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.