhibitor in non-mechanically ventilated COVID-19 patients with pneumonia and hyper inflammation. 68 The result of this study showed no deaths, improvement in fever, and shorter time to recovery in the mavrilimumab group compared to the control group. The safety and efficacy of this medication have been tested in a phase 2 clinical trial in Rheumatoid arthritis patients. 69 Further studies to determine the role of GM-CSF in COVID-19 patients should be carried out. There are ongoing clinical trials to determine the benefits of inhaled sargramostim in COVID-19 patients. More clinical trials are needed to also determine the effects of GM-CSF inhibitors in COVID-19 patients.

INTERFERONS
Interferons (IFNs) are a group of signaling glycoproteins produced and released from cells in response to a viral infection. The role of interferons is to inhibit viral replication and activate immune cells. Interferons have been used to treat multiple sclerosis, multiple cancers, and genital warts. Various forms exist which include interferon-α 2b, n3, interferon β 1a, 1b, interferon-γ 1b. Interferon-alpha was used during the 2003 SARS-CoV outbreak in Canada with good results. 70 The role of interferons in the treatment of COVID-19 patients is still under investigation. A study of interferon 1b given to COVID-19 patients with mild to moderate disease showed a significant reduction in viral shedding, duration of hospital stays as well as improvement in symptoms compared to those treated with lopinavir/ritonavir and ribavirin. 71 This effect was more pronounced among those treated within 7 days of symptom onset. Another study in Wuhan, China of 77 patients treated with interferon-α 2b with or without umifenovir showed a significantly reduced duration of detectable virus in the upper res-Pharmacological treatment of COVID-19: an update Journal of Global Health Reports piratory tract and a parallel reduced duration of elevated blood levels for the inflammatory markers IL-6 and C-reactive proteins (CRPs). 72 This study was also done on patients with mild to moderate disease. It is unclear whether interferons would have the same effect on severe COVID-19 patients. Some of the concerning adverse effects of interferon use include fever, flu-like syndrome, and leukopenia which may worsen COVID-19 symptoms. However, these effects were not seen in the patients in the studies mentioned above and may be due to the small sample size. Further clinical trials exploring the effects of this therapy are needed.

MESENCHYMAL STEM CELLS
Mesenchymal stem cells (MSCs) are multipotent adult stromal cells present in multiple tissues, including the umbilical cord, bone marrow, and fat tissue. MSCs can regenerate by dividing and can differentiate into multiple tissues including bone, cartilage, muscle, and adipose cells, and connective tissue. MSCs could exert widespread immunomodulatory effects by suppressing the activity of a broad range of immune cells, including T cells, natural killer T (NKT) cells, dendritic cells (DCs), B cells, neutrophils, monocytes, macrophages etc. 73 Mesenchymal stem cell transplant has markedly improved symptoms in COVID-19 patients. A study of 7 patients with COVID-19 including 2 severe cases, infused with MSCs showed an improvement in pulmonary function, reduced inflammatory markers, and increased interleukin-10 (an anti-inflammatory cytokine) within 2 days compared to those patients on placebo. 74 Another case report of an elderly patient with severe COVID-19 in the ICU treated with MSCs for 3 days showed improvement in symptoms and a subsequent negative throat swab test 4 days later. 75 MSC transfusion was not associated with any side effects in these patients indicating that it may be a safe treatment. Of note, the gene expression profile of the recovered MSC was ACE negative and TMPRSS2 negative which indicated that it remained negative for COVID-19. 74 It also continued to show high levels of anti-inflammatory activity indicating that immunomodulatory properties are long term. 76 These preliminary reports indicate that MSC transfusion may be beneficial to patients with severe COVID-19 especially the elderly. Limitations to the use of MSC therapy include high cost, specialized staff, and equipment, transfusion reactions including graft versus host disease, and delayed hypersensitivity reactions. The high cost, specialized staff, and equipment also mean that this therapy may not be readily available in resource-poor countries. There are several ongoing clinical trials to determine the benefit of MSC therapy in COVID-19 patients and results should be available soon.

STATINS
Statins are lipid-lowering drugs that decrease the cellular cholesterol content by inhibiting hydroxymethylglutaryl-CoA (HMG-CoA) reductase enzyme in the L-mevalonate pathway of cholesterol biosynthesis thereby lowering hepatic cholesterol concentrations. L-mevalonate pathway downstream products play critical roles in different steps of immune response including immune cell activation, migra-tion, cytokine production, immune metabolism, and survival. 77 Statins have shown immunomodulatory properties and have been used in the treatment of various infectious diseases such as community-acquired pneumonia and influenza. They have also shown benefit in the management of inflammatory and autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. 78 To date, there are no randomized controlled clinical trials that have demonstrated the benefit of statins in patients with COVID-19, however, an observational, multinational study that included more than 8,500 hospitalized patients with COVID-19 showed that the use of statins was associated with a better survival rate in these patients. 79 Statins are well studied and generally well-tolerated medications and the rationale for their use in COVID-19 patients is due to its immunomodulatory and anti-inflammatory effects. Limitations to its use may be due to its hepatotoxic side effects which may be compounded by the effect of the SARS-CoV-2 virus on liver cells. 80 However, a randomized controlled clinical trial is needed to further characterize its true benefit.

ANTIBODY THERAPY
CONVALESCENT PLASMA Convalescent Plasma is plasma obtained from patients who have recovered from COVID-19 infection with a high neutralizing antibody titer. COVID-19 convalescent plasma may be used for either prophylaxis of infection or treatment of disease. In a prophylactic mode, the benefit of convalescent plasma administration is that it can prevent infection and subsequent disease in those who are at high risk for disease, such as vulnerable individuals with underlying medical conditions, health care providers, and those with exposure to confirmed cases of COVID-19. 81 Passive antibody administration to prevent disease is already used in clinical practice. For example, patients exposed to hepatitis B and rabies viruses are treated with hepatitis B immune globulin (HBIG) and human rabies immune globulin (HRIG), respectively. 81 There is evidence that convalescent plasma if administered early may be effective in the prevention and treatment of COVID-19 infection. 82,83 A cohort study done in Mayo Clinics with >35000 participants showed that the seven-day mortality rate was reduced in patients transfused within three days of COVID-19 diagnosis compared with patients transfused four or more days after COVID-19 diagnosis. 84 On the other hand, a Chinese open lab, multicenter randomized controlled study evaluating the efficacy and safety of convalescent plasma therapy on 103 COVID-19 patients with severe or life-threatening disease found no significant difference in time to clinical improvement within 28 days, mortality, or time to hospital discharge but clinical improvement was only observed in a subgroup of patients. 85 However, in this study, it was observed that the majority of the 103 patients received their plasma 14 days after symptom onset compared to the Mayo clinic study in which participants received plasma therapy within 3 days of diagnosis. This suggests that convalescent plasma therapy may need to be initiated earlier to be able to see a significant improvement in patients with COVID-19. Although Pharmacological treatment of COVID-19: an update Journal of Global Health Reports convalescent plasma has been granted emergency use authorization by the United States Food and Drug Administration (FDA), more clinical trials are still needed to understand the efficacy of this treatment as well as its side effects.

INTRAVENOUS IMMUNOGLOBULIN (IVIG)
Intravenous immunoglobulin is a treatment therapy for patients with antibody deficiencies. It is a blood product prepared from the serum of healthy donors. It has been used in the treatment of dermatomyositis, polymyositis, idiopathic thrombocytopenic purpura as well as Kawasaki disease in children. A case series of 5 COVID-19 patients treated with high dose IVIG showed improvement in oxygen saturation and radiographic evidence demonstrated less consolidation. 86 IVIG may be also be used to confer passive immunity. IVIG is associated with the risk of transfer of infectious agents through blood products, as well as hypersensitivity reactions. Since IVIG has been used with a negligible risk of these adverse events, it is safe to say that it may be applied for use in COVID-19 patients. Another potential risk factor for immunoglobulin replacement therapy use in patients with COVID-19 may be due to mitigating antibody response that could interfere with establishing efficient immune responses against viremia. 87 A clinical trial is needed to confirm the benefits of this treatment both as a prophylactic and therapeutic option.

MONOCLONAL ANTIBODIES
Monoclonal antibodies (MAB) are medications designed in the laboratory that contain specific proteins naturally made by the immune system in response to a pathogen. They can bind directly to portions of the virus that mediate cell entry and attachment thereby preventing disease in early infection. They may also be able to provide short term immunity against SARS-CoV-2. Monoclonal antibodies have been used for years to treat autoimmune diseases and are generally safe. There are no studies that evaluate their effects on COVID-19 patients. However, there are 2 monoclonal antibody medications undergoing clinical trials. REGN-CoV-2 and LY-CoV-555 are being investigated to evaluate their effects in preventing COVID-19 in patients at risk. One major limitation to the use of monoclonal antibodies is the cost involved in manufacturing them. Even if an efficacious MAB is discovered, it would likely be too expensive for routine use. ANTICOAGULANTS Anticoagulants include the heparins; unfractionated heparin and low molecular weight heparin, warfarin, thrombin inhibitors such as argatroban, dabigatran, factor Xa inhibitors e.g. rivaroxaban, fondaparinux. Studies done show that SARS-CoV-2 causes a "cytokine storm" which is part of the systemic inflammatory response 88 that activates the coagulation cascade, leading to thrombosis. Also, generalized deposition of intravascular thrombi compromises the blood supply of several organs, leading to organ failure 89 similar to findings seen in severe sepsis caused by bacterial infections. SARS-CoV-2 has been shown to cause wide-spread coagulation which contributes to worse patient outcomes and mortality. 90 Anticoagulant treatment has been shown to improve this outcome. 91 Low Molecular Weight Heparin (LMWH) has been the mainstay of treating deep vein thrombosis (DVT) complications in COVID-19 patients, 92 the dose however needs to be titrated for the benefits to outweigh the risks. One of the serious adverse effects of LMWH is thrombocytopenia which can lead to lifethreatening bleeding complications in patients such as these who are already at risk of DIC and multi-organ failure. A meta-analysis of COVID-19 patients admitted in the intensive care unit who were given heparin (unfractionated and low molecular weight heparin) for thromboprophylaxis showed a high failure rate. 93 Argatroban, a direct thrombin inhibitor has been shown to improve thrombotic complications in COVID-19 patients who fail heparin therapy. 94 The role of other anticoagulants such as warfarin, dabigatran, bivalirudin, need to be investigated. Clinical trials are underway to study the effect of rivaroxaban and fondaparinux in COVID-19 patients with thrombotic complications. Further studies to determine anticoagulant selection and dosage are needed in critically ill COVID-19 patients admitted to intensive care units.

PULMONARY VASODILATORS NITRIC OXIDE
Nitric oxide is an inhaled gas that works by relaxing vascular smooth muscle, resulting in pulmonary vasodilation. Nitric oxide has been used to treat respiratory failure in preterm babies. One of the causes of mortality in severe COVID-19 is respiratory failure due to refractory hypoxemia. 95 Inhaled nitric oxide may be considered for use in COVID-19 patients with ARDS due to its potent vasodilator effect. A study done on 39 patients with moderate COVID-19 showed that 21(53.9%) did not require intubation after treatment with inhaled nitric oxide. 96 However, these patients were also treated with hydroxychloroquine, azithromycin, and IL-6 antagonists so it is unclear if they improved based on the nitric oxide alone or a synergistic effect of one of these medications. A case series of 10 severe COVID-19 patients treated with inhaled nitric oxide did not show any improvement in arterial oxygenation after 30minutes of use. 97 Because of the potential side effects of prolonged inhaled nitric oxide, 98 caution has to be employed in use in severe COVID-19 patients in order not to worsen outcome. The use of nitric oxide (NO) to treat COVID-19-related interstitial lung disease has been approved by the US FDA. Further investigation and clinical trials are needed to determine the population of patients who would benefit the most and the optimal dose with the least side effects. SILDENAFIL Sildenafil is a phosphodiesterase (PDE) inhibitor whose mechanism of action is to inhibit PDE-5 thereby increasing cyclic guanosine monophosphate to allow smooth muscle relaxation. It has been used to treat pulmonary arterial hypertension and erectile dysfunction. PDE-5 is highly expressed in the lungs, where its inhibition improves pul- Hydroxychloroquine and chloroquine are medications that have been used to treat malaria and rheumatologic conditions. The anti-inflammatory effects of these medications include inhibition of T and B cell receptors thereby decreasing cytokine production by macrophages such as IL-1 and IL-6. 100 These medications have also been shown to inhibit TNF-α, interferon-α, and γ. 101,102 These are all inflammatory cytokines that have been implicated in the SARS-CoV-2 cytokine storm. These medications have also demonstrated anti-viral properties against SARS-CoV-2 invitro. 103 Because of the antiviral and anti-inflammatory properties of these medications, researchers proposed that they may be helpful in the treatment of COVID-19 patients. Studies done early in the pandemic showed promise with these medications in the treatment of COVID-19 patients. 104,105 One of these studies was limited to one region and the other was underpowered. As this medication was used in more patients with COVID-19 around the world, conflicting evidence on its efficacy for COVID-19 treatment began to emerge. An observational study of 1376 patients showed that in patients administered hydroxychloroquine, it did not affect time to intubation or death. 106 An NIH sponsored trial of hydroxychloroquine was discontinued as the drug was shown to not be beneficial in hospitalized COVID-19 patients compared with placebo. 107 Another study done on hydroxychloroquine showed that it did not prevent illness compatible with COVID-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure. 108 Azithromycin is a macrolide antibiotic that has also shown some antiviral and anti-inflammatory properties 109,110 thus was recommended for use in COVID-19 patients in addition to hydroxychloroquine/chloroquine. However, a retrospective study done in the US showed that hydroxychloroquine use with or without co-administration of azithromycin did not improve mortality or reduce the need for mechanical ventilation. 111 An important side effect to note of this medication combination is prolonged QT interval which can lead to life-threatening arrhythmias especially in severe COVID-19 patients with underlying cardiovascular disease. A study done on severe COVID-19 patients who were administered high dose chloroquine showed that 18.9% of patients presented with prolonged QT interval compared to 11.1% in the low dose chloroquine group. 112 A meta-analysis of COVID-19 patients treated with hydroxychloroquine/chloroquine with or without azithromycin showed an increased risk of in-hospital mortality and ventricular arrhythmias with the use of any of these medications. 113 This study was later retracted as the authors could not provide their data for subsequent re-analysis. 114 There are several ongoing clinical trials to determine the effects of hydroxychloroquine/chloroquine, hydroxychloroquine/chloroquine plus azithromycin, azithromycin alone as well as hydroxychloroquine with other antiviral medications on COVID-19 patients. Inhaled hydroxychloroquine is also being tested. Some of the clinical trials involving these medications have been suspended or terminated due to concerns about the safety of these medications as well as lack of patient enrollment.
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS/ ANGIOTENSIN RECEPTOR BLOCKERS (ACEI/ARBS) Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are commonly used antihypertensives that act by inhibiting the renin-angiotensinaldosterone system (RAAS). These medications are cardio and renoprotective. 115 With the discovery that ACE2, a homolog of ACE, which is richly expressed in heart and lung tissue, aids the fusion of host cells and SARS-CoV-2 116 , interest has been generated in what role these medications may play in this disease process. The ACE2 receptor appears to counter regulate RAAS activation by degrading angiotensin II. 117 Concerns about the potentially harmful effect of ACEi in patients with COVID-19 have been expressed because angiotensin-converting enzyme 2 (ACE2) is the receptor-binding site for SARS-CoV-2 in the target cell. 12 In vitro and in vivo studies have demonstrated that ACE inhibitors (ACEIs), as well as angiotensin-II receptor blockers (ARBs), can significantly increase ACE2 expression, thereby facilitating SARS-CoV-2 entry into cells. 118,119 However, evidence from studies done so far show that prior use of ACEi or ARBs do not increase the risk of contracting SARS-CoV-2 or of being hospitalized with severe infection. 120,121 A recent meta-analysis of >28000 patients who were already on these medications had a lower risk of death from COVID-19 compared to patients who were not on these medications. 122 This study also added to the growing body of evidence that the use of ACEi/ARB does not have any association with the severity of disease or even death among patients admitted with COVID-19. The effect of commencing treatment with ACEi/ARBs in patients diagnosed with COVID-19 who were previously not on these medications has not been studied. In the interim, ACEi/ARBs should not be discontinued in patients with COVID-19 already on these medications as this may lead to worsened outcomes considering the high mortality among patients with underlying health conditions a significant number of whom are on these medications. More studies investigating the effects of these medications on the SARS-CoV-2 virus are needed.  somal cathepsins activate SARS-CoV-2 entry and both have cumulative effects with furin on SARS-CoV-2 entry. This goes to follow that inhibiting furin and TMPRSS2 may prevent SARS-CoV-2 from entering the host cell and causing COVID-19 infection. TMPRSS2 is more abundant in the lungs while furin is expressed in other organs. This may explain why SARS-CoV-2 is capable of invading and damaging multiple organs. This is not as straightforward, however, because several other factors such as human airway trypsinlike protease(s) also play a role in the fusion of SARS-CoV-2 to the target cell. 123 More in vitro and in vivo studies are needed to examine the role of this enzyme and its use as a potential treatment strategy. Camostat mesylate, a TM-PRSS2 inhibitor has been used in Japan for the treatment of acute symptoms of chronic pancreatitis and post-operative reflux. Experimental mouse studies showed that camostat was effective in preventing death following a lethal dose of SARS-CoV. 124 A study done using the TMPRSS2 inhibitor camostat on a sample of SARS-CoV-2 from a patient showed that the medication blocked the entry of the virus into the lung cell. 12 Another TMPRSS2 inhibitor nafamostat mesylate used in Asian countries as an anticoagulant therapy for patients undergoing continuous renal replacement therapy due to acute kidney injury, blocked SARS-CoV-2 infection of human lung cells with markedly higher efficiency than camostat mesylate. 125 The fact that it is being used as an anticoagulant may be of further benefit in critically ill COVID-19 patients who are at risk of thrombosis and thrombotic complications. There are ongoing clinical trials to test the benefits of these medications in COVID-19 patients. Medication to inhibit both furin and TMPRSS2 would likely be of the most benefit in preventing viral replication in host cells. Bromhexine hydrochloride is a mucolytic agent used in over the counter (OTC) cough suppressants. It has also been identified as a selective TMPRSS2 inhibitor. 126 An open-label randomized clinical trial of 78 patients in Iran showed that there was a significant reduction in ICU admissions, intubation, and death in the bromhexine treated group compared to standard therapy. 127 Considering that this medication has minimal side effects and an established safety pro-file, it could make a positive impact on the management of patients with SARS-CoV-2 both as a prophylactic and therapeutic agent. There are ongoing clinical trials to test this theory.

MAIN PROTEASE (M PRO ) INHIBITORS
Specific protease inhibitors have been used successfully for years to treat HIV and HCV. Main protease (M pro ) is an enzyme in coronaviruses that cuts the polyproteins translated from viral RNA to yield functional viral proteins. Inhibiting the activity of this enzyme would block viral replication. A study done with experimental compounds ebselen and N3 to inhibit this enzyme in SARS-CoV-2 cells has shown promising results in vitro. 128 Another study showed that a prodrug GC370, a dipeptidase protease inhibitor, and its parent drug GC373 used in feline coronavirus infection are potent inhibitors of SARS-CoV-2 replication in cell culture by inhibiting the M pro enzyme. 129 These studies lay the groundwork for further experimental studies and clinical trials of specific protease inhibitors for SARS-CoV-2 infection. EXPERIMENTAL  Ivermectin, an antiparasitic medication which has been shown to have inhibitory effects on the replication of the SARS-CoV-2 virus in-vitro. 130 Nitazoxanide (NTZ), anti-protozoal medication has been shown to have anti-viral activity against different viruses such as coronaviruses, influenza viruses, Ebola virus, hepatitis B and C viruses. [131][132][133][134][135] NTZ has also exhibited in vitro inhibition of SARS-CoV-2 virus. 136 Other beneficial fea-Pharmacological treatment of COVID-19: an update Journal of Global Health Reports tures of NTZ include its ability to suppresses the production of pro-inflammatory cytokines 137 emphasizing its potential to manage COVID-19-induced cytokine storm and its reported efficacy of bronchodilation of the extremely contracted airways in COVID-19 patients. 138 Pentoxifylline is a hemorheological agent used in the treatment of intermittent claudication. The properties of pentoxifylline which may be helpful in COVID-19 patients include reducing the production of the inflammatory cytokines without deleterious effects on the immune system which may delay viral clearance, restoring the balance of the immune response, reduce damage to the endothelium and alveolar epithelial cells, improve circulation, prevent microvascular thrombosis and improve ventilatory parameters. 139 Anti-fibrotic agents (pirfenidone, nintedanib) have also been proposed for use in treating the complication of pulmonary fibrosis following ARDS in COVID-19 patients. These agents are already approved for use in the treatment of idiopathic pulmonary fibrosis. Pirfenidone especially has been proposed due to its anti-inflammatory, anti-oxidative, and anti-fibrotic properties. 140 It has also been shown to downregulate ACE receptor expression which is the binding receptor for the S protein of the SARS-CoV-2 virus. 141 This is an area of research in treating COVID-19 patients that are lacking and clinical trials are needed to evaluate the effects of this medication based on the mechanism of action.
There is currently no evidence for the use of zinc and vitamin C in the prevention and treatment of COVID-19 patients. However, there are ongoing clinical trials to test the benefits of these medications as a combination with other medications. Vitamin D deficiency has been shown to increase the risk of contracting COVID-19. 142 However, it is unclear if supplementation could reduce this risk. Several clinical trials to ascertain the benefit of vitamin D supplementation in the prevention and treatment of COVID-19 are ongoing.

REGIONAL VARIATIONS IN COVID-19 TREATMENTS
COVID-19 treatments vary across countries and regions. In the United Kingdom (UK), the RECOVERY trial which involved 176 hospitals in the National Health Service system and about 12000 patients has made a huge and positive impact on COVID-19 treatment in the region. 19, 143 This trial revealed that lopinavir, ritonavir, and hydroxychloroquine were not effective medications for severely ill COVID-19 patients and that dexamethasone improved mortality in these patients. This was quickly adopted in other European countries and may have aided in reducing the mortality associated with the virus in some parts of this region. The RE-COVERY trial is still ongoing and is currently investigating the efficacy of low dose dexamethasone in children with COVID-19, as well as azithromycin, tocilizumab, and convalescent plasma in adult patients with the virus.
The United States on the other hand which has the most deaths in the world has different treatment protocols which may be because the healthcare system is not as cohesive as in the UK. This lack of cohesiveness may be a reason the mortality rate is very high. Different treatment protocols across different regions in the US may also be part of the problem. The US NIH has approved the use of steroids, remdesivir, and convalescent plasma for treating COVID-19 patients. There are other issues involved with the treatment of COVID-19 in the US such as the political climate but this is beyond the scope of this review.
Ivermectin is being used as a treatment protocol in many South American countries. This was based on a paper which stated that this medication lowered in-hospital mortality in COVID-19 patients. 144 It was later discovered that the methodology used was flawed and the study was retracted. However, many South American countries continue to prescribe this medication for patients with the virus even outside of clinical trials. Other substances such as chlorine dioxide are also being used and have ultimately led to chlorine dioxide poisoning. However, a study (NCT04343742) on clinicaltrials.gov is currently recruiting to test the effectiveness of this agent in COVID-19 patients.
Traditional Chinese medicine has also been used for COVID-19 patients and is said to improve outcomes in these patients. 145,146 This was however not done in a clinical trial, and the dosing, efficacy, and side effects of these treatments are not known. Published literature on the treatment protocol for COVID-19 in India includes hydroxychloroquine, chloroquine, azithromycin, and convalescent plasma. 147 Alternative medicine options such as ayurvedic potions (Ukalo), homeopathic drops (Arsenicum album) are also being used in India without any proof of efficacy. 148 In Africa, there is a paucity of data concerning COVID-19 treatments. However, a herbal remedy developed in Madagascar and consisting of Artemisia annua (the plant from which the antimalaria drug artemisinin is gotten from) was touted by some African leaders as a cure for COVID-19. 149 There are no results yet from clinical trials on artemisinin in COVID-19 patients. Hydroxychloroquine and chloroquine were also being used especially as prophylaxis. However, researchers have cautioned that this may lead to widespread malaria resistance which is endemic in the region. 150 In Australia and New Zealand, hydroxychloroquine/ chloroquine and lopinavir/ritonavir were initially being tested in COVID-19 patients in the ASCOT trial (AC-TRN12620000445976) however these arms of the trial were discontinued after the results of the RECOVERY trial were published but the convalescent plasma arm remains. 151 Remdesivir and dexamethasone became the new standard of care after positive results with the use of these medications in COVID-19 patients were published. 152 These countries, however, have one of the fewest cases worldwide and the lowest deaths. This may be because public health measures were largely used to contain the virus.

RECOMMENDATIONS AND CONCLUSIONS
To treat this disease, the virus has been targeted at different stages of its life cycle and attempts have been made to modulate the body's immune response to it. Each medication and treatment modality may be efficacious at different stages of illness and also in different manifestations of disease as discussed above. One limitation to getting a safe and efficacious treatment is the disproportionate number of Pharmacological treatment of COVID-19: an update Journal of Global Health Reports cases across regions which has slowed recruitment of a diverse patient population needed for robust clinical trials.
Until a definitive treatment is available, public health interventions such as social distancing, mask-wearing, contact tracing, and increased testing which limit the spread of the virus are paramount. While these efforts are being deployed, medications may bridge the gap pending the development of a vaccine. To date, there are no approved medications for the treatment of COVID-19 outside of clinical trials. Physicians should therefore take into consideration the side effects of these repurposed medications when prescribing them for COVID-19 patients. Since we are in the middle of a pandemic with a new virus, it is important for medications to be used systematically and adequate documentation of treatment outcomes and side effects made. This would help with retrospective analysis of data which may throw more light on treatment modalities and aid in future research. Because a lot of the available data from medications were used together with the standard of treatment at the time (hydroxychloroquine/chloroquine,) which has now been shown to not be beneficial and associated with possible serious adverse effects and/or antiviral medications (some of which have not been shown to be efficacious against this virus); there is the need for more clinical trials without the confounding effects of these medications. Also, the effects of hydroxychloroquine/chloroquine need to be confirmed with more retrospective studies on patients who had already had these medications. Experimental medications and compounds also need to go through the proper stages of randomized clinical trials for their best use and benefit to be ascertained. These experimental medications if found to be effective against this virus may need to be mass-produced for low to middle-income countries to also benefit because only when an efficacious treatment is widely available can we be able to end this pandemic globally. Sanders et al 153 in their study stated some recommendations and guidelines for use of medications during this pandemic such as taking into account the potential for toxicity with these repurposed medications, considering the use of IL-6 inhibitors in certain patients, continuing ACEis/ ARBs in patients who need them, and enrolling patients who qualify in clinical trials for certain medications. In addition to these, we recommend continuing statin medications and hydroxychloroquine in patients who need them, taking into account the various comorbidities of each patient to limit polypharmacy as much as possible, as well as the severity of the illness when prescribing these medications.
The world appears to be moving on from COVID-19 while awaiting a vaccine but patients affected by this virus continue to be hospitalized with high mortality. Considering the mounting body of evidence for and against the various medications that have been used in the fight against COVD-19, this review is needed to keep track of where we are concerning therapeutics for COVID-19 and what the future holds. Although developing an effective vaccine is viewed as the ultimate endpoint in preventing the morbidity and mortality associated with this virus, vaccines depend on individual participation. Appropriate medications with an established safety profile should be used in the interim when primary prevention is inadequate. More robust randomized controlled clinical trials of these medications are needed most importantly to include individuals of all age groups, gender, and race for more generalizable findings to ensue.