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Abstract

During the coronavirus disease 2019 (COVID-19) pandemic, numerous existing chemicals have been screened for antiviral potential against the emerging coronavirus severe acute respiratory syndrome coronavirus 2. Chloroquine and hydroxychloroquine, after exhibiting potent in vitro efficacy, have gained tremendous attention. Both therapeutics are derivatives of natural alkaloid quinine and were first synthesized to treat malaria. Thereafter, the pharmaceutical applications of the agents have expanded to many new areas. In this article, the medicinal history and pharmacological activities of chloroquine and hydroxychloroquine are summarized. Antimalarial, anti-inflammatory, antitumor, antiviral properties, and therapeutic potential in the emerging viral infection COVID-19 are discussed. Pharmacokinetics, adverse effects, and toxicities are reviewed.

Keywords

chloroquine hydroxychloroquine covid-19 broad-spectrum antiviral antitumor clinical pharmacology

Overview

Chloroquine (CQ) and hydroxychloroquine (HCQ) are both synthetic therapeutics first developed to mimic natural alkaloid quinine for its antimalarial effect.¹ For centuries, the bark of Cinochona trees (Cinchona spp., Rubiaceae) has been used to treat malaria and fevers.² The therapeutic application of this natural product originated in South America, before making its way to European countries. It was then realized that quinine and other alkaloids extracted from cinchona bark are responsible for the antimalarial properties. Quinine subsequently became the standard medicinal prophylaxis and treatment for malaria.² To mask its bitter taste, people started mixing quinine with sugar and gin,³ hence the creation of the popular modern drink gin and tonic. In World War II, Europeans lost access to the major Cinochona tree plantation in Java.⁴ With the advancement of medicinal chemistry, scientists soon synthesized quinine-alike chemicals including CQ and HCQ to continuously combat malaria.^1,4 Over the past decades, an array of therapeutics structurally derived from quinine has been developed. Clinical applications of the class have greatly diversified. Quinidine, for instance, has shown therapeutic effects for arrhythmia and Alzheimer’s disease.⁵ CQ and HCQ, 2 of the most commonly used quinine derivatives, have been constantly studied and utilized for more disease states beyond malaria.

Pharmacological Activities of CQ and HCQ

Antimalarial Activity

CQ (C₁₈H₂₆ClN₃) was first successfully synthesized in 1934. HCQ (C₁₈H₂₆ClN₃O) was developed in 1946 as a less toxic therapeutic alternative (Figure 1).⁶ At first, both were primarily indicated for malaria as quinine derivatives. Their role in malaria treatment has changed over the past decades due to increasing resistance.⁷

Figure 1

Molecular structures of 4-aminoquinolines: chloroquine and hydroxychloroquine.⁸

Quinine derivatives, including CQ and HCQ, are weak bases. They accumulate in acidic food vacuoles of intraerythrocytic trophozoites. The antimalarial mechanism of action is to induce selective toxicity to lysosomes, thereby preventing hemoglobin degradation.⁹

However, the evolving mutations in transporters PfCRT and PfMDR1 impair the entry of CQ to the digestive vacuole. Energy-coupled efflux of CQ is also observed to decrease the accumulation of CQ.¹⁰ Nowadays, CQ is rarely used against Plasmodium falciparum due to widespread resistance.¹¹ CQ remains as an effective therapy for malaria caused by Plasmodium ovale and Plasmodium malariae as well as Plasmodium vivax in most regions.^11,12 HCQ can be used as a substitute therapy for CQ-sensitive malaria. HCQ is ineffective in CQ-resistant Plasmodium strains.¹³

Anti-Inflammatory Activity

The use of quinines for anti-inflammatory purposes has been a subject of study since the 1890s. Presently, HCQ is the more commonly used of the 4-AQs as a disease-modifying antirheumatic drug in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Both drugs continue to be evaluated for additional inflammatory conditions, including Sjogren’s Syndrome, antiphospholipid syndrome, and inflammatory bowel disorders (IBD).¹⁴

As weakly basic compounds, CQ and HCQ enter the acidic lysosomal environment and disrupt lysosomal enzymatic activities. Specifically, they inhibit autophagy and prevent the activation of major histocompatibility complex class II-mediated antigens. CQ and HCQ also increase endosomal pH, which is believed to inhibit Toll-like receptors involved in cytokine production pathways. Additional pathways are still being explored, including ligand binding interference of cyclic guanosine monophosphate-adenosine monophosphate synthase and the reduction of antiphospholipid antibodies (aPL).^1,15,16

The efficacy of CQ and HCQ may depend on the disease state, as shown in in vitro studies. One study in antiphospholipid syndrome found that HCQ at 10 μM fully blocked the effects of interleukin-1β (IL-1β) and aPL on IL-8 but did not completely block tumor necrosis factor-α (TNFα) in murine cells or in monocytes.¹⁷ An in vitro study in patients with RA and SLE indicates that HCQ at a higher concentration (100 µM) significantly inhibits IL-6, IL-17, and IL-22 in monocytes.¹⁸A mouse model PK study of IBD synthesized a nondegradable polymeric CQ (pCQ). The research showed that 7 doses of pCQ and HCQ at 30 mg/kg HCQ equivalent every other day reduced colon inflammation (P ≤ 0.05) and proinflammatory activity to varying degrees in IL-6 (P ≤ 0.01), IL-2 (P ≤ 0.05), and IL-1β (P = not significant [NS]). Of note, the synthetic pCQ (half-maximal inhibitory concentration [IC₅₀] >2000 µg/mL) showed lower cytotoxicity against HepG2 cell line than HCQ (IC₅₀ = 42 µg/mL).¹⁹ Though used in a broad range of anti-inflammatory conditions, having larger-scale human trials testing specific targets for action will illuminate the best uses for CQ and HCQ.

Antitumor Activity

Starting in 1970, CQ and HCQ have been the subject of numerous oncology studies to treat cancers such as brain cancer, colorectal cancer, pancreatic cancer, renal cancer, and chronic myeloid leukemia.^14,20 They have been studied the most in glioblastoma (GBM), colon cancer, and pancreatic cancer.

Due to side effects at high doses of monotherapy, CQ or HCQ have been mainly trialed for synergistic effects with other antitumor agents in several forms of cancer. Presently, the most recognized antineoplastic mechanism of action for both CQ and HCQ is via lysosomal autophagic inhibition. As weakly basic compounds, CQ and HCQ gain proton ions within the acidic lysosomal environments of tumors, disrupting the enzymatic degradation chain of autophagy.^21,22 It has also been demonstrated that CQ affects autophagy by impairing the fusion of autophagosomes to lysosomes.²³ One study recently discovered that CQ and HCQ target palmitoyl-protein thioesterase 1, resulting in lysosomal mTORC1 displacement and autophagy.²⁴ Contrastingly, CQ and HCQ’s autophagic effects have also led to tumor promotion in earlier stages of tumor development; further studies will aid in discerning where CQ and HCQ can consistently target autophagy to ensure tumor-suppressant effects.^22,25

GBM Phase I, II, and III trials are elucidating when to optimally utilize CQ or HCQ in conjunction with other chemotherapies. A study of GBM cell lines found that the combination of HCQ (5  µg/mL) with bevacizumab (100  µg/mL) inhibited tumor cell proliferation and that HCQ increased cell sensitivity to bevacizumab.²⁶ A murine test of quinoline-based drugs showed that CQ and HCQ (25 mg/kg) induce apoptosis, autophagy, and endoplasmic reticulum stress in temozolomide (TMZ)-resistant GBM cells.²⁷ A 3 + 3 phase I study (N = 16) looked at HCQ 200-800 mg/day with TMZ (75 mg/m²) and found HCQ 600 mg/day to be the maximum tolerated dose, as all 3 subjects taking 800 mg daily experienced Grade III/IV myelosuppression. Thereafter, the noncomparative phase II portion of the study (N = 76) utilized a 2-compartment PK model for HCQ and demonstrated that HCQ’s dose-proportional exposure yielded inconsistent autophagy inhibition; multiple patients experienced grade III/IV adverse events with potential or definite relationships to HCQ or TMZ.²⁸ When given with carmustine (200 mg/m²), CQ (150 mg/day) in small Phase III GBM trials has yielded more encouraging results. An open-label randomized controlled trial (RCT) with paired controls (N = 18) showed significantly longer survival time (P < 0.0002) with study group (33 ± 5 months) versus controls (11 ± 2 months). A double-blind RCT (N = 30) yielded a nonsignificant prolonged survival (hazard ratio 0.52; 95% CI 0.21-1.26; P = 0.139) of treatment versus placebo (24 months vs 11 months). In both of these studies, seizures that may have been secondary to the tumor or to CQ were adequately treated with antiepileptics.^29
-31

In a study in CT26 murine colon cancer cells in vitro, CQ (3.125-100 µM) inhibited cell proliferation in a dose-dependent manner (P < 0.05 for CQ 25 and 50 µM); for the in vivo portion of the study, CQ (25 mg/kg and 50 mg/kg) more strongly inhibited the growth of CT26-induced tumors in BALB/c mice compared with control (P < 0.05).³² In a preclinical study on human colon cancer cell lines, CQ (100 μM) enhanced levels of autophagy marker LC3-II and increased growth inhibition in DLD-1 cells pretreated with 10 μM 5-fluorouracil (5-FU) compared with cells treated with 5-FU alone (27.9% vs 47.7%, P < 0.01).³³ After demonstrating safety in a Phase I HCQ 600 mg twice a day with the FOLFOX regimen in metastatic colorectal cancer, the ensuing single-arm Phase II trial in stage IV colorectal cancer of HCQ 600 mg twice a day with mFOLFOX6 and bevacizumab showed increases in autophagy marker LC3 with a complete response rate of 11% but without improved overall survival in the 28 evaluable patients.³⁴

Early pancreatic cancer studies indicate variable results with CQ and HCQ. Preclinical studies in xenograft models demonstrated that CQ (working concentration of 10 μM) increased pancreatic cell responsiveness to gemcitabine via increased reactive oxidative stress, leading to lysosomal apoptosis in PANC-1 and BxPC-3 cells.³⁵ Contrastingly, a later in vitro study showed wide variability in IC₅₀ and inconsistent sensitivity to the same concentration of CQ (10 μM) in gemcitabine-treated human pancreatic cancer cells (cell line unspecified).²¹ In a Phase I study, 9 elderly patients with symptomatic pancreatic cancer received CQ 100, 200, and 300 mg per week, timed to be given 1 day after gemcitabine treatment. Three patients in the CQ 100 and 200 mg per week groups showed tumor regression, which is not observed in the 300 mg weekly group.³⁶ In contrast, a Phase I/II study (N = 35) with pancreatic adenocarcinoma showed that HCQ taken at escalating doses (from 200/mg up to 1200 mg/day for 31 days) with gemcitabine showed no improvement in observable clinical outcomes. However, this study also measured changes in the HCQ autophagy marker LC3; the patients with >51% increase in LC3 had better survival, suggesting a future opportunity to identify patients who will respond to autophagy prior to treatment selection.³⁷

Antiviral Activity—Broad Spectrum and in COVID-19

As early as in the 1940s, quinine was studied in mice for potential efficacy against influenza virus.³⁸ Since then, quinine and its derivatives have been evaluated for various viral infections.³⁹ In the 1960s, CQ was researched in the mouse hepatitis virus and encephalomyocarditis virus.^39,40 Since then, CQ and HCQ have been tested against Zika, Ebola, human immunodeficiency virus, hepatitis C virus, coronaviruses, and others,^4,39,41 exhibiting broad-spectrum antiviral properties.

The mechanism of action for CQ / HCQ as antivirals is not fully understood. It appears to involve multiple pathways and is not identical in all viruses. A well-known broad-spectrum mechanism is to neutralize acidic endosomal pH, therefore blocking endosome-mediated viral entry.^14,42 CQ and HCQ also exhibit anti-inflammatory and immunomodulatory benefits in viral infections. They inhibit the production and release of cytokines, including IL-1, 2, 6, 18, TNF-α, and interferon-gamma (IFN-γ).^4,6,39 Among research for the ongoing coronavirus disease 2019 (COVID-19) pandemic, a recent in-silico test shows that CQ and HCQ can compromise the binding affinity of S protein on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to gangliosides on the host cell surface.⁴³

During the SARS outbreak, CQ was found to inhibit SARS-CoV in vitro, showing potential as both prophylactic and therapeutic treatment.⁴¹ Since the COVID-19 outbreak, CQ has shown a potent antiviral effect on SARS-CoV-2 in vitro, with the 90% effective concentration (EC₉₀) of 6.90 µM, which is clinically achievable.⁴⁴ SARS-CoV-2 in vitro studies have also revealed achievable effective concentrations of HCQ, with 1 study finding HCQ (EC₅₀ = 0.72 µM) to be more potent than chloroquine (EC₅₀ = 5.47 μM)⁴⁵ and another study finding CQ (EC₅₀ = 2.71, 3.81, 7.14, and 7.36 µM) more potent than HCQ (EC₅₀ = 4.51, 4.06, 17.31, and 12.96 µM).⁴⁶ An open-label nonrandomized clinical trial (N = 42) in France studied the HCQ regimen of 200 mg 3 times a day orally with and without azithromycin (AZM). The study reported 100% viral clearance on day 6 in the HCQ + AZM group versus 57.1% in the HCQ group versus 12.5% in the control group.⁴⁷ Notably, the HCQ group had a higher viral load at baseline. While the viral suppression data are promising, clinical outcomes were not studied. A follow-up study was conducted by the French team on the same HCQ + AZM regimen (N = 80).⁴⁸ Clinical outcomes were evaluated this time. Time from treatment initiation to discharge was 4.1 ± 2.2 days. End results included 15% (n = 12) utilization of oxygen therapy, 3.8% (n = 3) transfers to intensive care unit, and 1.2% (n = 1) mortality. This was an observational study without a control group.

A controlled pilot study in Shanghai presented HCQ as ineffective for expediting viral clearance, recovery from fever, and computed tomography image improvement (P > 0.05).⁴⁹ However, the study had a very small sample size (N = 30). It is not a treatment versus a placebo study. Both HCQ group and control group were treated with interferon (IFN), and most patients also received antiviral lopinavir/ritonavir or arbidol. The study design is questionable, especially when there are no definite conclusions on the effect of IFN and antivirals in COVID-19 yet.⁵⁰ In April 2020, a retrospective multicenter study (N = 368) in American veterans with COVID-19 showed HCQ as ineffective and potentially harmful.⁵¹ HCQ with or without AZM did not decrease ventilation risk significantly. The HCQ group, but not the HCQ + AZM group, even had a higher risk for death. However, patients with severe disease were potentially more likely to start HCQ treatment. The dosage, duration, and consistency of regimen across the study centers were not reported. A New York hospital reported QTc prolongation associated with HCQ + AZM (N = 84).⁵² QTc increased from a baseline of 435 ± 24 ms to a maximal value of 463 ± 32 ms (P < 0.001) on day 3.6 ± 1.6 of therapy. No TdP events were observed.

Currently, the National Institutes of Health recommends neither for nor against CQ /HCQ as a treatment for COVID-19.⁵³ However, the organization does not support the HCQ + AZM combination due to potential toxicity. With the ongoing research effort for COVID-19, results from well-designed RCTs are expected to evaluate the efficacy and safety of CQ and HCQ against SARS-CoV-2.

Pharmacokinetics

Both CQ and HCQ follow linear kinetics.⁶ Peak level of both drugs following oral administration is achieved in 2-4 hours with an average of 89% (CQ) and 74% (HCQ) dose absorption.^6,54 It is worth noting that a 30%-100% variation in CQ and HCQ absorption has been observed among individuals.^6,55

Half-lives of CQ and HCQ are between 40 and 50 days.^6,54 HCQ can be detected in urine 3 months after a single oral dose of 200 mg.⁵⁴ The long t1/2 is attributed to extensive tissue binding. The volumes of distribution for both drugs are reportedly thousands of liters.^15,55

CQ and HCQ are metabolized partially through the liver with the primary metabolites being desethylchloroquine and desethylhydroxychloroquine, respectively.^54,55 CQ and HCQ are subjects of metabolic enzymes CYP2C8, CYP3A4/5, and CYP2D6.^15,56 About 16%-30% HCQ is excreted via kidney unchanged and does not appear correlated with creatinine clearance.⁵⁴ While short-term use does not require renal dosing, prolonged use may warrant dose reduction in renal impairment.^54,55,57

Adverse Effects and Toxicities

In 1947, the first human toxicity studies noted electrocardiographic (EKG) changes and visual changes in 20 subjects taking CQ 0.3 g daily for 77 days.⁵⁸ Researchers have found that CQ/HCQ can impede conduction in sodium and potassium channels, leading to ST-segment depression, T wave inversion, and QT interval prolongation. QT interval prolongation is a particular concern when given concomitantly with AZM in COVID-19, as this combination increases the risk of torsades de pointes (TdP) and sudden cardiac death.^59

-62 CQ/HCQ can also cause a complete atrioventricular block.⁶⁰ These cardiotoxicities have been seen after chronic daily use as well as in acute overdoses of HCQ (≥8 g) or more commonly in CQ (≥2.25 g).^61,63,64

Since the 1960s, research on visual changes revealed that chronic use of CQ and HCQ could irreversibly impair retinal function. A recent study demonstrated that CQ and HCQ (10 μM) inhibit organic anion transporting polypeptide 1A2 (OATp1A2), leading to the accumulation of all-trans-retinol in human retinal pigment epithelium cells.⁶⁵ The American Academy of Ophthalmology recommends an annual screen after 5 years of treatment of daily CQ 2.3 mg/kg or HCQ 5 mg/kg (dosed at actual body weight).⁶⁶ Other major adverse effects of CQ/HCQ include dermatologic reactions, gastrointestinal discomfort, and a decrease in blood cell counts.^54,55

Conclusion and Outlook

CQ and HCQ have been around for decades. Ever since they were first synthesized, CQ and HCQ have remained as valuable therapeutic agents worldwide. Medical indications for CQ and HCQ have expanded from malaria to inflammatory diseases, now to cancers and emerging viral infections (Table 1). The research effort to explore their efficacy and new mechanism of action in various diseases has never ceased. Along with that, kinetics studies are ongoing to balance toxicity and effectiveness. Despite their long history in modern medicine, CQ and HCQ continue to be meaningful objects of study.

Table 1

Clinical Applications of Chloroquine and Hydroxychloroquine.

Pharmacologicalproperties	Clinical applications(Established and investigative)
Antimalarial	Malaria
Anti-inflammatory	Antiphospholipid syndrome Inflammatory bowel disease Rheumatoid arthritis Systemic lupus erythematosus Sjogren’s Syndrome
Antitumor	Blood cancers (leukemia, myeloma, lymphoma) Brain cancers Breast cancer Gastrointestinal cancers Genitourinary cancers Lung cancer Skin and bone cancers
Antiviral	Coronaviruses Ebola Hepatitis Human immunodeficiency virus Zika (will added more if applicable)

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Yang Song

References

Al-Bari

MAA

. Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases. J Antimicrob Chemother. 2015;70(6):1608-1621.doi:10.1093/jac/dkv018

http://www.ncbi.nlm.nih.gov/pubmed/25693996

Achan

Talisuna

AO.

Erhart

et al. Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malar J. 2011;10(1):144 doi:10.1186/1475-2875-10-144

http://www.ncbi.nlm.nih.gov/pubmed/21609473

Meyer

CG.

Marks

May

. Editorial: Gin tonic revisited. Trop Med Int Health. 2004;9(12):1239-1240.doi:10.1111/j.1365-3156.2004.01357.x

http://www.ncbi.nlm.nih.gov/pubmed/15598254

Bruce-Chwatt

. Three hundred and fifty years of the Peruvian fever bark. Br Med J. 1988;296(6635):1486-1487.doi:10.1136/bmj.296.6635.1486

http://www.ncbi.nlm.nih.gov/pubmed/3134079

Eyal

. The fever tree: from malaria to neurological diseases. Toxins. 2018;10(12):E491 doi:10.3390/toxins10120491

http://www.ncbi.nlm.nih.gov/pubmed/30477182

Browning

. Pharmacology of chloroquine and hydroxychloroquine. Hydroxychloroquine and Chloroquine Retinopathy. 2014:35-63.

White

. The treatment of malaria. N Engl J Med. 1996;335(11):800-806.doi:10.1056/NEJM199609123351107

http://www.ncbi.nlm.nih.gov/pubmed/8703186

Zhu

Chan

et al. Chloroquine and hydroxychloroquine are novel inhibitors of human organic anion transporting polypeptide 1A2. J Pharm Sci. 2016;105(2):884-890.doi:10.1002/jps.24663

http://www.ncbi.nlm.nih.gov/pubmed/26429523

Slater

. Chloroquine: mechanism of drug action and resistance in Plasmodium falciparum. Pharmacol Ther. 1993;57(2-3):203-235.doi:10.1016/0163-7258(93)90056-J

http://www.ncbi.nlm.nih.gov/pubmed/8361993

10.

Valderramos

SG.

Fidock

. Transporters involved in resistance to antimalarial drugs. Trends Pharmacol Sci. 2006;27(11):594-601.doi:10.1016/j.tips.2006.09.005

http://www.ncbi.nlm.nih.gov/pubmed/16996622

11.

Plewes

Leopold

SJ.

Kingston

HWF.

Dondorp

. Malaria: what's new in the management of malaria? Infect Dis Clin North Am. 2019;33(1):39-60.doi:10.1016/j.idc.2018.10.002

http://www.ncbi.nlm.nih.gov/pubmed/30712767

12.

Prevention C-C for DC and. CDC - malaria - travelers - malaria information and prophylaxis, by country.

13.

Warhurst

DC.

Steele

JCP.

Adagu

IS.

Craig

JC.

Cullander

. Hydroxychloroquine is much less active than chloroquine against chloroquine-resistant Plasmodium falciparum, in agreement with its physicochemical properties. J Antimicrob Chemother. 2003;52(2):188-193.doi:10.1093/jac/dkg319

http://www.ncbi.nlm.nih.gov/pubmed/12837731

14.

Plantone

Koudriavtseva

. Current and future use of chloroquine and hydroxychloroquine in infectious, immune, neoplastic, and neurological diseases: a mini-review. Clin Drug Investig. 2018;38(8):653-671.doi:10.1007/s40261-018-0656-y

http://www.ncbi.nlm.nih.gov/pubmed/29737455

15.

Schrezenmeier

Dörner

. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020;16(3):155-166.doi:10.1038/s41584-020-0372-x

http://www.ncbi.nlm.nih.gov/pubmed/32034323

16.

Yang

D-H.

Leong

P-Y.

Sia

S-K.

Wang

Y-H.

Wei

JC-C

. Long-Term hydroxychloroquine therapy and risk of coronary artery disease in patients with systemic lupus erythematosus. J Clin Med. 2019;8(6):796 doi:10.3390/jcm8060796

http://www.ncbi.nlm.nih.gov/pubmed/31195632

17.

Müller-Calleja

Manukyan

Canisius

Strand

Lackner

. Hydroxychloroquine inhibits proinflammatory signalling pathways by targeting endosomal NADPH oxidase. Ann Rheum Dis. 2017;76(5):891-897.doi:10.1136/annrheumdis-2016-210012

http://www.ncbi.nlm.nih.gov/pubmed/27903507

18.

Silva

JC.

Mariz

HA.

Rocha

et al. Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients. Clinics. 2013;68(6):766-771.doi:10.6061/clinics/2013(06)07

http://www.ncbi.nlm.nih.gov/pubmed/23778483

19.

Kanvinde

Chhonker

YS.

Ahmad

et al. Pharmacokinetics and efficacy of orally administered polymeric chloroquine as macromolecular drug in the treatment of inflammatory bowel disease. Acta Biomater. 2018;82:158-170.doi:10.1016/j.actbio.2018.10.027

http://www.ncbi.nlm.nih.gov/pubmed/30342282

20.

Bedoya

. Effect of chloroquine on malignant lymphoreticular and pigmented cells in vitro. Cancer Res. 1970;30(5):1262-1275.http://www.ncbi.nlm.nih.gov/pubmed/5426931

21.

Molejon

MI.

Swayden

Fanale

et al. Chloroquine plays a cell-dependent role in the response to treatment of pancreatic adenocarcinoma. Oncotarget. 2018;9(56):30837-30846.doi:10.18632/oncotarget.25745

http://www.ncbi.nlm.nih.gov/pubmed/30112111

22.

Verbaanderd

Maes

Schaaf

et al. Repurposing Drugs in Oncology (ReDO)-chloroquine and hydroxychloroquine as anti-cancer agents. Ecancermedicalscience. 2017;11:781 doi:10.3332/ecancer.2017.781

http://www.ncbi.nlm.nih.gov/pubmed/29225688

23.

Varisli

Cen

Vlahopoulos

. Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways. Immunology. 2020;159(3):257-278.doi:10.1111/imm.13160

http://www.ncbi.nlm.nih.gov/pubmed/31782148

24.

Rebecca

VW.

Nicastri

MC.

Fennelly

et al. Ppt1 promotes tumor growth and is the molecular target of chloroquine derivatives in cancer. Cancer Discov. 2019;9(2):220-229.doi:10.1158/2159-8290.CD-18-0706

http://www.ncbi.nlm.nih.gov/pubmed/30442709

25.

Sun

Guo

X-L.

Zhao

et al. Paradoxical role of autophagy in the dysplastic and tumor-forming stages of hepatocarcinoma development in rats. Cell Death Dis. 2013;4(2):e501-e501.doi:10.1038/cddis.2013.35

http://www.ncbi.nlm.nih.gov/pubmed/23429287

26.

Shao

Y-F.

Liu

L-Q.

Wang

S-B

et al. Hydroxychloroquine potentiates the anti-cancer effect of bevacizumab on glioblastoma via the inhibition of autophagy. Biomed Pharmacother. 2019;118:109339 doi:10.1016/j.biopha.2019.109339

31545270

27.

Golden

EB.

Cho

H-Y.

Hofman

FM.

Louie

SG.

Schönthal

AH.

Chen

. Quinoline-Based antimalarial drugs: a novel class of autophagy inhibitors. Neurosurg Focus. 2015;38(3):E12 doi:10.3171/2014.12.FOCUS14748

http://www.ncbi.nlm.nih.gov/pubmed/25727221

28.

Rosenfeld

MR.

Supko

et al. A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy. 2014;10(8):1359-1368.doi:10.4161/auto.28984

http://www.ncbi.nlm.nih.gov/pubmed/24991840

29.

Sotelo

Briceño

López-González

. Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2006;144(5):337-343.doi:10.7326/0003-4819-144-5-200603070-00008

http://www.ncbi.nlm.nih.gov/pubmed/16520474

30.

Briceño

Reyes

Sotelo

. Therapy of glioblastoma multiforme improved by the antimutagenic chloroquine. Neurosurg Focus. 2003;14(2):1-6.doi:10.3171/foc.2003.14.2.4

http://www.ncbi.nlm.nih.gov/pubmed/15727424

31.

Zhu

. The clinical value of using chloroquine or hydroxychloroquine as autophagy inhibitors in the treatment of cancers. Medicine. 2018;97(46):e12912 doi:10.1097/MD.0000000000012912

32.

Zheng

Zhao

Y-L.

Deng

et al. Chloroquine inhibits colon cancer cell growth in vitro and tumor growth in vivo via induction of apoptosis. Cancer Invest. 2009;27(3):286-292.doi:10.1080/07357900802427927

http://www.ncbi.nlm.nih.gov/pubmed/19194831

33.

Choi

J-H.

Yoon

JS.

Won

Y-W.

Park

B-B.

Lee

. Chloroquine enhances the chemotherapeutic activity of 5-fluorouracil in a colon cancer cell line via cell cycle alteration. APMIS. 2012;120(7):597-604.doi:10.1111/j.1600-0463.2012.02876.x

http://www.ncbi.nlm.nih.gov/pubmed/22716215

34.

O’Hara

MH.

Karasic

TB.

Vasilevskaya

et al. Phase II trial of the autophagy inhibitor hydroxychloroquine with FOLFOX and bevacizumab in front line treatment of metastatic colorectal cancer. JCO. 2017;35(15):3545-3545.doi:10.1200/JCO.2017.35.15_suppl.3545

35.

Cheng

Kuang

et al. Cq sensitizes human pancreatic cancer cells to gemcitabine through the lysosomal apoptotic pathway via reactive oxygen species. Mol Oncol. 2018;12(4):529-544.doi:10.1002/1878-0261.12179

http://www.ncbi.nlm.nih.gov/pubmed/29453806

36.

Samaras

Tusup

Nguyen-Kim

TDL

et al. Phase I study of a chloroquine-gemcitabine combination in patients with metastatic or unresectable pancreatic cancer. Cancer Chemother Pharmacol. 2017;80(5):1005-1012.doi:10.1007/s00280-017-3446-y

http://www.ncbi.nlm.nih.gov/pubmed/28980060

37.

Boone

BA.

Bahary

Zureikat

et al. Safety and biologic response of pre-operative autophagy inhibition in combination with gemcitabine in patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2015;22(13):4402-4410.doi:10.1245/s10434-015-4566-4

http://www.ncbi.nlm.nih.gov/pubmed/25905586

38.

Seeler

AO.

Graessle

Ott

. Effect of quinine on influenza virus infections in mice. J Infect Dis. 1946;79(2):156-158.doi:10.1093/infdis/79.2.156

http://www.ncbi.nlm.nih.gov/pubmed/20273894

39.

D'Alessandro

Scaccabarozzi

Signorini

et al. The use of antimalarial drugs against viral infection. Microorganisms. 2020;8(1):5-10.doi:10.3390/microorganisms8010085

http://www.ncbi.nlm.nih.gov/pubmed/31936284

40.

Inglot

. Comparison of the antiviral activity in vitro of some non-steroidal anti-inflammatory drugs. J Gen Virol. 1969;4(2):203-214.doi:10.1099/0022-1317-4-2-203

http://www.ncbi.nlm.nih.gov/pubmed/4306296

41.

Vincent

MJ.

Bergeron

Benjannet

et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2:69 doi:10.1186/1743-422X-2-69

http://www.ncbi.nlm.nih.gov/pubmed/16115318

42.

Al-Bari

MAA

. Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases. Pharmacol Res Perspect. 2017;5(1):e00293 doi:10.1002/prp2.293

http://www.ncbi.nlm.nih.gov/pubmed/28596841

43.

Fantini

Di Scala

Chahinian

Yahi

. Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection. Int J Antimicrob Agents. 2020;55(5):105960 doi:10.1016/j.ijantimicag.2020.105960

http://www.ncbi.nlm.nih.gov/pubmed/32251731

44.

Wang

Cao

Zhang

et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271.doi:10.1038/s41422-020-0282-0

http://www.ncbi.nlm.nih.gov/pubmed/32020029

45.

Yao

Zhang

et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2. Clin Infect Dis. 2020

46.

Liu

Cao

et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6(1):16.doi:10.1038/s41421-020-0156-0

http://www.ncbi.nlm.nih.gov/pubmed/32194981

47.

Gautret

Lagier

J-C.

Parola

et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020;56(1):105949 doi:10.1016/j.ijantimicag.2020.105949

http://www.ncbi.nlm.nih.gov/pubmed/32205204

48.

Gautret

Lagier

J-C.

Parola

et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: a pilot observational study. Travel Med Infect Dis. 2020;34:101663 doi:10.1016/j.tmaid.2020.101663

http://www.ncbi.nlm.nih.gov/pubmed/32289548

49.

Chen

Liu

et al. A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2020;49(2):215-219.doi:10.3785/j.issn.1008-9292.2020.03.03

http://www.ncbi.nlm.nih.gov/pubmed/32391667

50.

Song

Zhang

Yin

et al. COVID-19 treatment: close to a cure? a rapid review of pharmacotherapies for the novel coronavirus (SARS-CoV-2. Int J Antimicrob Agents. 2020;56(2):106080 doi:10.1016/j.ijantimicag.2020.106080

http://www.ncbi.nlm.nih.gov/pubmed/32634603

51.

Magagnoli

Narendran

Pereira

et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. medRxiv. 2020;56(2):20065920 doi:10.1016/j.medj.2020.06.001 21 Apr 2020.http://www.ncbi.nlm.nih.gov/pubmed/32511622

52.

Chorin

Dai

Shulman

et al. The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin. Nat Med. 2020;26(6):808-809.doi:10.1038/s41591-020-0888-2

http://www.ncbi.nlm.nih.gov/pubmed/32488217

53.

The National Institutes of Health (NIH) . COVID-19 Treatment Guidelines. Published April 2020. April 24, 2020. https://www.covid19treatmentguidelines.nih.gov/introduction/

54.

Plaquenil (hydroxychloroquine) [prescribing information]. Sanofi-Aventis US, LLC, April. 2012

55.

Aralen (chloroquine) [prescribing information]. Sanofi-Synthelabo, Inc; 2001.

56.

Kim

K-A.

Park

J-Y.

Lee

J-S.

Lim

. Cytochrome P450 2C8 and CYP3A4/5 are involved in chloroquine metabolism in human liver microsomes. Arch Pharm Res. 2003;26(8):631-637.doi:10.1007/BF02976712

http://www.ncbi.nlm.nih.gov/pubmed/12967198

57.

Tett

. Clinical pharmacokinetics of slow-acting antirheumatic drugs. Clin Pharmacokinet. 1993;25(5):392-407.doi:10.2165/00003088-199325050-00005

http://www.ncbi.nlm.nih.gov/pubmed/7904547

58.

Alving

AS.

Eichelberger

Craige

Jones

Whorton

CM.

Pullman

. Studies on the chronic toxicity of chloroquine (SN-7618) 1. J Clin Invest. 1948;27(3 Pt 2):60-65.doi:10.1172/JCI101974

59.

Tönnesmann

Kandolf

Lewalter

. Chloroquine cardiomyopathy - a review of the literature. Immunopharmacol Immunotoxicol. 2013;35(3):434-442.doi:10.3109/08923973.2013.780078

http://www.ncbi.nlm.nih.gov/pubmed/23635029

60.

de Olano

Howland

MA.

MK.

Hoffman

RS.

Biary

. Toxicokinetics of hydroxychloroquine following a massive overdose. Am J Emerg Med. 2019;37(12):e5-e8.doi:10.1016/j.ajem.2019.158387

http://www.ncbi.nlm.nih.gov/pubmed/31477360

61.

Giudicessi

JR.

Noseworthy

PA.

Friedman

PA.

Ackerman

. Urgent guidance for navigating and circumventing the QTc-Prolonging and torsadogenic potential of possible pharmacotherapies for coronavirus disease 19 (COVID-19). Mayo Clin Proc. 2020;95(6):1213-1221.doi:10.1016/j.mayocp.2020.03.024

http://www.ncbi.nlm.nih.gov/pubmed/32359771

62.

Jordan

Brookes

JG.

Nikolic

Le Couteur

. Hydroxychloroquine overdose: toxicokinetics and management. J Toxicol Clin Toxicol. 1999;37(7):861-864.doi:10.1081/CLT-100102466

http://www.ncbi.nlm.nih.gov/pubmed/10630270

63.

Riou

Barriot

Rimailho

Baud

. Treatment of severe chloroquine poisoning. N Engl J Med. 1988;318(1):1-6.doi:10.1056/NEJM198801073180101

http://www.ncbi.nlm.nih.gov/pubmed/3336379

64.

Zhu

Chan

et al. Chloroquine and hydroxychloroquine are novel inhibitors of human organic anion transporting polypeptide 1A2. J Pharm Sci. 2016;105(2):884-890.doi:10.1002/jps.24663

http://www.ncbi.nlm.nih.gov/pubmed/26429523

65.

Yusuf

IH.

Sharma

Luqmani

Downes

. Hydroxychloroquine retinopathy. Eye. 2017;31(6):828-845.doi:10.1038/eye.2016.298

http://www.ncbi.nlm.nih.gov/pubmed/28282061

66.

Marmor

MF.

Kellner

Lai

TYY.

Melles

RB.

Mieler

. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology. 2016;123(6):1386-1394.doi:10.1016/j.ophtha.2016.01.058

http://www.ncbi.nlm.nih.gov/pubmed/26992838

Pharmacological Advances of Chloroquine and Hydroxychloroquine: From Antimalarials to Investigative Therapies in COVID-19

Abstract

Keywords

Overview

Pharmacological Activities of CQ and HCQ

Antimalarial Activity

Anti-Inflammatory Activity

Antitumor Activity

Antiviral Activity—Broad Spectrum and in COVID-19

Pharmacokinetics

Adverse Effects and Toxicities

Conclusion and Outlook

Footnotes

Declaration of Conflicting Interests

Funding

ORCID iD

References