key: cord-1012958-otbpwm6d
authors: Lei, Zi-Ning; Wu, Zhuo-Xun; Dong, Shaowei; Yang, Dong-Hua; Zhang, Litu; Ke, Zunfu; Zou, Chang; Chen, Zhe-Sheng
title: Chloroquine and Hydroxychloroquine in the Treatment of Malaria and Repurposing in Treating COVID-19
date: 2020-09-08
journal: Pharmacol Ther
DOI: 10.1016/j.pharmthera.2020.107672
sha: 474924489b1f5622b4daa12bb1a864be1274b3eb
doc_id: 1012958
cord_uid: otbpwm6d

Chloroquine (CQ) and Hydroxychloroquine (HCQ) have been commonly used for the treatment and prevention of malaria, and the treatment of autoimmune diseases for several decades. As their new mechanisms of actions are identified in recent years, CQ and HCQ have wider therapeutic applications, one of which is to treat viral infectious diseases. Since the pandemic of the coronavirus disease 2019 (COVID-19), CQ and HCQ have been subjected to a number of in vitro and in vivo tests, and their therapeutic prospects for COVID-19 have been proposed. In this article, the applications and mechanisms of action of CQ and HCQ in their conventional fields of anti-malaria and anti-rheumatism, as well as their repurposing prospects in anti-virus are reviewed. The current trials and future potential of CQ and HCQ in combating COVID-19 are discussed.

treatment of malaria. Besides, the anti-malarial effects, the anti-rheumatic property of antimalarial drugs was discovered during World War II from the observation that the soldiers taken prophylactic CQ for malaria gained improvement in autoimmune-induced rashes and inflammatory arthritis (Md Abdul Alim Al- Bari, 2015; Ilan Ben-Zvi, et al., 2012) . In the past seven decades, CQ and HCQ have been commonly used to treat patients with rheumatologic disorders like rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) (Schrezenmeier & Dörner, 2020) .

Despite CQ and HCQ are being gradually restricted for the treatment of malaria due to the emergence of plasmodium strains resistant to chloroquine and the cross-resistant to CQ analogs (Haldar, et al., 2018; Warhurst, et al., 2003) , the repurposing potentials of CQ and HCQ in treating many other diseases have been reported in recent years. It has been shown that CQ and HCQ could have beneficial effects in preventing thrombosis (Petri, 2011; Ruiz-Irastorza, et al., 2006) , reducing the risk of cardiovascular disease in RA patients (D. Liu, et al., 2018) , treating neoplastic diseases (Plantone & Koudriavtseva, 2018) , and combating al., 2018), Iran (Azarian, et al., 2018) , Pakistan (Waqar, et al., 2016) , China-Myanmar border (Hui Liu, et al., 2014) , and Cambodia (Amaratunga, et al., 2014) . Only a few countries in Africa are with endemic of vivax malaria. It has been reported high a failure rate for CQ treatment in Ethiopia (Getachew, et al., 2015) , however, in Mauritania the efficacy of CQ retained 100% as reported in 2015 (Ould Ahmedou Salem, et al., 2015) . In addition, CQ is the first-line treatment for falciparum malaria in Guatemala, Haiti, Honduras, and Nicaragua (World Health Organization, 2019) . High CQ efficacy and low incidence of CQ resistancerelated mutations in P. falciparum were reported in Haiti (Neuberger, et al., 2012) , Honduras (Torres, et al., 2013) and Nicaragua (Sridaran, et al., 2014) .

The precise anti-malarial mechanism of action from CQ and HCQ has not been completely clarified. The major theory of the anti-malarial mechanism is related to the blockade of the detoxification process in the Plasmodium parasites (Thomé, et al., 2013) . At the blood stage when the Plasmodium invades the RBCs, the plasmodium ingests hemoglobin from the RBC cytosol into the food vacuole and decomposes hemoglobin to obtains amino acids proteins synthesis, which is necessary for their growth (Mohandas & An, 2012) . The toxic oxidized heme consisting of ferriprotoporphyrin IX (FPIX) hematin is generated from proteolytic degradation of hemoglobin, which is transformed into nontoxic crystalized polymers named hemozoin by heme polymerase of the parasite (Chou & Fitch, 1992) . As the food vacuole is a lysosomal isolated acidic compartment, the weak alkalinity of CQ could help it diffuse across the vacuole membrane, where CQ turns to protonated form that is not able to diffuse out (Krogstad & Schlesinger, 1986) . Different mechanisms of CQ inhibiting the detoxification of FPIX have been found. The accumulated CQ in the food vacuole could inhibit the polymerization of FPIX by complexing with FPIX, which is highly toxic inducing parasite cell lysis (Fitch, et al., 1982) . Sullivan et al. found that the complex of CQ and hematin could cap the growing hemozoin polymer to stop further polymerization, resulting in build ing up of toxic hematin and damaging the parasite (D. J. . The enzymes involved in the formation of hemozoin may also be considered as targets of CQ. The histidine-rich protein-2 of P. falciparum (Pfhrp-2) has been found to mediate the formation of hemozoin by binding to FPIX (D. J. Sullivan, Jr., et al., 1996) . It was reported that CQ, though did not bind to Pfhrp2 directly, could displace FPIX from Pfhrp2 and form CQ-FPIX complex, thereby exerting toxicity to the parasite cells (Pandey, et al., 2001) .

Another hypothesis suggested that the target of CQ is not in the lysosome but the nucleus. It was proposed that CQ could interact or directly bind to DNA and RNA causing disruption of replication and transcription process, which could lead to inhibition of growth and reproduction, or induction of apoptosis of parasite cells (Li, 2006) . Also, there are arguments regarding the mechanism of CQ uptake. Instead of diffusion, an importing transporter was suggested to be involved in CQ accumulation in parasite cells. Sanchez et al. demonstrated that a Na + /H + exchanger (NHE) on the cytoplasmic membrane may serve as a CQ importer failure and allergy reactions have been reported (Tönnesmann, et al., 2013) . Moreover, consideration of reduced dose should be taken for patients with liver disorders and alcoholic liver diseases since about half of oral administrated CQ/HCQ is metabolized in the liver (Tönnesmann, et al., 2013) .

CQ/HCQ can also cause serious and even fatal adverse reactions in heart and retina, epilepsy, extrapyramidal symptom, hypoglycemia, as well as poisoning caused by overdose (H. Yogasundaram, et al., 2018) . The irreversible toxic retinopathy developed after CQ/HCQ treatment is one of the main adverse effects. It has been reported that the incidence of retinopathy can reach 1% after continuous use of CQ for 5~7 years (Tehrani, et al., 2008) .

The mechanism underlying CQ/HCQ-induced retinopathy is the binding of CQ/HCQ to melanin, particularly in the pigment cells at the epithelial cell layer of the eye, and destroy rod cells and cone cells (Melles & Marmor, 2014; Michaelides, et al., 2011) . Therefore, clinical monitoring during CQ/HCQ treatment is essential for the prevention of retinopathy (Tehrani, et al., 2008) .

The data of clinical studies from a large number of samples showed that the incidence of these adverse reactions of CQ/HCQ was low and generally mild or moderate (Marmor, et al., 2002; Sato, et al., 2020) . As the efficacy of CQ/HCQ has been clinically certified, it is safer to use it under the strict control of indications and contraindications.

In 1957, the first case of CQ-resistant falciparum malaria was reported on the Thai-Cambodian border. Since then, the P. falciparum strains resistant to CQ spread from Southeast Asia and South America to Africa and has been found in nearly all endemic areas (Khatoon, et al., 2009; Mita, et al., 2009; Restrepo-Pineda, et al., 2008) . The emergence and spread of malaria resistance seriously hampered malaria control and became the main cause of the sharp rise in malaria incidence worldwide. As a result, CQ and HCQ are no longer effective in most falciparum malaria prevalent areas and are mainly used to treat CQ susceptible Plasmodium vivax (Nzila, 2006) . Besides, there is an increasing trend of CQresistance in P. vivax in recent years. There have been reports regarding the emergence of P.

vivax CQ-resistance in some countries and regions that use CQ or CQ-PQ as first-line malaria treatment, such as Bolivia (Añez, et al., 2015) , Brazilian Amazon (Marques, et al., 2014) , and the northeastern region of Myanmar (Yuan, et al., 2015) .

The drug resistance mechanisms of CQ and HCQ may be the result of multiple factors (Coppée, et al., 2020) . In CQ-resistant P. falciparum, the variation of two proteins may be the increased activity of some enzymes to strengthen the detoxification of FPIX could also induce the resistance of CQ/HCQ (J. Kim, et al., 2019) .

It has been found that a variety of compounds without fixed chemical properties can restore the sensitivity to CQ (de Souza, et al., 2019) . These compounds, when co-administrated with CQ, were observed to increase the sensitivity of some CQ resistant P. falciparum strains in vitro (Ch'ng, et al., 2013; Deane, et al., 2014; Edaye, et al., 2015; Kashyap, et al., 2018) . The major mechanism involved is the inhibition of the active drug efflux pump pfcrt (van Schalkwyk & Egan, 2006) . The CQ combination approaches in the past two decades are listed in Table 1 . Although CQ resistant reversal agents are not yet applicable in the clinical practice for CQ/HCQ resistant falciparum malaria, great breakthroughs may be made in the research of other reversal agents in the future. evidence showed that treatment with CQ or HCQ resulted in a significant improvement of RA as well as SLE (Bjelle, et al., 1983; Durcan, et al., 2019) . Both CQ and HCQ are able to increase the long-term survival of patients, while HCQ is associated with fewer adverse effects (Marmor, 2004) . Therefore, HCQ has become a more frequent option when treating rheumatic diseases compared to CQ. Although neither CQ nor HCQ went through conventional drug development, they have been recommended in current treatment guidelines for RA (Smolen, et al., 2017) and SLE (Fanouriakis, et al., 2020) .

Several mechanisms of action are postulated to explain how CQ/HCQ works in treating autoimmune rheumatic diseases. One mechanism suggests CQ/HCQ can affect the activity of lysosomes and autophagosomes. Lysosomes and autophagosomes are involved in antigen processing, presentation, and autoimmune activation (Ghislat & Lawrence, 2018; Münz, 2016) . It was widely believed that the basic side chain of CQ/HCQ allows drug accumulation in lysosomes and causes a substantial increase in the intra-lysosomal pH, leading to impairment of maturation of lysosomes and autophagosomes, thereby inhibiting the autoimmune activation (Ohkuma & Poole, 1978) . Recent studies suggest that CQ/HCQ can modulate the lysosomal function mainly by blocking lysosome-autophagosome fusion (Mauthe, et al., 2018; Sundelin & Terman, 2002) . It is suggested that other mechanisms are involved in the anti-rheumatic effect, such as inhibiting proinflammatory cytokine expression (Willis, et al., 2012) and/or Toll-like receptor signaling et al. (Chen, et al., 2016) .

Although CQ was first developed to treat malaria, the focus has largely moved from antimalaria to anti-rheumatic, and the anti-virus effect. The anti-viral effect of CQ has been extensively evaluated in the last two decades.

The anti-viral effect of CQ is mainly attributed to its alkalinity. As previously mentioned, CQ can cause alkalization within acidic organelles, including lysosomes and endosomes (Ohkuma & Poole, 1978) , thereby two mechanisms may explain its anti-viral activity. First, most viruses require low pH for fusion, penetration, or uncoating during infection. In addition, the endosomal pathway is critical for viruses to replicate and infect the host (Sieczkarski & Whittaker, 2002) . Since CQ prevents endosomal acidification, the elevated pH level results in inhibition of lysosome functions, thereby inhibiting the activity of viruses such as influenza B virus (Shibata, et al., 1983 ) and hepatitis A virus (M. A. A. Al-Bari, 2017). Second, CQ may inhibit the post-translational modification of the virus envelope glycoprotein by interfering Using CQ/HCQ as anti-HIV treatment has been extensively studied. It has been wellestablished that CQ/HCQ can inhibit HIV replication in vitro. The main mechanism may be the inhibition of post-translational protein modification in T cells and monocytes (Naarding, et al., 2007) . At high concentrations, CQ/HCQ showed preventive effect prior to HIV infection, while the curative effect was demonstrated with low concentrations of CQ/HCQ in HIV-infected cells. Moreover, the anti-HIV effect of CQ/HCQ has been demonstrated in several clinical studies. A randomized, double-blind, placebo-controlled clinical trial was carried out to investigate the anti-HIV-1 effect of HCQ in 40 asymptomatic patients (Sperber, et al., 1995) . The patients were assigned to either HCQ (800 mg/day) group or placebo group for 8 weeks of treatment. The data showed that treatment with HCQ was able to decrease the virus load compared to the placebo group. The recoverable HIV-1 RNA level decreased significantly in the HCQ group, while increased in the placebo group. Besides, reductions in cultured virus, interleukin-6 level, as well as stabilization of immune function were demonstrated in the HCQ treatment group after 8 weeks of treatment. The study suggests that HCQ may be useful to combat HIV-1 infection. In another 16-week clinical trial, the anti-HIV effect of HCQ (800 mg/day) was investigated along with zidovudine (500 mg/day) (Sperber, et al., 1997) . In accordance with the initial trial, HCQ showed a significant effect in reducing HIV-1 RNA levels. Moreover, while the zidovudine group showed a trend of drug resistance after 8 weeks of treatment, no patient in the HCQ group showed increased HIV-1 RNA levels or cultured virus throughout the trial. Notably, no significant adverse effect was observed with HCQ treatment in both trials. Altogether, these two trials suggested that HCQ J o u r n a l P r e -p r o o f may be a potential option for treating HIV-1 infected patients. One study indicated that CQ can hinder immune activation, therefore may benefit certain groups of HIV-infected patients (Murray, et al., 2010) . In this study, the patients were subjected to CQ (250 mg/day or 500 mg/day) or placebo for 2 months. The memory T cells population following CQ treatment showed a median decreased of 2.5%, with no significant change observed in the placebo group. Besides, it is demonstrated that Ki-67 expression and plasma LPS level were decreased after 1 month of CQ administration, suggesting a reduced immune activation.

However, no decrease in HIV RNA levels was observed in the trial, indicating 250 mg of CQ may be insufficient to decrease virus load. Other trials exploring the potential of using HCQ as part of the combinational treatment also gained promising results (N. I. Paton & Aboulhab, 2005) . However, the drug has not been recommended as an option of HIV treatment and it warrants further investigation. CQ/HCQ also has anti-viral effects against the Zika virus, influenza viruses, hepatitis viruses, and others. Delvecchio et al. reported that CQ can suppress ZIKV infection in different cell models (Delvecchio, et al., 2016) . Shiryaev et al. showed that CQ can limit ZIKV vertical transmission in pregnant mouse model, suggesting CQ might be a candidate for the treatment and prophylaxis of ZIKV (Shiryaev, et al., 2017) . In vitro studies reported that CQ was able to inhibit influenza A replication in a pH-dependent manner (Di Trani, et al., 2007; Ooi, et al., 2006) . Clinical studies suggested that CQ treatment may safely reduce the risk of relapse in patients with autoimmune hepatitis (Mucenic, et al., 2005; Raquel Benedita Terrabuio, et al., J o u r n a l P r e -p r o o f Journal Pre-proof 2019). In the recent trial, patients were randomized to receive CQ (250 mg/d), or placebo for 36 months. A significant difference in relapse-free survival was demonstrated between the CQ and placebo group (59.3% and 19.9%, respectively; hazard ratio, 2.4; 95% CI, 1.05-5.5; P=0.039). Besides, the adverse effects were moderate and can be controlled with symptomatic medication. Small scale pilot trials indicated that CQ might improve the symptoms of chronic hepatitis C patients (Helal, et al., 2016; Peymani, et al., 2016) index, poor drug penetration in a specific compartment, and selectivity against a different strain of influenza A viruses (Di Trani, et al., 2007; Savarino, 2011) . Another case of interest is the chikungunya virus. Although CQ exhibited great anti-viral effect in vitro (Delogu & de Lamballerie, 2011) , animal studies showed that it actually enhanced alphavirus replication (Maheshwari, et al., 1991; Roques, et al., 2018) . It is believed that the deleterious effect is due to the immunomodulatory and anti-inflammatory effects of CQ (Katz & Russell, 2011; . Also, a clinical trial conducted in 2006 suggested that CQ has no beneficial effect on the course of disease progression in patients with chikungunya virus (De Lamballerie, et al., 2008) .

The recent focus has largely shifted to the anti-Cov effect of CQ/HCQ due to the COVID-19 pandemic. Keyaerts et al. reported that CQ is able to inhibit HCoV-OC43 activity both in vitro and in vivo (Keyaerts, et al., 2009) . Kono et al reported that CQ can suppress the viral replication of HCoV-229E by affecting the MAPKs signaling pathway (Kono, et al., 2008) .

In 2004, CQ was found to have a significant inhibitory effect on SARS-Cov infection (Keyaerts, et al., 2004; . It is postulated that the mechanisms of action are though hindering the terminal glycosylation of angiotensin-converting enzyme-2 (ACE2), a functional receptor of SARS-CoV spike protein (W. . In addition, J o u r n a l P r e -p r o o f CQ/HCQ may also inhibit the biosynthesis of sialic acids, which are components of receptors of SARS-CoV (Savarino, et al., 2006) .

As of June 30 th , 2020, the COVID-19 has led to more than 10,273,001 confirmed cases and 505,295 deaths worldwide (www.ecdc.europa.eu/). So far, a tremendous effort has been made globally to search for efficacious drugs against COVID-19, and among all these potential candidates, anti-malarial drugs CQ and HCQ have gained considerable attention. . Liu et al. showed that HCQ could inhibit the infection of SARS-CoV-2 viruses in Vero E6 cells and might be a better option due to its less toxicity and anti-inflammatory function (J. Liu, et al., 2020) . It is also found that the antiviral ability of HCQ was more potent than that of CQ in Vero cells (Yao, et al., 2020) . Weston et al. tested the antiviral ability of 20 FDA approved drugs in Vero cells and found that CQ and HCQ could both reduce mRNA levels and replication process of SARS-CoV-2 (Weston, et al., 2020) . Touret et al. screened a chemical library containing 1520 approved drugs and identified 90 compounds with anti-COVID-19 activity and CQ/HCQ among the top hits (Touret, et al., 2020) . Table 2 . Huang et al. explored the effectiveness of CQ on 373 COVID-19 patients and found that CQ treatment accelerated the process of viral elimination , however, the dosage of CQ should be carefully considered because higher CQ dosage might be associated with higher lethality (Borba, et al., 2020) .

HCQ treatment is often combined with AZ (Azithromycin) or DOXY (Doxycycline), and several clinical studies have suggested the effectiveness of HCQ treatment in COVID-19 patients. Yu et al. showed that the usage of HCQ significantly decreased the mortalit y rate in critically ill COVID-19 patients (Yu, et al., 2020) . Chen et al. reported that the involvement of HCQ significantly shortened the clinical recovery time of COVID-19 patients (Z. , which was also confirmed in another clinical trial study in Spain ( de Novales, et al., 2020) . Gautret et al. showed that HCQ treatment was significantly associated with viral load reduction, and AZ could accelerate this process (Gautret, et al., 2020a; Gautret, et al., 2020b) .

The effectiveness of HCQ+AZ or HCQ+DOXY combinations in COVID-19 treatment was also supported in two other clinical studies (Ahmad, et al., 2020; Million, et al., 2020) .

Aside from these supportive studies, there is evidence opposing the effectiveness of CQ and HCQ in the prevention and treatment of COVID-19. Despite CQ and HCQ can block SARS-CoV-2 infection in kidney epithelial Vero E3 cells, this effect appears to be cell type-specific.

Hoffman et al. reported that CQ and HCQ did not inhibit the entry of SARS-CoV-2 virus into lung cells in vitro, as CQ and HCQ did not target to pH-independent transmembrane serine J o u r n a l P r e -p r o o f Journal Pre-proof protease TMPRSS2, which is a key molecule for viral infection in airway epithelial cells (Hoffmann, et al., 2020) . Moreover, many clinical studies have shown non-significant or even worse results in HCQ treatment groups. Chen et al. found that there was no significant difference in HCQ treated COVID-19 patients in comparison with patients in the control group (J. . Tang et al. found that the usage of HCQ did not result in a higher negative-conversion rate in COVID-19 patients (W. . A similar result was reported by Mahévas et al. showing the usage of HCQ did not help COVID-19 patients in another clinical study (Mahevas, et al., 2020) . Magagnoli et al. and Rosenberg et al. reported that HCQ+AZ treatment was not significantly associated with the mortality of COVID-19 patients (Magagnoli, et al., 2020; Rosenberg, et al., 2020) . In one study carried out by Mallat et al., patients with HCQ treatment required a longer recovery time in comparison with patients in the control group (Mallat, et al., 2020) . As more evidence showed that CQ and HCQ have limited benefit to the recovery of COVID-19 patients and are unlikely to effectively reduce mortality, the usage of CQ and HCQ in treating COVID-19 became restrained. On June 15 th , 2020, the US FDA has revoked the emergency use authorization of CQ and HCQ to treat hospitalized COVID-19 patients (US Food & Drug Administration, 2020) . The potential adverse effects on the cardiovascular system other serious side effects observed in CQ/HCQ-treated patients are considered to outweigh the benefits of CQ and HCQ in treating COVID-19.

J o u r n a l P r e -p r o o f

The typical process of viral infection usually involves the following steps: endocytosis of viral particles; transport and uncoating leading to the release of the viral genome; transcription/translation/post-translational modification of viral proteins and assembly followed by exocytosis. The possible mechanisms of CQ/HCQ in the treatment and prevention of COVID-19 may be related to inhibiting these steps.

The infection process of COVID-19 is mediated through the interaction of spike (S) protein on virus and ACE2 on host cells . CQ has been reported with the ability to inhibit glycosylation of the ACE2 receptor, which directly affects the spread of SARS-CoV infection in host cells (Martin J Vincent, et al., 2005) . Moreover, recently in silico simulation showed that CQ/HCQ could prevent the access of S proteins to host cell surface ACE2 proteins by interacting with S proteins (Fantini, et al., 2020) . Therefore, inhibiting the interaction between S protein and ACE-2 might partially explain the prevention process.

Besides, it has been demonstrated that CQ suppresses the expression of phosphatidylinositol binding clathrin assembly protein (PICALM), further affecting clathrin-mediated endocytosis of nanoparticles (Pelt, et al., 2018) . COVID-19 falls in the size and shapes of nanoparticles, and the general decrease of endocytosis ability by CQ/HCQ might also contribute to COVID-19 prevention (Hu, et al., 2020) .

After entry into host cells, coronavirus utilizes trypsin-like proteases in the lysosome to cleave the surface S proteins and facilitate the fusion with lysosome in a pH-dependent manner. CQ is a weak base molecule that accumulates in the acidic organelles such as lysosomes, leading to a change of their acidification status (Adrea Savarino, et al., 2003) . The elevated pH in lysosomes may inhibit the enzymatic activity of lysosome proteases and hence the infection process.

The inhibition of the autophagic process by CQ/HCQ might also account for the effects of COVID-19 prevention. The viral replication process occurs in the intermediate compartment of the endoplasmic reticulum and Golgi complex, which is directly linked to autophagosome biogenesis (Ujike & Taguchi, 2015) . After CQ/HCQ treatment, the elevated pH in lysosomes inhibits the autophagic process, which might affect the replication process of COVID-19 (Bonam, et al., 2020) . Besides, the recycled materials accompanying the autophagic process might be utilized in the nucleation process of COVID-19, and the inhibition of autophagic process could also halt the replication process, and hence prevent the process of viral infection. 

The authors declare that there are no conflicts of interest. Chloroquine + Verapamil (Martin, et al., 2009) 

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The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid antibodies

Mechanism of uncoating of influenza B virus in MDCK cells: action of chloroquine

Repurposing of the anti -malaria drug chloroquine for Zika Virus treatment and prophylaxis

Dissecting virus entry via endocytosis

The "pushmi -pully u" of resistance to chloroquine in malaria

The history of lupus erythematos us. From Hippocrat es to Osler

EULA R recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update

Cutaneous Adverse Drug Reactions with Antimalarials and Allergological Skin Tests

Comparison of hydroxychloroquine with zidovudine in asymptomatic patients infected with human immunodeficiency virus type 1

Molecular analysis of chloroquine and sulfadoxine -pyrimethamine resistance-associated alleles in Plasmodium falciparum isolates from Nicaragua. The American journal of tropical medicine and hygiene

Chloroquine. In Assessment of Long-Term Healt h Effects of Antimalarial Drugs When Used for Prophylaxis

On the molecular mechanism of chloroquine's antimalarial action

Plasmodium hemozoin formation mediated by histidine-rich proteins

Different effects of chloroquine and hydroxychloroquine on lysosomal function in cultured retinal pigment epithelial cells

Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. bmj

An Overview of Available Antimalarials: Discovery, Mode of Action and Drug Resistance

Ocular toxicity of hydroxychloroquine

Bioavailability of hydroxychloroquine tablets assessed with deconvolution techniques

Chloroquine: modes of action of an undervalued drug

Chloroquine cardiomyopathy -a review of the literature

Efficacy of chloroquine f or the treatment of unc omplicated Plasmodium f alciparum malaria in Honduras. The American journal of tropical medicine and hygiene

In vitro screening of a FDA approv ed chemical library reveals potential inhibitors of SARS -CoV-2 replication. bioRxiv

The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine

Incorporation of spike and membrane glycoproteins into coronavirus virions

Coronavirus (COVID-19) update: FDA revokes emergency use authorization for chloroquine and hydroxychloroquine

Request for emergency use authorization for use of chloroquine phosphate or hydroxychloroquine sulfat e supplied from the strategic National Stockpile for treatment of 2019 coronavirus disease

Transporters involved in resistance to antimalarial drugs

Quinoline-resistance reversing agents for the malaria parasite Plasmodium falciparum

Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

Pharmacokinetics of chloroquine in renal insufficiency

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Where chloroquine still works: the genetic make-up and susceptibility of Plasmodium vivax to chloroquine plus primaquine in Bhutan. Malaria journal, 15, 277

Efficacy of chloroquine as a first line agent in the treatment of uncomplicated malaria due to Plasmodium vivax in children and treatment practices in Pakistan: a pilot study

Hy droxychloroquine is much less active than chloroquine against chloroquine-resistant Plasmodium falciparum, in agreement with its physicochemical properties

Broad anti-coronaviral activity of FDA approved drugs against SARS -CoV-2 in vitro and SARS-CoV in vivo

Effect of hydroxychloroquine treatment on pro -inflammatory cytokines and disease activity in SLE patients: data from LUMINA (LXXV), a multiethnic US cohort

Guidelines for the treatment of malaria

Testing for G6P D deficiency for safe use of primaquine in radical cure of P. vivax and P. ovale: Policy brief

World malaria report 2019. Geneva: World Health Organization

Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. science

In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine f or the treatment of severe acute respiratory syndrome coronavirus 2 (SARS -CoV-2)

Effective treatment with a tetrandrine/chloroquine combination for chloroquine-resistant falciparum malaria in Aotus monkeys

Chloroquin e-induced cardiomyopathy: a reversible cause of heart failure

Hydroxychloroquine application is associated with a decreased mortality in critically ill patients with COVID-19

Therapeutic responses of Plasmodium vivax malaria to chloroquine and primaquine treatment in northeastern Myanmar

At Day 13 post inclusion, the mortality rate is 27%, and a trend toward higher lethality was found in High CQ group in comparison with patients in Low CQ group High CQ dosage should not be recommended in COVID19 treatment J o u r n a l P r e -p r o o f