Therapeutics and Drugs
There is no currently licensed specific antiviral treatment for MERS- and SARS-CoV infections, and the main focus in clinical settings remains on lessening clinical signs and providing supportive care (183–186). Effective drugs to manage COVID-19 patients include remdesivir, lopinavir/ritonavir alone or in a blend with interferon beta, convalescent plasma, and monoclonal antibodies (MAbs); however, efficacy and safety issues of these drugs require additional clinical trials (187, 281). A controlled trial of ritonavir-boosted lopinavir and interferon alpha 2b treatment was performed on COVID-19 hospitalized patients (ChiCTR2000029308) (188). In addition, the use of hydroxychloroquine and tocilizumab for their potential role in modulating inflammatory responses in the lungs and antiviral effect has been proposed and discussed in many research articles. Still, no fool-proof clinical trials have been published (194, 196, 197, 261–272). Recently, a clinical trial conducted on adult patients suffering from severe COVID-19 revealed no benefit of lopinavir-ritonavir treatment over standard care (273).
The efforts to control SARS-CoV-2 infection utilize defined strategies as followed against MERS and SARS, along with adopting and strengthening a few precautionary measures owing to the unknown nature of this novel virus (36, 189). Presently, the main course of treatment for severely affected SARS-CoV-2 patients admitted to hospitals includes mechanical ventilation, intensive care unit (ICU) admittance, and symptomatic and supportive therapies. Additionally, RNA synthesis inhibitors (lamivudine and tenofovir disoproxil fumarate), remdesivir, neuraminidase inhibitors, peptide (EK1), anti-inflammatory drugs, abidol, and Chinese traditional medicine (Lianhuaqingwen and ShuFengJieDu capsules) could aid in COVID-19 treatment. However, further clinical trials are being carried out concerning their safety and efficacy (7). It might require months to a year(s) to design and develop effective drugs, therapeutics, and vaccines against COVID-19, with adequate evaluation and approval from regulatory bodies and moving to the bulk production of many millions of doses at commercial levels to meet the timely demand of mass populations across the globe (9). Continuous efforts are also warranted to identify and assess viable drugs and immunotherapeutic regimens that revealed proven potency in combating other viral agents similar to SARS-CoV-2.
COVID-19 patients showing severe signs are treated symptomatically along with oxygen therapy. In such cases where the patients progress toward respiratory failure and become refractory to oxygen therapy, mechanical ventilation is necessitated. The COVID-19-induced septic shock can be managed by providing adequate hemodynamic support (299). Several classes of drugs are currently being evaluated for their potential therapeutic action against SARS-CoV-2. Therapeutic agents that have anti-SARS-CoV-2 activity can be broadly classified into three categories: drugs that block virus entry into the host cell, drugs that block viral replication as well as its survival within the host cell, and drugs that attenuate the exaggerated host immune response (300). An inflammatory cytokine storm is commonly seen in critically ill COVID-19 patients. Hence, they may benefit from the use of timely anti-inflammation treatment. Anti-inflammatory therapy using drugs like glucocorticoids, cytokine inhibitors, JAK inhibitors, and chloroquine/hydroxychloroquine should be done only after analyzing the risk/benefit ratio in COVID-19 patients (301). There have not been any studies concerning the application of nonsteroidal anti-inflammatory drugs (NSAID) to COVID-19-infected patients. However, reasonable pieces of evidence are available that link NSAID uses with the occurrence of respiratory and cardiovascular adverse effects. Hence, as a cautionary approach, it is better to recommend the use of NSAIDs as the first-line option for managing COVID-19 symptoms (302). The use of corticosteroids in COVID-19 patients is still a matter of controversy and requires further systematic clinical studies. The guidelines that were put forward to manage critically ill adults suggest the use of systemic corticosteroids in mechanically ventilated adults with ARDS (303). The generalized use of corticosteroids is not indicated in COVID-19, since there are some concerns associated with the use of corticosteroids in viral pneumonia. Stem cell therapy using mesenchymal stem cells (MSCs) is another hopeful strategy that can be used in clinical cases of COVID-19 owing to its potential immunomodulatory capacity. It may have a beneficial role in attenuating the cytokine storm that is observed in severe cases of SARS-CoV-2 infection, thereby reducing mortality. Among the different types of MSCs, expanded umbilical cord MSCs can be considered a potential therapeutic agent that requires further validation for managing critically ill COVID-19 patients (304).
Repurposed broad-spectrum antiviral drugs having proven uses against other viral pathogens can be employed for SARS-CoV-2-infected patients. These possess benefits of easy accessibility and recognized pharmacokinetic and pharmacodynamic activities, stability, doses, and side effects (9). Repurposed drugs have been studied for treating CoV infections, like lopinavir/ritonavir, and interferon-1β revealed in vitro anti-MERS-CoV action. The in vivo experiment carried out in the nonhuman primate model of common marmosets treated with lopinavir/ritonavir and interferon beta showed superior protective results in treated animals than in the untreated ones (190). A combination of these drugs is being evaluated to treat MERS in humans (MIRACLE trial) (191). These two protease inhibitors (lopinavir and ritonavir), in combination with ribavirin, gave encouraging clinical outcomes in SARS patients, suggesting their therapeutic values (165). However, in the current scenario, due to the lack of specific therapeutic agents against SARS-CoV-2, hospitalized patients confirmed for the disease are given supportive care, like oxygen and fluid therapy, along with antibiotic therapy for managing secondary bacterial infections (192). Patients with novel coronavirus or COVID-19 pneumonia who are mechanically ventilated often require sedatives, analgesics, and even muscle relaxation drugs to prevent ventilator-related lung injury associated with human-machine incoordination (122). The result obtained from a clinical study of four patients infected with COVID-19 claimed that combination therapy using lopinavir/ritonavir, arbidol, and Shufeng Jiedu capsules (traditional Chinese medicine) was found to be effective in managing COVID-19 pneumonia (193). It is difficult to evaluate the therapeutic potential of a drug or a combination of drugs for managing a disease based on such a limited sample size. Before choosing the ideal therapeutic agent for the management of COVID-19, randomized clinical control studies should be performed with a sufficient study population.