PMC:7441788 / 39125-42371 JSONTXT

{"project":"LitCovid-PD-FMA-UBERON","denotations":[{"id":"T128","span":{"begin":382,"end":390},"obj":"Body_part"},{"id":"T129","span":{"begin":1120,"end":1124},"obj":"Body_part"},{"id":"T130","span":{"begin":2387,"end":2391},"obj":"Body_part"}],"attributes":[{"id":"A128","pred":"fma_id","subj":"T128","obj":"http://purl.org/sig/ont/fma/fma67180"},{"id":"A129","pred":"fma_id","subj":"T129","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A130","pred":"fma_id","subj":"T130","obj":"http://purl.org/sig/ont/fma/fma62100"}],"text":"7. Discussion\nAt present, the COVID-19 pandemic is continuing worldwide. It is still an urgent need to find effective therapies and vaccines for treatment and prevention. CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified. Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. 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]. However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18]. 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,]. However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72]. 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]. 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]. In addition, the optimal daily dose and duration of treatment course are not yet clear. 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]. 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]. Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear. A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14]. 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. 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]. 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]. 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."}

{"project":"LitCovid-PD-UBERON","denotations":[{"id":"T23","span":{"begin":2387,"end":2391},"obj":"Body_part"}],"attributes":[{"id":"A23","pred":"uberon_id","subj":"T23","obj":"http://purl.obolibrary.org/obo/UBERON_0001913"}],"text":"7. Discussion\nAt present, the COVID-19 pandemic is continuing worldwide. It is still an urgent need to find effective therapies and vaccines for treatment and prevention. CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified. Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. 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]. However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18]. 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,]. However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72]. 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]. 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]. In addition, the optimal daily dose and duration of treatment course are not yet clear. 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]. 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]. Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear. A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14]. 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. 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]. 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]. 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."}

{"project":"LitCovid-PD-MONDO","denotations":[{"id":"T159","span":{"begin":31,"end":39},"obj":"Disease"},{"id":"T160","span":{"begin":259,"end":267},"obj":"Disease"},{"id":"T161","span":{"begin":556,"end":564},"obj":"Disease"},{"id":"T162","span":{"begin":672,"end":680},"obj":"Disease"},{"id":"T163","span":{"begin":708,"end":716},"obj":"Disease"},{"id":"T164","span":{"begin":811,"end":819},"obj":"Disease"},{"id":"T165","span":{"begin":918,"end":926},"obj":"Disease"},{"id":"T166","span":{"begin":1096,"end":1101},"obj":"Disease"},{"id":"T167","span":{"begin":1244,"end":1255},"obj":"Disease"},{"id":"T168","span":{"begin":1311,"end":1320},"obj":"Disease"},{"id":"T169","span":{"begin":1458,"end":1466},"obj":"Disease"},{"id":"T170","span":{"begin":1504,"end":1512},"obj":"Disease"},{"id":"T171","span":{"begin":1882,"end":1890},"obj":"Disease"},{"id":"T172","span":{"begin":2158,"end":2166},"obj":"Disease"},{"id":"T173","span":{"begin":2472,"end":2480},"obj":"Disease"},{"id":"T174","span":{"begin":2483,"end":2492},"obj":"Disease"},{"id":"T175","span":{"begin":2872,"end":2880},"obj":"Disease"},{"id":"T176","span":{"begin":3007,"end":3015},"obj":"Disease"},{"id":"T177","span":{"begin":3131,"end":3139},"obj":"Disease"}],"attributes":[{"id":"A159","pred":"mondo_id","subj":"T159","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A160","pred":"mondo_id","subj":"T160","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A161","pred":"mondo_id","subj":"T161","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A162","pred":"mondo_id","subj":"T162","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A163","pred":"mondo_id","subj":"T163","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A164","pred":"mondo_id","subj":"T164","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A165","pred":"mondo_id","subj":"T165","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A166","pred":"mondo_id","subj":"T166","obj":"http://purl.obolibrary.org/obo/MONDO_0005737"},{"id":"A167","pred":"mondo_id","subj":"T167","obj":"http://purl.obolibrary.org/obo/MONDO_0017941"},{"id":"A168","pred":"mondo_id","subj":"T168","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A169","pred":"mondo_id","subj":"T169","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A170","pred":"mondo_id","subj":"T170","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A171","pred":"mondo_id","subj":"T171","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A172","pred":"mondo_id","subj":"T172","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A173","pred":"mondo_id","subj":"T173","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A174","pred":"mondo_id","subj":"T174","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A175","pred":"mondo_id","subj":"T175","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A176","pred":"mondo_id","subj":"T176","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A177","pred":"mondo_id","subj":"T177","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"}],"text":"7. Discussion\nAt present, the COVID-19 pandemic is continuing worldwide. It is still an urgent need to find effective therapies and vaccines for treatment and prevention. CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified. Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. 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]. However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18]. 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,]. However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72]. 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]. 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]. In addition, the optimal daily dose and duration of treatment course are not yet clear. 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]. 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]. Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear. A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14]. 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. 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]. 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]. 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."}

{"project":"LitCovid-PD-CLO","denotations":[{"id":"T285","span":{"begin":203,"end":213},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T286","span":{"begin":423,"end":431},"obj":"http://purl.obolibrary.org/obo/UBERON_0000158"},{"id":"T287","span":{"begin":469,"end":477},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T288","span":{"begin":532,"end":533},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T289","span":{"begin":566,"end":567},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T290","span":{"begin":723,"end":725},"obj":"http://purl.obolibrary.org/obo/CLO_0050510"},{"id":"T291","span":{"begin":784,"end":792},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T292","span":{"begin":1102,"end":1107},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_10239"},{"id":"T293","span":{"begin":1108,"end":1124},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T294","span":{"begin":1168,"end":1174},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_33208"},{"id":"T295","span":{"begin":1207,"end":1210},"obj":"http://purl.obolibrary.org/obo/CLO_0051582"},{"id":"T296","span":{"begin":1256,"end":1261},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_10239"},{"id":"T297","span":{"begin":1279,"end":1285},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_33208"},{"id":"T298","span":{"begin":1847,"end":1849},"obj":"http://purl.obolibrary.org/obo/CLO_0050510"},{"id":"T299","span":{"begin":1852,"end":1853},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T300","span":{"begin":2282,"end":2283},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"},{"id":"T301","span":{"begin":2339,"end":2347},"obj":"http://purl.obolibrary.org/obo/CLO_0001658"},{"id":"T302","span":{"begin":2410,"end":2416},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_9606"},{"id":"T303","span":{"begin":2641,"end":2646},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_10239"},{"id":"T304","span":{"begin":2781,"end":2782},"obj":"http://purl.obolibrary.org/obo/CLO_0001020"}],"text":"7. Discussion\nAt present, the COVID-19 pandemic is continuing worldwide. It is still an urgent need to find effective therapies and vaccines for treatment and prevention. CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified. Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. 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]. However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18]. 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,]. However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72]. 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]. 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]. In addition, the optimal daily dose and duration of treatment course are not yet clear. 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]. 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]. Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear. A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14]. 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. 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]. 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]. 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."}

{"project":"LitCovid-PD-CHEBI","denotations":[{"id":"T409","span":{"begin":172,"end":174},"obj":"Chemical"},{"id":"T410","span":{"begin":325,"end":327},"obj":"Chemical"},{"id":"T411","span":{"begin":614,"end":616},"obj":"Chemical"},{"id":"T412","span":{"begin":796,"end":798},"obj":"Chemical"},{"id":"T413","span":{"begin":872,"end":874},"obj":"Chemical"},{"id":"T414","span":{"begin":1084,"end":1086},"obj":"Chemical"},{"id":"T415","span":{"begin":1204,"end":1206},"obj":"Chemical"},{"id":"T416","span":{"begin":1481,"end":1483},"obj":"Chemical"},{"id":"T417","span":{"begin":2211,"end":2213},"obj":"Chemical"},{"id":"T418","span":{"begin":2309,"end":2311},"obj":"Chemical"},{"id":"T419","span":{"begin":2434,"end":2436},"obj":"Chemical"},{"id":"T420","span":{"begin":2610,"end":2622},"obj":"Chemical"},{"id":"T421","span":{"begin":2745,"end":2747},"obj":"Chemical"},{"id":"T422","span":{"begin":2783,"end":2792},"obj":"Chemical"},{"id":"T423","span":{"begin":2983,"end":2985},"obj":"Chemical"},{"id":"T424","span":{"begin":3063,"end":3074},"obj":"Chemical"},{"id":"T425","span":{"begin":3078,"end":3080},"obj":"Chemical"},{"id":"T426","span":{"begin":3121,"end":3126},"obj":"Chemical"}],"attributes":[{"id":"A409","pred":"chebi_id","subj":"T409","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A410","pred":"chebi_id","subj":"T410","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A411","pred":"chebi_id","subj":"T411","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A412","pred":"chebi_id","subj":"T412","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A413","pred":"chebi_id","subj":"T413","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A414","pred":"chebi_id","subj":"T414","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A415","pred":"chebi_id","subj":"T415","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A416","pred":"chebi_id","subj":"T416","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A417","pred":"chebi_id","subj":"T417","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A418","pred":"chebi_id","subj":"T418","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A419","pred":"chebi_id","subj":"T419","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A420","pred":"chebi_id","subj":"T420","obj":"http://purl.obolibrary.org/obo/CHEBI_2955"},{"id":"A421","pred":"chebi_id","subj":"T421","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A422","pred":"chebi_id","subj":"T422","obj":"http://purl.obolibrary.org/obo/CHEBI_25106"},{"id":"A423","pred":"chebi_id","subj":"T423","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A424","pred":"chebi_id","subj":"T424","obj":"http://purl.obolibrary.org/obo/CHEBI_33232"},{"id":"A425","pred":"chebi_id","subj":"T425","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A426","pred":"chebi_id","subj":"T426","obj":"http://purl.obolibrary.org/obo/CHEBI_23888"}],"text":"7. Discussion\nAt present, the COVID-19 pandemic is continuing worldwide. It is still an urgent need to find effective therapies and vaccines for treatment and prevention. CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified. Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. 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]. However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18]. 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,]. However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72]. 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]. 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]. In addition, the optimal daily dose and duration of treatment course are not yet clear. 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]. 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]. Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear. A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14]. 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. 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]. 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]. 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."}

{"project":"LitCovid-sample-MedDRA","denotations":[{"id":"T22","span":{"begin":1125,"end":1132},"obj":"http://purl.bioontology.org/ontology/MEDDRA/10022891"},{"id":"T23","span":{"begin":2540,"end":2552},"obj":"http://purl.bioontology.org/ontology/MEDDRA/10022891"}],"attributes":[{"id":"A22","pred":"meddra_id","subj":"T22","obj":"http://purl.bioontology.org/ontology/MEDDRA/10061447"},{"id":"A23","pred":"meddra_id","subj":"T23","obj":"http://purl.bioontology.org/ontology/MEDDRA/10062026"}],"text":"7. Discussion\nAt present, the COVID-19 pandemic is continuing worldwide. It is still an urgent need to find effective therapies and vaccines for treatment and prevention. CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified. Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. 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]. However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18]. 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,]. However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72]. 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]. 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]. In addition, the optimal daily dose and duration of treatment course are not yet clear. 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]. 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]. Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear. A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14]. 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. 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]. 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]. 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."}

{"project":"LitCovid-sample-CHEBI","denotations":[{"id":"T240","span":{"begin":172,"end":174},"obj":"Chemical"},{"id":"T241","span":{"begin":325,"end":327},"obj":"Chemical"},{"id":"T242","span":{"begin":614,"end":616},"obj":"Chemical"},{"id":"T243","span":{"begin":796,"end":798},"obj":"Chemical"},{"id":"T244","span":{"begin":872,"end":874},"obj":"Chemical"},{"id":"T245","span":{"begin":1084,"end":1086},"obj":"Chemical"},{"id":"T246","span":{"begin":1204,"end":1206},"obj":"Chemical"},{"id":"T247","span":{"begin":1481,"end":1483},"obj":"Chemical"},{"id":"T248","span":{"begin":2211,"end":2213},"obj":"Chemical"},{"id":"T249","span":{"begin":2309,"end":2311},"obj":"Chemical"},{"id":"T250","span":{"begin":2434,"end":2436},"obj":"Chemical"},{"id":"T251","span":{"begin":2610,"end":2622},"obj":"Chemical"},{"id":"T252","span":{"begin":2745,"end":2747},"obj":"Chemical"},{"id":"T253","span":{"begin":2783,"end":2792},"obj":"Chemical"},{"id":"T254","span":{"begin":2983,"end":2985},"obj":"Chemical"},{"id":"T255","span":{"begin":3078,"end":3080},"obj":"Chemical"}],"attributes":[{"id":"A253","pred":"chebi_id","subj":"T253","obj":"http://purl.obolibrary.org/obo/CHEBI_25106"},{"id":"A255","pred":"chebi_id","subj":"T255","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A254","pred":"chebi_id","subj":"T254","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A242","pred":"chebi_id","subj":"T242","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A245","pred":"chebi_id","subj":"T245","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A252","pred":"chebi_id","subj":"T252","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A240","pred":"chebi_id","subj":"T240","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A243","pred":"chebi_id","subj":"T243","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A241","pred":"chebi_id","subj":"T241","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A250","pred":"chebi_id","subj":"T250","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A246","pred":"chebi_id","subj":"T246","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A244","pred":"chebi_id","subj":"T244","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A251","pred":"chebi_id","subj":"T251","obj":"http://purl.obolibrary.org/obo/CHEBI_2955"},{"id":"A248","pred":"chebi_id","subj":"T248","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A249","pred":"chebi_id","subj":"T249","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"},{"id":"A247","pred":"chebi_id","subj":"T247","obj":"http://purl.obolibrary.org/obo/CHEBI_3638"}],"text":"7. Discussion\nAt present, the COVID-19 pandemic is continuing worldwide. It is still an urgent need to find effective therapies and vaccines for treatment and prevention. CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified. Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. 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]. However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18]. 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,]. However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72]. 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]. 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]. In addition, the optimal daily dose and duration of treatment course are not yet clear. 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]. 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]. Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear. A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14]. 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. 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]. 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]. 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."}

{"project":"LitCovid-sample-PD-NCBITaxon","denotations":[{"id":"T139","span":{"begin":31,"end":39},"obj":"Species"},{"id":"T140","span":{"begin":259,"end":269},"obj":"Species"},{"id":"T141","span":{"begin":556,"end":564},"obj":"Species"},{"id":"T142","span":{"begin":672,"end":680},"obj":"Species"},{"id":"T143","span":{"begin":690,"end":698},"obj":"Species"},{"id":"T144","span":{"begin":708,"end":718},"obj":"Species"},{"id":"T145","span":{"begin":811,"end":821},"obj":"Species"},{"id":"T146","span":{"begin":918,"end":926},"obj":"Species"},{"id":"T147","span":{"begin":1096,"end":1107},"obj":"Species"},{"id":"T148","span":{"begin":1244,"end":1261},"obj":"Species"},{"id":"T149","span":{"begin":1458,"end":1466},"obj":"Species"},{"id":"T150","span":{"begin":1504,"end":1512},"obj":"Species"},{"id":"T151","span":{"begin":1882,"end":1890},"obj":"Species"},{"id":"T152","span":{"begin":2158,"end":2166},"obj":"Species"},{"id":"T153","span":{"begin":2284,"end":2290},"obj":"Species"},{"id":"T154","span":{"begin":2329,"end":2338},"obj":"Species"},{"id":"T155","span":{"begin":2410,"end":2416},"obj":"Species"},{"id":"T156","span":{"begin":2472,"end":2482},"obj":"Species"},{"id":"T157","span":{"begin":2872,"end":2880},"obj":"Species"},{"id":"T158","span":{"begin":3007,"end":3015},"obj":"Species"},{"id":"T159","span":{"begin":3131,"end":3139},"obj":"Species"}],"attributes":[{"id":"A149","pred":"ncbi_taxonomy_id","subj":"T149","obj":"NCBItxid:2697049"},{"id":"A140","pred":"ncbi_taxonomy_id","subj":"T140","obj":"NCBItxid:2697049"},{"id":"A150","pred":"ncbi_taxonomy_id","subj":"T150","obj":"NCBItxid:2697049"},{"id":"A153","pred":"ncbi_taxonomy_id","subj":"T153","obj":"NCBItxid:9989"},{"id":"A154","pred":"ncbi_taxonomy_id","subj":"T154","obj":"NCBItxid:31631"},{"id":"A145","pred":"ncbi_taxonomy_id","subj":"T145","obj":"NCBItxid:2697049"},{"id":"A144","pred":"ncbi_taxonomy_id","subj":"T144","obj":"NCBItxid:2697049"},{"id":"A146","pred":"ncbi_taxonomy_id","subj":"T146","obj":"NCBItxid:2697049"},{"id":"A147","pred":"ncbi_taxonomy_id","subj":"T147","obj":"NCBItxid:1570291"},{"id":"A143","pred":"ncbi_taxonomy_id","subj":"T143","obj":"NCBItxid:1335626"},{"id":"A157","pred":"ncbi_taxonomy_id","subj":"T157","obj":"NCBItxid:2697049"},{"id":"A156","pred":"ncbi_taxonomy_id","subj":"T156","obj":"NCBItxid:2697049"},{"id":"A152","pred":"ncbi_taxonomy_id","subj":"T152","obj":"NCBItxid:2697049"},{"id":"A158","pred":"ncbi_taxonomy_id","subj":"T158","obj":"NCBItxid:2697049"},{"id":"A148","pred":"ncbi_taxonomy_id","subj":"T148","obj":"NCBItxid:37124"},{"id":"A155","pred":"ncbi_taxonomy_id","subj":"T155","obj":"NCBItxid:9605"},{"id":"A159","pred":"ncbi_taxonomy_id","subj":"T159","obj":"NCBItxid:2697049"},{"id":"A141","pred":"ncbi_taxonomy_id","subj":"T141","obj":"NCBItxid:2697049"},{"id":"A139","pred":"ncbi_taxonomy_id","subj":"T139","obj":"NCBItxid:2697049"},{"id":"A151","pred":"ncbi_taxonomy_id","subj":"T151","obj":"NCBItxid:2697049"},{"id":"A142","pred":"ncbi_taxonomy_id","subj":"T142","obj":"NCBItxid:694009"}],"namespaces":[{"prefix":"NCBItxid","uri":"http://purl.bioontology.org/ontology/NCBITAXON/"}],"text":"7. Discussion\nAt present, the COVID-19 pandemic is continuing worldwide. It is still an urgent need to find effective therapies and vaccines for treatment and prevention. CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified. Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. 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]. However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18]. 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,]. However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72]. 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]. 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]. In addition, the optimal daily dose and duration of treatment course are not yet clear. 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]. 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]. Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear. A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14]. 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. 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]. 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]. 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."}

{"project":"LitCovid-sample-sentences","denotations":[{"id":"T265","span":{"begin":0,"end":2},"obj":"Sentence"},{"id":"T266","span":{"begin":4,"end":14},"obj":"Sentence"},{"id":"T267","span":{"begin":15,"end":73},"obj":"Sentence"},{"id":"T268","span":{"begin":74,"end":171},"obj":"Sentence"},{"id":"T269","span":{"begin":172,"end":298},"obj":"Sentence"},{"id":"T270","span":{"begin":299,"end":478},"obj":"Sentence"},{"id":"T271","span":{"begin":479,"end":565},"obj":"Sentence"},{"id":"T272","span":{"begin":566,"end":727},"obj":"Sentence"},{"id":"T273","span":{"begin":728,"end":830},"obj":"Sentence"},{"id":"T274","span":{"begin":831,"end":1045},"obj":"Sentence"},{"id":"T275","span":{"begin":1046,"end":1190},"obj":"Sentence"},{"id":"T276","span":{"begin":1191,"end":1355},"obj":"Sentence"},{"id":"T277","span":{"begin":1356,"end":1601},"obj":"Sentence"},{"id":"T278","span":{"begin":1602,"end":1689},"obj":"Sentence"},{"id":"T279","span":{"begin":1690,"end":1851},"obj":"Sentence"},{"id":"T280","span":{"begin":1852,"end":2188},"obj":"Sentence"},{"id":"T281","span":{"begin":2189,"end":2281},"obj":"Sentence"},{"id":"T282","span":{"begin":2282,"end":2397},"obj":"Sentence"},{"id":"T283","span":{"begin":2398,"end":2553},"obj":"Sentence"},{"id":"T284","span":{"begin":2554,"end":2731},"obj":"Sentence"},{"id":"T285","span":{"begin":2732,"end":2902},"obj":"Sentence"},{"id":"T286","span":{"begin":2903,"end":3246},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"7. Discussion\nAt present, the COVID-19 pandemic is continuing worldwide. It is still an urgent need to find effective therapies and vaccines for treatment and prevention. CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified. Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. 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]. However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18]. 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,]. However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72]. 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]. 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]. In addition, the optimal daily dose and duration of treatment course are not yet clear. 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]. 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]. Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear. A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14]. 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. 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]. 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]. 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."}

{"project":"LitCovid-sample-PD-UBERON","denotations":[{"id":"T21","span":{"begin":2387,"end":2391},"obj":"Body_part"}],"attributes":[{"id":"A21","pred":"uberon_id","subj":"T21","obj":"http://purl.obolibrary.org/obo/UBERON_0001913"}],"text":"7. Discussion\nAt present, the COVID-19 pandemic is continuing worldwide. It is still an urgent need to find effective therapies and vaccines for treatment and prevention. CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified. Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. 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]. However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18]. 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,]. However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72]. 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]. 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]. In addition, the optimal daily dose and duration of treatment course are not yet clear. 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]. 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]. Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear. A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14]. 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. 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]. 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]. 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."}

{"project":"LitCovid-sample-Pubtator","denotations":[{"id":"1478","span":{"begin":872,"end":878},"obj":"Gene"},{"id":"1479","span":{"begin":796,"end":802},"obj":"Gene"},{"id":"1480","span":{"begin":244,"end":248},"obj":"Species"},{"id":"1481","span":{"begin":259,"end":269},"obj":"Species"},{"id":"1482","span":{"begin":368,"end":372},"obj":"Species"},{"id":"1483","span":{"begin":656,"end":660},"obj":"Species"},{"id":"1484","span":{"begin":672,"end":680},"obj":"Species"},{"id":"1487","span":{"begin":811,"end":821},"obj":"Species"},{"id":"1488","span":{"begin":1244,"end":1261},"obj":"Species"},{"id":"1489","span":{"begin":1444,"end":1452},"obj":"Species"},{"id":"1490","span":{"begin":1513,"end":1521},"obj":"Species"},{"id":"1491","span":{"begin":1891,"end":1899},"obj":"Species"},{"id":"1492","span":{"begin":2167,"end":2175},"obj":"Species"},{"id":"1493","span":{"begin":2410,"end":2416},"obj":"Species"},{"id":"1494","span":{"begin":2520,"end":2525},"obj":"Species"},{"id":"1495","span":{"begin":1096,"end":1101},"obj":"Species"},{"id":"1496","span":{"begin":2329,"end":2338},"obj":"Species"},{"id":"1497","span":{"begin":172,"end":178},"obj":"Chemical"},{"id":"1498","span":{"begin":325,"end":331},"obj":"Chemical"},{"id":"1499","span":{"begin":614,"end":616},"obj":"Chemical"},{"id":"1500","span":{"begin":617,"end":620},"obj":"Chemical"},{"id":"1501","span":{"begin":1084,"end":1086},"obj":"Chemical"},{"id":"1502","span":{"begin":1204,"end":1206},"obj":"Chemical"},{"id":"1503","span":{"begin":1403,"end":1406},"obj":"Chemical"},{"id":"1504","span":{"begin":1481,"end":1483},"obj":"Chemical"},{"id":"1505","span":{"begin":1727,"end":1730},"obj":"Chemical"},{"id":"1506","span":{"begin":1875,"end":1878},"obj":"Chemical"},{"id":"1507","span":{"begin":2068,"end":2071},"obj":"Chemical"},{"id":"1508","span":{"begin":2211,"end":2213},"obj":"Chemical"},{"id":"1509","span":{"begin":2217,"end":2220},"obj":"Chemical"},{"id":"1510","span":{"begin":2309,"end":2311},"obj":"Chemical"},{"id":"1511","span":{"begin":2434,"end":2436},"obj":"Chemical"},{"id":"1512","span":{"begin":2592,"end":2595},"obj":"Chemical"},{"id":"1513","span":{"begin":2610,"end":2622},"obj":"Chemical"},{"id":"1514","span":{"begin":2745,"end":2751},"obj":"Chemical"},{"id":"1515","span":{"begin":2783,"end":2792},"obj":"Chemical"},{"id":"1516","span":{"begin":2983,"end":2985},"obj":"Chemical"},{"id":"1517","span":{"begin":2986,"end":2989},"obj":"Chemical"},{"id":"1518","span":{"begin":3078,"end":3080},"obj":"Chemical"},{"id":"1519","span":{"begin":3081,"end":3084},"obj":"Chemical"},{"id":"1520","span":{"begin":31,"end":39},"obj":"Disease"},{"id":"1521","span":{"begin":556,"end":564},"obj":"Disease"},{"id":"1522","span":{"begin":918,"end":926},"obj":"Disease"},{"id":"1523","span":{"begin":1311,"end":1320},"obj":"Disease"},{"id":"1524","span":{"begin":1458,"end":1466},"obj":"Disease"},{"id":"1525","span":{"begin":1504,"end":1512},"obj":"Disease"},{"id":"1526","span":{"begin":1553,"end":1562},"obj":"Disease"},{"id":"1527","span":{"begin":1567,"end":1592},"obj":"Disease"},{"id":"1528","span":{"begin":1882,"end":1890},"obj":"Disease"},{"id":"1529","span":{"begin":2158,"end":2166},"obj":"Disease"},{"id":"1530","span":{"begin":2472,"end":2492},"obj":"Disease"},{"id":"1531","span":{"begin":2872,"end":2880},"obj":"Disease"},{"id":"1532","span":{"begin":3007,"end":3015},"obj":"Disease"},{"id":"1533","span":{"begin":3131,"end":3139},"obj":"Disease"},{"id":"690","span":{"begin":2748,"end":2751},"obj":"Chemical"},{"id":"695","span":{"begin":2986,"end":2989},"obj":"Chemical"},{"id":"719","span":{"begin":3131,"end":3139},"obj":"Disease"}],"attributes":[{"id":"A1521","pred":"pubann:denotes","subj":"1521","obj":"MESH:C000657245"},{"id":"A1483","pred":"pubann:denotes","subj":"1483","obj":"Tax:11118"},{"id":"A690","pred":"pubann:denotes","subj":"690","obj":"MESH:D006886"},{"id":"A1490","pred":"pubann:denotes","subj":"1490","obj":"Tax:9606"},{"id":"A1518","pred":"pubann:denotes","subj":"1518","obj":"MESH:D002738"},{"id":"A1513","pred":"pubann:denotes","subj":"1513","obj":"MESH:D017963"},{"id":"A1481","pred":"pubann:denotes","subj":"1481","obj":"Tax:2697049"},{"id":"A1491","pred":"pubann:denotes","subj":"1491","obj":"Tax:9606"},{"id":"A1503","pred":"pubann:denotes","subj":"1503","obj":"MESH:D006886"},{"id":"A1500","pred":"pubann:denotes","subj":"1500","obj":"MESH:D006886"},{"id":"A1531","pred":"pubann:denotes","subj":"1531","obj":"MESH:C000657245"},{"id":"A1508","pred":"pubann:denotes","subj":"1508","obj":"MESH:D002738"},{"id":"A1480","pred":"pubann:denotes","subj":"1480","obj":"Tax:11118"},{"id":"A1512","pred":"pubann:denotes","subj":"1512","obj":"MESH:D006886"},{"id":"A1502","pred":"pubann:denotes","subj":"1502","obj":"MESH:D002738"},{"id":"A1504","pred":"pubann:denotes","subj":"1504","obj":"MESH:D002738"},{"id":"A1496","pred":"pubann:denotes","subj":"1496","obj":"Tax:31631"},{"id":"A1526","pred":"pubann:denotes","subj":"1526","obj":"MESH:D003643"},{"id":"A1511","pred":"pubann:denotes","subj":"1511","obj":"MESH:D002738"},{"id":"A1532","pred":"pubann:denotes","subj":"1532","obj":"MESH:C000657245"},{"id":"A1524","pred":"pubann:denotes","subj":"1524","obj":"MESH:C000657245"},{"id":"A1527","pred":"pubann:denotes","subj":"1527","obj":"MESH:D008133"},{"id":"A695","pred":"pubann:denotes","subj":"695","obj":"MESH:D006886"},{"id":"A1495","pred":"pubann:denotes","subj":"1495","obj":"Tax:1570291"},{"id":"A1489","pred":"pubann:denotes","subj":"1489","obj":"Tax:9606"},{"id":"A1516","pred":"pubann:denotes","subj":"1516","obj":"MESH:D002738"},{"id":"A1510","pred":"pubann:denotes","subj":"1510","obj":"MESH:D002738"},{"id":"A1507","pred":"pubann:denotes","subj":"1507","obj":"MESH:D006886"},{"id":"A1529","pred":"pubann:denotes","subj":"1529","obj":"MESH:C000657245"},{"id":"A1530","pred":"pubann:denotes","subj":"1530","obj":"MESH:C000657245"},{"id":"A1482","pred":"pubann:denotes","subj":"1482","obj":"Tax:11118"},{"id":"A1505","pred":"pubann:denotes","subj":"1505","obj":"MESH:D006886"},{"id":"A1528","pred":"pubann:denotes","subj":"1528","obj":"MESH:C000657245"},{"id":"A1506","pred":"pubann:denotes","subj":"1506","obj":"MESH:D006886"},{"id":"A1523","pred":"pubann:denotes","subj":"1523","obj":"MESH:D007239"},{"id":"A1533","pred":"pubann:denotes","subj":"1533","obj":"MESH:C000657245"},{"id":"A1515","pred":"pubann:denotes","subj":"1515","obj":"MESH:D018942"},{"id":"A1517","pred":"pubann:denotes","subj":"1517","obj":"MESH:D006886"},{"id":"A1509","pred":"pubann:denotes","subj":"1509","obj":"MESH:D006886"},{"id":"A1525","pred":"pubann:denotes","subj":"1525","obj":"MESH:C000657245"},{"id":"A1484","pred":"pubann:denotes","subj":"1484","obj":"Tax:694009"},{"id":"A1492","pred":"pubann:denotes","subj":"1492","obj":"Tax:9606"},{"id":"A1488","pred":"pubann:denotes","subj":"1488","obj":"Tax:37124"},{"id":"A1494","pred":"pubann:denotes","subj":"1494","obj":"Tax:9606"},{"id":"A1520","pred":"pubann:denotes","subj":"1520","obj":"MESH:C000657245"},{"id":"A1487","pred":"pubann:denotes","subj":"1487","obj":"Tax:2697049"},{"id":"A1501","pred":"pubann:denotes","subj":"1501","obj":"MESH:D002738"},{"id":"A1499","pred":"pubann:denotes","subj":"1499","obj":"MESH:D002738"},{"id":"A1519","pred":"pubann:denotes","subj":"1519","obj":"MESH:D006886"},{"id":"A1493","pred":"pubann:denotes","subj":"1493","obj":"Tax:9606"},{"id":"A1522","pred":"pubann:denotes","subj":"1522","obj":"MESH:C000657245"},{"id":"A719","pred":"pubann:denotes","subj":"719","obj":"MESH:C000657245"}],"text":"7. Discussion\nAt present, the COVID-19 pandemic is continuing worldwide. It is still an urgent need to find effective therapies and vaccines for treatment and prevention. CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified. Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. 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]. However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18]. 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,]. However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72]. 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]. 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]. In addition, the optimal daily dose and duration of treatment course are not yet clear. 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]. 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]. Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear. A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14]. 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. 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]. 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]. 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."}

{"project":"LitCovid-sample-PD-IDO","denotations":[{"id":"T147","span":{"begin":906,"end":914},"obj":"http://purl.obolibrary.org/obo/OGMS_0000020"},{"id":"T148","span":{"begin":987,"end":994},"obj":"http://purl.obolibrary.org/obo/OGMS_0000031"},{"id":"T149","span":{"begin":1102,"end":1107},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_10239"},{"id":"T150","span":{"begin":1120,"end":1124},"obj":"http://purl.obolibrary.org/obo/CL_0000000"},{"id":"T151","span":{"begin":1256,"end":1261},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_10239"},{"id":"T152","span":{"begin":1311,"end":1320},"obj":"http://purl.obolibrary.org/obo/IDO_0000586"},{"id":"T153","span":{"begin":2248,"end":2255},"obj":"http://purl.obolibrary.org/obo/OGMS_0000031"},{"id":"T154","span":{"begin":2483,"end":2492},"obj":"http://purl.obolibrary.org/obo/IDO_0000586"},{"id":"T155","span":{"begin":2641,"end":2646},"obj":"http://purl.obolibrary.org/obo/NCBITaxon_10239"}],"text":"7. Discussion\nAt present, the COVID-19 pandemic is continuing worldwide. It is still an urgent need to find effective therapies and vaccines for treatment and prevention. CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified. Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. 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]. However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18]. 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,]. However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72]. 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]. 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]. In addition, the optimal daily dose and duration of treatment course are not yet clear. 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]. 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]. Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear. A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14]. 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. 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]. 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]. 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."}

{"project":"LitCovid-sample-PD-FMA","denotations":[{"id":"T127","span":{"begin":382,"end":390},"obj":"Body_part"},{"id":"T128","span":{"begin":1120,"end":1124},"obj":"Body_part"},{"id":"T129","span":{"begin":2387,"end":2391},"obj":"Body_part"}],"attributes":[{"id":"A127","pred":"fma_id","subj":"T127","obj":"http://purl.org/sig/ont/fma/fma67180"},{"id":"A128","pred":"fma_id","subj":"T128","obj":"http://purl.org/sig/ont/fma/fma68646"},{"id":"A129","pred":"fma_id","subj":"T129","obj":"http://purl.org/sig/ont/fma/fma62100"}],"text":"7. Discussion\nAt present, the COVID-19 pandemic is continuing worldwide. It is still an urgent need to find effective therapies and vaccines for treatment and prevention. CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified. Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. 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]. However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18]. 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,]. However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72]. 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]. 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]. In addition, the optimal daily dose and duration of treatment course are not yet clear. 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]. 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]. Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear. A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14]. 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. 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]. 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]. 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."}

{"project":"LitCovid-sample-PD-GO-BP-0","denotations":[{"id":"T77","span":{"begin":391,"end":404},"obj":"http://purl.obolibrary.org/obo/GO_0045851"},{"id":"T78","span":{"begin":423,"end":438},"obj":"http://purl.obolibrary.org/obo/GO_0061025"}],"text":"7. Discussion\nAt present, the COVID-19 pandemic is continuing worldwide. It is still an urgent need to find effective therapies and vaccines for treatment and prevention. CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified. Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. 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]. However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18]. 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,]. However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72]. 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]. 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]. In addition, the optimal daily dose and duration of treatment course are not yet clear. 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]. 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]. Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear. A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14]. 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. 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]. 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]. 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."}

{"project":"LitCovid-sample-PD-MONDO","denotations":[{"id":"T151","span":{"begin":31,"end":39},"obj":"Disease"},{"id":"T152","span":{"begin":259,"end":269},"obj":"Disease"},{"id":"T153","span":{"begin":556,"end":564},"obj":"Disease"},{"id":"T154","span":{"begin":672,"end":680},"obj":"Disease"},{"id":"T155","span":{"begin":708,"end":718},"obj":"Disease"},{"id":"T156","span":{"begin":811,"end":821},"obj":"Disease"},{"id":"T157","span":{"begin":918,"end":926},"obj":"Disease"},{"id":"T158","span":{"begin":1096,"end":1101},"obj":"Disease"},{"id":"T159","span":{"begin":1244,"end":1255},"obj":"Disease"},{"id":"T160","span":{"begin":1311,"end":1320},"obj":"Disease"},{"id":"T161","span":{"begin":1458,"end":1466},"obj":"Disease"},{"id":"T162","span":{"begin":1504,"end":1512},"obj":"Disease"},{"id":"T163","span":{"begin":1882,"end":1890},"obj":"Disease"},{"id":"T164","span":{"begin":2158,"end":2166},"obj":"Disease"},{"id":"T165","span":{"begin":2472,"end":2482},"obj":"Disease"},{"id":"T166","span":{"begin":2483,"end":2492},"obj":"Disease"},{"id":"T167","span":{"begin":2872,"end":2880},"obj":"Disease"},{"id":"T168","span":{"begin":3007,"end":3015},"obj":"Disease"},{"id":"T169","span":{"begin":3131,"end":3139},"obj":"Disease"}],"attributes":[{"id":"A160","pred":"mondo_id","subj":"T160","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A154","pred":"mondo_id","subj":"T154","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A159","pred":"mondo_id","subj":"T159","obj":"http://purl.obolibrary.org/obo/MONDO_0017941"},{"id":"A153","pred":"mondo_id","subj":"T153","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A157","pred":"mondo_id","subj":"T157","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A163","pred":"mondo_id","subj":"T163","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A169","pred":"mondo_id","subj":"T169","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A165","pred":"mondo_id","subj":"T165","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A152","pred":"mondo_id","subj":"T152","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A158","pred":"mondo_id","subj":"T158","obj":"http://purl.obolibrary.org/obo/MONDO_0005737"},{"id":"A151","pred":"mondo_id","subj":"T151","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A162","pred":"mondo_id","subj":"T162","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A161","pred":"mondo_id","subj":"T161","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A155","pred":"mondo_id","subj":"T155","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A156","pred":"mondo_id","subj":"T156","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A164","pred":"mondo_id","subj":"T164","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A166","pred":"mondo_id","subj":"T166","obj":"http://purl.obolibrary.org/obo/MONDO_0005550"},{"id":"A167","pred":"mondo_id","subj":"T167","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"},{"id":"A168","pred":"mondo_id","subj":"T168","obj":"http://purl.obolibrary.org/obo/MONDO_0100096"}],"text":"7. Discussion\nAt present, the COVID-19 pandemic is continuing worldwide. It is still an urgent need to find effective therapies and vaccines for treatment and prevention. CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified. Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. 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]. However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18]. 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,]. However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72]. 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]. 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]. In addition, the optimal daily dose and duration of treatment course are not yet clear. 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]. 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]. Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear. A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14]. 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. 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]. 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]. 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."}

{"project":"LitCovid-sample-GO-BP","denotations":[{"id":"T68","span":{"begin":391,"end":404},"obj":"http://purl.obolibrary.org/obo/GO_0045851"},{"id":"T69","span":{"begin":423,"end":438},"obj":"http://purl.obolibrary.org/obo/GO_0061025"}],"text":"7. Discussion\nAt present, the COVID-19 pandemic is continuing worldwide. It is still an urgent need to find effective therapies and vaccines for treatment and prevention. CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified. Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. 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]. However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18]. 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,]. However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72]. 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]. 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]. In addition, the optimal daily dose and duration of treatment course are not yet clear. 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]. 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]. Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear. A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14]. 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. 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]. 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]. 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."}

{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T64","span":{"begin":391,"end":404},"obj":"http://purl.obolibrary.org/obo/GO_0045851"},{"id":"T65","span":{"begin":423,"end":438},"obj":"http://purl.obolibrary.org/obo/GO_0061025"}],"text":"7. Discussion\nAt present, the COVID-19 pandemic is continuing worldwide. It is still an urgent need to find effective therapies and vaccines for treatment and prevention. CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified. Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. 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]. However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18]. 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,]. However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72]. 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]. 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]. In addition, the optimal daily dose and duration of treatment course are not yet clear. 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]. 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]. Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear. A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14]. 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. 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]. 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]. 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."}

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Discussion\nAt present, the COVID-19 pandemic is continuing worldwide. It is still an urgent need to find effective therapies and vaccines for treatment and prevention. CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified. Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. 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]. However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18]. 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,]. However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72]. 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]. 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]. In addition, the optimal daily dose and duration of treatment course are not yet clear. 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]. 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]. Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear. A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14]. 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. 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]. 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]. 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."}

{"project":"LitCovid-sentences","denotations":[{"id":"T265","span":{"begin":0,"end":2},"obj":"Sentence"},{"id":"T266","span":{"begin":4,"end":14},"obj":"Sentence"},{"id":"T267","span":{"begin":15,"end":73},"obj":"Sentence"},{"id":"T268","span":{"begin":74,"end":171},"obj":"Sentence"},{"id":"T269","span":{"begin":172,"end":298},"obj":"Sentence"},{"id":"T270","span":{"begin":299,"end":478},"obj":"Sentence"},{"id":"T271","span":{"begin":479,"end":565},"obj":"Sentence"},{"id":"T272","span":{"begin":566,"end":727},"obj":"Sentence"},{"id":"T273","span":{"begin":728,"end":830},"obj":"Sentence"},{"id":"T274","span":{"begin":831,"end":1045},"obj":"Sentence"},{"id":"T275","span":{"begin":1046,"end":1190},"obj":"Sentence"},{"id":"T276","span":{"begin":1191,"end":1355},"obj":"Sentence"},{"id":"T277","span":{"begin":1356,"end":1601},"obj":"Sentence"},{"id":"T278","span":{"begin":1602,"end":1689},"obj":"Sentence"},{"id":"T279","span":{"begin":1690,"end":1851},"obj":"Sentence"},{"id":"T280","span":{"begin":1852,"end":2188},"obj":"Sentence"},{"id":"T281","span":{"begin":2189,"end":2281},"obj":"Sentence"},{"id":"T282","span":{"begin":2282,"end":2397},"obj":"Sentence"},{"id":"T283","span":{"begin":2398,"end":2553},"obj":"Sentence"},{"id":"T284","span":{"begin":2554,"end":2731},"obj":"Sentence"},{"id":"T285","span":{"begin":2732,"end":2902},"obj":"Sentence"},{"id":"T286","span":{"begin":2903,"end":3246},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"7. Discussion\nAt present, the COVID-19 pandemic is continuing worldwide. It is still an urgent need to find effective therapies and vaccines for treatment and prevention. CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified. Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. 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]. However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18]. 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,]. However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72]. 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]. 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]. In addition, the optimal daily dose and duration of treatment course are not yet clear. 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]. 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]. Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear. A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14]. 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. 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]. 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]. 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."}

{"project":"2_test","denotations":[{"id":"32496926-15351731-132195715","span":{"begin":682,"end":684},"obj":"15351731"},{"id":"32496926-16115318-132195716","span":{"begin":685,"end":687},"obj":"16115318"},{"id":"32496926-24841269-132195717","span":{"begin":700,"end":702},"obj":"24841269"},{"id":"32496926-32020029-132195718","span":{"begin":720,"end":722},"obj":"32020029"},{"id":"32496926-32194981-132195718","span":{"begin":720,"end":722},"obj":"32194981"},{"id":"32496926-32194981-132195719","span":{"begin":823,"end":825},"obj":"32194981"},{"id":"32496926-23577127-132195720","span":{"begin":1183,"end":1185},"obj":"23577127"},{"id":"32496926-26459826-132195721","span":{"begin":1186,"end":1188},"obj":"26459826"},{"id":"32496926-19506054-132195722","span":{"begin":2393,"end":2395},"obj":"19506054"}],"text":"7. Discussion\nAt present, the COVID-19 pandemic is continuing worldwide. It is still an urgent need to find effective therapies and vaccines for treatment and prevention. CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified. Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. 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]. However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18]. 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,]. However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72]. 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]. 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]. In addition, the optimal daily dose and duration of treatment course are not yet clear. 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]. 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]. Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear. A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14]. 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. 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]. 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]. 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."}