LitCovid-sentences  

PMC:7696151 / 25695-41349 JSONTXT 3 Projects

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Id Subject Object Predicate Lexical cue
T177 0-6 Sentence denotes 2.2.4.
T178 7-34 Sentence denotes Coronavirus Disease of 2019
T179 35-245 Sentence denotes Coronaviruses, belonging to the Coronaviridae family, are enveloped positive-sense single-stranded RNA viruses highly distributed in humans and vertebrates like bats, which are proposed as their main reservoir.
T180 246-428 Sentence denotes Specifically, Coronavirus Disease of 2019 (COVID-19) was first identified in December 2019 in Wuhan, the capital city of Hubei (China), and it is caused by the SARS-CoV-2 virus [49].
T181 429-603 Sentence denotes Since COVID-19 has spread rapidly in many countries, it has quickly become a global pandemic, so it is necessary to develop drugs able to exert antiviral activity against it.
T182 604-699 Sentence denotes A recent study showed HCQ in vitro antiviral activity against SARS-CoV-2 (EC50 = 0.72 μM) [50].
T183 700-901 Sentence denotes HCQ seemed to be able to inhibit the first step of the viral replication cycle by interfering with the link between spike (S) viral protein and the angiotensin-converting enzyme 2 (ACE-2) receptor [8].
T184 902-1061 Sentence denotes It would also appear that HCQ was able to induce changes in cell membrane pH resulting in reduced viral entry and inhibition of the last stages of replication.
T185 1062-1184 Sentence denotes Moreover, HCQ may abolish the cytokine storm related to the advanced stages of COVID-19 through immunomodulatory activity.
T186 1185-1294 Sentence denotes To date, several clinical studies are underway to evaluate the efficacy of HCQ for the treatment of COVID-19.
T187 1295-1441 Sentence denotes In a randomized clinical trial conducted in China, 62 patients with COVID-19 were randomly assigned to two groups: the control and the HCQ groups.
T188 1442-1680 Sentence denotes Either group received standard treatment including antiviral agents, oxygen therapy, immunoglobulin, and antibacterial agents, with or without corticosteroids, but patients in the HCQ group also received oral HCQ 400 mg/day for five days.
T189 1681-1826 Sentence denotes During treatment, clinical characteristics, clinical recovery time (TTCR), and radiological results were assessed to determine the effect of HCQ.
T190 1827-2076 Sentence denotes It was seen that in the HCQ group, the recovery time of body temperature was shorter than in the control group and that the cough remission time was also significantly decreased, while only patients in the control group progressed to severe illness.
T191 2077-2173 Sentence denotes Furthermore, in the HCQ group, 61.3% of patients showed significant absorption of pneumonia [6].
T192 2174-2306 Sentence denotes In another open-label non-randomized French clinical trial, the efficiency of HCQ in reducing the viral count was also demonstrated.
T193 2307-2363 Sentence denotes In this study, 36 subjects were divided into two groups:
T194 2364-2459 Sentence denotes 16 patients for the control group and 20 subjects for HCQ who were administered 600 mg/day HCQ.
T195 2460-2625 Sentence denotes Among the HCQ group, six patients also received 500 mg of AZM for the first day, followed by 250 mg/day for the next four days to prevent super bacterial infections.
T196 2626-2771 Sentence denotes PCR results from nasopharyngeal samples were negative for 70% of patients treated with HCQ and 12.5% in the control group (p = 0.001) on day six.
T197 2772-3020 Sentence denotes Furthermore, when the effect of HCQ as monotherapy was compared to that of HCQ + AZM, it was found that at day six, 100% of HCQ + AZM treated subjects were virologically negative compared with 57.1% of patients treated with HCQ as monotherapy [32].
T198 3021-3238 Sentence denotes These results suggest a synergistic effect between HCQ and AZM and are supported by an uncontrolled non-comparative observational study conducted by the same France group, in a cohort of 80 slightly infected patients.
T199 3239-3406 Sentence denotes In this study, HCQ + AZM treated people were 83% virologically negative on day 7 and 93% on day 8; after 10 days of treatment, only 2 subjects still remain contagious.
T200 3407-3531 Sentence denotes Furthermore, the average duration of hospitalization was found to be 4.6 days after the administration of HCQ plus AZM [33].
T201 3532-3613 Sentence denotes However, these last two studies have a limit, as Gautret et al. carried both out.
T202 3614-3789 Sentence denotes In particular, in the first study, data are available up to 6 days despite the planned 10 days, and in the second study, 6 patients from the previous study were also included.
T203 3790-3988 Sentence denotes Gautret also conducted a retrospective analysis of 1061 cases in which, after treatment with HCQ + AZM, good virological care and clinical outcomes were found in 973 patients (91.7%) within 10 days.
T204 3989-4158 Sentence denotes A prolonged viral carriage was observed in only 47 (4.4%) subjects with a high viral load at the moment of hospitalization, but on day 10 the viral culture was negative.
T205 4159-4212 Sentence denotes Finally, all but one on day 15 were PCR cleared [51].
T206 4213-4348 Sentence denotes By contrast, there are results obtained by several clinical studies that dismiss the possible use of HCQ for the treatment of COVID-19.
T207 4349-4694 Sentence denotes In particular, a prospective study on 11 severe COVID-19 infected patients treated with the same dosage used by Gautret et al. (600 mg/day HCQ and 500 mg AZM for the first day followed by 250 mg/day from day 2 to 5) was shown to provide no evidence of clinical benefits or a strong antiviral activity through the combination of HCQ and AZM [34].
T208 4695-4910 Sentence denotes The ineffectiveness of HCQ has also been declared in a multicenter, open-label, randomized controlled trial involving 150 hospitalized infected patients (148 with mild or moderate disease and 2 with severe disease).
T209 4911-5109 Sentence denotes All subjects were divided into two groups (in a 1:1 ratio): the control group that received only SOC, consisting of antiviral, glucocorticoid, and antiviral, and the group treated with HCQ plus SOC.
T210 5110-5265 Sentence denotes The administrated dose of HCQ consisted of 200 mg/day for the first three days, followed by 800 mg/day as maintained dosage until the end of the treatment.
T211 5266-5405 Sentence denotes After 28 days of treatment, there was no significant difference in SARS-CoV-2 negative conversion in either the HCQ + SOC or the SOC group.
T212 5406-5596 Sentence denotes Similarly, there were no significant differences in the median time to negative conversion and the probability of symptom alleviation within 28 days between HCQ + SOC and the SOC group [35].
T213 5597-5744 Sentence denotes Another multicenter, randomized controlled Egyptian trial evaluated, in 194 subjects with COVID-19, the safety and efficacy of HCQ compared to SOC.
T214 5745-5971 Sentence denotes In terms of mechanical ventilation need and mortality, the addition of HCQ (400 mg twice daily (in day 1) followed by 200 mg tablets twice daily) to SOC was not associated with an improvement of COVID-19 patients’ health [36].
T215 5972-6096 Sentence denotes These results were confirmed by a recent randomized, double-blind, placebo-controlled trial conducted in the USA and Canada.
T216 6097-6331 Sentence denotes In this study, 419 early and mild COVID-19 subjects were randomly assigned to two groups, the HCQ group treated with 800 mg HCQ once, followed by 600 mg in 6 to 8 h, then 600 mg daily for 4 more days, and the placebo or control group.
T217 6332-6601 Sentence denotes Within 14 days of treatment, there was no change in the severity of symptoms in non-hospitalized patients between the HCQ group and the placebo group (difference in symptom severity: relative, 12%; absolute, −0.27 points (95% CI, −0.61 to 0.07 points); p = 0.117) [37].
T218 6602-6797 Sentence denotes Likewise, 2 studies carried out by Mahévas et al. supported the ineffectiveness of HCQ and highlighted that HCQ administration to COVID-10 patients was highly related to ECG modification [38,39].
T219 6798-7000 Sentence denotes ECG modification, resulting in QT-interval prolongation, is a characteristic side effect associated with HCQ treatment that has been shown in several clinical studies on patients infected with COVID-19.
T220 7001-7200 Sentence denotes In particular, the risk of QT-interval prolongation was increased when HCQ was associated with AZM, as demonstrated in a cohort of 84 patients who received 400 mg twice-daily HCQ plus 500 mg/day AZM.
T221 7201-7376 Sentence denotes In these patients, on day 3.6 ± 1.6 of therapy, the EGC showed a QTc prolongation from a baseline average of 435 ± 24 ms (mean ± SD) to a maximal average value of 463 ± 32 ms.
T222 7377-7545 Sentence denotes Moreover, in nine subjects (11%) there was a severe prolongation of QTc to > 500 ms (baseline average of 447 ± 30 ms to 527 ± 17 ms (p < 0.01 (one-sample t-test)) [52].
T223 7546-7659 Sentence denotes This complication was also confirmed in a retrospective study of 251 COVID-19 patients treated with HCQ/AZM [53].
T224 7660-7787 Sentence denotes It seems that a predictor of extreme QTc prolongation was renal failure and that its incidence increased with longer treatment.
T225 7788-8065 Sentence denotes The probability of QTc prolongation may also increase in the presence of other factors such as previous cardiovascular diseases, metabolic degeneration (hypoxia, pH, multiorgan system failure, and electrolyte abnormalities), age, and sex (females seem to be more at risk) [54].
T226 8066-8351 Sentence denotes Therefore, since QTc prolongation to more than 500 ms is known to be associated with a high risk for malignant arrhythmia and fatal stroke, recent guidance suggests the ECG screening with QTc evaluation in COVID-19-infected patients treated with novel therapies including HCQ/AZM [55].
T227 8352-8654 Sentence denotes It has also been suggested that the use of drugs that block late sodium channels (mexiletine or lidocaine) and close attention to serum electrolytes, in addition to the evaluation of heart rate and QT intervals, may allow the administration of HCQ/AZM even in subjects with prolonged QT intervals [54].
T228 8655-8800 Sentence denotes Despite the lack of real antiviral evidence related to HCQ administration, this drug has also been investigated as a possible prophylactic agent.
T229 8801-9004 Sentence denotes In fact, the pharmacokinetics of HCQ, like its long half-life and the high concentration in the lung (500-times higher than blood concentration), has made it an ideal candidate for prophylactic use [56].
T230 9005-9150 Sentence denotes The first study conducted on this line was performed in South Korea on 211 virus-exposed individuals, including 189 patients and 22 care-workers.
T231 9151-9383 Sentence denotes The HCQ administration (400 mg day) as post-exposure prophylaxis resulted in the negative follow-up PCR tests after the end of 14 days of quarantine period (only 97.4% of patients and 95.5% of care-workers completed the study) [40].
T232 9384-9552 Sentence denotes However, it is necessary to consider that this is a single-center clinical study with a high risk of bias and that a subsequent randomized clinical study has denied it.
T233 9553-9717 Sentence denotes In particular, Boulware D.R. et al., in a randomized, double-blind, placebo-controlled trial, tested HCQ as a prophylactic agent within 4 days after virus exposure.
T234 9718-9899 Sentence denotes There were 821 asymptomatic participants randomly assigned to receive either placebo or HCQ (800 mg once, followed by 600 mg in 6 to 8 h, then 600 mg per day for 4 additional days).
T235 9900-10195 Sentence denotes After 14 days of treatment, it was demonstrated that HCQ did not prevent COVID-19 infection when compared to placebo, since the incidence of illnesses compatible with Covid-19 disease did not differ significantly between subjects receiving HCQ (49 of 414 (11.8%)) or placebo (58 of 407 (14.3%)).
T236 10196-10318 Sentence denotes Furthermore, the onset of side effects was more frequent in patients treated with HCQ than placebo (40.1% vs. 16.8%) [41].
T237 10319-10481 Sentence denotes To better assess the incidence of side effects linked to HCQ administration as post-exposure prophylaxis, a cross-sectional study was conducted among 140 doctors.
T238 10482-10730 Sentence denotes Sixty nine adverse events were documented in 44 subjects (31%); the most common reported symptoms were headache followed by nausea, dizziness, abdominal cramps, and loose stools, while hypoglycemia was seen in only three diabetic participants [57].
T239 10731-10882 Sentence denotes Hence, even if the side effects highlighted were not serious, it is recommended to take the utmost care before using HCQ for COVID-19 chemoprophylaxis.
T240 10883-11013 Sentence denotes The ineffectiveness of HCQ administration as post-exposure prophylaxis has also been demonstrated by an in vivo study on macaques.
T241 11014-11148 Sentence denotes Maisonnasse P. et al. tested different treatment strategies, including HCQ alone or in combination with AZM, in comparison to placebo.
T242 11149-11214 Sentence denotes All the treatments were administrated before or after viral load.
T243 11215-11348 Sentence denotes It was seen that when HCQ was administrated as pre-exposure prophylaxis, it did not protect against the acquisition of the infection.
T244 11349-11521 Sentence denotes Similarly, neither HCQ nor HCQ + AZM had beneficial effects in improving viral infection’s symptoms [58], confirming previously analyzed clinical studies’ negative results.
T245 11522-11709 Sentence denotes Several case reports have supported all these results since people already using HCQ for a long time to treat inflammatory diseases also showed severe illness related to COVID-19 [59,60].
T246 11710-11904 Sentence denotes In the light of collected data, despite the success of the first clinical trials, the latest studies have shown the ineffectiveness of HCQ for the treatment and prevention of COVID-19 infection.
T247 11905-11925 Sentence denotes So that, if the U.S.
T248 11926-12219 Sentence denotes Food and Drug Administration (FDA) had initially authorized the use of HCQ in case of emergency [61], in June 2020, the FDA revoked this authorization [62] since the potential HCQ effectiveness in treating COVID-19 was overtaken by severe cardiac adverse events and other serious side effects.
T249 12220-12463 Sentence denotes In fact, there is the need to consider that in subjects with severe COVID-19, the abundance of inflammatory molecules like interleukins and tumor necrosis factors generate a cytokine storm, leading to a septic shock and multiple organ failure.
T250 12464-12570 Sentence denotes In hepatic and renal dysfunction, HCQ metabolism and clearance were compromised and its safety is altered.
T251 12571-12806 Sentence denotes Moreover, recently the Surviving Sepsis Campaign guidelines on the management of critically ill patients with COVID-19 concluded that there was insufficient evidence to recommend the routine use of HCQ in patients admitted in ICU [63].
T252 12807-12934 Sentence denotes In the same way, the American College of Physicians practice guidelines do not recommend HCQ for prophylaxis or treatment [64].
T253 12935-13195 Sentence denotes International trials like SOLIDARITY (International trial by World Health Organisation) [65], RECOVERY (Randomised Evaluation of Covid-19 Therapy) [66], and DISCOVERY (Trial of Treatments for COVID-19 in Hospitalized Adults) [67] have also stopped the HCQ arm.
T254 13196-13426 Sentence denotes In particular, the World Health Organisation (WHO), in the SOLIDARITY trial project, has arrested all arms involving HCQ, as evidence showed that it did not reduce the mortality of hospitalized COVID-19 patients compared with SOC.
T255 13427-13566 Sentence denotes However, this decision was not applied to HCQ use or evaluation in pre- or post-exposure prophylaxis for subjects exposed to COVID-19 [68].
T256 13567-13657 Sentence denotes To conclude, the HCQ treatment of SARS-CoV-2 infection was not met with its hoped success.
T257 13658-13815 Sentence denotes This is probably related to the inability of the dosing regimens currently in use to achieve the blood concentration required for the HCQ antiviral activity.
T258 13816-14054 Sentence denotes Initially, based on physiological pharmacokinetic models, Yao et al. recommended for SARS-CoV-2 infection a loading oral HCQ dose of 400 mg twice daily, followed by a maintenance dose of 200 mg administered twice daily for four days [50].
T259 14055-14392 Sentence denotes However, this recommended HCQ dosage regimen was based only on the ratio of free lung trough concentration to in vitro EC50 values (the EC50 of HCQ for SARS-CoV-2 ranged between 0.72 and 17.31µM) and did not consider the tendency of HCQ to accumulate within acidic cellular organelles like endosomes, lysosomes, and Golgi apparatus [69].
T260 14393-14548 Sentence denotes In fact, it has been demonstrated that HCQ concentration in lysosomes is higher than the extracellular concentration (80 µM vs. 0.5 µM, respectively) [70].
T261 14549-14712 Sentence denotes Based on these results, it was considered necessary to compare the EC50 values obtained in vitro with the plasma concentration and not with the lung concentration.
T262 14713-15001 Sentence denotes In a study investigating HCQ pharmacokinetics in COVID-19 patients treated with 600 mg/day of HCQ, it was found that the mean blood concentration of HCQ was 0.46 mg/day [32], which was below the lowest estimated levels of 0.48 mg/mL corresponding to the in vitro concentration of 0.72 µM.
T263 15002-15209 Sentence denotes Further, a plasma concentration predicted for HCQ antiviral EC50 made by Garcia-Cremades et al. found that it should be 4,7 µM corresponding to 1.58 mg/mL, which is much higher than in vivo plasmatic values.
T264 15210-15400 Sentence denotes To reach this plasma concentration, it should be necessary to take an amount of HCQ higher than 400 mg twice a day for five days or more [71], which would increase the onset of side effects.
T265 15401-15654 Sentence denotes Thus, the ineffectiveness of HCQ antiviral activity again SARS-CoV-2 can be related to the low current dosing regimens and the impossibility to increase the administered doses due to the increased risk of severe side effects, especially QT prolongation.