3.1 Chloroquine and Chloroquine derivatives
Chloroquine (CQ) and hydroxychloroquine (HCQ), have been widely used to prevent or treat malarial or immune-mediated diseases like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). To date, these medications are not suitable to treat viral infections and there is no evidence supported by well-controlled, prospective, randomized clinical studies that demonstrate the efficacy of their use in patients with COVID-19. Nevertheless, CQ and HCQ are being studied alone or in combination with other agents to assess their effectiveness in the treatment or prophylaxis for COVID-19 (Nicol et al., 2020). The two drugs showed positive in vitro and clinical antiviral activity against SARS-CoV-2 (Gautret et al., 2020; Liu et al., 2020; Yao et al., 2020), which suggests that CQ and HCQ can be potential treatments for COVID-19. Many studies show that the two 4-aminoquinolines drugs have in vitro activity against a range of viruses (D’Alessandro et al., 2020). Their efficacy has been attributed to different mechanisms. For instance, because they have weakly basic pH, whereas the endosome in the host cell is pH-dependent, they can inhibit viral entry to the host cell, the autophagosome-lysosomal fusion, and glycolsyltransferase (Salata, Calistri, Parolin, Baritussio, & Palù, 2017). The antiviral mechanism associated with glycosyltransferase is achieved by inhibiting viral glycosylation (Savarino, Boelaert, Cassone, Majori, & Cauda, 2003). Besides, there are recent reports saying that CQ may be an inhibitor of quinone reductase-2, a concerned enzyme in sialic acid biosynthesis, which may impact on HIV, SARS-CoV, and orthomyxoviruses due to the presentation of sialic acid on HIV-1 glycoproteins, ACE2 receptor of SARS, and orthomyxovirus receptors (Kwiek, Haystead, & Rudolph, 2004; Savarino, Di Trani, Donatelli, Cauda, & Cassone, 2006). Thus, CQ may have an impact on SARS-CoV-2 due to ACE2 receptor.
Studies have revealed that CQ has a therapeutic effect in animal infection models induced by HCoV-OC43 and has a strong antiviral effect against SARS-CoV infection in cell cultures (Keyaerts et al., 2009; Vincent et al., 2005), This indicates that CQ has therapeutic activity against viruses. CQ has shown in vitro activity against clinical isolates of COVID-19 at low (micromolar) concentrations. CQ was successfully used to treat >100 cases of COVID-19 leading to improved radiological findings, enhanced virus clearance; reducing disease progression (J. Gao, Tian, & Yang, 2020). Besides, Astudy in Vero E6 indicated that CQ plays a functional role in the entry and post-entry stages of SARS-CoV-2 infection and can modulates the immune response, which may synergistically enhance its in vivo antiviral effect (M. Wang et al., 2020).
A hydroxyl group makes HCQ safer than CQ. An In vitro study revealed that the EC50 values for HCQ, at 24 and 48 hours, were lower than the EC50 values for CQ in both treatment and prophylaxis groups. This indicates that HCQ is more effective in vitro than CQ for both prophylaxis and treatment (Yao et al., 2020). The in vitro experiments got positive outcomes, which set clinical trials in motion to explore more about the HCQ effect on COVID-19. Twenty patients were treated using HCQ and were confirmed by comparing the PCR results with 16 controls in France. HCQ was effective in viral load reduction of asymptomatic and patients with both lower and upper respiratory tract infections. The decreased viral load continued after 3, 4, 5, and 6 days of treatment (Gautret et al., 2020), which suggests that HCQ is a promising therapy for inhibiting the virus entry.
Currently, the dose of CQ against COVID-19 is 500 mg orally once or twice a day, for ≤10 days (Colson, Rolain, Lagier, Brouqui, & Raoult, 2020). However, data on the optimal dose to ensure its safety and effectiveness are not sufficient. The recommendation from pharmacokinetic modeling study suggests the optimal dose for HCQ in COVID-19 treatment, the patients can take a loading dose of 400 mg twice in the first day of treatment and then take 200 mg twice a day (Yao et al., 2020). However, both drugs have several adverse reactions, including prolonged QT interval, hypoglycemia, anaphylaxis, and retinopathy (Kalil, 2020). HCQ is relatively better tolerated than CQ, and its adverse reactions mainly include gastrointestinal reactions, skin damage, neurological symptoms, and retinopathy (Yusuf, Sharma, Luqmani, & Downes, 2017). Animal experiments show that CQ is more toxic than HCQ (P. Jordan, Brookes, Nikolic, & Le Couteur, 1999). Studies show that severe fatal arrhythmia can occur after a single intake of more than 4.0 g HCQ, which is regarded as a severe syndrome (Yanturali, Aksay, Demir, & Atilla, 2004). It is also reported that patients treated with 36g HCQ were successfully rescued (de Olano, Howland, Su, Hoffman, & Biary, 2019). Some elderly patients who have died from COVID-19 had cardiovascular comorbidities; the use of HCQ and CQ may increase the risk of cardiac death (Wu & McGoogan, 2020; Young et al., 2020). Hepatitis and neutropenia are clinical manifestations of COVID-19, and both hepatic and bone marrow dysfunctions could be worsened in the off-label use of these drugs. Besides the antiviral effect of CQ and HCQ, their affordability and safety make them more suitable for clinical use against COVID-19 infections. Further studies are needed to determine the optimal dose for COVID-19 and physicians should pay more attention to the adverse reactions when treating COVID-19 patients with CQ and HCQ.
Chloroquine phosphate is a derivative of CQ and is also an antimalarial drug. The drug also inhibits SARS-CoV replication in vitro , mainly by reducing the terminal glycosylation of the ACE2 on the surface of Vero E6 cells, therefore, interfering with the combination of SARS-CoV and ACE2 (Q. Gao, 2020). The cases of lung imaging in a study show an effective response in > 100 patients: the exacerbation of pneumonia is inhibited, with a virus-negative conversion put forward and a shortened disease course. No obvious serious adverse reactions could be found among the patients (J. Gao et al., 2020). The adverse reactions of chloroquine phosphate are usually mild and reversible after withdrawal (Y. J. Duan et al., 2020). However, its acute poisoning and accumulated toxicity require attention in the case of large-dose and long-term treatment. It is recommended to include chloroquine phosphate in the next version of the Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19 issued by the National Health Commission of the People’s Republic of China, to treat a wide range of COVID-19 infections.
3.2 Arbidol
Arbidol, a drug used for prophylaxis and treatment of influenza and respiratory viral infections in Russia and China, targeted ACE2 S protein interaction and blocked viral fusion to the target cell membrane (Kadam & Wilson, 2017). This drug has demonstrated activity against several viruses including SARS (P. C. Jordan, Stevens, & Deval, 2018). A study showed that arbidol and arbidol mesylate can inhibit the reproduction of SARS-CoV in vitro (Khamitov et al., 2008). Several lines of evidence revealed that single use of arbidol or combination with antiviral drugs may provide beneficial effects in patients with COVID-19 pneumonia (Wang, Chen, Lu, Chen, & Zhang, 2020; X. W. Xu et al., 2020; J. Zhang et al., 2020). Data from a small number of patients treated with arbidol combined with Lopinavir/ritonavir showed that these drugs delayed the progression of lung lesions and lowered the possibility of respiratory and gastrointestinal transmission thereby decreased the viral load of COVID-19 (Deng et al., 2020). Currently, many randomized clinical controlled trials are in progress to investigate how efficacious arbidol is for COVID-19 pneumonia in China.