cord-024786-f33eb1nf	2020	Multiple trials across the globe are currently underway to assess the efficacy of CQ for the treatment and prevention of COVID-19, but no published, peer-reviewed results are available at the time of writing. [33] The rationale for the use of lopinavir/ritonavir (LPV/r) in COVID-19 stems from its in vitro activity against SARS-CoV-1, [34] as well as from a retrospective, multicentre cohort study evaluating LPV/r as early treatment in SARS-CoV-1, which demonstrated decreased mortality and intubation rates. [50] At the time of writing, there were no published peer-reviewed trials or case studies evaluating favipiravir in COVID-19, and its use is not currently recommended outside of clinical trials. A systematic review of treatment options in SARS-CoV-1 infection included corticosteroids'' effects on mortality, in vitro inhibition of SARS viral replication and acute respiratory distress syndrome. Drugs that purportedly inhibit SARS-CoV-2 replication (such as the investigational antivirals) or viral entry and replication (CQ and HCQ) may therefore be more effective when given earlier in the COVID-19 disease course.
cord-026340-2nf97zvc	2020	In this review article, we have systematically searched for details of COVID-19 pandemic till May 2020 and assembled few data pertaining to (i) Corona viruses; (ii) SARS-CoV2, the virus that causes COVID-19'' and (iii) How chloroquine and hydroxychloroquine mediates anti-viral effect in both prophylactic and therapeutic setting. The Corona Study Group (CSG) of the International Committee on Taxonomy of Viruses (ICTV) after assessing the etiological agent named it SARS-CoV2 (Severe Acute Respiratory Syndrome Corona Virus2) and the disease outbreak as COVID-19 (Corona Virus Disease-Year of Identification). During COVID-19, SARS-CoV2 S-protein binds to host cell''s receptor ACE2 (Belouzard et al. As for the case of SARS-CoV, it was shown that the binding specificity of virus to host cell was due to 3 prime amino acid residues in S1 protein at positions 360, 479, and 487.
cord-026811-6bdzut3d	2020	We have highlighted here the potential therapeutic role of remdesivir, chloroquine/ hydroxychloroquine (HCQ), lopinavir/ritonavir, and convalescent plasma in patients with SARS-CoV-2 infection. However, interpretation of the result of this study is limited by the lack of a randomized control group, small sample size, exclusion of serious cases (creatinine clearance <30 mL/min and >five-time elevation of serum aminotransferase), variable duration of remdesivir administration, noncollection of viral load data, adverse effects, and short-term follow-up. Early results obtained from more than 100 patients enrolled in studies conducted in the China showed the superiority of chloroquine compared with the controls in terms of reduction of exacerbation of pneumonia, duration of symptoms, and delay of viral clearance, all in the absence of severe side effects. A systematic review and exploratory meta-analysis from 32 studies of SARS coronavirus infection and severe influenza showed a statistically significant reduction in the pooled odds of mortality following treatment with convalescent plasma compared with placebo (odds ratio = 0.25; 95% confidence interval [CI]:0.14-0.45; I[2] = 0%).
cord-028530-hpgrbhkl	2020	Hydroxychloroquine in the treatment of COVID-19: how to use it waiting for conclusive scientific evidence Autores: Ernesto Cairoli MD, PhD a, b , Gerard Espinosa MD, PhD c . In the COVID-19 patient, possible cardiac involvement is mainly related to 4 factors: 1) underlying heart disease (often silent in older patients); 2) myocardial involvement caused by the infection and the inflammatory response itself, which leads to myocarditis with elevated troponins; 3) acute toxicity probably associated with the use of antimalarials in high doses, more evident in chloroquine treatments and 4) concomitant use of other treatments that, together with HCQ, prolong the corrected QT interval (QTc), with the risk of serious ventricular arrhythmias 3-5 . -Pending the result of several active studies, HCQ should not be indicated prophylactically as there is no evidence to support its preventive use or postexposure to avoid COVID-19 infection.
cord-029882-kufs0fxe	2020	HCQ is touted for treatment of Covid 19 primarily based on its anti-viral properties, thus the timing of administration becomes very important for a meaning full assessment of study results. Recently it been shown that this score is not accurate for predicting severity of disease in Covid 19 patients . Covid 19 is a multisystem disease and the disease itself promotes proarrhythmic milieu with prolonged QT intervals at baseline .5,6 Risk assessment of HCQ therapy is not complete if such patients are excluded. Finally , mechanism of action of HCQ against is a part of its broad anti-viral and immunomodulatory properties and no specific pharmacologic actions are described for SARS-CoV-2 infection. 9,10 Weather HCQ as initial anti-viral agent prevents progression to severe disease is not known clearly . Ventricular arrhythmia risk due to chloroquine / hydroxychloroquine treatment for COVID-19: Should it be given Effects of chloroquine on viral infections: an old drug against today''s diseases?
cord-031079-9lxhvyyb	2020	CQ and HCQ may be potential inhibitors of SARS-CoV-2 entry into host cells, which is mediated via the angiotensin-converting enzyme 2 (ACE2), and may also inhibit subsequent intracellular processes which lead to COVID-19, including damage to the cardiovascular system. CQ and HCQ could potentially be useful drugs in the treatment of COVID-19 and other ACE2 involved virus infections, but the antiviral effects of CQ and HCQ need to be tested in more well-designed clinical randomized studies and their actions on the cardiovascular system need to be further elucidated. CQ and its more soluble and less toxic metabolite HCQ are primarily used for prophylaxis and treatment of malaria, but they have also been reported to effectively inhibit the effects of certain viruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and influenza A H5N. 40, 41 Several studies have reported that 3% to 29% of COVID-19 patients develop acute respiratory distress syndrome (ARDS) which is a common complication and cause of death as a result of SARS-CoV-2 infection.
cord-253196-et1ekgdl	2020	Two medications often used for treatment of immune-mediated conditions, hydroxychloroquine and chloroquine, have recently attracted widespread interest as potential therapies for coronavirus disease 2019. The antimalarials hydroxychloroquine (HCQ) and chloroquine (CQ) have demonstrated antiviral activity against severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) in vitro and in small, poorly controlled or uncontrolled clinical studies (1) (2) (3) . Here, we try to provide guidance regarding clinical decision making both for patients with COVID-19 and those with immune-mediated conditions, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), and strategies to mitigate further harm to these patients. At this time of crisis, it is our ethical obligation as physicians and researchers to organize and refer patients to expedited, well-performed randomized trials that can clarify if, when, and for whom antimalarial medications are helpful in COVID-19. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19)
cord-253513-zn87f1lk	2020	Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro Jia Liu 1 , Ruiyuan Cao 2 , Mingyue Xu 1,3 , Xi Wang 1 , Huanyu Zhang 1,3 , Hengrui Hu 1,3 , Yufeng Li 1,3 , Zhihong Hu 1 , Wu Zhong 2 and Manli Wang 1 Dear Editor, The outbreak of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/2019-nCoV) poses a serious threat to global public health and local economies. To better compare the antiviral activity of CQ versus HCQ, the dose-response curves of the two compounds against SARS-CoV-2 were determined at four different multiplicities of infection (MOIs) by quantification of viral RNA copy numbers in the cell supernatant at 48 h post infection (p.i.). Time-of-addition experiment confirmed that HCQ effectively inhibited the entry step, as well as the post-entry stages of SARS-CoV-2, which was also found upon CQ treatment (Supplementary Fig. S2 ).
cord-253609-vi2fb43t	2020	Sixty of 489 respondents (12.3%) reported having to discontinue therapy with HCQ + AZM due to significant QTc prolongation and 20 (4.1%) reported cases of Torsade de Pointes in patients on HCQ/chloroquine and AZM. To better understand the cardiac arrhythmic manifestations and treatment strategies employed in hospitalized COVID-19 patients through a worldwide cross-sectional survey of arrhythmia professionals. The major findings of this global survey include the following: (a) In hospitalized COVID-19 patients, EP professionals across the globe reported a wide variety of arrhythmic manifestations, with several reporting potentially life-threatening ventricular arrhythmias (sustained monomorphic VT, polymorphic VT/Torsade de Pointes, VT/VF arrest) as well as Fig. 3 Difference between US and non-US respondents regarding the percentage of hospitalized COVID-19 patients being treated with HCQ/chloroquine + azithromycin Fig. 2 Characteristics of bradyarrhythmias observed in hospitalized COVID-19 patients pulseless electrical activity.
cord-255690-xc4bxin4	2007	Here we review available in vitro and in vivo data on the effects of CQ/HCQ on bacterial, fungal and viral infections, with the concept that manipulation of the intracellular pH in cells and modification of glycosylation of proteins by lysosomotropic agents instead of antimicrobial compounds is a powerful approach as new therapeutic strategies for the prevention and therapeutic management of several infectious diseases, including some of great public health concern worldwide. Coxiella burnetii [5, 13] Histoplasma capsulatum [24] HIV [2, [29] [30] [31] [32] ] Tropheryma whipplei [7, 8] Cryptococcus neoformans [15, 25] SARS-CoV [33, 34] Legionella pneumophila [11] Paracoccidioides brasiliensis [26] Influenza viruses [35] [36] [37] [38] Francisella tularensis [12] Penicillium marneffei [15, 27] Flavivirus, including yellow fever virus [39] Mycobacterium tuberculosis [14] Aspergillus fumigatus [28] Rubella virus [ tetracycline and quinolone regimen for at least 4 years, with a high percentage of relapses [6] .
cord-256294-9gmn4fcj	2020	title: Comparing the impact of Hydroxychloroquine based regimens and standard treatment on COVID-19 patient outcomes: A retrospective cohort study Despite the recommendation to use HCQ in COVID-19 patients in the MOH protocol, no observational studies or RCTs that evaluate the efficacy of these drugs in the Saudi Arabian population have been published. Therefore, the objective of this observational study is to compare the effects of HCQ and standard care (SC) on length of hospital stay, ICU admission, and mechanical ventilation use among COVID-19 patients. Collected data included patients'' basic information (e.g. age, gender, nationality); medication prescribed; and information on hospitalization, cases requiring ICU care, and mechanical ventilation. Despite the shorter length of hospital stay and time in ICU among patients who received HCQ based treatment, as well as the smaller proportions of patients who needed ICU care and mechanical ventilation in this group, the results indicated no significant differences in these outcomes between the two cohorts.
cord-257144-3q0un5rl	2020	title: Mutagenic, Genotoxic and Immunomodulatory effects of Hydroxychloroquine and Chloroquine: a review to evaluate its potential to use as a prophylactic drug against COVID-19 Hydroxychloroquine (HCQ) and Chloroquine (CQ) are two anti-malarial drugs that are now being extensively used by front-line healthcare workers and other common people as a prophylactic drug against the Corona Virus Disease − 19 (COVID-19) in India and as well as in many parts of the world. Thus, we recognize the need to critically review the mutagenic, genotoxic, and immunomodulatory effects of these drugs, to find out whether it is safe to use as a prophylactic drug against COVID-19. Moreover, the potentials of these drugs as Fig. 5 Endosomal TLR 7 and 9 inhibition by HCQ and CQ: Mammalian Toll-like receptors (TLR) 7 and 9 initiate immune response when it encounters microbial nucleic acids (only shown here is a viral particle).
cord-258684-lq4knxgf	2020	Hydroxychloroquine (HCQ) is a drug approved by several countries to treat malaria and immune-mediated diseases in humans, and its antiviral effects on other viral infections (e.g., SARS-CoV-2, dengue virus) have been confirmed. Interestingly, the combination of 100 μM of HCQ and 10(4) U/mL of recombinant feline IFN-ω (rfIFN-ω, veterinary registered drug) increased its antiviral activity against type I FIPV infection. As shown in Figure 4 , type I FIPV replication was significantly inhibited by HCQ and rfIFN-ω, and the combination of these drugs strongly decreased the replication of virus. As shown in Figure 4 , type I FIPV replication was significantly inhibited by HCQ and rfIFN-ω, and the combination of these drugs strongly decreased the replication of virus. As shown in Figure 4 , type I FIPV replication was significantly inhibited by HCQ and rfIFN-ω, and the combination of these drugs strongly decreased the replication of virus.
cord-259663-fjvumaby	2020	PURPOSE OF REVIEW: Concerning adverse neuromuscular effects, there are quite a few reports about the incidence and prevalence of chloroquine (CQ) and hydroxychloroquine (HCQ) myopathy. Currently, emerging therapies and repurposing of old drugs have been considered therapeutic strategies, including chloroquine (CQ) and hydroxychloroquine (HCQ) [1, 2] , both drugs showing activity against COVID-19 in vitro [3] ; however, the level of preclinical and clinical data is not strong and must be approved by a higher level of evidence [4, 5] . The rimmed vacuolar changes found in muscle have been considered the most representative aspect in muscle biopsies of patients with myopathy induced by antimalarials; however, the absence of these vacuoles in some cases does not exclude the diagnosis [25] . By contrast, Kalajian and Callen [55] did not find an association between elevated serum muscle enzymes and underlying antimalarial-induced myopathy in patients taking CQ or HCQ.
cord-259957-temt8b6f	2020	Both drugs are approved to treat malaria, lupus, and rheumatoid arthritis but must still be assessed in clinical trials before being declared a safe and effective COVID-19 treatment. However, it is utilized extensively by both physicians and dentists (oral medicine clinicians) in the treatment of rheumatologic conditions, such as systemic lupus erythematosus, Sjogren syndrome, rheumatoid arthritis, chronic ulcerative stomatitis, immune thrombocytopenia purpura, lichen planopilaris, and oral lichen planus. Therefore, there appears to be the possibility of additive drug interactions when prescribing HCQ to patients already taking citalopram and other drugs that significantly prolong the QT duration and increase the risk of a torsade de pointes arrhythmia. However, oral medicine clinicians and other health care providers should be advised of the potential issues with the use of HCQ, such as drugÀdrug interactions, the additive toxicity of QT duration prolongation, and the association with sudden death, in the treatment of older patients.
cord-260857-oxxle915	2020	BACKGROUND: There is limited data regarding the electrophysiological abnormalities and arrhythmias in children with COVID-19, including those associated with treatment using potentially pro-arrhythmic Hydroxychloroquine (HCQ) and Azithromycin (AZN). Additionally, some of the medications that have been used for treatment of COVID-19 infection, such as Hydroxychloroquine (HCQ) and Azithromycin (AZN), are known to cause corrected QT (QTc) interval prolongation, therefore potentially predisposing patients to malignant ventricular arrhythmia.s 6, 7 However, there is little current data on the electrophysiologic consequences of these drugs in the setting of active COVID-19 in pediatric patients. As per hospital protocol, COVID-19 specific medications including HCQ with or without AZN were initiated at the discretion of the Infectious Disease team for patients needing supplemental oxygen for hypoxia in the setting of positive SARS-CoV-2, if the baseline QTc was less than 480 milliseconds (msec) measured on lead II via 15 lead ECG or telemetry.
cord-261186-4p1cwb2e	2020	
cord-262193-p7foay4k	2020	title: Doxycycline and Hydroxychloroquine as Treatment for High-Risk COVID-19 Patients: Experience from Case Series of 54 Patients in Long-Term Care Facilities The effectiveness of doxycycline (DOXY) and hydroxychloroquine (HCQ) combination therapy in high risk COVID-19 patients in long-term care facilities is not yet understood. Results: A series of fifty-four (54) high-risk patients, who developed a sudden onset of fever, cough, and shortness of breath (SOB) and were diagnosed or presumed to have COVID-19, were started with a combination of DOXY-HCQ and 85% (n=46) patients showed clinical recovery defined as: resolution of fever and SOB, or a return to baseline setting if patients are ventilator-dependent. From March 19 to March 30, 2020, we analyzed the clinical outcomes of fifty-four (54) high-risk patients who developed a sudden onset of fever, cough, and SOB, were diagnosed or presumed to have COVID-19, and were treated with DOXY (100 mg PO BID for 7 days) and HCQ (two regimens: i) 200 mg PO TID for 7 days or ii) 400 mg PO BID one day, then 400 mg daily for 6 days).
cord-262454-bccrvapy	2020	
cord-262467-epqqd8n8	2020	The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 disease as originally shown in Wuhan, China, as early as documented from 1 December 2019 (ref. A recent prospective study failed to find antiviral activity or clinical benefit of this combination for the treatment of our hospitalized patients with severe COVID-19 (ref. More recently, a randomized, controlled study conducted in Wuhan, China also failed to identify beneficial effect of LPV/r beyond standard therapy in hospitalized patients with severe Covid-19 (ref. Clinical trials also showed that in patients with severe H1N1 influenza A, in the 2009 pandemic, therapy with convalescent plasma from patients who recovered, especially within 5 days of symptom onset, resulted in a lower viral load and lower mortality 66, 67 . The duration from onset of symptoms to viral clearance is significantly longer in severe and critical ill SARS-CoV-2infected patients compared with that in the mild cases 48 .
cord-262780-ilu5oskk	2020	The use of chloroquine (CQ) and hydroxychloroquine (HCQ) for COVID-19 exemplifies the risks of both overinterpreting and amplifying preliminary data by those outside of the scientific community and was followed by swift corrective measures by researchers. By early March, interest in HCQ abruptly transitioned from mechanistic plausibility that would support its study in a clinical trial setting to rapid off-label use in patients with COVID-19, primarily fueled by promotion on social media, lay press, and celebrity influence [8] . By late March, two new studies became publicly available: a second study from the group of IHU-Méditerranée Infection using HCQ and AZM in 80 patients with mild COVID-19 infection released on their webpage, and a preprint of the first randomized controlled trial of 62 patients from Wuhan reporting a difference in clinical time to recovery and radiologic findings with HCQ treatment [22, 23] .
cord-267762-mzon01fd	2020	Methods: By analyzing the Portuguese anonymized data on private and public based medical prescriptions we have identified all cases chronically receiving HCQ for the management of diseases such as systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases. Cross linking the two sets of data has allowed us to compare the proportion of HCQ chronic treatment (at least 2 grams per month) in laboratory confirmed cases of SARS-CoV-2 infection with laboratory confirmed negative cases. Several in vitro studies have shown chloroquine phosphate and hydroxychloroquine sulphate (HCQ) to be effective in both preventing and treating SARS-CoV-2 infection in isolated cells (1) (2) (3) . By analyzing these sets of data, we were able to detect all patients with SARS-CoV-2 confirmed infections and all clinically suspected but non-confirmed patients between Mars 2, 2020 (the date of the first Portuguese case) and the moment of the analysis. The proportion of HCQ chronic treatment was higher in negative patients is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
cord-268425-xg8xnjf9	2020	
cord-268453-87b298uk	2020	In the absence of a vaccine and specifically designed antivirals, the medical community has proposed the use of various previously available medications in order to reduce the number of patients requiring prolonged hospitalizations, oxygen therapy, and mechanical ventilation and to decrease mortality from coronavirus disease 2019 (COVID-19). HCQ was, in vitro, at least as effective as chloroquine in inhibiting SARS-CoV-2 infection, although it should be noted that studies on its mechanisms of action are not as extensive as with CQ [30] . The evidence for the use of hydroxychloroquine or chloroquine in COVID-19 is not good so far, not only because of the negative results of most of the studies but also because of their design, when publishing results of a very low number of patients, when reporting favorable results but without having a control group that allows comparison, when choosing results for which it will be very difficult to find significant differences, such as mortality, or for which their clinical relevance is uncertain.
cord-268519-t15yvy5s	2020	title: Safety use of hydroxychloroquine and its combination with azithromycin in the context of Sars-CoV-2 outbreak: Clinical experience in a Belgian tertiary center Despite some encouraging preliminary clinical data (2,3), major concerns have been raised about the use of HCQ to treat COVID-19 (5), particularly regarding potential cardiac toxicity (i.e. QTc increase and risk of torsade de pointe). Repeat ECG was not systematically performed during HCQ treatment, except in case of drug-drug interaction which could potentially increase QTc (see foot note of Table1). The efficacy of HCQ and its combination with azithromycin on COVID-19 infection needs, of course, to be strengthened with further evidence from large randomized clinical trials. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study
cord-270290-i4p4p0o4	2020	The proposed doses of chloroquine (CQ) and hydroxychloroquine (HCQ) for treatment of COVID-19 (1000 mg/day for 10 days, CQ; 800 mg first day then 400 mg/day for 5 days, HCQ) in many guidelines worldwide, are considerably higher than the maximum recommended daily safe doses of both agents (≤2.3 mg/kg/day, CQ; ≤5.0 mg/kg/day, HCQ) for development of retinal toxicity. [6] [7] [8] [9] [10] [11] As the therapeutic doses of CQ and HCQ recommended in the trials and guidelines are relatively high compared with the maximum daily safe dose that is related to CQ and HCQ retinal toxicity, this issue of retinal toxicity should be taken into consideration when employing these 2 medications for treatment of COVID-19 worldwide. According to the recommendation by the American Academy of Ophthalmology, the most significant major risk factors for CQ and HCQ retinal toxicity are high dose and long duration of use.
cord-270723-cjfglili	2020	Age > 65 years, congestive heart failure, severity of disease, C‐reactive protein level, hypokalemia and furosemide treatment, were all associated with QTc prolongation. CONCLUSION: In patients treated with HCQ, QTc prolongation was associated with the presence of traditional risk factors such as hypokalemia and furosemide treatment. All rights reserved Univariate analysis revealed that in COVID-19 patients treated with HCQ, age above 65 years, severe or critical illness, congestive heart failure, hypokalemia, furosemide treatment and increased CRP level were all significantly associated with the composite endpoint (Table 2) . However, multivariate analysis in this small dataset also suggested that in COVID-19 patients treated with HCQ, concomitant hypokalemia and furosemide treatment were strongly associated with QTc prolongation. In conclusion, our study shows that QTc prolongation among HCQ-treated patients was associated with traditional, modifiable risk factors such as hypokalemia and furosemide treatment which are both commonly observed in COVID-19 patients.
cord-272296-1gn1zhvt	2020	We compared the risk of congenital malformations in women with HCQ use during the first trimester versus no use, restricting the cohort to women with rheumatic disorders and using propensity score matching to control for indication, demographics, medical comorbidities, and concomitant medications (N= 1,867 HCQ exposed; 19,080 unexposed pregnancies). [10] [11] [12] [13] However, data 134 regarding the risk of major congenital malformations associated with early pregnancy exposure 135 is very limited, with the largest published cohort study including fewer than 200 exposed 136 pregnancies (Supplementary Table 1 ). Utilizing data from health plans that provide coverage for large populations of both commercially 250 and publicly insured individuals in the US, we identified a cohort of pregnant women with 251 chronic autoimmune rheumatic diseases and assessed the relative prevalence of major 252 congenital malformations in their newborns following exposure to HCQ during early pregnancy.
cord-272419-y3ebt4jm	2020	
cord-274545-r03g7w0b	2020	In this open-label non-randomized clinical trial, a total of 20 patients were treated with HCQ at a dose of 200 mg three times daily for 10 days, and the data showed a significant reduction in viral carriage at day 6 post-inclusion compared to controls (70.0% clearance by day 6 vs. e outcomes assessed with double-arm studies include virologic efficacy [8, 20, 21] , clinical efficacy (mortality [4, 8, 13, 14, 30, 31] and disease progression [4, 8, 13, 14, 22, 31, 32] ), safety (risk of adverse effects) [8, [20] [21] [22] , and tolerability and QT prolongation [14, 26, 34] . e data from four controlled clinical trials [8, [20] [21] [22] of 278 COVID-19 patients (141 HCQ and 137 from the non-HCQ group) were included to assess overall adverse effects (except QTc prolongation) among HCQ-exposed patients.
cord-275037-sji0u8nu	2020	In this issue of the Journal, Di Castelnuovo and colleagues report the findings of the observational multicentre Italian CORIST Study on the use of hydroxychloroquine (HCQ) in hospitalised COVID-19 patients [1] . While these findings may provide clinical evidence in support of the use of HCQ therapy in patients with COVID-19, the study findings ought to be considered with caution, in light of several limitations, which are inherent to the retrospective, observational design of this study. These include bias by indication (why did some patients receive HCQ in addition to standard management, whereas others did not?), a possible immortal time bias (patients who died before treatment administration tend to be included as controls in retrospective studies), and of the fact that residual confounders typically remain even after stringent propensity matching is applied (not all clinically relevant variables are included in or captured by covariate analyses). Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study GM-CSF blockade with mavrilimumab in severe COVID-19 pneumonia and systemic hyperinflammation: a single-centre, prospective cohort study
cord-275041-fcdwitxy	2020	The following variables were extracted for this study: age, gender, temperature, and saturation of oxygen on admission, treatment with hydroxychloroquine, azithromycin, heparin, steroids, tocilizumab, a combination of lopinavir with ritonavir, and oseltamivir, together with data on mortality. Using limited evidence and clinical experience, doctors have treated COVID-19 patients with different drugs to eliminate or reduce the presence of the virus, including hydroxychloroquine (HCQ) [9] [10] [11] [12] . The association between treatment with HCQ and mortality was examined with four different logistic regression models: model one was adjusted for age and gender; model two included age and gender, together with temperature > 37 °C, and saturation of oxygen < 90% on admission, which were both associated with mortality in an exploratory analysis; model three had all the variables previously mentioned together with treatment with azithromycin, steroids, heparin, tocilizumab, a combination of lopinavir with ritonavir, and oseltamivir; finally, to account for the change in clinical management during the study period, model four was adjusted for all the previously mentioned demographic, clinical severity measures, and drugs, together with a categorical variable for date of admission (before the 10th of March, 11-20th of March, 20-31st March, 1st-10th of April, and 11-20th of April).
cord-275340-q8d7rvnj	2020	CQ/HCQ may synergistically exert antiviral and immunomodulatory effects on COVID-19 through multiple mechanisms including hindering the receptor recognition process by influencing the affinity of ACE2 and S protein, and the affinity for sialic acid and ganglioside; inhibiting the membrane fusion process by suppressing endolysosome acidification; suppressing the p38 activation and affecting host defense machinery, and preventing MHC class II expression (block expression of CD154 on the surface of CD4 + T cell) and TLR signaling and reducing the production of cytokines through inhibiting the activation of T cells and B cells. ACE2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019; CQ, chloroquine; HCQ, hydroxychloroquine; CoVs, coronaviruses; MAPK, mitogen-activated protein kinase; MHC-II, major histocompatibility complex class II; TLR, toll-like receptor; cGAS, cyclic GMP-AMP synthase; IFN, interferon; IL, interleukin; TNF-α, tumor necrosis factor-α. The authors deemed that the anti-inflammatory effect of low-dose HCQ and the activity of inhibiting viral replication may have important significance in critically ill patients with COVID-19.
cord-277555-tsd6npma	2020	Despite an unconfirmed efficacy and potential serious side-effects the presidents of France, Brazil and the United States subsequently publicly promoted the use of HCQ, resulting in an absolute run on HCQ, a shortage of the drug for patients with traditional indications, and a lively debate in the respective countries [1, 2] . In the study by van den Broek et al., 95 patients were treated with CQ (loading dose 600 mg, followed by 2 × 300 mg for 4 days; 22% of patients in the intensive care unit), which resulted in a mean QTc prolongation of 35 ms (95% confidence interval 28-43 ms) [15] . Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label nonrandomized clinical trial Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial Chloroquine-induced QTc prolongation in COVID-19 patients The risk for QTc interval prolongation in COVID-19 patients treated with chloroquine
cord-277916-b4yqek29	2020	
cord-278068-3kg71nf4	2020	
cord-278246-mnj0zmkn	2020	HCQ treated patients had higher rates of adverse clinical outcomes and side effects compared with the control populations. The treatment of COVID-19 positive patients with HCQ has been met with controversy, as there have been no large multicenter randomized control trials to support its use. Studies 1 and 2 both do not cross the effect line at 0, indicating that they are not in agreement with the mortality rate of HCQ treated COVID-19 positive patients. All studies, except Study 6, are in agreement with the results of a disease progression rate of HCQ treatment in patients with COVID [19] . These results seem to be in line with the meta-analysis'' of a slight disease improvement in COVID-19 patients treated with HCQ as compared with the controls. Our study looks at three disease outcome measures of treatment with HCQ in patients with COVID-19: mortality rates, progression rates, and severity rates.
cord-280528-7ivw72l0	2020	
cord-281285-5g1rw202	2020	
cord-281411-la8njxc1	2020	During March and April of 2020, a study was conducted in our hospital to analyze the effect of treatment with HCQ (either alone or in combination with AZ) on the QTc and the incidence of ventricular arrhythmias in patients admitted with SARS-CoV-2 pneumonia who met the high-risk criteria for QTc prolongation (female, age░>░65 years, history of heart disease, chronic renal disease, or diabetes, or taking both medications together). This protocol included a series of precautions to be taken before and during treatment: a) review what other medications the patient is taking that could prolong the QTc; b) correct electrolyte imbalances; c) avoid bradycardia; and d) perform close electrocardiographic monitoring.
cord-283064-ncyhvkwl	2020	
cord-283903-e20v88ge	2020	BACKGROUND: The aim of this clinical trial was to evaluate the effects of febuxostat (FBX) in comparison with hydroxychloroquine (HCQ) on clinical symptoms, laboratory tests and chest CT findings in outpatients with moderate symptoms of COVID‐19 infection. The measured variables were needs to hospitalization, clinical and laboratory data including fever, cough, breathing rate, C‐Reactive Protein level, lymphocytes count at onset of admission and was well as at 5 days of treatments. On admission, fever (66.7%), cough (87%), tachypnea (44.4%), dyspnea (35%), elevated CRP value (94.4%) and lung involvement according to chest CT (100%) were documented in enrolled patients with insignificant difference between FBX and HCQ groups. In adult outpatients with moderate COVID‐19 infection, the effectiveness of FBX and HCQ was not different in terms of resolution of clinical manifestations, laboratory tests and lung CT findings. This clinical trial was conducted to assess the effects of FBX and hydroxychloroquine (HCQ) on clinical symptoms, laboratory tests and chest CT findings of patients with COVID-19 infection.
cord-285486-99trkti1	2020	Univariate logistic regression analysis showed that HCQ treatment was not significantly associated with decreased mortality in COVID-19 patients. So, adding HCQ to standard care did not add significant benefit, did not decrease the need for ventilation, and did not reduce mortality rates in COVID-19 patients. 1. Hydroxychloroquine group: This group included 97 patients who received HCQ 400 mg twice daily (in day 1) followed by 200 mg tablets twice daily added to the standard of care treatment adopted by the Egyptian MOH for 15 days. 18 Although cardiac toxicity is a known adverse event requiring monitoring during treatment, HCQ showed promise in treating SARS-CoV-2-infected patients with multiple comorbidities including coronary artery disease. 12 studied the change in symptom severity over 14 days in nonhospitalized patients between HCQ and control groups and did not find any significant difference (P = 0.12).
cord-286038-a62k3lma	2020	
cord-286413-a7wue2e3	2020	
cord-286579-u87lx38h	2020	
cord-287680-vdrix1cp	2020	The strategy of chiral switches has emergedthe development of a single enantiomer from a chiral drug that has previously been developed (and often approved and marketed) as a racemate or as a mixture of diastereomers. The chiral switch of HCQ was initiated in the early 1990swith method-of-use patents US 5,314,894 (priority date 15-09-1992, assignee Sterling Winthrop, New York) and EP 0588439B1 claiming the enantiomer (S)-(+)-hydroxychloroquine [(S)-(+)-HCQ] for treatments of malaria, RA and LE. We aim preferentially at (S)-(+)-hydroxychloroquine [(S)-(+)-HCQ], the more-promising enantiomer (patents: US 5,314,894 and EP 0588430B1, proprietor Sanofi, priority date 15-09-1992, now expired), followed by (S)-(+)-chloroquine [(S)-(+)-CQ]. Our call for repurposing HCQ and/or CQ by urgently developing the chiral switches of these racemates to their (S)-(+)-enantiomers for the treatment of COVID-19 is based on the expectations of safer pharmacological profiles of the selected enantiomers, favorable risk:benefit profiles and shortened development and approval processes.
cord-288017-f9b3t0ts	2020	
cord-288311-8kcturbn	2020	This lack of clinical efficacy in treating asthma cannot be translated to COVID-19, which has a different etiology for pulmonary inflammation and is a disease process that stands to benefit from the anti-viral effects of HCQ. Although further evidence is needed to determine the efficacy of aerosolized HCQ in the treatment of COVID-19, low-dose targeted pulmonary delivery represents a safe and potentially preferred delivery method, particularly given the purported mechanisms by which HCQ acts against SARS-CoV-2. In light of the consequences seen with widespread use of high-dose, orally-administered HCQ in the treatment of COVID-19, clinical testing of the pharmacological parameters of inhaled or nebulized HCQ should be a high priority. However, if HCQ is to be administered in critically ill COVID-19 patients, low-dose inhaled or nebulized therapy may confer the collective benefits of similar or greater drug concentrations in pulmonary tissues, less systemic adverse effects (including cardiotoxicity), decreased burden on the healthcare system, and diminished strain on the existing supply of hydroxychloroquine.
cord-289091-djv4syy4	2020	
cord-289916-rgvcimk3	2020	
cord-290955-m2igkcxv	2020	
cord-293159-oagv4q1u	2020	
cord-293304-kakxmc14	2020	
cord-293428-8hj06hzt	2020	
cord-295144-tyyc81uc	2020	
cord-295973-41jqgsv0	2020	
cord-296649-h6oyjz56	2020	In this study, an adapted mouse model was chosen to demonstrate its suitability to provide sufficient information on the model substances GS-441 524 and HCQ regarding plasma concentration and distribution into relevant tissues a prerequisite for treatment effectiveness. Blood and organ samples were taken at several time points and drug concentrations were quantified in plasma and tissue homogenates by two liquid chromatography/tandem mass spectrometry methods. For GS-441 524, measured tissue concentrations exceeded the reported in vitro EC50 values by more than 10-fold and in consideration of its high efficacy against feline infectious peritonitis, GS-441 524 could indeed be effective against SARS-CoV-2 in vivo. The value obtained from our experiments falls in that range and is comparable to the V z obtained in mice from blood concentrations and to plasma V z measured in humans (see Table 4 ).
cord-297010-imciixde	2020	
cord-303819-w1785lap	2020	
cord-303968-ikr6eeov	2020	
cord-304669-aiuiotds	2020	
cord-306351-ka6asw3m	2020	
cord-307570-8f83k2ce	2020	
cord-312875-gn6hg6oc	2020	(3) Although the exact mechanisms of action underlying the glucose-lowering properties of HCQ are still not entirely clear and may differ between patients with and without diabetes, pre-clinical and clinical data suggest that HCQ could exert multifaceted effects on glucose homeostasis, namely: improvement of insulin sensitivity, increase of insulin secretion, reduction of hepatic insulin clearance and intracellular insulin and insulin-receptor complex degradation, increase of adiponectin levels, reduction of systemic inflammation, and/or reduction of inflammation-induced insulin resistance in adipocytes and skeletal muscle cells. (13) More recently, a 24-week prospective randomized trial (14) and two real-world, prospective observational studies of short duration (up to 24-48 weeks) (5, 15) conducted in India have shown that the use of HCQ (400 mg/day) as an add-on treatment in patients with T2D uncontrolled on a combination of two or more oral hypoglycemic agents (including metformin, sulfonylureas, pioglitazone, DPP-4 inhibitors, SGLT2 inhibitors, and alpha-glucosidase inhibitors) was welltolerated and led to a significant improvement of glucose control (assessed by HbA1c, fasting-and postprandial blood glucose) from baseline (without occurrence of severe hypoglycemia).
cord-315598-qwh72inx	2020	De otorgarse un Consentimiento Informado amplio, éste debería ser única y exclusivamente para los procesos asociados con COVID-19".(71) AMCI ® Se recomienda considerar la transición del cuidado intensivo al cuidado paliativo en todo paciente con sospecha o diagnóstico de COVID-19 sin mejoría a pesar de las intervenciones óptimas, con empeoramiento progresivo de su pronóstico vital y ante un evidente deterioro; aplicando medidas generales en control de síntomas ( Manejo de secreciones -Tratamiento del dolor -Tratamiento de la disnea -Sedación paliativa), así como apoyo espiritual, siempre acompañando al paciente y nunca abandonarlo en el final de la vida. En cuanto hace referencia a la situación actual de pandemia por SARS-CoV-2 y compromiso pulmonar; Wu y cols, en Marzo de 2.020 realizaron un estudio retrospectivo de 201 pacientes con COVID-19 en China; para aquellos pacientes que desarrollaron SDRA, el tratamiento con metilprednisolona estuvo asociado con una disminución del riesgo de muerte (23/50 [46%] con esteroides vs 21/34 [62%] sin esteroides; HR, 0.38 [IC 95%, 0.20-0.72]), con las limitaciones de los estudios retrospectivo, de un solo centro, con un limitado número de pacientes (400).
cord-315864-zadogqiu	2020	
cord-316992-fe5u2oi0	2020	These effects are achieved through the modulation of the autoimmune response by (i) impairing functions of the endolysosomal system through its lysosomotropic effects (Ziegler & Unanue, 1982; Kaufmann & Krise, 2007; Yoon et al, 2010) , (ii) decreasing the levels of circulating pro-inflammatory cytokines (Sperber et al, 1993; Van Den Borne et al, 1997) , (iii) inhibiting T-cell proliferation (Landewe et al, 1995; Costedoat-Chalumeau et al, 2014) , (iv) blocking Tolllike receptors (TLRs) (Kyburz et al, 2006) and (v) autophagy inhibition (An et al, 2017c) . Activation of TLRs, especially in macrophages, monocytes and T helper cells, but also in neutrophils and endothelial cells, induces the production and secretion of pro-inflammatory cytokines, a hallmark of RADs (Beutler & Cerami, 1989 (A) CQ and HCQ are weak bases that accumulate inside acidic subcellular compartments, e.g. endosomes and lysosomes.
cord-317561-ewo6vvlr	2020	
cord-317624-qdzhncs0	2020	METHODS: Nationwide retrospective case-control study was conducted to compare the effect of HCQ and LPV/r on viral shedding duration among patients with mild-to-moderate COVID-19 using the reimbursement data of National Health Insurance Service. This study aimed to compare the effect of HCQ and LPV/r on the viral shedding duration among patients with mild-to-moderate COVID-19 cases using South Korea''s National Health J o u r n a l P r e -p r o o f Insurance Service (NHIS) database. Among these, only mild-to-moderate grade 1 patients were included in the analysis, and the effect of LPV/r or HCQ use on viral shedding duration was evaluated ( Figure 1 ). In the previous studies including mild COVID-19 patients in CTCs, the mean viral shedding duration from symptom onset was 21-24.5 days, which is longer than the results of our control group , Noh et al., 2020 .
cord-317761-tkqmu1va	2020	
cord-318092-errwp80i	2020	Methods: We systematically searched PubMed, MEDLINE, Cochrane, the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, and the ClinicalTrials.gov for all the RCTs comparing CQ or HCQ with placebo or other active agents, published before March 31, 2020. Our objective was to identify all randomized clinical trials (RCTs) that compared the safety profiles of chloroquine or hydroxychloroquine with placebo or other active agents. This review was not restricted to studies conducted in the English language; it includes reports from any countries that compared CQ or HCQ with placebo or other active agents, since there is a wealth of information in RCTs from many different countries. Together, these stratified data provide ample information regarding the percentage of participants who experienced specific AEs. Subgroup meta-analysis for CQ and HCQ with respect to age, duration, and dosage. For HCQ, there was no evidence that age, duration of trial, or dosage affected total AEs. Further meta-regression analyses can be found in Supplementary Figure 1 .
cord-319571-fspmgg4s	2020	Although, functional importance of different targets has been linked to the viral replication and maturation of coronaviruses'' family such as Chymotrypsin-like protease(3CLpro) or known as Mpro (Khan et al., 2020; Muralidharan et al., 2020) or Envelope protein (E) (Gupta et al., 2020; Boopathi et al., 2020) but it has been confirmed that the binding of the viral trimeric surface spike glycoprotein (SProtein) of SARS-CoV-2 to the human receptor angiotensin-converting enzyme 2 (hACE2) is the first step in host infection . Therefore, it is very likely that selective interaction of HCQ with the surface of SARS-CoV-2 SProtein through the formation of an inclined tape over the hydrophobic pocket responsible for hosting the Lys353 hotspot (the OH group in this case is acting like a hook by forming a hydrogen bond with Asn501), can be responsible for the prevention of tighter binding with hACE2 protein via restricting penetration of Lys353 into its finally assigned destination on the SProtein RBD (Figure 2 ).
cord-320499-76o2zj0v	2020	
cord-321337-tg8kfiot	2020	Statistical evidence for the positive effect model ranged from strong for the original data (BF ~11), to moderate when including patients who deteriorated (BF ~4.35), to anecdotal when excluding untested patients (BF ~2), and to anecdotal negative evidence if untested patients were assumed positive (BF ~0.6). Here we perform the test HCQ mono versus comparison group, and assess its sensitivity to the variants of the data under different assumptions regarding deteriorated and untested patients. As is evident from this, the strength of the evidence for the positive effect of HCQ mono over the comparison group is highly sensitive to the assumptions regarding what to do with the deteriorated or untested patients. Performing a Bayesian A/B test, we found that for the original data, there was strong statistical evidence for the positive effect of HCQ mono improving the chances of viral reduction when compared to the comparison group.
cord-323647-q67fa0m3	2020	
cord-324166-6ydn2bvy	2020	We found that Noscapine-Hydroxychloroquine (Nos-Hcq) conjugate has strong binding affinity for the main protease (Mpro) of SARS-CoV-2, which performs key biological function in virus infection and progression. Also, dynamical residue cross-correlation map with principal component analysis depicted the stable binding of Nos-Hcq conjugate to Mpro domains with optimal secondary structure statistics of complex dynamics. Similar binding sites were employed for performing the molecular docking of the noscapine conjugations with the target Mpro of coronavirus using the Hex 8.0 and SwissDock servers. With these significant results, it can be attributed that Nos-Hcq conjugate has a high potential to bind the target Mpro enzyme and further can be used as effective therapeutics for SARS-CoV-2. We report the efficient combinatorial therapy by conjugating the noscapine (antitussive drug) with potential hydroxychloroquine (Nos-Hcq) against the SARS-CoV-2, through the computational assays with insights into the experimental results.
cord-324707-9ld73wv1	2020	Study outcomes were the reduction of viral RNA load in nasopharyngeal swabs up to 7 days after treatment start, patient disease progression using the WHO scale up to 28 days, and time to complete resolution of symptoms. Adult patients aged 18 years or more were eligible if they had mild symptoms of Covid-19 (i.e., fever, acute cough, shortness of breath, sudden olfactory or gustatory loss, or influenza-like-illness) for less than five days before enrollment, were non-hospitalized, and had a positive PCR test for SARS-CoV-2 in the baseline nasopharyngeal swab. We estimated that a sample size of 280 patients would provide the trial with 80% power to detect a difference of 0.5 log 10 in the mean reduction of SARS-CoV-2 viral load at a two-sided significance level of α = 0.05, assuming an expected standard deviation of 1.5 [23] .
cord-326154-01es0zv4	2020	
cord-327006-m847xdzk	2020	
cord-327360-4qpk99x9	2020	
cord-327575-5pcnuqgy	2020	
cord-328257-kl4wh2zg	2020	
cord-328714-jg562twk	2020	
cord-329920-s928u6g3	2020	
cord-332654-nav15g8k	2020	The major focus of the present review is to discuss about the pharmacokinetic and pharmacodynamic properties of CQ and HCQ that may be influenced by epigenetic mechanisms, and consequently cause several side effects especially retinopathy during SARS-CoV-2 therapy. Furthermore, growing body of evidence demonstrated that several factors including CYP450 single nucleotide polymorphisms (SNPs), and epigenetic molecules such as non-coding RNAs (ncRNAs), DNA methylation and histone acetylation influenced the expression levels of CYP450, and consequently might influence HCQ metabolism. The major purpose of this review is to discuss the pharmacokinetic and pharmacodynamic characteristics of CQ and HCQ that may be influenced by epigenetic mechanisms including ncRNAs and CYP2D6 SNPs, and thereby cause several side effects such as cardiotoxicity, prolonged QT interval, gastrointestinal problems (like dyspepsia and abdominal cramps), central nervous system or skin disorders, and especially retinopathy.
cord-333144-gyuh2fvl	2020	Therefore, this review focuses on the current use of various drugs as single agents (hydroxychloroquine, ivermectin, azithromycin, favipiravir, remdesivir, umifenovir, teicoplanin, nitazoxanide, doxycycline, and dexamethasone) or in combinations with immunomodulators additionally. While some drugs have shown therapeutic effect against COVID-19 infection such as hydroxychloroquine (Al-Kofahi et al., 2020; Choudhary & Sharma 2020; Liu et al., 2020; Sinha & Balayla 2020) , azithromycin, (Andreani et al., 2020a; Choudhary & Sharma 2020) ivermectin (Caly et al., 2020; Chaccour et al., 2020; Choudhary & Sharma 2020) and some other antivirals (Asai et al., 2020; Boopathi et al., 2020; Lian et al., 2020) . Consequently, this review will provide an insight and comprehensive view on different therapeutic approaches including combining of different known anti-parasitic drugs, as well as proposing novel suggestions of chemoprophylaxis drug therapy, which can be used in the current treatment and vaccine development strategies against COVID-19 disease.
cord-336572-n6juf8tw	2020	
cord-337198-4sors3bg	2020	In this study, we evidence that the anti-SARS-CoV2 activity of a clinically achievable hydroxychloroquine concentration is maximized only when administered before and after the infection of Vero E6 and Caco-2 cells. In this study, we tested HCQ against a SARS-CoV-2 Italian clinical isolate, by using different protocols of drug administration corresponding to its possible prophylactic, therapeutic, and prophylactic/therapeutic use in patients. A clinical isolate hCoV-19/Italy/UniSR1/2020 (GISAID accession ID: EPI_ISL_413489) was isolated and propagated in Vero E6 cells, and viral titer was determined by 50% tissue culture infective dose (TCID 50 ) and plaque assay for confirming the obtained titer. HCQ EC 50 against SARS-CoV-2 was obtained by both CPE and RT-PCR analysis on results from full-time experimental setting on Vero E6 cells. Different concentrations of HCQ were tested on Vero E6 to determine the effective concentration of the drug against SARS-CoV-2 in vitro infection (Figure 1) .
cord-339669-p61j2caf	2020	
cord-339717-2a8zv9xl	2020	
cord-339737-7qdjea6f	2020	-Using a large non-selected population of inpatients hospitalized for COVID-19 infection in 39 hospitals in France and robust methodological approaches, we found no evidence for efficacy of HCQ on 28-day mortality -Our results suggest an excess risk of mortality in patients treated by a combination of HCQ and AZI, but not with HCQ alone -Significantly higher rates of discharge home were observed in patients treated by HCQ, a novel finding warranting further confirmation in replicative studies . Results from competing risks multivariable analyses for 28-day mortality and hospital discharge are displayed in Table 3 , showing both raw unadjusted estimates for the average treatment effect of ''HCQ alone ''or ''HCQ plus AZI'', and AIPTW results from double robust estimation accounting for confounders for the outcome and the treatment allocation.
cord-339838-8okrjbfn	2020	key: cord-339838-8okrjbfn authors: Wang, Ya‐Ling; Wang, Shih‐Han; Yang, Ai‐Yu After oral absorption, HCQ is widely distributed in various tissues in the body. 1 This finding is similar to another in-vitro study on Although HCQ is safer and more effective than Chloroquine, special attention should be paid to the interaction and side effects when it is used with Azithromycin. 4 There''s no guidance for the treatment of COVID-19 has indicated that the dose of HCQ can be calculated according to body weight and adjusted according to different races. All authors declare no conflict of interest. Tissue distribution of chloroquine, hydroxychloroquine, and desethylchloroquine in the rat Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection Observational study of hydroxychloroquine in hospitalized patients with COVID-19
cord-340090-dqhdws5k	2020	
cord-341101-5yvjbr5q	2020	While approved specific antiviral drugs against SARS-CoV-2 are still lacking, a large number of existing drugs are being explored as a possible treatment for COVID-19 infected patients. In general, studies showed no significant effect of CQ on CoVs including SARS-CoV and feline infectious peritonitis virus (FIPV) replication or clinical scores in mice and cats, respectively [105, 110] . There are very limited published clinical trials that studied the possible antiviral effect of CQ or HCQ in CoV and non-CoV infected patients (Table 5 ). Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro
cord-341377-mjdg84ny	2020	
cord-342746-2hbcbvt6	2020	
cord-344120-7t5ce2hb	2020	CONCLUSION: According to level 1 evidence reviewed here, the most effective SARS-Co-V-2 pharmacologic treatments include remdesivir for mild to severe disease, and a triple regimen therapy consisting of lopinavir-ritonavir, ribavirin and interferon beta-1b for mild to moderate disease. 20 Another randomized controlled open-label trial in 199 hospitalized patients with confirmed SARS-CoV-2 with severe COVID-19 was done to compare the clinical effectiveness of lopinavir-ritonavir to standard care alone. According to the level 1 evidence reviewed here, the most effective treatments against SARS-CoV-2, measured by time to negative RT-PCR and time to clinical improvement, are remdesivir therapy and a triple medication regimen (lopinavir-ritonavir, ribavirin, and interferon beta-1b). First, in patients with severe COVID-19, treatment with lopinavir-ritonavir showed no significant difference in time to clinical improvement, mortality at day 28, or detectable viral load compared to standard care alone.
cord-347186-tbtmqmpr	2020	
cord-347731-eqxn6auk	2020	
cord-347775-hidb8q1u	2020	Model-based simulations of HCQ concentrations revealed that high initial doses followed by low and sparse doses may offer significant benefits to patients by decreasing the viral load without reaching levels considered to produce adverse effects. 4. Based on the results from simulations performed and the currently published knowledge regarding HCQ in COVID-19 treatment, this study provides evidence that a high loading dose followed by sparse doses could offer significant benefits to the patients. Dosing schemes were designed in order to achieve a fast onset of "high" concentrations during the initial phase of the disease, since an initial higher viral load is anticipated, especially for patients with severe COVID-19, and then keep HCQ blood levels below 2250 ng/ml and over 500 ng/ml, at all times.
cord-348987-3jpdvy7n	2020	1 Prior research including with human immunodeficiency virus (HIV) and SARS-CoV-1 has shown that in vitro antiviral activity of CQ and HCQ does not necessarily translate to in vivo clinical efficacy. 3 It is unclear how the differences in the EC 50 values will impact the in vivo prophylactic antiviral efficacy at their recommended doses of HCQ 400 mg twice daily (bd) on day 1 and then 200 mg bd for 5 days. Until then, CQ and HCQ should only be used in the setting of clinical trials with a clear understanding among physicians and patients of uncertain efficacy and potentially harmful side effects. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial
cord-349868-lb2jcl8m	2020	We present the cases of two COVID-19-positive patients treated with HCQ at our institution, which showed adverse effects of the medication. Hydroxychloroquine (HCQ), a common antimalarial and lupus drug, has been shown to potentially reduce viral carriage and the number of symptomatic days in COVID-19 patients according to an open-label non-randomized French case study of 36 patients [2] . The purpose of this case series was to highlight some of the cardiovascular complications related to HCQ and to engage in a risk-benefit analysis of its use in mild/moderate presentations of COVID-19. We believe these are among the first few cases illustrating adverse cardiovascular effects of the experimental five-day HCQ therapy in mild/moderate presentations of COVID-19. Case 2, considered as low risk, demonstrated how HCQ therapy initiated in an outpatient resulted in an adverse outcome that led to hospital admission.
cord-350992-l6l24pco	2020	Here we review what is currently known on the mechanisms of action of CQ and HCQ as anti-viral, anti-inflammatory and anti-thrombotic drugs and discuss the up-to-date experimental evidence on the potential mechanisms of action of CQ/HCQ in Sars-Cov2 infection and the current clinical knowledge on their efficacy in the treatment of COVID-19 patients. We also propose a different insight into some of CQ and HCQ effects, suggesting a potential role of iron homeostasis in Sars-Cov-2 disease (COVID-19), similarly to several other human viral infections [2] [3] [4] . The search strategy was to use different search terms alone and in any combination, such as "Sars-Cov-2 disease", "COVID-19", "Sars-Cov-2", "coronavirus", "clinical trial", "treatment", "drug", "chloroquine", "hydroxychloroquine", "iron", "virus", "viral entry", "viral spread", "anti-viral activity", "infection", "inflammation", "immunity", "innate immunity", "cytokine", "IL-6", "TNF-", "IL-1", "adaptive immunity", "thrombosis", "in vitro".
cord-351510-8m4930bc	2020	
cord-352557-l7sahv5t	2020	
cord-353749-2vlc11rx	2020	24 In one uncontrolled study, HCQ prophylaxis in a hospital setting with a known SARS-CoV-2 exposure prevented dissemination of viral infection. 40 The second case-control study of HCWs found that four or more weekly doses of HCQ resulted in significantly less infection with SARS-CoV-2 (adjusted odds ratio 0.44, p<0.001). 45 In a retrospective cohort study of 32,109 rheumatic disease patients from the US Veterans Health Administration, the incidence of SARS-CoV-2 infection was equivalent regardless of chronic HCQ use (0.3% in users versus 0.4% in non-users), but mortality was significantly decreased in patients taking HCQ (odds ratio 0.70, p=0.0031). SARS-CoV-2 infection in a patient on chronic hydroxychloroquine therapy: implications for prophylaxis Long-term hydroxychloroquine use in patients with rheumatic conditions and development of SARS-CoV-2 infection: a retrospective cohort study Hydroxychloroquine in the COVID-19 pandemic era: in pursuit of a rational use for prophylaxis of SARS-CoV-2 infection
cord-354653-m0717ywt	2020