LitCovid-sample-sentences  

PMC:7441788 JSONTXT 37 Projects

Annnotations TAB TSV DIC JSON TextAE

Id Subject Object Predicate Lexical cue
T1 0-87 Sentence denotes Advances in the use of chloroquine and hydroxychloroquine for the treatment of COVID-19
T2 88-90 Sentence denotes J.
T3 91-101 Sentence denotes SUN ET AL.
T4 102-123 Sentence denotes POSTGRADUATE MEDICINE
T5 125-133 Sentence denotes Abstract
T6 134-142 Sentence denotes ABSTRACT
T7 143-275 Sentence denotes Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading worldwide.
T8 276-339 Sentence denotes Antiviral therapy is the most important treatment for COVID-19.
T9 340-487 Sentence denotes Among the drugs under investigation, anti-malarials, chloroquine (CQ) and hydroxychloroquine (HCQ), are being repurposed as treatment for COVID-19.
T10 488-665 Sentence denotes CQ/HCQ were shown to prevent receptor recognition by coronaviruses, inhibit endosome acidification, which interferes with membrane fusion, and exhibit immunomodulatory activity.
T11 666-752 Sentence denotes These multiple mechanisms may work together to exert a therapeutic effect on COVID-19.
T12 753-902 Sentence denotes A number of in vitro studies revealed inhibitory effects of CQ/HCQ on various coronaviruses, including SARS-CoV-2 although conflicting results exist.
T13 903-1128 Sentence denotes Several clinical studies showed that CQ/HCQ alone or in combination with a macrolide may alleviate the clinical symptoms of COVID-19, promote viral conversion, and delay disease progression, with less serious adverse effects.
T14 1129-1289 Sentence denotes However, recent studies indicated that the use of CQ/HCQ, alone or in combination with a macrolide, did not show any favorable effect on patients with COVID-19.
T15 1290-1393 Sentence denotes Adverse effects, including prolonged QT interval after taking CQ/HCQ, may develop in COVID-19 patients.
T16 1394-1685 Sentence denotes Therefore, current data are not sufficient enough to support the use of CQ/HCQ as therapies for COVID-19 and increasing caution should be taken about the application of CQ/HCQ in COVID-19 before conclusive findings are obtained by well-designed, multi-center, randomized, controlled studies.
T17 1687-1689 Sentence denotes 1.
T18 1691-1703 Sentence denotes Introduction
T19 1704-1910 Sentence denotes Coronavirus disease-19 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is rapidly spreading worldwide, resulting in the third outbreak of coronaviruses in the 21st century.
T20 1911-1988 Sentence denotes The pandemic of COVID-19 constitutes a serious threat to the whole world [1].
T21 1989-2196 Sentence denotes To control the pandemic of COVID-19, effective and easily accessible antiviral drugs and vaccines are urgently needed, in addition to the implementation of epidemiological measures such as strict quarantine.
T22 2197-2282 Sentence denotes However, until now, no drugs have been demonstrated to be effective against COVID-19.
T23 2283-2553 Sentence denotes Among the various drugs under investigation are repurposed anti-malarial drugs chloroquine (CQ) and its analog hydroxychloroquine (HCQ), which are among the most used drugs because they are easy to obtain and have a proven favorable safety record at relatively low cost.
T24 2554-2597 Sentence denotes CQ/HCQ are derivatives of 4-aminoquinoline.
T25 2598-2761 Sentence denotes They are lipophilic weak bases that quickly pass across cell membranes and accumulate in acidic organelles, such as lysosomes, endoplasmic reticulum and Golgi [2].
T26 2762-3004 Sentence denotes CQ/HCQ are used to treat and prevent malaria attacks due to their anti-plasmodium activity and to treat autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) owing to their immunomodulatory activity [3].
T27 3005-3088 Sentence denotes In addition, CQ/HCQ display antibacterial, antifungal and antiviral activities [4].
T28 3089-3320 Sentence denotes In vitro studies have shown that CQ/HCQ possess antiviral activity against RNA viruses, such as HIV [5], rabies virus [6] and polio virus [7] and various DNA viruses as diverse as hepatitis B virus [8] and herpes simplex virus [9].
T29 3321-3433 Sentence denotes This article reviews the current status of CQ/HCQ against SARS-CoV-2 and their use in the treatment of COVID-19.
T30 3435-3437 Sentence denotes 2.
T31 3439-3514 Sentence denotes Antiviral activity of CQ/HCQ against human coronavirus in vitro and in vivo
T32 3515-3882 Sentence denotes The antiviral activity of CQ against MERS-CoV and HCoV-229E was assessed in the human hepatoma cell line (Huh-7) and found that the 50% effective concentrations (EC50) were 3.0(±1.1) μM and 3.3(±1.2) μM, the 50% cytotoxic concentrations (CC50) were 58.1(±1.1) μM and >50, and the selectivity indexes (SI; calculated as CC50/EC50) were 19.4 and >15, respectively [10].
T33 3883-3948 Sentence denotes CQ could inhibit an early step in the MERS-CoV replication cycle.
T34 3949-4041 Sentence denotes Addition of CQ to VeroE6 cells 1 h after MERS-CoV infection did not affect virus production.
T35 4042-4209 Sentence denotes However, when CQ was added 1 h before MERS-CoV infection, 16 μm and 32 μM concentrations of CQ could reduce the virus production of 1-log and 2-log, respectively [10].
T36 4210-4397 Sentence denotes In VeroE6 cells, the antiviral activity of CQ/HCQ against SARS-CoV had an EC50 of 4.1 (±1.0) μM and 34(±5) μM, CC50 of >128 μM and CC50 > 100 and SI of >31 and SI>3, respectively [10,11].
T37 4398-4479 Sentence denotes SARS-CoV replication was inhibited by 99% at 16 μM CQ 3 days post-infection [12].
T38 4480-4552 Sentence denotes The data indicates that CQ has stronger anti-SARS-CoV activity than HCQ.
T39 4553-4621 Sentence denotes In addition, CQ has both a prophylactic and a therapeutic advantage.
T40 4622-5112 Sentence denotes Vincent et al. tested various concentrations of CQ (0.1–10 µM) added 20–24 h prior to SARS-CoV infection and found that 0.1, 1, and 10 µM CQ reduced infectivity by 28%, 53%, and 100%, respectively; when CQ was added immediately after virus adsorption, 0.1–1 µM and 33–100 µM reduced the infection by 50% up to 90–94%; addition of CQ 3 and 5 h after virus adsorption was still significantly effective, yet to achieve equivalent antiviral effect, a higher concentration of CQ was needed [13].
T41 5113-5259 Sentence denotes In HRT-18 cells, the antiviral activity of CQ against HCoV-OC43 had an EC50 of 0.306 (±0.091) μM, CC50 of 419.0 (±192.5) μM, and SI of 1.369 [14].
T42 5260-5365 Sentence denotes An in vivo study found that CQ could exert anti-HCoV-OC43 activity transplacentally or via maternal milk.
T43 5366-5628 Sentence denotes The data from mouse models showed that 98.6% of the pups survived when pregnant mice were treated with 15 mg/kg of CQ, and survival rates decreased in a dose-dependent manner, with 88% and 13% survival when treated with 5 mg/kg and 1 mg/kg CQ, respectively [14].
T44 5629-5716 Sentence denotes The survival rate of newborn mice via maternal milk was 69.0% with 15 mg/kg of CQ [14].
T45 5717-5866 Sentence denotes In another mouse study, CQ strongly attenuated HCoV-OC43 replication in the brain and prevented the infection from spreading to the spinal cord [15].
T46 5867-5969 Sentence denotes The above studies confirmed that CQ/HCQ have a broad-spectrum anti-HCoV activity in vitro and in vivo.
T47 5971-5973 Sentence denotes 3.
T48 5975-6031 Sentence denotes Antiviral activity of CQ/HCQ against SARS-CoV-2 in vitro
T49 6032-6140 Sentence denotes In VeroE6 cells, the EC50, CC50 and SI of CQ against SARS-CoV-2 were 1.13 μM, >100 and >88.50, respectively.
T50 6141-6225 Sentence denotes CQ functioned at the entry, and post-entry stages of SARS-CoV-2 infected cells [16].
T51 6226-6456 Sentence denotes In the same cell line, at different multiplicities of infection (MOIs, 0.01, 0.02, 0.2, and 0.8) of SARS-CoV-2, the EC50 for CQ (2.71, 3.81, 7.14, and 7.36 μM) was slightly lower than that of HCQ (4.51, 4.06, 17.31, and 12.96 μM).
T52 6457-6589 Sentence denotes Consequently, the SI of CQ (100.81, 71.71, 38.26, and 37.12) was slightly higher than that of HCQ (55.32, 61.45, 14.41, 19.25) [17].
T53 6590-6695 Sentence denotes These results indicate that the anti-SARS-CoV-2 activity of CQ seems to be more potent than HCQ in vitro.
T54 6696-7123 Sentence denotes However, another in vitro cell experiment showed that after SARS-CoV-2 infection of VeroE6 cells, the EC50 values for CQ were 23.90 μM and 5.47 μM, and EC50 values for HCQ were 6.14 μM and 0.72 μM, at 24 and 48 h, respectively; When administered prior to SARS-CoV-2 infection of VeroE6 cells, EC50 values for CQ were >100 μM and 18.01 μM, and the EC50 values for HCQ were 6.14 μM and 0.72 μM, at 24 and 48 h, respectively [18].
T55 7124-7213 Sentence denotes These results showed that the anti-SARS-CoV-2 activity of CQ was worse than HCQ in vitro.
T56 7214-7336 Sentence denotes The conflicting results of these two studies may be related to different cell culture methods and experimental conditions.
T57 7337-7424 Sentence denotes In short, these in vitro studies show that CQ/HCQ have strong anti-SARS-CoV-2 activity.
T58 7426-7428 Sentence denotes 4.
T59 7430-7471 Sentence denotes Mechanisms of CQ/HCQ in treating COVID-19
T60 7473-7477 Sentence denotes 4.1.
T61 7479-7497 Sentence denotes Antiviral activity
T62 7499-7505 Sentence denotes 4.1.1.
T63 7507-7548 Sentence denotes Hindrance of receptor recognition process
T64 7549-7640 Sentence denotes The S protein of SARS-CoV-2 is cleaved by host proteases into two subunits, S1 and S2 [19].
T65 7641-7824 Sentence denotes The S1 subunit binds to the host cell surface receptor angiotensin-converting enzyme 2 (ACE2) for virus attachment, and the S2 subunit fuses the virus and the host cell membrane [19].
T66 7825-8213 Sentence denotes The investigation of the effect of CQ on ACE2 in VeroE6 cells showed that effective anti-SARS-CoV-2 concentrations of CQ had no significant effect on the synthesis and glycosylation of S protein on the surface of SARS-CoV, and although it had no significant effect on the cell surface expression of ACE2, CQ could destroy the glycosylation at the terminal glycosylation site of ACE2 [13].
T67 8214-8487 Sentence denotes Therefore, the mechanism of anti-CoV activity of CQ/HCQ may be at least partly related to the impairment of terminal glycosylation of ACE2, which may result in reduced binding affinities between ACE2 and SARS CoV S protein, thereby blocking receptor recognition (Figure 1).
T68 8488-8497 Sentence denotes Figure 1.
T69 8498-8616 Sentence denotes Schematic representation of the possible mechanisms of CQ/HCQ against CoVs replication and modulating immune response.
T70 8617-9248 Sentence denotes CQ/HCQ may synergistically exert antiviral and immunomodulatory effects on COVID-19 through multiple mechanisms including hindering the receptor recognition process by influencing the affinity of ACE2 and S protein, and the affinity for sialic acid and ganglioside; inhibiting the membrane fusion process by suppressing endolysosome acidification; suppressing the p38 activation and affecting host defense machinery, and preventing MHC class II expression (block expression of CD154 on the surface of CD4 + T cell) and TLR signaling and reducing the production of cytokines through inhibiting the activation of T cells and B cells.
T71 9249-9599 Sentence denotes ACE2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019; CQ, chloroquine; HCQ, hydroxychloroquine; CoVs, coronaviruses; MAPK, mitogen-activated protein kinase; MHC-II, major histocompatibility complex class II; TLR, toll-like receptor; cGAS, cyclic GMP-AMP synthase; IFN, interferon; IL, interleukin; TNF-α, tumor necrosis factor-α.
T72 9600-9885 Sentence denotes In addition to protein membrane receptors, infection of host cells by HCoVs also relies on sialic acid-containing glycoproteins and gangliosides, which are used by a broad range of viruses as receptors, such as influenza [20] and HCoVs including SARS-CoV [21] and HCoV-OC43 [13,22,23].
T73 9886-10084 Sentence denotes A recent molecular structure analysis showed that SARS-CoV-2 not only uses ACE2 as a receptor, but also recognizes highly conserved gangliosides on the host cell surface through sialic acid [24,25].
T74 10085-10225 Sentence denotes CQ/HCQ binds sialic acids and gangliosides with high affinity, which can prevent the attachment of SARSCoV-2 S protein to gangliosides [25].
T75 10226-10333 Sentence denotes CQ had inhibitory effect on quinone reductase 2 (QR2) involved in the biosynthesis of sialic acids [26,27].
T76 10334-10485 Sentence denotes Hence, the mechanism of anti-CoV activity of CQ/HCQ may also be related to hindering the recognition process of sialic acid and ganglioside (Figure 1).
T77 10487-10493 Sentence denotes 4.1.2.
T78 10495-10538 Sentence denotes Interference of the membrane fusion process
T79 10539-10666 Sentence denotes CoVs are enveloped RNA viruses, and their cell entry processes involve a principal route of receptor-mediated endocytosis [28].
T80 10667-10831 Sentence denotes Membrane fusion takes place in the endosomal compartment after endocytosis, which needs additional triggers such as pH acidification or proteolytic activation [29].
T81 10832-11071 Sentence denotes Multiple cellular proteases, such as trypsin, furin, proprotein convertase (PC) family, cathepsins, transmembrane protease/serine (TMPRSS) proteases and elastase, are involved in S protein activation, which can induce membrane fusion [30].
T82 11072-11306 Sentence denotes Among them, cathepsin L, with anoptimal pH of 3.0 to 6.5, is most commonly associated with activation of a variety of CoV S proteins [30], such as SARS-CoV [19], MERS-CoV [31], HCoV-229E [32], and mouse hepatitis virus 2 (MHV-2) [33].
T83 11307-11469 Sentence denotes A recent study found that SARS-CoV-2 enters 293/hACE2 cells mainly through endocytosis, in which cathepsin L is critical for priming of SARS-CoV-2 S protein [24].
T84 11470-11819 Sentence denotes A study investigated the detailed mechanism of action of CQ/HCQ in inhibiting SARS-CoV-2 entry, and co-localization of SARS-CoV-2 with early endosomes (EEs) or endolysosomes (ELs) in VeroE6 cells, and the results showed that CQ/HCQ hampered the transport of SARS-CoV-2 from EEs to ELs, indicating that CQ/HCQ might inhibit endosomal maturation [17].
T85 11820-12083 Sentence denotes These studies revealed that the mechanism of anti-CoV activity of CQ/HCQ may involve the inhibition of the endosome acidification process, which might inactivate lysosomal proteases, thus interfering with the fusion of virus and host membranes [34,35] (Figure 1).
T86 12085-12091 Sentence denotes 4.1.3.
T87 12093-12153 Sentence denotes Effects on cell signaling pathway and host defense machinery
T88 12154-12330 Sentence denotes The mitogen-activated protein kinase (MAPK) pathway transmits signals from the cell surface to the nucleus involved in the infection of CoVs such as MHV [36] and SARS-CoV [37].
T89 12331-12470 Sentence denotes CQ could inhibit HCoV-229E replication in human embryonic lung epithelial cells (L132) through suppressing the activation of p38 MAPK [38].
T90 12471-12636 Sentence denotes Moreover, HCQ could markedly induce the production of cellular reactive oxygen species (ROS), which play an important role in the activation of innate immunity [39].
T91 12637-12794 Sentence denotes HCQ also could trigger the host defense mechanism through the mitochondrial antiviral signaling (MAVS) pathway, resulting in anti-dengue virus activity [39].
T92 12795-12955 Sentence denotes Therefore, CQ/HCQ may also exert their antiviral activity by suppressing the activation of p38 MAPK pathway and affecting the host defense machinery (Figure 1).
T93 12957-12961 Sentence denotes 4.2.
T94 12963-13025 Sentence denotes Inhibitory effect on T cell activation and cytokine production
T95 13026-13128 Sentence denotes CQ/HCQ regulate the release of various pro-inflammatory factors, which are important immunomodulators.
T96 13129-13314 Sentence denotes Intracellular alkalinization by CQ/HCQ inhibits lysosomal activity, preventing antigen processing, major histocompatibility complex (MHC) class II expression and immune activation [40].
T97 13315-13425 Sentence denotes This process can inhibit T cell activation and block expression of CD154 on the surface of CD4 + T cells [41].
T98 13426-13558 Sentence denotes CQ also reduces cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor-α (TNF-α) produced by T cells and B cells [42].
T99 13559-13749 Sentence denotes At the same time, changes of endosomal pH can interfere with Toll-like receptor (TLR) signaling, such as TLR7 and TLR9 processing, inhibiting the activation and production of cytokines [43].
T100 13750-13901 Sentence denotes CQ/HCQ also weaken the cyclic GMP-AMP (cGAMP) synthase (cGAS) activity by inhibiting cytosolic DNA, thereby reducing type I interferon production [44].
T101 13902-14050 Sentence denotes In vitro, CQ/HCQ can also inhibit phospholipase A2, altering the metabolism of arachidonic acid, and reducing the production of prostaglandins [45].
T102 14051-14346 Sentence denotes Some clinical studies have found that high concentrations of cytokines and pro-inflammatory factors such as IL-6 and IL-10 are elevated in the plasma of critically ill patients infected with SARS-CoV-2 [46,47], suggesting that cytokine release syndrome (CRS) is associated with disease severity.
T103 14347-14473 Sentence denotes In the aspect of immune response, HCQ/CQ therefore are likely to inhibit CRS, delaying the progression of COVID-19 (Figure 1).
T104 14475-14477 Sentence denotes 5.
T105 14479-14535 Sentence denotes Clinical efficacy of CQ/HCQ in the treatment of COVID-19
T106 14536-14635 Sentence denotes Only two published clinical reports have studied the efficacy of CQ in COVID-19 patients (Table 1).
T107 14636-14889 Sentence denotes One study used CQ to treat more than 100 patients with COVID-19 and claimed that CQ was superior to the control group in suppressing the deterioration of pneumonia, improving lung imaging, promoting viral conversion and shortening the course of disease.
T108 14890-14955 Sentence denotes Serious adverse effects were not observed in these patients [48].
T109 14956-15092 Sentence denotes However, this report did not provide any details about the study design and patient data, thus it is difficult to evaluate the validity.
T110 15093-15195 Sentence denotes Recently, a parallel, double-blind, randomized, phase IIB clinical trial was performed in Brazil [49].
T111 15196-15277 Sentence denotes In this study, 81 severe COVID-19 patients were randomly divided into two groups:
T112 15278-15445 Sentence denotes 41 patients received high-dose CQ (600 mg/2 times/day for 10 day) and 40 patients received low-dose CQ (450 mg/2 times on day 1 and then 450 mg/1 time/day for 4 days).
T113 15446-15557 Sentence denotes The 13-day mortality rate in the high-dose group was more than double that in low-dose group (39.0% vs. 16.0%).
T114 15558-15734 Sentence denotes The high-dosage group exhibited more instance of corrected QT (QTc) interval prolongation (>500 milliseconds (ms); 7 of 37 [18.9%]) than the low-dosage group (4 of 36 [11.1%]).
T115 15735-15857 Sentence denotes These findings suggest that the higher CQ dosage should not be recommended for critically ill patients with COVID-19 [49].
T116 15858-15866 Sentence denotes Table 1.
T117 15867-15976 Sentence denotes Outcomes and advantage/limitation of chloroquine (CQ)/hydroxychloroquine (HCQ) clinical studies for COVID-19.
T118 15977-16058 Sentence denotes Author (Reference) Study design Patients Treatment Outcomes Advantage Limitations
T119 16059-16074 Sentence denotes Gao et al [48].
T120 16075-16304 Sentence denotes Rough and simple description Not mentioned CQ (No specific dosage was mentioned) CQ was superior to control in suppressing pneumonia deterioration, improving lung imaging, promoting viral conversion and shortening disease course.
T121 16305-16321 Sentence denotes Not significant.
T122 16322-16448 Sentence denotes No study design and the specific number of patients and controls were provided and thus the result appears to be unconvincing.
T123 16449-16466 Sentence denotes Borba et al [49].
T124 16467-16953 Sentence denotes Randomized controlled trial High-dose CQ group: n = 40;Low-dose CQ group:n = 41 high-dose CQ (600 mg/2 times/day, for 10 day);low-dose CQ (450 mg/2 times/day for 5 days, double dose on 1st day) The mortality rate in the high-dose group was more than double that in low-dose group Double-blind study; 2 dosages of CQ for the first time in severe COVID-19 Small sample size; single-center design; Lack of a placebo control; Lack of exclusion criteria based on the QTc interval at baseline
T125 16954-17172 Sentence denotes Chen et al.[50] Randomized trial HCQ group: n = 31; control group: n = 30 HCQ (200 mg/2 times/day for 5 days) HCQ group have small improvement in body temperature and cough compered with control group Randomized trial.
T126 17173-17257 Sentence denotes Small sample size; Single-center design; Small improvement in temperature and cough.
T127 17258-17277 Sentence denotes Mahévas et al [53].
T128 17278-17496 Sentence denotes Comparative study HCQ group: n = 84; control group: n = 97 HCQ 600 mg/day for 7 days Compared with control group, a reduction of admissions to ICU or death 7 days after hospital admission was not observed in HCQ group.
T129 17497-17563 Sentence denotes Relatively larger sample size in HCQ treatment and control groups.
T130 17564-17674 Sentence denotes Nonrandomized design; In propensity score model, four possible important prognostic variables were unbalanced.
T131 17675-17691 Sentence denotes Tang et al [54].
T132 17692-17773 Sentence denotes Open label, randomized controlled trial HCQ group: n = 70; control group: n = 80.
T133 17774-17980 Sentence denotes HCQ 1200 mg daily for 3 days, 800 mg daily for 2 weeks (mild to moderate disease)/3 weeks(severe disease) HCQ did not show additional benefits of vial elimination in patients with mild to moderate COVID-19.
T134 17981-18009 Sentence denotes Randomized controlled study.
T135 18010-18208 Sentence denotes Lack of a placebo control group; Design introduces the possibility of biased investigator determined assessment and unbalanced dosage adjustment; Randomization of sequential envelopes may be biased.
T136 18209-18392 Sentence denotes The antiviral efficacy of HCQ was not assessed at an earlier stage; Most patients are mild to severe, and the effect of HCQ on disease progression or regression could not be provided.
T137 18393-18469 Sentence denotes The trial terminated early due to the difficulty to recruit enough patients.
T138 18470-18682 Sentence denotes Some secondary endpoints could not be analyzed by the cutoff date; Viral RNA specimens are mostly from the upper respiratory tract rather than bronchoalveolar lavage fluid, which may cause false negative results.
T139 18683-18702 Sentence denotes Geleris et al [55].
T140 18703-18946 Sentence denotes Observational study HCQ group: n = 811; no-HCQ group: n = 565 HCQ (600 mg/2 times on the first day, then 400 mg once a day for 4 days) No correlation between the HCQ use and significant higher or lower risk of intubation or death was observed.
T141 18947-19118 Sentence denotes Large sample size; Minimization of the unmeasured confusion and error through multivariable Cox model with inverse probability weighting according to the propensity score.
T142 19119-19228 Sentence denotes Single-center design; missing of some variables; Potential for inaccuracies in the electronic health records.
T143 19229-19243 Sentence denotes Yu et al [56].
T144 19244-19418 Sentence denotes Retrospective study HCQ group: n = 48; no-HCQ group: n = 502 HCQ (200 mg/2 times/day, for 7 to 10 days) The fatalities of HCQ group was significantly lower than no-HCQ group.
T145 19419-19547 Sentence denotes HCQ treatment was related to significantly reduced mortality in critically ill COVID-19 patients and greatly lowered IL-6 level.
T146 19548-19638 Sentence denotes Mortality was used as a measure of outcome and the study included critically ill patients.
T147 19639-19720 Sentence denotes Retrospective design of the study and the number of HCQ group patients was small.
T148 19721-19991 Sentence denotes Gautret et al.[57] Open label, nonrandom cohort study HCQ group: n = 12; HCQ＋azithromycin group: n = 6; control group: n = 12 HCQ (200 mg/3 times/day for 10 days) HCQ alone or in combination with azithromycin could effectively eliminate nasopharyngeal virus in 3–5 days.
T149 19992-20053 Sentence denotes Nasopharyngeal virus determination was used as main endpoint.
T150 20054-20203 Sentence denotes Small sample size; Six patients dropped out due to critical illness or intolerance to the drug; Lack of clinical outcomes; Limited follow-up results.
T151 20204-20223 Sentence denotes Gautret et al [58].
T152 20224-20467 Sentence denotes Observational study HCQ group: n = 80; no control HCQ, 200 mg/3 times/day for 10 days combined with azithromycin 500 mg on the 1st day, 250 mg/day afterward for 5 days The nasopharynx viral load in most patients received HCQ decreased rapidly.
T153 20468-20506 Sentence denotes Observation of nasopharynx viral load.
T154 20507-20591 Sentence denotes Observational study design and no control group; No clinical outcomes were analyzed.
T155 20592-20639 Sentence denotes Possible confounding factors were not adjusted.
T156 20640-20661 Sentence denotes Magagnoli et al [59].
T157 20662-20758 Sentence denotes Retrospective study HCQ group:n = 97HCQ＋azithromycin: n = 113No HCQ group:n = 158 Not specified.
T158 20759-20981 Sentence denotes The use of HCQ, either with or without azithromycin, didn’t reduce the risk of mechanical ventilation in patients hospitalized with COVID-19; Patients treated with HCQ alone was associated with increased overall mortality.
T159 20982-21203 Sentence denotes The study data comes from a comprehensive electronic medical record; Strictly defined covariates and outcomes; Using propensity scores adjustment for a large number of relevant confounders to make results more persuasive.
T160 21204-21397 Sentence denotes Retrospective nature of the study; The subjects included only men and most of them were black; Despite adjustments to many possible confounding factors, there may still be undiscovered factors.
T161 21398-21904 Sentence denotes Rosenberg et al[60] Retrospective multicenter cohort study HCQ group:n = 271;HCQ ＋azithromycin group:n = 735control group:n = 221 HCQ:200 mg/400 mg/600 mg/other/unknown, frequency: once a day/twice a day/other/unknownazithromycin:200 mg/250 mg/400 mg/500 mg/other/unknown, methods:Oral/IV/unknown,frequency: only once/once a day/twice a day/other/unknown Treatment with HCQ, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality.
T162 21905-21987 Sentence denotes This study include a large, random sample from 25 metropolitan New York hospitals.
T163 21988-22152 Sentence denotes The sample was drawnearly in the epidemic to include patients with long, complicated, and ongoing hospital stays; In-hospital mortality was used as primary outcome.
T164 22153-22294 Sentence denotes Retrospective study design; There may be missing information; Mortality was limited to in-hospital death; There may be potential confounders.
T165 22295-22374 Sentence denotes The dosing in the doses and frequencies of HCQ and azithromycin varied greatly.
T166 22375-22434 Sentence denotes The confidence intervals for some of the findings are wide.
T167 22435-22893 Sentence denotes Mehraet al[61] Multinational real-world analysis Teatment groups: n = 14,888Control group: n = 81,144 Mean daily dose: CQ 765 mg, (SD 308); HCQ 596 mg(126); CQ with a macrolide 790 mg(320); HCQ with a macrolide 597 mg(128).mean duration:CQ 6.6 days(2.4); HCQ 4.2 days(1.9);CQ with a macrolide 6.8 days(2.5); HCQ with a macrolide 4.3 days (2.0) A benefit of HCQ or CQ, when used alone or witha macrolide, on in-hospital outcomes for COVID-19 was not observed.
T168 22894-22968 Sentence denotes Large multinational real-world data and large number of study populations.
T169 22969-23287 Sentence denotes There may be potential confounders; It did not measure QT intervals and stratify the arrhythmia pattern; It did not determine whether the increased risk of death in-hospital and use of drug treatment regimens were directly related to cardiovascular risk; It did not observe the risk of the drug dose-response analysis.
T170 23288-23373 Sentence denotes Several trials evaluated the efficacy of HCQ for the treatment of COVID-19 (Table 1).
T171 23374-23526 Sentence denotes In a randomized clinical trial from Wuhan about HCQ treatment of mild COVID-19 [50], 31 out of 62 patients received HCQ (200 mg/2 times/day for 5 days).
T172 23527-23882 Sentence denotes The results showed that the temperature recovery time in the HCQ group was improved compared with the control group (average days, 2.2 vs. 3.2); the cough relief time was shorter in the HCQ group than the control group (average days, 2.4 vs. 3.1); and the improvement rate of pneumonia in the HCQ group was higher than the control group (80.6% vs. 54.8%).
T173 23883-24045 Sentence denotes However, only 48% of patients (15/31) in HCQ group and 71% of patients (22/31) in control group had cough at baseline and the duration of cough was not described.
T174 24046-24122 Sentence denotes Improvement of symptoms were small and the trial was terminated prematurely.
T175 24123-24217 Sentence denotes These factors and the low sample size compromise the reliability of the results of this study.
T176 24218-24424 Sentence denotes Importantly, evaluation of HCQ in the COVID-19 pandemic areas have shown that HCQ can help patients with mild symptoms, and may potentially reduce transmission in areas lacking isolation facilities [51,52].
T177 24425-24609 Sentence denotes However, in areas with strict isolation standards, the use of HCQ to reduce transmission or for treatment of mild COVID-19 cases may not be beneficial in risk-benefit analysis [51,52].
T178 24610-24735 Sentence denotes Nevertheless, there is an urgent need for drugs and therapeutics in severe cases, which require randomized controlled trials.
T179 24736-24862 Sentence denotes A study from four French tertiary care centers included 181 patients hospitalized for COVID-19 and requiring oxygen (2 L/min):
T180 24863-24977 Sentence denotes 84 patients received HCQ (600 mg/day) within 48 hours of admission (HCQ group) and 97 did not (no-HCQ group) [53].
T181 24978-25163 Sentence denotes The results showed that the patients transferred to the ICU or died within 7 days and developed ARDS within 7 days had no significant differences between the HCQ group and no-HCQ group.
T182 25164-25257 Sentence denotes Eight patients in the HCQ group (9.5%) discontinued HCQ due to electrocardiogram alterations.
T183 25258-25372 Sentence denotes These results do not support the use of HCQ for treating hospitalized COVID-19-related hypoxic pneumonia patients.
T184 25373-25580 Sentence denotes It is worth noting that in the study’s propensity score model, four possible important prognostic variables were unbalanced and a center effect was not considered, which all can cause bias for study results.
T185 25581-25875 Sentence denotes In a multicenter, randomized, parallel trial about HCQ in patients with mainly mild to moderate COVID-19 [54], 80 patients received ‘standard care’ and 70 patients received HCQ (1200 mg daily for 3 days, and then 800 mg daily for 2 weeks [mild to moderate disease] or 3 weeks [severe disease]).
T186 25876-26029 Sentence denotes The results showed that the 28-days negative conversion probability in ‘standard care’＋HCQ group was 85.4%, similar to the ‘standard care’ group (81.2%).
T187 26030-26131 Sentence denotes HCQ did not show additional benefits of viral elimination in patients with mild to moderate COVID-19.
T188 26132-26276 Sentence denotes However, the study could not evaluate the antiviral effect of HCQ at early stages of disease, which is a critical period of antiviral treatment.
T189 26277-26436 Sentence denotes In addition, viral RNA specimens were mostly from the upper respiratory tract rather than bronchoalveolar lavage fluid, which may cause false negative results.
T190 26437-26588 Sentence denotes Due to the small number of severe patients, this study could not provide evidence regarding the effect of HCQ on the disease progression or regression.
T191 26589-26825 Sentence denotes In another large observational study involving 1376 cases of COVID-19 from New York, 811 patients received HCQ (600 mg/2 times on the first day, then 400 mg once a day for 4 days) within 24 or 48 hours of admission and 565 did not [55].
T192 26826-26936 Sentence denotes This study found no correlation between HCQ use and significantly higher or lower risk of intubation or death.
T193 26937-27112 Sentence denotes However, in this study, even after the propensity score-matching, the diseases in patients receiving HCQ were more severe at baseline than those in the patients not receiving.
T194 27113-27262 Sentence denotes Notably, according to another recent study [56], low dose of HCQ reduced fatality of critically ill patients with COVID-19 without apparent toxicity.
T195 27263-27432 Sentence denotes This retrospective study included 550 patients who need mechanical ventilation, of which 48 received HCQ treatment (200 mg/2 times/day for 7 to 10 days) and 502 did not.
T196 27433-27723 Sentence denotes The fatalities of the HCQ group was significantly lower than no-HCQ group (18.8% vs 47.4%, P < 0.05), and the inflammatory cytokine IL-6 in the HCQ group decreased significantly from 22.2 (8.3 to 118.9 pg/mL) at the beginning of treatment to 5.2 (3.0 to 23.4 pg/mL) at the end of treatment.
T197 27724-27915 Sentence denotes The authors deemed that the anti-inflammatory effect of low-dose HCQ and the activity of inhibiting viral replication may have important significance in critically ill patients with COVID-19.
T198 27916-28028 Sentence denotes Yet, this study is flawed due to its retrospective nature and the small number of HCQ treated patients included.
T199 28029-28293 Sentence denotes In short, some initial studies have shown that HCQ appears to have a curative effect on patients with mild COVID-19, but subsequent studies indicate that HCQ had no significant benefit in COVID-19 patients with viral conversion and the risk of intubation or death.
T200 28294-28508 Sentence denotes Although some recent studies show that low-dose HCQ could potentially reduce the mortality of severe COVID-19 patients, there are other studies showing that the HCQ use had no effect on risk of intubation or death.
T201 28509-28655 Sentence denotes There are also several reports that investigated the efficacy of CQ or HCQ in combination with a macrolide in the treatment of COVID-19 (Table 1).
T202 28656-28839 Sentence denotes In an open nonrandom clinical trial conducted in France [57], of the 36 participants, 20 patients were given HCQ (200 mg/3 times) with 6 receiving added azithromycin, and 16 controls.
T203 28840-29004 Sentence denotes The results showed that compared with the control group, HCQ alone or in combination with azithromycin could effectively eliminate nasopharyngeal virus in 3–5 days.
T204 29005-29174 Sentence denotes On the 6th day after treatment, the virus clearance rates of HCQ combined with azithromycin, HCQ alone and controls were 100%, 57.1% and 12.5%, respectively (P < 0.001).
T205 29175-29287 Sentence denotes This study indicated that the combined application of azithromycin and HCQ appears to have a synergistic effect.
T206 29288-29497 Sentence denotes However, the trial design and the results were unreliable, as six patients in the HCQ group discontinued treatment early due to critical illness or intolerance to the drugs and were excluded from the analysis.
T207 29498-29581 Sentence denotes The assessment of efficacy was based on viral load rather than a clinical endpoint.
T208 29582-29927 Sentence denotes An observational study in 80 COVID-19 patients evaluated the efficacy of HCQ (200 mg/3 times/day for 10 days) in combination with azithromycin (500 mg on the first day, 250 mg/day afterward for 5 days) and showed that all patients’ clinical symptoms were improved, except for one patient aged over 86 years who died due to critical illness [58].
T209 29928-30100 Sentence denotes The nasopharynx viral load in most patients decreased rapidly, and the negative rates of viral nucleic acid conversion on days 7 and 8 were about 83% and 93%, respectively.
T210 30101-30194 Sentence denotes About 97.5% of patients had negative virus culture in respiratory specimens on the fifth day.
T211 30195-30287 Sentence denotes However, this study had no control group, thus the results were difficult to interpret [58].
T212 30288-30392 Sentence denotes Some recent studies have yielded different results about the efficacy of HCQ combined with azithromycin.
T213 30393-30669 Sentence denotes A retrospective study including 368 patients (97 patients received HCQ, 113 patients received HCQ + azithromycin and 158 patients received no HCQ) from USA [59] showed that the rates of ventilation in the HCQ, HCQ+azithromycin and no HCQ groups had no significant differences.
T214 30670-30801 Sentence denotes Unfortunately, theHCQ group (but not in the HCQ+azithromycin group) had a higher risk of death from any case than the no HCQ group.
T215 30802-30972 Sentence denotes This study showed no evidence that the use of HCQ, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with COVID-19.
T216 30973-31087 Sentence denotes Noticeably, in patients treated with HCQ alone, an association with increased overall mortality was observed [59].
T217 31088-31215 Sentence denotes In this study, the subjects included were only men and most of them were black, which may affect the generality of the results.
T218 31216-31327 Sentence denotes In addition, the patients who received HCQ or azithromycin were more severe, which may also affect the results.
T219 31328-31615 Sentence denotes In a retrospective multicenter cohort study of a random sample of COVID-19 patients from 25 hospitals in New York [60], totaling 1438 patients, 735 received HCQ and azithromycin, 271 received HCQ alone, 211 received azithromycin alone and 221 received neither drug (HCQ or azithromycin).
T220 31616-31795 Sentence denotes The results showed that the hospital mortality rate of patients receiving HCQ＋azithromycin was 25.7%, HCQ alone was 19.9%, azithromycin alone was 10.0% and neither drug was 12.7%.
T221 31796-32026 Sentence denotes In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in hospital mortality rate for patients receiving HC＋azithromycin, HCQ alone, or azithromycin alone.
T222 32027-32141 Sentence denotes In this study, the sample size is large and includes patients with long-term, complex and ongoing hospitalization.
T223 32142-32332 Sentence denotes However, the mortality rate of this study was limited to in-hospital deaths, and patients discharged during the study period were considered alive, which may underestimate the morality rate.
T224 32333-32525 Sentence denotes Recently, a multinational registry analysis about HCQ or CQ with or without second-generation macrolides (especial azithromycin and clarithromycin) for treatment of COVID-19 was reported [61].
T225 32526-32581 Sentence denotes A total of 96,032 patients were included in this study.
T226 32582-32737 Sentence denotes Of these, 1868 received CQ, 3783 received CQ with a macrolide, 3016 received HCQ and 6221 received HCQ with a macrolide and 8114 patients as control group.
T227 32738-33070 Sentence denotes After controlling various confounding factors related to disease, when compared with the mortality in the control group (9.3%), CQ group was 16.4%, CQ with a macrolide group was 22.2%, HCQ group was 18.0% and HCQ group with a macrolide was 23.8%; each group was associated with an increased risk of hospital mortality independently.
T228 33071-33331 Sentence denotes Apart from this, compared with the control group (0.3%), CQ group (4.3%), CQ with a macrolide group (6.5%), HCQ group (6.1%) and HCQ with a macrolide group (8.1%) were independently associated with a risk for ventricular arrhythmia during hospitalization [61].
T229 33332-33521 Sentence denotes This study showed that CQ or HCQ (used alone or combination with a macrolide) was associated with an increased hazard for in-hospital death and an increased risk of ventricular arrhythmias.
T230 33522-33612 Sentence denotes This study included a large number of patients, but it is not a randomized clinical trial.
T231 33613-33830 Sentence denotes In short, some small studies have shown that HCQ combined with azithromycin could quickly and effectively eliminate viruses, but the design of these studies was flawed in many aspects, making the results unconvincing.
T232 33831-34097 Sentence denotes Several subsequent studies have shown that the combination of HCQ or CQ and macrolides (azithromycin or clarithromycin) has no obvious correlation with a reduced risk for mechanical ventilation, and may even increase the risk of arrhythmia and in-hospital mortality.
T233 34098-34419 Sentence denotes In summary, although CQ/HCQ appeared to exhibit a favorable effect on COVID-19 patients in some initial studies of small numbers of patients, the most recent studies with larger sample sizes revealed that CQ/HCQ exhibited no significant improvement of disease but even an increased overall mortality in COVID-19 patients.
T234 34420-34545 Sentence denotes The studies on the combination of HCQ or CQ and macrolides (azithromycin or clarithromycin) also showed conflicting findings.
T235 34546-34736 Sentence denotes Therefore, caution should be taken regarding the use of CQ/HCQ treatment in COVID-19 due to the uncertainty of efficacy, the potential adverse effects and the various defects in the studies.
T236 34737-35000 Sentence denotes According to the Chinese Clinical Trial Registry (ChiCTR) (http://www.chictr.org.cn/index.aspx) and the International Clinical Trials Registry Platform (ICTRP) (https://www.who.int/ictrp/en/), currently, there are more than 200 ongoing clinical trials for CQ/HCQ.
T237 35001-35163 Sentence denotes Current findings suggest that CQ/HCQ alone or in combination with macrolides should not be recommended for widespread use in COVID-19 (except in clinical trials).
T238 35164-35313 Sentence denotes Results from these ongoing prospective, randomized, controlled studies are required before these drugs are recommended for the treatment of COVID-19.
T239 35315-35317 Sentence denotes 6.
T240 35319-35325 Sentence denotes Safety
T241 35326-35421 Sentence denotes CQ/HCQ are basic medications for malaria with a long history of reliable safety records [3,62].
T242 35422-35542 Sentence denotes However, the therapeutic window of CQ is narrow, and the toxic dose is 3 times higher than the therapeutic dose [55,63].
T243 35543-35671 Sentence denotes The most common adverse effects of taking CQ are gastrointestinal discomforts, such as nausea, vomiting, diarrhea, and anorexia.
T244 35672-35743 Sentence denotes These symptoms are mild and can be controlled by reducing the dose [3].
T245 35744-36000 Sentence denotes However, long-term and high-dose CQ intake can cause irreversible damage to the ear, cardiovascular system, and blood system, such as neurological deafness, conduction disorder cardiomyopathy, and leukopenia, though these adverse effects are very rare [3].
T246 36001-36091 Sentence denotes Compared to CQ, HCQ has fewer adverse effects, which may be related to its lower toxicity.
T247 36092-36152 Sentence denotes In animal models, HCQ was about 40% less toxic than CQ [64].
T248 36153-36291 Sentence denotes Reportedly, only overdoses (average daily dose > 5.0 mg/kg) and long-time (more than 5 years) ingestion of HCQ can cause retinopathy [65].
T249 36292-36469 Sentence denotes CQ/HCQ have similar pharmacokinetic characteristics, fast absorption in the gastrointestinal tract, fast excretion in liver and kidney, and a long half-life (40–50 days) [3,66].
T250 36470-36540 Sentence denotes Therefore, liver and kidney dysfunction may aggravate adverse effects.
T251 36541-36717 Sentence denotes High-dose CQ (600 mg/2 times/day for 10 day) is associated with increased QTc interval prolongation in critically ill patients with COVID-19 [49] and should not be recommended.
T252 36718-36865 Sentence denotes In the initial trial from France, of the 84 patients receiving HCQ treatment, 8 patients discontinued HCQ owing to ECG modifications within 4 days.
T253 36866-37018 Sentence denotes Among them, 7 patients had a prolonged QTc interval more than 60 ms, and one patient developed a first-degree atrioventricular block within 2 days [53].
T254 37019-37158 Sentence denotes In a randomized clinical trial from Wuhan, 2 out of 31 patients receiving HCQ treatment had minor adverse effects (headache and rash) [50].
T255 37159-37245 Sentence denotes Prolonged QT interval after taking HCQ may also develop in ICU COVID-19 patients [67].
T256 37246-37495 Sentence denotes A recent observation showed that patients who received HCQ for the treatment of pneumonia associated with COVID-19 were at high risk of QTc prolongation (19%), and concurrent use of azithromycin was associated with greater changes in QTc (21%) [68].
T257 37496-37914 Sentence denotes Another observation in COVID-19 patients admitted to ICU showed that QTc intervals increased in 93% of patients receiving HCQ with or without azithromycin, prolonged QTc was observed in 36% of patients after a duration of the treatment for 2 to 5 days, and 6 of 18 (33%) patients treated with HCQ and azithromycin and 1 of 22 (5%) of those treated with HCQ alone developed an increase in QTc of 500 ms or greater [69].
T258 37915-38112 Sentence denotes The use of CQ, CQ with a macrolide, HCQ and HCQ with a macrolide were all found to be independently associated with increased risk for ventricular arrhythmia in hospitalized COVID-19 patients [61].
T259 38113-38227 Sentence denotes Therefore, clinicians should carefully weigh risks and benefits if considering CQ/HCQ with or without a macrolide.
T260 38228-38400 Sentence denotes When CQ/HCQ are used, electrocardiogram examination should be routinely performed before taking the medicine, with close monitoring of QTc and concomitant medication usage.
T261 38401-38606 Sentence denotes CQ/HCQ should be more cautiously used in patients with existing heart disease, and the use of QT interval prolonging drugs, such as antiarrhythmic drugs, antihistamines, and moxifloxacin should be avoided.
T262 38607-38765 Sentence denotes In addition, close attention should be paid to symptoms after taking drugs and the drugs should be stopped in time if there are intolerable adverse reactions.
T263 38766-38934 Sentence denotes In addition, CQ is extremely dangerous for patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency because of the possible induction of hemolytic anemia [70].
T264 38935-39123 Sentence denotes Therefore, more caution should be given for patients with G6PD deficiency when CQ is considered for the treatment and the best way should be to detect G6PD deficiency before the use of CQ.
T265 39125-39127 Sentence denotes 7.
T266 39129-39139 Sentence denotes Discussion
T267 39140-39198 Sentence denotes At present, the COVID-19 pandemic is continuing worldwide.
T268 39199-39296 Sentence denotes It is still an urgent need to find effective therapies and vaccines for treatment and prevention.
T269 39297-39423 Sentence denotes CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified.
T270 39424-39603 Sentence denotes Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity.
T271 39604-39690 Sentence denotes These multiple mechanisms may work together to exert a therapeutic effect on COVID-19.
T272 39691-39852 Sentence denotes A number of in vitro studies have revealed that CQ/HCQ have inhibitory effects on various CoVs, including SARS-CoV [12,13], MERS-CoV [10] and SARS-CoV-2 [16–18].
T273 39853-39955 Sentence denotes However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18].
T274 39956-40170 Sentence denotes Several clinical studies have shown that CQ/HCQ may alleviate the clinical symptoms of COVID-19, promote viral conversion, and delay the progression of the disease, with less serious adverse effects [48,50,57,58,].
T275 40171-40315 Sentence denotes However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72].
T276 40316-40480 Sentence denotes In addition, CQ has shown beneficial results against chikungunya virus in vitro, but in animal models it aggravates the infection and lacks therapeutic effect [73].
T277 40481-40726 Sentence denotes More importantly, in recent studies the use of HCQ did not show any favorable effect on patients with COVID-19 and high-dose CQ treatment of severe COVID-19 patients may even increase the risks of mortality and QTc interval prolongation [49,55].
T278 40727-40814 Sentence denotes In addition, the optimal daily dose and duration of treatment course are not yet clear.
T279 40815-40976 Sentence denotes One study suggested that the dose of HCQ should be 400 mg/2 times for 1 day, 200 mg/2 times/day for 4 days based on the physiological pharmacokinetic model [18].
T280 40977-41313 Sentence denotes A prospective study of HCQ on COVID-19 patients (13 cases) admitted to the ICU in France showed that the first daily dose of 800 mg/1 time for 1 day, and 200 mg/2 times/day for 7 days was recommended to maintain the HCQ treatment level (1–2 mg/l) based on physiologically pharmacokinetic (PBPK) models for COVID-19 patients in ICU [67].
T281 41314-41406 Sentence denotes Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear.
T282 41407-41522 Sentence denotes A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14].
T283 41523-41678 Sentence denotes However, in humans, the efficacy of CQ in the prevention and treatment of SARS-CoV-2 infection to both the mother and the child remains to be investigated.
T284 41679-41856 Sentence denotes Clinical trials in France showed that HCQ combined with azithromycin could enhance the virus clearance [50], but the subsequent reports did not support this combination [59,61].
T285 41857-42027 Sentence denotes Furthermore, CQ/HCQ alone or in combination with a macrolide induced high rate of adverse effects, especially prolonged QTc, in the use for COVID-19 treatment [61,68,69].
T286 42028-42371 Sentence denotes Therefore, current data are not sufficient enough to support the routine use of CQ/HCQ as therapies for COVID-19 and increasing caution should be taken for the application of CQ/HCQ, alone or in combination with other drugs, in COVID-19 before the conclusive findings are obtained by well-designed, multicenter, randomized, controlled studies.
T287 42373-42388 Sentence denotes Acknowledgments
T288 42389-42499 Sentence denotes We are very grateful to Dr. Adam Kim from Cleveland Clinic for the English language editing of our manuscript.
T289 42501-42545 Sentence denotes Declaration of financial/other relationships
T290 42546-42611 Sentence denotes The authors have no financial or other relationships to disclose.
T291 42612-42708 Sentence denotes Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
T292 42710-42730 Sentence denotes Author contributions
T293 42731-42972 Sentence denotes JKS and ZWL wrote the article, and contributed to the concept of this article, definition of intellectual content, and data acquisition; YTC, XDF, XYW contributed to data acquisition; QYH reviewed the manuscript for its intellectual content.
T294 42974-42997 Sentence denotes Declaration of interest
T295 42998-43060 Sentence denotes No potential conflict of interest was reported by the authors.