Introduction
With the advent of SARS CoV-2, much research has been done in formulating preventive and therapeutic strategies in the form of drugs inhibiting viral entry into host cells, viral Protease inhibitors, viral RdRp inhibitor, import in channel inhibitors, drugs with multicentric action, immuno-modulators, and adjuvants. Other management modalities like regenerative medicine and the use of convalescent plasma therapy have also come up.
Potential Drugs for Therapeutic and Preventive Management of COVID-19
1. Viral Entry Inhibitors (Targeting Transmembrane Serine Protease 2 (TMPRSS2) and Viral Spike Glycoprotein)
TMPRSS2 is highly expressed on cells of epithelial cells of lungs [1] and subsegmental bronchial branches [2] while Angiotensin-Converting Enzyme 2 (ACE2) is present on both Pneumocytes 1 and 2 [3] while also on transient secretory cells of subsegmental bronchial branches that have high Rho Guanosine Triphosphatase (GTPase) activity making them vulnerable to infection [2]. The spike protein of SARS CoV 2 undergoes proteolytic activation by numerous host proteases like Elastase, Cathepsins, and Trypsin, TMPRSS 2 [4,5] and together with the help of ACE2 infects the pneumocytes [3,6].
The following drugs target this interaction
• Nafamostat (Camostat Mesilate):
Mechanism of action: It is a synthetic Serine Protease Inhibitor developed for the treatment of chronic pancreatitis [7] and oral squamous cell carcinoma [8,9]. It can target the TMPRSS2 and can be used as a potential drug for treatment [10]. It also inhibits intravascular coagulopathy hence can prevent microvascular thrombosis in patients of severe COVID-19 [11].
Trials and outcomes: Outcomes from a case series show low mortality in patients of severe COVID-19 on combination therapy of Favipiravir and Nafamostat [12].
Adverse events: Case reports of Nafamostat induced hyperkalaemia have been reported [13].
Final verdict: The combination of Favipiravir and Nafamostat should be considered for further research for their use in decreasing mortality in severely ill patients of COVID-19. Nafamostat should be administered with close monitoring of serum potassium levels.
• Umifenovir (Arbidol)
Mechanism of action: This drug blocks the trimerization of Spike glycoprotein31 and prevents viral entry.
Trials and outcomes: A study showed that while on Arbidol monotherapy, patients showed no viral load after day 14, this is in contrast to patients on Lopinavir (LPV)/Ritonavir (44.1% of whom showed viral load) [14]. A retrospective cohort study showed favourable response with improvement in Chest CT of patients (69% in LPV/r and Arbidol combination group Vs 29% in Arbidol monotherapy group) receiving Arbidol with LPV/r, but another observational study later stated that the combination may not benefit significantly in clinical improvement of patients [15,16].
Adverse events: No severe side-effects were reported in an exploratory randomised and controlled study of 30 patients, where all of the patients recovered and were found to be healthy at follow-up [17].
Final verdict: Umefenovir has only mild to moderate adverse effects like diarrhoea and nausea (11% patients in Umifenovir group Vs 8% patients in control groups as seen in a retrospective study), and can be considered for further trials to determine its clinical efficacy in combination with LPV/r [18].
Experimental inhibitors: DX600 is a potent inhibitor that is human ACE2 specific [6,7]. Many other molecules like Small peptides and tripeptides, MLN-4760, N-(2-aminoethyl)-1 aziridine-ethanamine [8,9] and the TNF-α Converting Enzyme (TACE) have also been found to be potent human ACE2 inhibitors in-vitro [10,14,19,20]. Another candidate is phytochemical Nicotianamine (present in soybean, hence dietary in origin and completely safe) that also inhibits ACE2 [21,22]. The latest development is a recombinant human ACE2 protein (hrsACE2) that prevents infection of engineered human capillary and kidney organoids [23].
2. Aminoquinolines with Multicentric Action
Hydroxychloroquine (HCQ) and Chloroquine (CQ) are known to mankind since 1939 when it was substituted Quinacrine for treatment of Malaria during the end of World War 2 [22,24].
Mechanism of action: The suggested mechanism involves the anti-inflammatory, antiviral and inhibition of viral entry by HCQ [Table/Fig-1] [25-27].
Shows the suggested mechanism of action of HCQ in SARS CoV-2.
SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2; ACE2: Angiotensin-Converting Enzyme 2; HCQ: Hydroxychloroquine; BCR: Breakpoint Cluster Region; TCR: T-cell receptor
Trials and outcomes: Initial clinical trials (mostly conducted in the month of Feb-March 2020) showed increased viral clearance with HCQ usage [28], significant reduction in fever, and shortening of recovery time and cough remission time with a larger proportion of people with pneumonia showing improvement with better radiological features [29]. Also, it was seen that CRP declined faster with HCQ [30]. Newer studies (May-June 2020) suggest a different picture. While the combination of HCQ with Azithromycin which was initially claimed to guarantee 100% viral clearance [28] in six patients’ nasopharyngeal swabs, a new study on 11 patients on the same drug combination showed shocking responses with almost all patients remaining positive for SARS CoV2 as found on their nasopharyngeal swabs. In one patient, QT prolongation was seen, while another one patient succumbed to COVID-19 [31].
In another open-label randomised trial on 150 laboratory confirmed cases of COVID-19, comparing standard care with HCQ against standard care alone, a difference of 4.1% was seen in the negative conversion by 28 days, while in case of adverse effects, the difference was 21%. The study concluded that HCQ does not increase the significant probability of negative conversion in mild to moderate infection while causing deleterious adverse events [30].
In a randomised trial including 821 asymptomatic patients, 87.6% of whom had confirmed high-risk exposure to SARS CoV-2, the incidence of illness in the group which received HCQ prophylaxis was found to be 11.8% against 14.3% in the placebo group. Hence, there was not a convincing absolute difference of -2.4% [32]. But the problem is “off label use” which itself has reported 102 adverse cardiac events, 86% with HCQ alone or 60% in combination with Azithromycin [33]. But recently, CQ was found to be only effective in protecting virus-induced cytopathic effect at around 30 μM with a therapeutic index of 1.5 [34].
Adverse events: The common adverse effects associated with these drugs include gastrointestinal upset, more with HCQ than CQ [35,36]. Retinopathy is seen only on chronic use or high dose (>5mg/kg) [37], therefore, no ophthalmological screening is required for patients [38]. The most fatal side-effect is QTc prolongation and fatal Ventricular arrhythmias [39].
Final verdict: The viral clearance by CQ and its prophylactic use is doubtful and needs further evaluation. It should be administered with care due to its serious adverse effects and should be strictly avoided in cardiac patients.
3. Triple Combination of an Anti-Inflammatory/Anti-Neoplastic with Anti-Parasitic and Anti-Helminthic
The spike protein of Coronavirus GX_P2V shares 92.6% identity with SARS CoV-2 hence using it as a model. Cepharanthine demonstrated the most potent resistance to GX_P2V infection by inhibiting both viral entry and replication. It is also suggestive of effectivity against pan-betacoronavirus [40]. Examples include Cepharanthine (anti-inflammatory anti-neoplastic alkaloid) [41], Selamectin/Ivermectin (Antiparasitic and Anti-helminthic) [42], and Ivermectin.
Ivermectin is also seen to inhibit Importin channel required for entry of RNA dependent RdRp in the nucleus [42], inhibiting SARS CoV-2 in-vitro [43]. Mefloquine (used for the treatment of malaria) [44] showed complete inhibition of cytopathic effects in cell culture [40]. Another strong evidence comes from the effectiveness of Cepharanthine along with its homologous (natural alkaloids) anticancer agents like bis-benzylisoquinoline tetrandrine (TET) and fangchinoline (FAN) against human coronavirus strain OC43 strain in MRC-5 human lung cells [45]. The OC43 strain causes 15-30% of mild upper respiratory infections in humans [46].
4. Viral Protease Inhibitors
Mechanism of action: LPV is used with Ritonavir(r) as a booster. These are viral protease inhibitors, hence the combination LPV/r has been found to inhibit the virus in-vitro [47].
Trials and outcomes: In a study where LPV/r was administered to patients, it was observed that there was reduction in need of supplemental oxygen in 60% patients (3 out of 5) within 3 days. In the same study, it was also seen that the viral shedding in Nasopharyngeal swab was cleared in 40% patients within 2 days of treatment by LPV/r [46]. In another trial on 199 patients (99 on LPV/r and 100 on standard care), mortality with LPV/r was 19.2% and 25% in a control group (-5.8% percentage group). Patients with detectable viral RNA were similar in both groups at various points. Median time to clinical improvement was shortened by 1 day in LPV/r group [48].
Adverse events: Patients on LPV/r may have minor gastrointestinal adversities [48].
Final verdict: Triple combination of LPV/r, Interferon Beta-1b, and Ribavirin is superior in alleviating symptoms and shortening viral shedding [49].
5. RNA Polymerase Inhibitor
Favipiravir
Mechanism of action: It is a nucleotide analog which is a broad-spectrum inhibitor of RNA Dependent RNA Polymerase (RdRp) of RNA viruses. It has been proved effective against influenza, yellow fever virus, arena virus, bunyavirus, foot and mouth viruses [50]. In context to Ebola virus, its monotherapy proved ineffective in very high viremia while intermediate and high viremia need meritorious investigation. Based on a study, in Group A where Ct (cyclic threshold) was <20, mortality was 7% higher and no decrease in viral load was seen; while in a Group with Ct ≥20, mortality was 33% lower with rapid viral clearance [51]. Based on its known efficacy in RNA viruses; it became a prime candidate for investigation against SAR CoV-2.
Trials and outcomes: In a randomised study on 240 patients, there was not much difference in clinical recovery rate with Favipiravir (71/116) compared to Arbidol (62/120), while Favipiravir reduce the latencies of fever and cough [52].
Adverse events: The common adverse effects include increased serum uric acid levels [50]. This drug also affects QT interval [53].
Final verdict: Patients treated with Favipiravir have faster viral clearance and better chest imaging changes when compared to patients treated with LPV/r [51]. Favipiravir may be used in combination with other drugs to treat COVID-19, although more such detailed studies are needed.
Remdesivir
Mechanism of action: It is a nucleotide analog inhibiting RdRp, which was devised for the treatment of Ebola and Marburg virus infection. It has a broad-spectrum action against members of Filoviridae and Coronaviridae in nonclinical models. In-vitro, it is effective against SARS CoV-2 with EC50 of 1.76 uM in Vero E6 cells [54].
Trials and outcomes: Its first use for treating COVID-19 cases in the US showed significant effectiveness [55] and soon in a study of a cohort of patients of severe COVID-19 infection, compassionate use of Remdesivir showed clinical improvement in 68% patients [56]; while another study showed that it was associated with numerically faster clinical improvement [57]. In an evaluation of 19 antiviral drugs, Remdesivir was found to be the most effective drug [34].
Adverse events: In a cohort of 61 patients, a total of 32 patients reported adverse effects, the most common being increased hepatic enzymes, diarrhoea, rash, hypotension, and renal impairment [56].
Final verdict: Remedisvir can be the potential drug for clinical treatment of COVID-19 as it has shown appreciable clinical improvement in patients.
Other RdRp inhibitors like Ribavirin [49,58], Beta hydroxycytidine [59], and Merimepodib [60] need to undergo further trials.
6. Immunomodulators
An important example of HCQ as immunomodulators has already been discussed above [Table/Fig-1]. Emerging studies suggest that the damage associated with COVID-19 stems from the release of pro-inflammatory cytokines leading to damage to lung tissue [61-67].
Corticosteroids
Mechanism of action: These are having broad anti-inflammatory activity.
Trials and outcomes: A retrospective study was conducted on 401 patients, where 152 were critical and 249 were noncritical. One hundred twenty one patients out of 152 critical patients (79.6%) received steroids and 25 out of them (20.7%) died; 147 of 249 noncritical patients (59%) received steroids and there were no deaths in this group. This data suggested that there was no significant reduction in death rate or hospital stay in patients but when analysed with a focus on 152 critical patients, steroids lead to reduced overall mortality rates and shorter hospital stay [68].
Adverse events: The adverse effects of steroids are inevitable, a retrospective cohort study showed higher adverse events in the group treated with corticosteroids (37.9 Vs 16.7%). This study also showed a very high mortality (26.9%) and even increase plasma viral load in non-ICU patients [69].
Final verdict: All these data analyses suggest judicious use of steroids. Too early administration of steroids will suppress the body’s defense and lead to increase plasma viral load, resulting in severe adverse consequences; while use in critical patients with features of pro-inflammatory cytokine storm will lead to suppression of excessive inflammation. Hence, in patients with deteriorating oxygenation, imaging studies, and excessive inflammation, the use of glucocorticoids is considered appropriate [70].
Tocilizumab and Sarilumab are anti-Interleukin (IL)-6 and have a therapeutic effect on infection-induced cytokine storm. As IL-6 is detected in high levels in COVID-19 patients, hence these drugs seem to be promising [71].
Bevacizumab, an anti-Vascular Endothelial Growth Factor (VEGF), is under exploration. COVID-19 patients have elevated VEGF and it is believed it can play a key role in the pathogenesis of the disease [72].
7. Potential Miscellaneous Adjuvants
Plitidepsin inhibits Elongation factor [73]
Bemcentinib is an Anexelekto (AXL) Kinase inhibitor [74]
Rintatolimod is a Toll Like Receptor 3 (TLR)-3 Inhibitor [75]
Melatonin has been known for its anti-inflammatory, anti-oxidative and immune-modulative response with a high safety profile hence is a potential candidate for use as an adjuvant in COVID-19 patients [76]
Regenerative Medicine
Exosomes derived from allogeneic bone marrow mesenchymal stem cells for the treatment of COVID-19 have been tried and have shown promising results, with 71% of patients showing recovery/discharge after a mean 5.6 days post iv infusion of ExoFlo. There were no severe adverse effects. In this study, where bmMSC derived exosomes were used in an inpatient setting is the first known clinical study of its own kind. This branch of regenerative medicine shows hope for treatment of not only COVID-19 but a myriad of inflammatory diseases [77].
Convalescent Plasma Therapy (CPT)
CPT has long been used for management of viral infection like H1N1 [78], SARS [79], Ebola [80], H5N1 [81].
Mechanism of action: It is proposed that high antibodies from patients recovering from these infections might suppress viremia and salvage other patients [Table/Fig-2] [82].
Proposed mechanism of CPT in COVID-19 patients.
CPT: Convalescent plasma therapy
Trials and outcomes: A study shows that one dose of 200 mL CP is well tolerated and results in better oxygenation within three days with rapid neutralisation of viremia [83]. The key factor lies in neutralisation antibody titer and treatment time point. There are no severe adverse effects seen with CPT [83]. In a breakthrough study on five critically ill patients, it was seen that post-CPT fever solved in three days (4/5 patients), Arterial Oxygen Partial Pressure/Fractional Inspired Oxygen (Pao2/Fio2) increased with negative viral load and resolution of ARDS occurred within 12 days [84]. CPT can act as a last resort for salvaging critically ill patients. Another clinical randomised trial on 103 patients was conducted where 101 patients completed the trial. They were randomised in CPT and Control groups in a 1:1 ratio. 23 patients in CPT group and 22 patients in control group had severe COVID-19 while 29 patients in both CPT and control group had life-threatening COVID-19. The study showed clinical improvement in 53.9% in the CPT group (27/52) vs. 43.1% in the control group (22/51); while in severely affected individuals of each group, there was clinical improvement in 91.3% in the CPT group (21/23) vs. 68.2% in the control group (15/22). For patients suffering from life-threatening COVID-19, clinical improvement was seen in 20.7% (6/29) of the CPT group vs 24.1% (7/29) of control group. This which clearly shows that CPT therapy is very beneficial in severe patients of COVID-19 [85].
There is a direct effect of neutralising Antibody that binds to the COVID-19 Receptor binding domain without any competition with ACE-2 [86]. It is also seen that some antibodies inhibit the complement cascade and the formation of immune complexes, also neutralise IL-1β and TNF-α thereby suppressing the systemic inflammation [87-89]. Antibody-Dependent Enhancement (ADE) is a phenomenon where pre-existing neutralising antibodies favours viral replication in a host cell with help of Fragment Crystallizable (Fc) and Complement receptor interaction [90] and is seen in feline coronaviruses and is a concern to be investigated, however, no reports of ADE in Human coronaviruses is found.
Dosage of CPT
An optimal dose cannot be determined due to variability of factors involved in various case reports. It usually ranges from a single dose of 200 mL plasma with neutralising antibody titer>1:640 while another report stated a maximum of use of 2400 mL plasma in a 73-year-old patient [79,91,92].
Conclusion(s)
Remedisvir has shown very positive outcomes with minimal adverse events. Combination therapies of LPV/r or Favipiravir with Nafamostat are emerging as possible therapies for patients of COVID-19. The clinical efficacy of HCQ is highly questionable and needs further evaluation. HCQ, steroids need to be carefully administered to patients. CPT therapy is beneficial for salvaging severe patients of COVID-19 because of its antiviral and immuno-modulatory effects. Newer advancements like regenerative medicine is very promising but has a long way to go. There has been extensive research and development going on to develop the best therapeutic, prophylactic and preventive treatment modalities for SARS CoV-2.
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