LitCovid-sentences  

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Id Subject Object Predicate Lexical cue
T421 0-31 Sentence denotes Drug Options Against SARS-CoV-2
T422 32-192 Sentence denotes Although some drugs appear to be effective against SARS-CoV-2 and are able to improve COVID-19 symptoms, there is no specific antiviral compound for this virus.
T423 193-453 Sentence denotes In the face of such a global health emergency, several clinically used drugs are being reviewed and redirected to be tested in patients who have critical complications of COVID-19 in an attempt to eliminate the virus and modulate the patient’s immune response.
T424 455-465 Sentence denotes Antivirals
T425 466-713 Sentence denotes Due to the large amount of experimental and clinical studies assessing the effectiveness of antiviral therapy against SARS-CoV-2, we have seen the importance of this class of drugs in reducing the viral load peak at the beginning of the infection.
T426 714-944 Sentence denotes Evidence from laboratory, animal, and clinical studies demonstrate that the use of associated or isolated antivirals can delay the progression of lung lesions and decrease the possibility of respiratory transmission of SARS-CoV-2.
T427 945-1101 Sentence denotes In this study, we selected the following most promising treatment options: lopinavir/ritonavir, arbidol, ribavirin, remdesivir, favipiravir, and type I IFN.
T428 1102-1493 Sentence denotes In the context of discovering new drugs, it is efficient to test the efficacy of existing antiviral drugs regarding the treatment of related viral infections. After the emergence of SARS in 2003, the screening of approved drugs identified an effective SARS-CoV-2 antiviral-drug candidate: the combination of the human immunodeficiency virus (HIV) protease inhibitors lopinavir and ritonavir.
T429 1494-1649 Sentence denotes However, lopinavir has insufficient oral bioavailability for significant therapeutic activity due to rapid catabolism by the cytochrome P450 enzyme system.
T430 1650-1862 Sentence denotes Thus, ritonavir is a cytochrome P450 and glycoproteins inhibitor, which increases the lopinavir plasma half-life, enhancing the pharmacokinetic and pharmacodynamic activities against the viral HIV-protease (303).
T431 1863-2173 Sentence denotes Chu et al. (304) described the possible mechanism of action of these drugs on SARS-CoV-1, suggesting that they act by inhibiting intracellular viral multiplication, preventing the action of the protease enzyme, which leads to the formation of an immature and less infectious virus with no ability to replicate.
T432 2174-2319 Sentence denotes Choy et al. (305) were successful at demonstrating the antiviral effect of lopinavir against SARS-CoV-2, but this was not the case for ritonavir.
T433 2320-2485 Sentence denotes In turn, Kang et al. (306) found a lower viral load in infected SARS-CoV-2 Vero cells treated with lopinavir/ritonavir in relation to the untreated infected control.
T434 2486-2763 Sentence denotes Although no consensus has been reached on its efficacy, dosage, or administration period, the literature includes some case reports, case series, and observational studies reporting a protective effect of the lopinavir/ritonavir combination in COVID-19 patients (110, 307–312).
T435 2764-2994 Sentence denotes Conversely, Cao et al. (313) conducted a controlled open‐label study with 199 hospitalized severe COVID‐19 patients randomly divided into two groups: a standard care group and a lopinavir/ritonavir treatment group (400 mg/100 mg).
T436 2995-3181 Sentence denotes No benefit was observed in the lopinavir/ritonavir treatment group, showing no significant results for faster clinical improvement, lower mortality, or decreased viral RNA detectability.
T437 3182-3388 Sentence denotes Although there are 85 clinical trials in progress testing lopinavir/ritonavir associated with other drugs on SARS-CoV-2 and/or COVID-19, WHO stopped the study of lopinavir/ritonavir in the Solidarity Trial.
T438 3389-3606 Sentence denotes Deng et al. (312) have studied the association of lopinavir/ritonavir with arbidol treatment and demonstrated a significant improvement in COVID-19 patients compared with a group treated only with lopinavir/ritonavir.
T439 3607-3741 Sentence denotes Arbidol (umifenovir) is a broad-spectrum antiviral and immunomodulatory compound used to treat influenza and many other viruses (314).
T440 3742-4047 Sentence denotes Analyses of molecular dynamics and structure-guided drug-binding have suggested an efficiency of arbidol at blocking or hampering the trimerization of the SARS-CoV-2 spike glycoprotein, in addition to inhibiting virus-cell interactions, which supports the potential use of arbidol to treat COVID-19 (315).
T441 4048-4284 Sentence denotes Chen et al. (316) demonstrated that arbidol therapy was able to shorten the course of the disease and promote clinical improvement, resulting in low fever and improvements in dry cough without side effects faster than the control group.
T442 4285-4416 Sentence denotes Zhu et al. (317) also demonstrated the effects of arbidol by retrospectively analyzing the clinical data from 50 COVID-19 patients.
T443 4417-4791 Sentence denotes The study demonstrated that the use of arbidol monotherapy, without association with other drugs, was more effective than the treatment with lopinavir/ritonavir, showing clinical improvement of the disease, presenting a total elimination of viral load over a shorter duration; in addition, no fever or ARDS were reported compared with those in the lopinavir/ritonavir group.
T444 4792-5006 Sentence denotes Ribavirin is another antiviral drug used in association with lopinavir/ritonavir to treat SARS-CoV-1 and was able to reduce viral load, risk of adverse clinical outcomes, ARDS, or death in SARS patients (304, 318).
T445 5007-5234 Sentence denotes Ribavirin has a broad antiviral spectrum as it is a nucleotide analog that competes for the active site of RdRp, a crucial enzyme in the life cycle of RNA viruses, inhibiting viral replication and transcription (221, 319, 320).
T446 5235-5441 Sentence denotes Elfiky (320) conducted an in silico study demonstrating that ribavirin and other antivirals such as sofosbuvir can strongly bind to coronavirus RdRp, preventing the transcription of new copies of viral RNA.
T447 5442-5652 Sentence denotes Only a few clinical studies have investigated the effect of ribavirin on COVID-19 patients, with the studies available generally focusing on the association of ribavirin and other therapeutic schemes (321–323).
T448 5653-5750 Sentence denotes Nevertheless, China’s government (324) has recommended the use of ribavirin in COVID-19 patients.
T449 5751-5842 Sentence denotes Remdesivir (RDV) is also among the several potential drugs tested for SARS-CoV-2 treatment.
T450 5843-6017 Sentence denotes Originally developed to treat Ebola virus infection, RDV is active against RNA viruses from different families, including Coronaviridae (e.g., SARS-CoV-1 and MERS-CoV) (325).
T451 6018-6095 Sentence denotes RDV showed an in vitro effective antiviral activity against SARS-CoV-2 (326).
T452 6096-6321 Sentence denotes Grein et al. (327) conducted a cohort study with 53 COVID-19 patients treated with RDV and found that 68% of them had improved oxygen-support class, whereas 57% of the patients receiving mechanical ventilation were extubated.
T453 6322-6472 Sentence denotes Overall mortality reached 13% over a median follow-up of 18 days, however, viral load data were not collected to confirm the antiviral effects of RDV.
T454 6473-6699 Sentence denotes The biggest issue with this study is that the authors did not include a group without RDV, which hampers the performance of comparative statistical analyses to prove whether the data found resulted from the treatment with RDV.
T455 6700-6930 Sentence denotes Another double-blind, randomized, placebo-controlled trial of intravenous RDV conducted in adults hospitalized with COVID-19 with evidence of lower respiratory tract involvement was performed in different parts of the world (328).
T456 6931-7151 Sentence denotes The study of Beigel and colleagues (328) enrolled 1,063 COVID19 pneumonia patients, 538 of whom were assigned to the treatment with RDV and 521 to a placebo, showed the effectiveness of RDV in treating COVID-19 patients.
T457 7152-7364 Sentence denotes The drug was superior to the placebo in reducing the recovery time in hospitalized COVID-19 patients and decreased the mortality rate in the RDV group, however, this result did not reach statistical significance.
T458 7365-7623 Sentence denotes Antionori et al. (329), analyzing patients with severe COVID-19 pneumonia in an intensive care unit (ICU) who were treated for 10 days with RDV, found that on the 28th day, 38.9% showed improvement, 16.7% were still on mechanical ventilation, and 44.4% died.
T459 7624-7804 Sentence denotes The data suggest that this treatment can benefit hospitalized patients who are not in the ICU, where the clinical result was better and adverse events are observed less frequently.
T460 7805-8023 Sentence denotes Alternatively, the randomized, double-blind, placebo-controlled, multicenter trial with 273 ill individuals performed by Wang et al. revealed that RDV intravenous administration was well-tolerated in COVID-19 patients.
T461 8024-8115 Sentence denotes However, the authors did not find any clinical improvement or significant antiviral effect.
T462 8116-8327 Sentence denotes Goldman et al. (330), in another phase 3 clinical trial on 397 patients with severe COVID-19 without mechanical ventilation support, also did not find differences between 5-day and 10-day courses of RDV therapy.
T463 8328-8535 Sentence denotes The RDV data currently available are still controversial, however, dozens of clinical studies are currently using this drug as an alternative treatment for COVID-19, possibly further elucidating its effects.
T464 8536-8712 Sentence denotes The efficiency of favipiravir, another anti-influenza RdRp inhibitor, has also been clinically assessed and was approved for COVID-19 treatment in China, March 2020 (331, 332).
T465 8713-8839 Sentence denotes An experimental study carried out with the VERO cell line showed that the drug has in vitro activity against SARS-CoV-2 (326).
T466 8840-9156 Sentence denotes Aiming at comparing the effects of favipiravir and lopinavir/ritonavir, Cai et al. (333) conducted an open, non-randomized, before-after controlled study with 80 patients and found that favipiravir favored viral clearance and improved chest CT, having caused fewer adverse effects than the lopinavir/ritonavir group.
T467 9157-9225 Sentence denotes Currently, 31 clinical trials using this medication are in progress.
T468 9226-9434 Sentence denotes Regarding antivirals, type I IFN is a group of cytokines comprising the α and β subtypes, among others, with an important role in antiviral immunity that interferes with viral replication, as discussed above.
T469 9435-9722 Sentence denotes Many studies have shown the protective effect of type I IFN associated with antiviral therapies for patients with SARS and MERS [reviewed by Sallard et al. (334)], which arouses the interest of the scientific community in type I IFN as a potential treatment against SARS-CoV-2 (334–337).
T470 9723-9875 Sentence denotes Despite their efficacy against SARS-CoV-2 (338, 339), the results of in vitro studies using IFN-α and -β to treat COVID-19 patients remain inconclusive.
T471 9876-10087 Sentence denotes Such uncertain nature of the results is associated with biases present in these studies, which include limited-size sample, heterogeneous experimental designs/clinical status, and the type of IFN isoform tested.
T472 10088-10282 Sentence denotes In addition, since COVID-19 treatments rarely involve monotherapy, it is difficult to assess whether the results derived from the tested IFN or the drugs used in combination (322, 323, 340–343).
T473 10283-10539 Sentence denotes It is also worth mentioning that, as discussed above, type I IFN appears to exacerbate inflammation in the progression to severe COVID-19; the timing of administration and subgroups targeted for treatment with type I IFN need to be considered with caution.
T474 10540-10896 Sentence denotes A recent retrospective multicenter cohort study of 446 Chinese patients with COVID-19 reported that among severe to critical COVID-19 patients, early administration (≤5 days after admission) of IFN-α2b decreased mortality in comparison with no admission of IFN-α2b, whereas no significant benefit was associated with IFN-α2b use in moderately ill patients.
T475 10897-11013 Sentence denotes However, late use of IFN-α2b increased mortality and delayed recovery of severe to critical COVID-19 patients (344).
T476 11014-11239 Sentence denotes Zhou et al. (341), investigated the isolated effect of IFN-α in a cohort study comparing 77 patients with moderate COVID-19 treated with nebulized IFN-α2b (5 mU b.i.d.), oral arbidol (200 mg t.i.d.), or a combination of both.
T477 11240-11521 Sentence denotes Although the study did not include a control group, the treatment with IFN-α2b, either containing arbidol or not, significantly reduced the duration of detectable virus in the upper respiratory tract and the circulating of inflammatory markers (IL-6 and C-reactive protein levels).
T478 11522-11851 Sentence denotes Still, in a retrospective multicenter cohort study with 141 mild COVID-19 patients by Xu et al. (342), the arbidol/IFN-α2b combination proved more effective in accelerating pneumonia recovery than IFN-α2b monotherapy, but this was not the case for viral clearance or reducing the length of hospital stay than IFN-α2b monotherapy.
T479 11852-12193 Sentence denotes Hung et al. (322) assessed the effect of IFN-β on COVID-19 patients and found that the triple combination of IFN-β1b, lopinavir/ritonavir, and ribavirin was safer and more effective than lopinavir/ritonavir alone at alleviating symptoms, shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19.
T480 12194-12323 Sentence denotes Similarly, an open randomized clinical trial was carried out by Danoudi-Monfared et al. (345), analyzing treatment with IFN-β-1a.
T481 12324-12564 Sentence denotes The IFN group of COVID-19 patients (n=42) received IFN β-1a in addition to the protocol medications (hydroxychloroquine plus lopinavir-ritonavir or atazanavir-ritonavir) while the control group (n=39) received only the protocol medications.
T482 12565-12692 Sentence denotes The IFN-β-1a-treated patients showed a significantly increased discharge rate on day 14 and decreased mortality within 28 days.
T483 12693-12801 Sentence denotes A better survival rate was also observed when patients received IFN- β-1a in the early stage of the disease.
T484 12802-12898 Sentence denotes The COVID-19 treatment guidelines of many countries already recommend the use of IFNs α/β (335).
T485 12899-13025 Sentence denotes Currently, all over the world, more than 20 clinical trials are using IFN-α and/or β alone or in association with other drugs.
T486 13027-13061 Sentence denotes Chloroquine and Hydroxychloroquine
T487 13062-13215 Sentence denotes Chloroquine and hydroxychloroquine have been used worldwide for more than 70 years, and they are part of the WHO model list of essential medicines (346).
T488 13216-13554 Sentence denotes They were synthesized specifically for the treatment and chemoprevention of malaria, but their immunomodulatory activity led these drugs to be used against autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and other inflammatory rheumatic diseases; they also show broad-spectrum antiviral effects (347–349).
T489 13555-13741 Sentence denotes Regarding the chemical structure, hydroxychloroquine differs from chloroquine in the presence of a hydroxyl group at the end of the side chain: the N-ethyl substituent is β-hydroxylated.
T490 13742-13997 Sentence denotes Both drugs have similar pharmacokinetics, with rapid gastrointestinal absorption and renal elimination, but different clinical indications and toxic doses, in which hydroxychloroquine is less toxic and more clinically used in the malaria model (348, 350).
T491 13998-14126 Sentence denotes The action mechanism of these drugs has direct molecular effects on lysosomal activity, autophagy, and signaling pathways (347).
T492 14127-14325 Sentence denotes As antivirals, chloroquine is known to block SARS-CoV-1-infection by increasing endosomal pH required for virus entry, as well as interfering with the glycosylation of cellular receptors (351, 352).
T493 14326-14622 Sentence denotes The possible mechanism against SARS-CoV-2 is the inhibition of virus entry by altering the glycosylation of ACE2, reducing the binding efficiency between ACE2 in host cells and the S protein on the surface of the SARS-CoV-2, thus preventing the virus from binding to target cells (348, 351, 353).
T494 14623-14752 Sentence denotes In addition to a potent antiviral inhibition, the immunomodulatory activity of these drugs is well established in the literature.
T495 14753-15207 Sentence denotes Proposed effects of chloroquine on the immune system include increasing the export of soluble antigens into the cytosol of dendritic cells, the blocking of TLR7 and TLR9 signaling, thus reconstructing CD8+ cytotoxic viral response, and inhibiting and/or reducing the production of inflammatory cytokines like IL-1, IL-6, TNF, and IFN-α (347, 354–359), which has an important role in the immunopathogenesis of COVID-19, as previously reported in item 4.1.
T496 15208-15363 Sentence denotes In vitro studies on SARS-CoV-2 have demonstrated the low-dose action of these drugs, having found the lowest half-maximal effective concentrations (EC50s).
T497 15364-15470 Sentence denotes In addition, their association with azithromycin significantly inhibited viral replication (326, 360–362).
T498 15471-15723 Sentence denotes In humans, a study by Gao, Tian, and Yang (363) showed that patients treated with chloroquine phosphate had inhibited exacerbation of pneumonia, improving lung imaging findings, promoting a virus-negative conversion, and shortening the COVID-19 course.
T499 15724-15966 Sentence denotes The association of hydroxychloroquine with other drugs is also suggested, with emphasis on studies using azithromycin, a broad-spectrum macrolide antibiotic primarily used to treat respiratory, enteric, and genitourinary bacterial infections.
T500 15967-16116 Sentence denotes Despite not yet being approved for antiviral therapy, it has been studied in vitro and in clinical trials for activity against several viruses (364).
T501 16117-16281 Sentence denotes Gautret et al. (365) demonstrated the effectiveness of the hydroxychloroquine-azithromycin combination in a non-randomized clinical trial with 36 COVID-19 patients.
T502 16282-16441 Sentence denotes A 57.1% rate of cure was attributed to the patients treated with hydroxychloroquine, however, when combined with azithromycin, 100% of the patients were cured.
T503 16442-16600 Sentence denotes The authors suggested a synergistic effect of the drug combination since both were reported to have antiviral and immunomodulatory activity in the literature.
T504 16601-16855 Sentence denotes Gautret et al. (366) conducted another analysis to provide evidence of a beneficial effect of co-administration of hydroxychloroquine with azithromycin in a non-comparative and uncontrolled observational study with 80 mildly infected SARS-CoV-2 patients.
T505 16856-17075 Sentence denotes The hydroxychloroquine/azithromycin treatment showed that 81.3% of the patients had a favorable result with a rapid decrease in nasopharyngeal viral load at day 8 (93%), reducing the mean length of stay in the hospital.
T506 17076-17179 Sentence denotes Arshad et al. (367) performed a multicenter observational study, which included 2541 COVID-19 patients.
T507 17180-17375 Sentence denotes Patients were separated into four groups: untreated (n = 409), treated with hydroxychloroquine (n = 1202), the association of hydroxychloroquine and azithromycin, and azithromycin only (n = 147).
T508 17376-17595 Sentence denotes The authors suggested that the treatment with hydroxychloroquine alone and in combination with azithromycin was associated with a reduction in the hazard ratio for death when compared with receipt of neither medication.
T509 17596-17801 Sentence denotes However, a lot of controversy has been raised about these data, and many important limitations of this study were considered by several authors (368–373), threatening the validity of the reported findings.
T510 17802-18093 Sentence denotes Among these, there is the potential for immortal time bias and selection bias, the administration of corticosteroids in most patients treated with hydroxychloroquine than in other groups, and a disproportionately high share of patients with cardiovascular comorbidity in the untreated group.
T511 18094-18282 Sentence denotes Seeking to analyze the efficacy of early treatment using hydroxychloroquine and azithromycin, Million et al. (374) carried out a retrospective study with 1061 SARS-CoV-2 infected patients.
T512 18283-18445 Sentence denotes In the study, 91.7% of the patients reached good clinical results and virological cure within 10 days, while 4.3% had a poor outcome associated with advanced age.
T513 18446-18551 Sentence denotes However, it is worth mentioning that the study did not include a control group to establish a comparison.
T514 18552-18794 Sentence denotes To assess the use of hydroxychloroquine as a prophylactic measure, Boulware et al. (375) performed a randomized, double-blind trial in adults who had been exposed to individuals diagnosed with COVID-19, either in the home or work environment.
T515 18795-18890 Sentence denotes The authors found that postexposure prophylaxis did not prevent the development of the disease.
T516 18891-19134 Sentence denotes An important question that may be considered about chloroquine and its derivate is the numerous adverse effects reported, such as nausea, pruritus, headache, hypoglycemia, neuropsychiatric effects, and idiosyncratic hypersensitivity reactions.
T517 19135-19299 Sentence denotes In long-term treatments, effects such as retinopathy, vacuolar myopathy, neuropathy, restrictive cardiomyopathy, and cardiac conduction disorders are also reported.
T518 19300-19443 Sentence denotes Furthermore, its concomitant use with azithromycin may predispose patients to arrhythmias (213), which represents a major negative implication.
T519 19444-19589 Sentence denotes Huang et al. (376) conducted a randomized clinical trial with 22 patients in China to compare the effects of chloroquine and lopinavir/ritonavir.
T520 19590-19793 Sentence denotes Even though chloroquine led to some clinical improvement, half of the patients experienced adverse effects such as vomiting, abdominal pain, nausea, diarrhea, skin rashes, cough, and shortness of breath.
T521 19794-20133 Sentence denotes Satlin et al. (377), Magagnoli et al. (378), Rosenberg et al. (379), and Ip et al. (380) reported that treatment with hydroxychloroquine, azithromycin, or both were not associated with a survival benefit among patients and there were no significant differences in mortality for patients receiving hydroxychloroquine during hospitalization.
T522 20134-20346 Sentence denotes Similarly, Mahévas et al. (381) analyzed the efficacy of hydroxychloroquine in patients hospitalized with coronavirus pneumonia who needed oxygen but not intensive care, through a comparative observational study.
T523 20347-20414 Sentence denotes 181 patients were analyzed, 84 of whom received hydroxychloroquine.
T524 20415-20685 Sentence denotes Data showed there was no effect on reducing admissions to intensive care or deaths on day 21 after hospital admission and the hydroxychloroquine treatment did not have any effect on survival without acute respiratory distress syndrome on day 21 after hospital admission.
T525 20686-20902 Sentence denotes Tang et al. (382) carried out a multicenter, open, randomized, and controlled clinical trial evaluating 150 patients admitted with confirmed mild to severe COVID-19; of these, 75 were treated with hydroxychloroquine.
T526 20903-20995 Sentence denotes The authors demonstrated that treatment does not contribute to the elimination of the virus.
T527 20996-21268 Sentence denotes Borba et al. (383) conducted a phase IIb, double-blind, randomized clinical trial comparing the effects of high doses (600 mg/twice daily for 10 days) and low doses (450 mg twice daily at day 1 and once daily for 4 days) of chloroquine in 81 and 40 patients, respectively.
T528 21269-21384 Sentence denotes The results did not evidence lower viral load in respiratory secretions, not even in combination with azithromycin.
T529 21385-21491 Sentence denotes The mortality rate for the high-dose group was over twice as high as the low-dose group (39.0% vs. 16.0%).
T530 21492-21717 Sentence denotes Additionally, some patients, mainly in the high-dose group, showed adverse effects, such as increased creatine phosphokinase (CK) and CK-MB, while the high-dosage group exhibited more corrected QT (QTc) interval prolongation.
T531 21718-21773 Sentence denotes Neither of the dosages was able to influence lethality.
T532 21774-21870 Sentence denotes The authors concluded that critically ill patients should not receive chloroquine at high doses.
T533 21871-22109 Sentence denotes In the meantime, a cohort study with 201 patients showed that the use of chloroquine or hydroxychloroquine combined with azithromycin generated a higher increase in QT prolongation than chloroquine or hydroxychloroquine monotherapy (384).
T534 22110-22307 Sentence denotes More recently, another large observational study involving 1376 cases of COVID-19 from New York found no significant association between the use of hydroxychloroquine and intubation or death (385).
T535 22308-22481 Sentence denotes Currently, chloroquine and hydroxychloroquine are the most largely studied compounds in the context of COVID-19 treatment, encompassing at least 320 ongoing clinical trials.
T536 22482-22682 Sentence denotes However, considering that more recent studies failed to prove any favorable effect of their use in COVID-19 patients, the WHO discontinued the study of hydroxychloroquine in the Solidarity Trial (13).
T537 22684-22699 Sentence denotes Antihelminthics
T538 22700-22990 Sentence denotes Amid the COVID-19 pandemic, the search for active molecules against the coronavirus should use advanced tools of computational biology and artificial intelligence for the recognition of drugs already approved and commercialized with potential effects on the replication of SARS-CoV-2 (386).
T539 22991-23270 Sentence denotes In this context, over the past few years, research has shown the antiviral potential in vitro, especially against RNA viruses, of Ivermectin, the best known and most widely used antiparasitic drug in human and veterinary medicine, with promising results against SARS-CoV-2 (387).
T540 23271-23504 Sentence denotes The model of Vero/hSLAM cells infected with a SARS-CoV-2 isolate showed the ivermectin antiviral effect in which 24h-ivermectin treatment reduced 93% of RNA viral load in the cell supernatant and 99.8% of the intracellular viral RNA.
T541 23505-23727 Sentence denotes The authors hypothesized that its probable mechanism of action occurs through the inhibition of nuclear import of importin-α/β1–mediated the IMPα/β1 heterodimer of viral proteins, as shown for other RNA viruses (387, 388).
T542 23728-23982 Sentence denotes Corroborating, Lehrer and Rheinstein (389) identified the ivermectin docking site between the region of leucine 91 of viral spike and the histidine 378 of the ACE2 receptor, which may interfere with the attachment of the spike to the human cell membrane.
T543 23983-24335 Sentence denotes Although the in vitro proliferation inhibition effect of Ivermectin against SARS-CoV-2 has been shown, there is no evidence that the IC50 of ~ 2 µM determined by Caly and colleagues can be achieved in the clinic where pharmacokinetics studies showed that even the maximum tested dosage of 1700 μg/kg presented only 0.28μM of plasma concentration (390).
T544 24336-24577 Sentence denotes According to Navarro et al. (391), no adverse effects of high doses of ivermectin have so far been demonstrated in clinical studies with patients, with only a few transient ocular events in those who experienced high doses (up to 400 μg/kg).
T545 24578-24823 Sentence denotes However, Duthaler et al. (392) demonstrated that the adverse effects of ivermectin in the body can vary according to the patient’s nutritional status, and the effects of high doses can be harmful, especially in patients with malnutrition levels.
T546 24824-24992 Sentence denotes The general consensus of the authors is that further studies are needed to evaluate the efficacy and safety of ivermectin administered in high doses against SARS-CoV-2.
T547 24993-25217 Sentence denotes Xu et al. (386) published a review article regarding niclosamide, an old anthelmintic used to treat tapeworm infections, showing promising antiviral activity against various viral infections, such as SARS-CoV-1 and MERS-CoV.
T548 25218-25323 Sentence denotes This drug has shown to act in vitro by enhancing autophagy and efficiently reducing MERS-CoV replication.
T549 25324-25519 Sentence denotes Originally developed as an antiprotozoal agent, nitazoxanide is another broad-spectrum antiviral agent that has been currently developed to treat influenza and other viral respiratory infections.
T550 25520-25705 Sentence denotes Nitazoxanide exhibited in vitro activity against MERS-CoV by inhibiting the expression of viral N protein, in addition to reducing the production of IL-6 in an in vivo model (393, 394).
T551 25706-26021 Sentence denotes Despite the lack of studies in the literature showing the effect of these anthelmintics on the COVID-19 model, clinical trials have currently included this type of antiviral agent in many countries; there are 37 clinical trials using ivermectin alone or associated with hydroxychloroquine, and 19 with nitazoxanide.
T552 26022-26124 Sentence denotes These studies are yet to be published and preliminary results are expected in the second half of 2020.
T553 26126-26140 Sentence denotes Anticoagulants
T554 26141-26310 Sentence denotes A high mortality risk in severe COVID-19 patients has been described, especially due to the development of disseminated intravascular coagulation and coagulopathy (395).
T555 26311-26489 Sentence denotes Patients with sepsis and disseminated intravascular coagulation may develop thromboembolic complications or microvascular clot deposition, contributing to multiple organ failure.
T556 26490-26772 Sentence denotes In patients with severe pneumonia, the activation of vascular endothelium, platelets, and leukocytes results in the unregulated generation of thrombin, both locally, in the lungs, and systemically, leading to fibrin deposition and subsequent tissue damage and microangiopathy (396).
T557 26773-27002 Sentence denotes In COVID-19 patients, severe pulmonary inflammation is believed to be associated with the regulation of pro-inflammatory cytokines, which can cause the dysfunction of endothelial cells and consequently higher thrombin production.
T558 27003-27095 Sentence denotes Therefore, the use of anticoagulant therapy could be beneficial for COVID-19 patients (397).
T559 27096-27356 Sentence denotes In a retrospective study with 449 patients with severe COVID-19, Tang et al. (395) observed a lower mortality rate in individuals treated with prophylactic heparin associated with coagulopathy compared with those who had not been treated with an anticoagulant.
T560 27357-27577 Sentence denotes The study associated the use of thrombosis prophylaxis with lower 28-day mortality in COVID-19 patients, but only for those presenting a high value of either sepsis-induced coagulopathy score (≥4) or D-dimer (≥3.0 mg/L).
T561 27578-27823 Sentence denotes Paranjpe et al. (398) carried out a large cohort analysis with 2773 COVID-19 patients in the United States, among which 28% received anticoagulant therapy, and also found an association of anticoagulant-based treatment with lower mortality risk.
T562 27824-27994 Sentence denotes The mortality rate in patients who required mechanical ventilation and received anticoagulant therapy was lower than those who had not been treated with an anticoagulant.
T563 27995-28219 Sentence denotes It is important to highlight that heparin has an anti-inflammatory effect that can bind to inflammatory cytokines, chemokines, and proinflammatory proteins, inhibiting neutrophil chemotaxis and leukocyte migration (399–401).
T564 28220-28427 Sentence denotes In the current COVID-19 context, there are over 60 ongoing clinical trials covering the use of thromboprophylaxis, which will certainly clarify the potential role of anticoagulants in patients with COVID-19.
T565 28429-28442 Sentence denotes Dexamethasone
T566 28443-28838 Sentence denotes Recent studies have demonstrated great interest in the role of corticosteroids to attenuate the pulmonary and systemic damage in COVID-19 patients because of their potent anti-inflammatory and antifibrotic properties, especially dexamethasone, a synthetic corticosteroid which is on the list of essential medicines of the World Health Organization and is readily available worldwide at low cost.
T567 28839-28969 Sentence denotes This drug acts as a broad-spectrum immunosuppressor and has greater activity in inflammatory and autoimmune conditions (402, 403).
T568 28970-29188 Sentence denotes Recently, the randomized RECOVERY study, conducted by the University of Oxford, declared dexamethasone as the world’s first treatment proven effective in reducing the risk of death among severely ill COVID-19 patients.
T569 29189-29303 Sentence denotes The trial accompanied a total of 2104 patients treated with dexamethasone and 4321 who received conventional care.
T570 29304-29555 Sentence denotes The dexamethasone group showed reduced 28-day mortality in COVID-19 patients receiving invasive mechanical ventilation or oxygen therapy without invasive mechanical ventilation, but not in patients who were not receiving any respiratory support (404).
T571 29556-29745 Sentence denotes Similar results were published by Tomazini et al. (405) in a Brazilian multicenter, randomized, open-label, clinical trial involving 299 adults with moderate or severe ARDS due to COVID-19.
T572 29746-29954 Sentence denotes The study showed that 144 patients who received dexamethasone treatment plus the standard treatment showed a significant increase in the number of days without mechanical ventilation during the first 28 days.
T573 29955-30292 Sentence denotes In the same way, Villar et al. (406) also published a multicenter randomized clinical trial and showed that early administration of dexamethasone in COVID-19 patients who had moderate and severe ARDS presented an increased average number of days without mechanical ventilation, as well as reduced mortality compared to the control group.
T574 30293-30406 Sentence denotes There are currently 29 clinical trials evaluating the therapeutic efficacy of dexamethasone in COVID-19 patients.
T575 30407-30702 Sentence denotes In the face of the huge amount of studies involving clinical trials to test drugs for SARS-CoV-2 and COVID-19 treatment, in addition to the different research methodologies and criteria addressed, on March 22, 2020 the WHO and partners launched the “SOLIDARITY”, an international clinical trial.
T576 30703-30887 Sentence denotes The purpose is to help find an effective treatment for COVID-19, seeking to establish consistent endpoints, control arms, and inclusion-exclusion criteria for this umbrella trial (13).
T577 30888-31106 Sentence denotes The SOLIDARITY trial includes hospitalized patients with COVID-19 from more than 90 countries around the world to compare treatment options with standard care and assess their relative effectiveness against SARS-CoV-2.
T578 31107-31272 Sentence denotes By enrolling patients from multiple countries, the SOLIDARITY trial aims at rapidly discovering if any of the drugs mitigate disease progression or improve survival.
T579 31273-31410 Sentence denotes According to the WHO director-general, the study will dramatically cut the time needed to generate robust evidence on how the drugs work.
T580 31411-31517 Sentence denotes Thus, the two most promising treatment options selected were Remdesivir or Lopinavir/Ritonavir with IFN-β.
T581 31518-31575 Sentence denotes Other drugs can be added based on emerging evidence (13).