5.3.2 Chloroquine, hydroxychloroquine and azithromycin
Chloroquine, as a drug extensively utilized in anti-malaria and autoimmune diseases, has been found to be a potential broad-spectrum antiviral agent (Savarino et al., 2006). It can prevent viral infections via elevating the endosomal pH needed for virus-cell fusion and disturbing the glycosylation of SARS-CoV cell receptors (Figure 7) (Vincent et al., 2005). Gao et al. revealed that chloroquine phosphate was effective in the therapy of COVID-19-associated pneumonia (Gao et al., 2020). Wang and coworkers also conducted in vitro study, and they found that it is an ideal candidate antiviral drug against SARS-CoV-2 infection in Vero E6 cells with EC50 value of around one μM (Wang et al., 2020b). Although several trials had verified that chloroquine suppresses the exacerbation of COVID-19, the optimal dosage of chloroquine will require to be evaluated in future trials (Gao et al., 2020).
Hydroxychloroquine is an analog of chloroquine, and there are few studies on its interaction (Jallouli et al., 2015). In previous SARS outbreaks, hydroxychloroquine was found to possess anti-SARS-CoV capacity in vitro (Figure 7) (Biot et al., 2006). In line with the research of Yao et al., by applying a physiologically based pharmacokinetic model, they found that hydroxychloroquine is more effective than chloroquine in Vero cells infected with SARS-CoV-2 (Yao et al., 2020). Of note, it has been revealed that cytokines IL-6 and IL-10 are elevated in response to SARS-CoV-2 infection, which may induce the cytokine storm (Figure 5), which in turn cause multiple organ failure and death (Huang et al., 2020). Both chloroquine and hydroxychloroquine possess immunomodulatory effects and can inhibit such immune responses (Schrezenmeier and Dörner, 2020). Hence, Chinese hospitals and Oxford University had initiated 21 clinical studies to evaluate the efficacy of these drugs in COVID-19 infection. The further crucial study may relate with the determination of whether the benefit of chloroquine treatment is hinged on the age of the patients as well as the clinical manifestations (Touret and de Lamballerie, 2020).
According to reports, azithromycin is can suppress Zika virus and Ebola virus in vitro and can be harnessed to restrain severe respiratory infections in infected patients. Gautret and colleagues found that azithromycin can significantly reinforce the efficacy of hydroxychloroquine after treating 20 patients with severe COVID-19 (Gautret et al., 2020). In this regard, the regimen of hydroxychloroquine, in combination with azithromycin may be a potential alternative to remdesivir in the therapy of COVID-19 diseases in the future.