key: cord-0900742-er6u8hhw
authors: Joshi, Gaurav; Thakur, Shikha; Mayank; Poduri, Ramarao
title: Exploring insights of hydroxychloroquine, a controversial drug in Covid-19: An update
date: 2021-03-15
journal: Food Chem Toxicol
DOI: 10.1016/j.fct.2021.112106
sha: 93538f7e9a54b83fe92e45eef47ad35d10b800ed
doc_id: 900742
cord_uid: er6u8hhw

The review summarizes chloroquine (CQ) and its safer derivative hydroxychloroquine (HCQ) and its utility in Covid-19. Recently this well-established drug made its way back to the headlines during the SARS-CoV-2 pandemic. This led to an upsurge in the scientific arena with multiple research and review articles along with expert opinions and commentaries. The HCQ has received mixed judgements so far about its efficacy for Covid-19 patients in a limited trial conducted all across the Globe. The purpose of our article is to put forth the history, pharmacodynamics, and pharmacokinetics, along with the existing studies favouring and disapproving the role of HCQ in the treatment of Covid-19. We grouped HCQ use at three various stages. The stages include the use of HCQ for i. prophylactic use by asymptomatic health workers or peoples at higher risk; ii. patients having mild symptoms; iii. patients with extreme symptoms. The review critically discusses the underlying plausible reasons and mechanisms exploring HCQ in prophylactic management or treatment of SARS-CoV-2. Furthermore, we have critically analysed the reported pharmacokinetic parameters and compiled the proponent, opponent, or neutral opinions on the use of HCQ in Covid-19. Authors discretion is to conduct more studies considering the optimal dosing regimen and pharmacokinetics assessment.

Coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pandemic disease that has deteriorated the World in terms of health and wealth. Considering the treatment, the World is still deprived of an efficacious drug or a vaccine to combat Covid-19 (Poduri et al., 2020) . Since SARS-CoV-2 has left the World unparalleled and unbiased in this pandemic, this has driven the scientific community to go all out to search for a solution (Thakur et al., 2021) . Considering the scientific advancements, many drugs are being repurposed for testing against SARS-CoV-2 but with little success so far as the World awaits its first USFDA drug approval for Covid-19 . Among hundreds of drugs repurposed, chloroquine (CQ) and its safer derivative hydroxychloroquine (HCQ) have been explored for their role in SARS-CoV-2 owing to their prior use in SARS-CoV and also considering the much higher similarity in two virus strains (Frie and Gbinigie, 2020; Spinelli et al., 2020) . CQ and HCQ are medications that have been used for a long time. The USFDA first approved HCQ on 18 April 1955 for the treatment of malaria. HCQ has been further explored as an immunomodulator in treating autoimmune diseases, including lupus erythematosus and rheumatoid arthritis. It is also known to possess antiviral activity for hepatitis B, HIV, H1N1, Zika virus (Browning, 2014; D'Alessandro et al., 2020) . The drug is reported to act in 392 diseases. Recently this well-established drug made its way back to the headlines during the SARS-CoV-2 pandemic and was further fuelled by the United States of America's President Donald Trump, calling it a "game-CQ/HCQ reduces phosphatidylinositol binding clathrin assembly protein (PICALM) expression that plays a vital role as a cargo-selecting adaptor and regulates the rate of cellular clathrin-mediated endocytosis assisting SARS-CoV-2 entry (Inoue et al., 2007; Wolfram et al., 2017) . Besides, CQ/HCQ is reported to possess zinc ionophore physiognomies and thereby specifically target extracellular trace element zinc and allow its intracellular transit to lysosomes where it interferes explicitly with Nsp-12 (RNA-dependent RNA polymerase;

RdRp) activity and consequently blocks SARS-CoV-2 replication. Zinc is already reported to enhance antiviral immunity (Shittu and Afolami, 2020; Xue et al., 2014) .

Some studies underlie the effect of CQ/HCQ that may allow cellular iron starvation in the virus and thereby inhibit SARS-CoV-2 replication. Mechanistically, CQ/HCQ inhibits ironregulatory hormone hepcidin (HAMP), known to block cellular iron export mediated via ferroportin1 (FPN1). This results in reduced iron absorption, increasing iron retention in hepatocytes and macrophages; thus, provoking infection/inflammation. HAMP is produced in the immune system (lymphocytes, monocytes, and macrophages along with alveolar macrophages) and airway epithelial cells and have been reported to contribute to lung injury (Roldan et al., 2020) . Furthermore, considering lysosomes, which own hydrolytic enzymes that mediate autophagy or endocytosis pathways. Thus, CQ/HCQ interference with lysosomal activity is thought to inhibit/alter the functions of lymphocytes leading to anti-inflammatory or immunomodulatory effects (Adeel, 2020) . Importantly, lysosomes are also indirectly involved in immune system activation by antigen processing via CD4+ T-cells and histocompatibility factors activation (MHC II), leading to autophagy (Alijotas-Reig et al., 2020) . Thus CQ/HCQ is also known to inhibit lysosomal and autophagosome functions that activate the immune system indirectly (Mauthe et al., 2018) . The studies also report that these drugs also lead to downregulation of TLR receptors. Upon accumulation of drugs in host cell endosomes, the alteration in pH hampers the TLR processing. Also, these drugs bind to J o u r n a l P r e -p r o o f double-stranded DNAs minor groove and prevent ligand binding to TLR7 (RNA) and TLR9 (DNA) (Müller-Calleja et al., 2017; Torigoe et al., 2018) . The HCQ is also reported to inhibit Cyclic guanosine monophosphate-adenosine (cGAMP) synthase activity, which acts as a stimulator of interferon (type I IFNs) genes (An et al., 2015) . The drug inhibits cGAMP synthase dependent transcription of type I IFNs by binding with cytosolic DNA via transcription factor IFN regulatory factor 3 (IRF3). Thus, via combinatorial inhibition of TLR and cGAMP synthase, it reduces the production of proinflammatory cytokines along with including type I interferons. Some in vitro reports suggest that CQ/HCQ inhibits IL-1, IL-6, TNF, and IFNγ production . One recent study has also identified that drug also interferes with lipid-modified proteins' catabolism by inhibiting palmitoyl-protein thioesterase 1 (PPT1) overexpressed in the synovial tissue of patients with Rheumatoid arthritis (Rebecca et al., 2019; Schrezenmeier and Dörner, 2020) . Further attempt to delineate the plausible mechanism of HCQ was attempted using computational approaches. The basic sketch to illustrate the mechanism of CQ/HCQ in Covid-19 is provided in Figure 2 . Beyond Covid-19, CQ and HCQ have also been explored to treat various other diseases and infections (Gies et al., 2020) . The important utility of these drugs has been explored in human malaria, hepatic amoebiasis, lupus erythematosus, rheumatoid arthritis, Porphyria cutanea tarda, primary Sjögren syndrome, Q fever, Sarcoidosis and dermatomyositis. Beside antiviral effects, these drugs have also been known to possess antibacterial, antifungal, antiprotozoal and antiparasitic assets. Further few in vitro and in vivo studies have highlighted their use in several forms of cancer, glioblastoma along with possessing immunomodulatory effects.

Considering their pivotal immunomodulatory and anti-inflammatory potentials, CQ and HCQ are known to inhibit TLRs (TLR-3,7, 8 and 9); Interferons (IFN-α, IFN-γ); T-cells (Th1, 2 and 17); TNF-α and interleukins 2, 6, 17, 22, ) and act as a facilitator for IL-10. Among numerous ILs effected by CQ/HCQ IL-1, IL-1β cell concentration was found to get reduced J o u r n a l P r e -p r o o f by CQ in rheumatoid arthritis patients by interfering with endolysosome-associated vesicles mediated pathway in monocytes (Gasmi et al., 2021; Gies et al., 2020) . CQ is also known to inhibit IL-2 by modulating αCD3 in MoAb-triggered T-cells plausibly in an autocrine fashion. However, inhibition of IL-2 does not affect the secretory concentration of IL-2 receptor complex. Further, synthesis of IL-6, a pleiotropic cytokine and plays a role in B-cell maturation, is known to inhibit CQ. HCQ is known to inhibit IL-17 and IL-22 and consequently reduces Th-17 cytokine levels and antigen presentation. Further few other inhibitors have also been explored for their utility as anti-inflammatory agents, thus proving their utility in Covid-19(dos Reis Neto et al., 2020b) . A recent study by Ignaitos and group disclosed the beneficial effect of Tocilizumab on endothelial glycocalyx and myocardial efficiency via IL-6 inhibition in rheumatoid arthritis patients. The favourable outcomes like improvement of vascular permeability in these patients were correlated with an apparent beneficial effect in Covid-19, characterized by excess IL-6 release .

Lambadiari and the group explored the possibilities and mechanisms for higher risk of Covid-19 in diabetic patients. The team hypothesised that diabetes-associated hyperactivation of NLRP3 (NOD-, LRR-and pyrin domain-containing protein 3) inflammasome, chronic inflammation, hypercytokinemia, followed by increased vascular permeability might majorly contribute to the severity of Covid-19. The group also advised using colchicine, anti-IL1a, anti-IL1β, or anti-IL6 as a therapeutic intervention in overcoming the associated complications in Covid-19 (Lambadiari et al., 2020) . This could be minimized by appropriate drug dosage, considering essential parameters such as body weight and disease condition.

Understanding the dose-response relationships due to their complex pharmacokinetics and an (Miller et al., 1991; Schrezenmeier and Dörner, 2020 (Lim et al., 2009 ).

Based on these study findings, a dose range of HCQ in the treatment of Covid-19 that follows linear pharmacokinetics is to be determined. The V d depends on the extent of protein binding, a rate-limiting step in eliminating the drug from the human body. The average percentage of unbound HCQ was 50% (Furst, 1996; Smit et al., 2020) .

Cytochrome P450 (CYP) isoenzymes, CYP1A2, CYP2C8, CYP2C19, CYP2D6, CYP3A4/5, CYP2C8, and CYP3A4/5, catalyses the dealkylation of CQ/HCQ, leading to the formation of active metabolites desethylchloroquine (common metabolite for both CQ/HCQ) and desethylhydroxychloroquine, respectively. The effectiveness of desethylchloroquine in Covid-19 is unknown (Smit et al., 2020; Yazdany and Kim, 2020) . These metabolites undergo further metabolism to a toxic metabolite, bisdesethylchloroquine, which is reported to cause heart failure after long-term use (Karunajeewa et al., 2010) . A single dose of HCQ J o u r n a l P r e -p r o o f and CQ is cleared via the renal route to the extent of 40-50% and 57%, respectively.

Published studies have shown that the plasma concentrations of HCQ useful in malaria were achieved in treating patients with Covid-19. Similar QTc measurements were considered during pre-and post-treatment in both diseases. However, HCQ was found not effective in preventing, treating, or slowing the disease's progression in most of the studies reported so far (Lim et al., 2009 Besides, some studies are involved using crushed HCQ for feeding to patients via tube, though HCQ is a film-coated drug listed in ''Do Not Crush'' medication list; (Mitchell, 2011) ii. uncertainty in absorption following various routes, with indefinite bioavailability; iii.

Distribution studies are confined to animal models, which will highly differ in humans due to lower drug recovery rates and metabolic patterns of drugs as influenced by Cyps; iv. no research investigating genetic association (notably with CYP3A, 2D6; and 2C8) monitoring HCQ drug levels in patients have been done so far; v. No data on drug transporters associated with HCQ or excretion data have been reported so far for Covid-19.

Further, recently the pharmacokinetics-based studies were performed for HCQ in Covid-19 patient by Perinel and group. The work suggested a mix of scientific experiments followed by model-based analysis to predict optimized efficacy and safe dose for HCQ. In the study, 13 patients were included comprising 12 mechanically ventilated patients (median weight: 82.7 kg, median age: 68 years). The initial dose was given was 200 mg t.i.d via the oral route that led only 61% of patients in the study to achieve therapeutic levels (1 mcg/ml), and 15% were found to acquire toxic levels (2 mcg/ml). Further, based on these initial inputs, a simulation study was done to decide an optimal dosing regimen. The analysis revealed with 800 mg of loading dose on the first day followed with 200 mg bid for 7 days, provide optimal effects (Mitchell, 2011) . using similar studies and concluded that CQ is more efficacious than HCQ (5.47 and 6.14 μM, respectively) with a similar mechanism of blocking endocytotic vesicle maturation, that is, blocking infection with SARS-CoV-2 at both entry and post-entry levels . However, Yao et al. reported HCQ was statistically significantly more potent than CQ (0.72 and 5.47 μM, respectively) in in vitro studies) (Yao et al., 2020) . There have been limited in vivo studies elucidating the mechanism of HCQ in SARS-CoV-2 infection.

Clinical study results on HCQ in Covid-19 patients were first briefed in February 2020 by the Chinese government. It was revealed that a significant improvement of pneumonia and lung imaging, along with a reduction in the span of illness, was observed in 100 patients treated with CQ with no observable adverse effects. The dose suggested in the study was 300 mg for CQ twice a day, for 10 days (Gao et al., 2020) . This was further followed by another Chinese study in which HCQ (in comparison to placebo) could reduce the time to clinical recovery in 62 patients (Chen et al., 2020b) . The first report on non-randomized clinical trial came was Based on these results, the USFDA revoked the status of HCQ in treatment for Covid-19 from its global drug trials. However, the ban was imposed based on trial results from inhospital patients; however, out-patients results are still expected probably by September 2020. An outpatient study recently conducted by Caleb and group also pointed that HCQ do not found much active in reducing the severity of symptoms severity in Covid-19 patients.

The assigned dose was 800 mg once, followed by 600 mg in 6-8 h on same day, further followed by 600 mg 4 days in comparison to placebo on 491 patients (Skipper et al., 2020) .

published by Oriol and group explored the efficacy of HCQ in postexposure cases for prevention of Covid-19. The group disclosed a similar outcome as found by Barnabas and group. The study disclosed no efficacy of HCQ on postexposure therapy when dosed at 800 mg for day 1, followed by 400 mg once for next six days for healthy persons exposed to a patient with Covid-19 positive status. The conclusion was drawn out of the randomized trial conducted on healthy contacts of Covid-19 patients that were subjected to HCQ treatment (1116 participants) in comparison to control intervention or usual care (1198 participants).

The highlights of the study were, HCQ did not lower the incidence to acquire Covid-19 in the exposed healthy participants, and at the time the group reported more incidences of adverse events as compared to control group (Mitja et al.) . Another study by Cavalcanti et al. and ORCHID trials for more conclusive results. (Hernandez et al., 2020c) The second report was more focused on evidence provided by RECOVERY trial, which again failed to demonstrate the compelling evidence. Further, SOLIDARITY and ORCHID trials also failed to establish required results and were discontinued prematurely (Hernandez et al., 2020a) .

The third report also ended in the same conclusion that HCQ/CQ are ineffective for hospital J o u r n a l P r e -p r o o f patients use; however, the study underlined the evidence for outpatient use of HCQ (Hernandez et al., 2020b) . 

In the significant randomized trials conducted so far, no major significance was found.

However, observational studies proved some sort of beneficial effect of HCQ alone or in 

As per evidence (latest of February 16, 2021), 4396 publications (distributed as per Figure   4A ) have come in a year for the critical search of "Hydroxychloroquine AND Covid-19". The majority of papers have been published chronologically by United States (1247) disease, which is of concise duration (Mavrikakis et al., 1996; Melles and Marmor, 2014 Thus there is are essential research gaps that hamper the HCQ use at this stage.

Also, assessing the cause of organ damage via use of CQ/HCQ is a complex diagnostic task.

This is major because disease like rheumatoid arthritis and systemic lupus erythematosus in which CQ/HCQ is prescribed most often involves a cardiovascular system, and the associated symptoms are frequently nonspecific enough to initiate a diagnosis. Moreover, as diagnostic J o u r n a l P r e -p r o o f tools are the concerned determination of CQ/HCQ blood level is not accurate by them plausibly due to complex pharmacokinetics of these drug inter-individual variation in metabolism. Still, there lie few diagnostic tools, used to measure the impact of these drugs on cardiotoxicity. The important one includes cardiac imaging majorly via magnetic resonance imaging (T1 mapping), endomyocardial biopsy, echocardiography, histological assessment using ultra electron microscopy and differential diagnostic. (Chatre et al., 2018; Tönnesmann et al., 2013) . Among these, echocardiography has emerged to found utility in the diagnosis of acute cardiac complications and treatment monitoring in Covid-19. Echocardiography deploys ultrasound waves to create an assessment of heart, its size, thickness, wall movement, working of heart valves, and conditions of regurgitation and stenosis. It is divided into various subtypes depending on utility, important one includes, Transthoracic echocardiography; Transesophageal echocardiography; Stress echocardiography; 3Dechocardiography and Fetal echocardiography. Among all transthoracic echocardiography is widely used in the detection of cardiac toxicities induced by therapeutic drugs. It allows assessment of myocardial strain and thus supports the diagnosis of myocarditis. The echocardiography thus may reveal early detection of myocardial dysfunction and thus allow possible treatment discontinuation before severe toxicity precipitates (Vrettou et al., 2020) .

At last, the third category confines to the inflammation in the form of cytokine storm and severe ARDS take over; therefore, using CQ/HCQ treatment at this stage would be beneficial owing to the reports it can overcome cytokine storm and improves ARDS. Though clinical evidence disfavors the use of this anti-malarial drug at this point, substantial shreds of evidence from planned randomized trial taking along its pharmacokinetics parameters are the need of an hour before drawing the final conclusion.

Finally, as it has been exemplary, saying "prevention is better than cure," so the use of CQ/HCQ is the rationale to prevent the entry of viruses in patients with high risk, including health workers. Many studies are currently ongoing to explore the beneficial effect of HCQ , 2020) . However, the model predicted studies were not corroborated biologically, which thus hampers their authenticity and did not disclose much about the proven target(s) if any.

It is suggested that the timing of administration and the PK properties of HCQ are a significant influencer on the outcome of the treatment of disease. In the current compilation, we expedite through various literature and available evidence for a plausible role of CQ/HCQ in Covid-19. The critical gaps identified during this work include i. In vitro and in vivo, assays need much more calibration to adequately and precisely define the inhibitory potential of HCQ; ii. Development of optimal pharmacokinetics models, both theoretically and biologically, to define the therapeutic dosing system to lower the viral load without provoking side effects or doses regimen for prophylactic use; iii. experiments to assess the concentration of HCQ in lungs, along with V d in the various compartment during treatment duration in human model affected with Covid-19 are required; and iv. more experimentation exploring the combination role of HCQ with other important repurposed molecules in Covid-19 to decrease the viral load and improve the efficacy further via synergistic mechanism; v.

thorough and robust experiments to explore HCQ utility in prophylaxis versus mild versus J o u r n a l P r e -p r o o f moderate versus severe disease. Further, the critical gap which we believe comes is from the clinical trials conducted concerning the need for good well defined unbiased randomized clinical trial to corroborate the same findings. Although the things went very well during in vitro studies and in the initial phases of the pandemic, which was shortly dampened by clouds of unefficacious results detected in a handful of clinical trials conducted. Some studies though suggested better outcomes for HCQ use in patients of Covid-19 or for its prophylactic use, and the studies still have some methodological limitations. The critical limitation in clinical evidence is i. high risk and biased studies, ii. no studies were done on critically ill patients with co-morbidities existing, iii. the period of treatment was concise, which again points towards the authenticity of trials, iv. dosing error was almost there with every trial, with dose ranging from 400 mg to 1200 mg within a span of 5-10 days, with no due consideration given to obese patients, paediatric population, pregnancy, and patients with other complications like diabetes, cancer, respiratory or cardiovascular disorders. The research/editorials by pioneer journals, including the New England Journal of Medicine and Lancet has also emphasized randomized controlled trials that should be well designed and adequately powered to prove the efficacy of HCQ. Further, we are in 14 months since the pandemic started, and there is indistinct evidence as to which drug regimen may work well. 

The manuscript has been prepared and drafted with mutual understanding and contributions of all the authors.

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GJ thanks Central University of Punjab and Graphic Era Hill University for necessary support and Infrastructure.

The authors declare that they have no competing financial interests.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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