LitCovid-sentences  

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Id Subject Object Predicate Lexical cue
T324 0-18 Sentence denotes COVID-19 Treatment
T325 19-164 Sentence denotes To date, no effective vaccines or therapeutic antiviral agents have been approved for the treatment of COVID-19 or any other human CoV infection.
T326 165-232 Sentence denotes The main approach to disease management focuses on supportive care.
T327 233-498 Sentence denotes To contain the viral transmission and disease, rapid public health interventions using immune cell-based therapies, antibodies, antivirals, new drugs, or vaccine strategies have focused on reducing mortality, virus spread, and mitigating potential future outbreaks.
T328 499-786 Sentence denotes In this context, we conducted a survey of the main SARS-CoV-2 drugs/treatments following three criteria: peer-reviewed published scientific literature, with clinical trials that are underway, and that display a broad spectrum of action in the face of various viral and parasitic disease.
T329 787-901 Sentence denotes The researched data (until September 2020) for ongoing and completed trials were searched in “clinicaltrials.gov”.
T330 903-921 Sentence denotes Enhancing Immunity
T331 922-1104 Sentence denotes As exposed in the previous topics, currently there are no proven treatments for SARS-CoV-2 infections, thus, much has been discussed about the maintenance of a healthy immune system.
T332 1105-1283 Sentence denotes In this sense, the use of vitamins and other essential components for the proper functioning of the immune response can be an important approach in times of risk like this (205).
T333 1284-1668 Sentence denotes Several studies have shown that the use of supplements helps in enhancing the immune response and recovery from viral infections, as is the case with the use of vitamin A and D or selenium to improve the humoral immunity of individuals vaccinated against influenza virus (206, 207), or the use of zinc to improve the immune response of individuals infected with torquetenovirus (208).
T334 1669-1850 Sentence denotes Among vitamin supplements, vitamin D stands out for having an immunomodulatory effect on both adaptive and innate immune responses, helping in the development of B, T, and NK cells.
T335 1851-2005 Sentence denotes In addition, it has the ability to stimulate the production of antioxidant responses and microbicidal molecules such as defensins and cathelicidins (209).
T336 2006-2268 Sentence denotes The use of vitamin D has also been associated with the prevention of respiratory diseases associated with viral infections (210), and epidemiological data suggest that vitamin D deficiency increases the susceptibility to acute viral respiratory infections (211).
T337 2269-2493 Sentence denotes However, a study in the United Kingdom that evaluated plasmatic concentrations of vitamin D in samples from COVID-19 patients found no association between circulating vitamin D levels and the risk for disease severity (212).
T338 2494-2780 Sentence denotes The use of supplementation with other types of vitamins has also been described in viral infections; the use of vitamin C, for example, a potent antioxidant and an important enzyme cofactor, contributes to the development of the immune response, helping in the production of type I IFN.
T339 2781-2931 Sentence denotes However, a systematic review with meta-analysis found no evidence that the use of vitamin C has any effect in preventing common cold infections (213).
T340 2932-3043 Sentence denotes As for vitamin E, it has been shown that its deficiency can impair cellular and humoral immune responses (214).
T341 3044-3226 Sentence denotes However, the use of vitamin E has been associated with an increased risk of pneumonia and has shown no significant effect in preventing lower respiratory tract infections (215, 216).
T342 3227-3535 Sentence denotes In view of the controversial results, more than 50 ongoing clinical trials are seeking to clarify the role of vitamins, minerals, and other dietary supplementation in the prophylaxis and treatment of COVID-19, analyzing parameters such as the risk of infection, risk of hospitalization, and clinical outcome.
T343 3537-3550 Sentence denotes Immunotherapy
T344 3552-3574 Sentence denotes Antibody-Based therapy
T345 3575-3805 Sentence denotes Considered an efficient method for the clinical treatment of different infectious diseases, including MERS-CoV and SARS-CoV-1 (217), antibody-based immunotherapy has been studied as a potentially applicable tool to treat COVID-19.
T346 3806-3957 Sentence denotes The mechanisms involved with its effects against SARS-CoV-2 are related to preventing the virus from entering the host cells, blocking its replication.
T347 3958-4152 Sentence denotes The virus entry block was studied for acting both in the cell receptor ACE2 and directly on the virus (neutralizing antibodies [nAbs]), specifically in the S1 subunit of the S protein (218–220).
T348 4153-4409 Sentence denotes Regarding the blocking of ACE2 receptors, the application of some mechanisms stand out: the soluble version of ACE2 fused to an immunoglobulin Fc domain (ACE2-Fc), RDB domain attached to Fc (RDB-Fc), and receptor-targeted monoclonal antibodies (mAb) (221).
T349 4410-4532 Sentence denotes Viral neutralization by nAbs is also an immunotherapeutic approach and directly recognizes epitopic regions of SARS-CoV-2.
T350 4533-4843 Sentence denotes This effect can be achieved either directly through mAbs manufactured in laboratories or by using polyclonal antibodies (pAbs) (218). nAbs act directly on the virus, preventing its infectivity by activating several pathways, such as the complement system, cell cytotoxicity, and phagocytic clearance (222–224).
T351 4844-4932 Sentence denotes The therapeutic use of mAbs has shown good outcomes, mainly due to its high specificity.
T352 4933-5107 Sentence denotes Recently, several mAbs against viruses have been developed, including SARS-CoV-1 and MERS-CoV, in which the S protein is the major target described both in vitro and in vivo.
T353 5108-5245 Sentence denotes According to some studies, the specific nAbs against SARS-CoV-1 RBD in the S protein could effectively block SARS-CoV-2 entry (218, 225).
T354 5246-5464 Sentence denotes However, Wrapp et al. (226) tested several published SARS-CoV-1 RBD-specific nAbs and found that they do not have substantial binding to the S protein of SARS-CoV-2, suggesting that the cross-reactivity may be limited.
T355 5465-5569 Sentence denotes Thus, the combination of nAbs with different viral targets and sources could improve treatment efficacy.
T356 5570-5771 Sentence denotes In addition to experimental studies, to date, more than 10 clinical trials have aimed at testing human mAbs against SARS-Cov-2 (227–235), which could also represent an alternative, effective treatment.
T357 5772-5856 Sentence denotes Furthermore, some immunomodulatory mAbs have been tested in the context of COVID-19.
T358 5857-6196 Sentence denotes It is remarkable that until now most of the data published regarding the use of immunomodulatory mAbs derive from studies using either anti-IL-6 or anti-IL-6R, probably because using IL-6 blockers seems promising at controlling the cytokine storm associated with the development of ARDS in more aggressive patterns of SARS-CoV-2 infection.
T359 6197-6249 Sentence denotes However, clinical observations remain controversial.
T360 6250-6555 Sentence denotes Although some studies found considerable clinical improvements resulting from treatment with IL-6 blockers (236–239), others do not report any significant difference between the clinical features of groups treated with anti-IL6/IL-6R mAbs and their respective controls (without anti-IL-6/IL-6R) (240–243).
T361 6556-6781 Sentence denotes These controversial results can be explained by the pleiotropic function of IL-6, which also play an important anti-inflammatory role, questioning the use of IL-6 blockade to suppress inflammation-induced tissue damage (244).
T362 6782-6984 Sentence denotes Additionally, severe side effects have been associated with the use of IL-6 blockers, including enhanced hepatic enzymes, thrombocytopenia, severe bacterial and fungal infections, and sepsis (241, 245).
T363 6985-7084 Sentence denotes In general, data from analyses on the use of this type of mAbs remain inconclusive (243, 246, 247).
T364 7085-7359 Sentence denotes Recent findings are optimistic, but data validation by robust scientific evidence has been hampered by the small sample size in most case reports and studies on the use of mAbs blocking other immune mediators, such as IL-1β, GM-CSF, and complement protein C5 (238, 248–250).
T365 7360-7501 Sentence denotes However, seeking to verify the effectiveness of using mAbs blocking inflammatory mediators, dozens of clinical trials are currently underway.
T366 7502-7911 Sentence denotes Aiming at reducing the hyper inflammation found in the lungs of SARS-CoV-2-infected patients, different clinical studies are currently investigating the activities of mAbs anti-JAK, anti-GM-CSF, anti-GM-CSF receptor, anti-M-CSF receptor, anti-CD14, anti-IFNγ, anti-VEGF, anti-BKT, anti-CCR5, anti-IL-6, anti-IL-6 receptor, anti-TNFα, anti-IL1β, anti-IL1β receptor, and complement C5 inhibitor (220, 251, 252).
T367 7912-8110 Sentence denotes Similarly, ongoing clinical trials have sought to reverse the hyper-thrombotic state found in critically ill patients by using anti-P-selectin, anti-CTGF, and factor XIIa antagonist mAbs (253, 254).
T368 8111-8324 Sentence denotes Furthermore, to restore the exhausted T lymphocytes’ and NK cells’ immunity, other clinical studies applied anti-PD1 mAbs under the hypothesis of a stimulus of anti-viral response and prevention of ARDS (255–257).
T369 8325-8744 Sentence denotes More recently, the passive administration of pAbs has also been tested in COVID-19 patients (222–224, 258–267), also known as convalescent plasma (CP) or immune plasma, which is already used effectively and safely in the treatment of other severe acute respiratory syndrome infections of viral etiology, such as SARS, MERS, and H1N1, and offers only a short-term but rapid immunity to the susceptible individuals (268).
T370 8745-8883 Sentence denotes A strict criterion to select the CP donor states that the individual must show clinical recovery and test negative for the virus presence.
T371 8884-9013 Sentence denotes Thus, after being confirmed, a high titer of neutralizing antibodies against SARS-CoV-2 must be stored in blood banks (269, 270).
T372 9014-9220 Sentence denotes Some reviews related to patients who received transfusion with CP showed a reduction in viral load, improvement in clinical symptoms, better radiological findings, and improved survival (260, 261, 271–273).
T373 9221-9441 Sentence denotes In addition, after having received CP containing nAbs, COVID-19 patients had significant improvements from the beginning of treatment (until 22 days), presenting lower fever, decreased viral load, and higher nAbs levels.
T374 9442-9523 Sentence denotes Further, 60% of the patients were discharged one month after the treatment (271).
T375 9524-9675 Sentence denotes Better outcomes were found in early administration of CP (before SARS-CoV-2 seroconversion), preferably on day 5, for obtaining maximum efficacy (268).
T376 9676-9851 Sentence denotes More recently, Li et al. found no statistically significant clinical improvement or mortality reduction in a randomized clinical trial with CP-treated COVID-19 patients (274).
T377 9852-10021 Sentence denotes However, the authors reported that CP treatment is potentially beneficial to critically ill patients by suggesting a possible antiviral efficiency of high titer of nAbs.
T378 10022-10333 Sentence denotes Notably, there are clinical controversies, ethical issues, and potential risks associated with convalescent plasma therapy (275), such as the possibility of ADE development, exacerbating the disease severity, and causing a significant illness in future exposure to coronaviruses infection (268, 276, 277) (REF).
T379 10334-10621 Sentence denotes Divergences between studies may be caused by variations in the composition of CP, which is highly variable and includes a variety of blood-derived components, timing of CP administration, titer of the specific antibody in administered plasma, and presence of blood borne pathogens (268).
T380 10622-10743 Sentence denotes Nonetheless, understanding the efficacy and safety of CP therapy relies on the completion of the ongoing clinical trials.
T381 10744-11030 Sentence denotes Another therapeutic strategy using antibodies is intravenous immunoglobulin (IVIg) that contains polyclonal IgG isolated from healthy donors, which can be further enhanced by using IgG antibodies collected from recovered COVID-19 patients in the same geographical region as the patient.
T382 11031-11208 Sentence denotes Results have been mostly positive, although many of these therapies have not been formally evaluated through a randomized, double-blind, placebo-controlled clinical trial (278).
T383 11209-11479 Sentence denotes According to recent studies, IVIg can be used effectively in early stages of SARS-CoV-2 infection (before the initiation of systemic damage), reducing the use of mechanical ventilation, preventing the progression of pulmonary lesions, and promoting early recovery (268).
T384 11480-11685 Sentence denotes Also, cross-neutralization activity was shown against SARS-CoV-2 in commercial IVIg manufactured prior to the COVID-19 pandemic and are currently under evaluation as potential therapies for COVID-19 (279).
T385 11686-12034 Sentence denotes Thus, intravenous use of immunoglobulins can prove helpful in therapy against SARS-CoV-2, however, adjustments in the therapeutic regimen are necessary for all IVIg possibilities, as well as a complete understanding of the possible adverse effects, such as the risk of ADE (278, 279), that are being studied in more than 10 ongoing clinical trials.
T386 12035-12219 Sentence denotes Some works have shown that therapies focusing on the interaction between SARS-CoV-1 and the ACE2 receptor may be extended for use in SARS-CoV-2 patients as an immunotherapy tool (218).
T387 12220-12390 Sentence denotes However, other authors refute this idea based on the fact that recent studies showed limited cross-neutralization between SARS-CoV-1 antibodies and SARS-CoV-2 (280, 281).
T388 12391-12565 Sentence denotes Furthermore, it was shown that SARS-CoV-2 S protein binds ACE2 with a higher affinity than SARS-CoV-1, suggesting that such interaction differs between the two viruses (266).
T389 12567-12592 Sentence denotes Immune Cell-Based Therapy
T390 12593-12760 Sentence denotes In addition to antibody-based therapies, scientists have been studying immune cell-based therapies as a tool to combat COVID-19, focusing especially on NK and T cells.
T391 12761-12964 Sentence denotes The importance of NK cells as the first antiviral responders can be seen in patients with NK cell deficiency and immunocompromised individuals who have increased susceptibility to viral infections (282).
T392 12965-13220 Sentence denotes In this sense, Market et al. (282) gathered the main reports so far addressing potential therapies focusing on mediating NK cell activity to mitigate the immunopathological consequences of COVID-19, and consequently lighten the load on our health systems.
T393 13221-13325 Sentence denotes Some ongoing clinical trials have been studying the use of NK cell therapy through different approaches.
T394 13326-13578 Sentence denotes A randomized phase I/II trial studied the infusions of CYNK-001 cells, an allogeneic off-the-shelf cell therapy enriched for CD56+/CD3- NK cells expanded from human placental CD34+ cells in 86 hospitalized patients with moderate COVID-19 disease (283).
T395 13579-13712 Sentence denotes Another randomized phase I/II study explored the use of NKG2D-ACE2 CAR-NK cells with each common, severe, and critical type COVID-19.
T396 13713-13957 Sentence denotes The authors hypothesize that these cells target the S protein of SARS-CoV-2 and NKG2DL on the surface of infected cells with ACE2 and NKG2D, respectively, seeking out the elimination of SARS-CoV-2 virus particles and their infected cells (284).
T397 13958-14183 Sentence denotes The unregulated profile of the immune response in critically ill COVID-19 patients may be due to the reduction of Treg cells, which culminates in excessive release of inflammatory mediators and cytokine storms (153, 191–193).
T398 14184-14334 Sentence denotes Thus, the use of adoptive transfer of these cells as a measure of inflammatory control in critically ill patients is a promising therapeutic approach.
T399 14335-14690 Sentence denotes The infusion of autologous polyclonal Treg has already been used to treat inflammatory diseases, such as type 1 diabetes (285), however the use of autologous cells takes a long time, due to the period necessary for differentiation and clonal expansion, making this an unviable and costly method for infectious diseases, as is the case with COVID-19 (286).
T400 14691-14865 Sentence denotes A viable alternative is the use of allogeneic human leukocyte antigen-matched umbilical cord-derived Tregs (UBC-Treg) which can be widely expanded and used on a larger scale.
T401 14866-15119 Sentence denotes A recent case study used 1x108 administration of UBC-Treg in two patients with COVID-19 who had severe respiratory failure, and both demonstrated significant clinical improvement and reduced inflammatory markers four days after starting treatment (287).
T402 15120-15241 Sentence denotes There are currently two clinical trials underway that aim to infuse Treg cells in patients with severe COVID-19 and ARDS.
T403 15242-15426 Sentence denotes The first one is a multi-center, prospective, double-blinded, placebo-controlled phase 1 randomized clinical trial, which has 45 patients who will receive cryopreserved UBC-Treg (288).
T404 15427-15607 Sentence denotes The second one is a randomized, double-blind, placebo-controlled phase 2 study with 88 participants who will receive off-the-shelf allogeneic hybrid Treg/Th2 cells (RAPA-501-ALLO).
T405 15608-15735 Sentence denotes RAPA-501-ALLO cells will be generated from healthy donors, cryopreserved, banked, and made available for off-the-shelf therapy.
T406 15736-15966 Sentence denotes The cells are manipulated ex vivo to differentiate into two anti-inflammatory phenotypes simultaneously, generating hybrid Treg/Th2 cells, with the potential to reduce inflammation and mediate a protective effect on tissues (289).
T407 15967-16209 Sentence denotes In addition to therapeutic approaches using Treg cell infusion, another three clinical trials are underway with the aim of evaluating treatment using specific SARS-CoV-2 T cells isolated from individuals who recovered from COVID-19 (290–292).
T408 16210-16396 Sentence denotes The use of virus-specific T cells for off-the-shelf treatment has been used in several viral infections, such as cytomegalovirus, HHV6, adenoviruses, Ebola virus, and BK virus (293–296).
T409 16397-16715 Sentence denotes Although vaccination provides T cells-based virus-specific immunity, the path to its development is long, so the use of adoptive cell transfer techniques from healthy individuals who recovered from COVID-19 and developed an effective cell response is probably the fastest way to treat critically ill individuals (297).
T410 16716-16991 Sentence denotes Besides that, as mentioned before, asymptomatic or mild symptomatic patients may possibly mount robust SARS-CoV-2 specific CD8+ T cell responses (200, 201), therefore, the use of these individuals’ cells to treat critically ill patients with COVID-19 can be a promising tool.
T411 16992-17214 Sentence denotes The clinical use of IL-7 has been implemented in the treatment of cancer patients and infectious diseases, mainly with the objective of improving the immune response by stimulating the generation of lymphocytes (298, 299).
T412 17215-17525 Sentence denotes In addition, IL-7 administration has been reported to increase CD4 + and CD8 + T lymphocyte counts without inducing the production of pro-inflammatory mediators, making it a promising method of recovering immune function in patients with disorders related to cytokine storms, such as sepsis and COVID-19 (300).
T413 17526-17791 Sentence denotes In a case study conducted by Monneret et al. (301), compassionate administration of IL-7 to a patient with severe COVID-19 significantly improved total lymphocyte count and HLA-DR expression in circulating monocytes four days after administration of the first dose.
T414 17792-17886 Sentence denotes The patient also showed a significant improvement in lung involvement and negative viral load.
T415 17887-18259 Sentence denotes Another study conducted by Laterre et al. (302), who administered IL-7 to COVID-19 patients found that there was a significant improvement in the lymphocyte count after starting treatment, in addition, the patients did not show any change in TNF-α levels, IL-1β, and IL-12p70, which may indicate that IL-7 therapy may be safe for patients with severe inflammatory changes.
T416 18260-18400 Sentence denotes Thus, the use of IL-7-based immunotherapy can be an important tool to be used in future clinical trials in patients with severe lymphopenia.
T417 18401-18623 Sentence denotes Therefore, the data available to date do not ensure the success of immunotherapy applied in patients with COVID-19, thus, further studies specifically targeting SARS-CoV-2 should be performed to provide more specific data.
T418 18624-18706 Sentence denotes However, immunotherapy is effective and of immediate use, being of short duration.
T419 18707-18879 Sentence denotes This approach also presented limitations, such as the possibility of abnormal reactions and other serious risks, such as induction of severe acute lung injury or ADE (225).
T420 18880-19157 Sentence denotes Although we are living through a unique moment in science, with some mismatched information and novel, important discoveries being made every day, immunotherapy seems to be a possibly effective option to help patients until an effective, safe vaccine or treatment is developed.
T421 19159-19190 Sentence denotes Drug Options Against SARS-CoV-2
T422 19191-19351 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 19352-19612 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 19614-19624 Sentence denotes Antivirals
T425 19625-19872 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 19873-20103 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 20104-20260 Sentence denotes In this study, we selected the following most promising treatment options: lopinavir/ritonavir, arbidol, ribavirin, remdesivir, favipiravir, and type I IFN.
T428 20261-20652 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 20653-20808 Sentence denotes However, lopinavir has insufficient oral bioavailability for significant therapeutic activity due to rapid catabolism by the cytochrome P450 enzyme system.
T430 20809-21021 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 21022-21332 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 21333-21478 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 21479-21644 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 21645-21922 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 21923-22153 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 22154-22340 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 22341-22547 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 22548-22765 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 22766-22900 Sentence denotes Arbidol (umifenovir) is a broad-spectrum antiviral and immunomodulatory compound used to treat influenza and many other viruses (314).
T440 22901-23206 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 23207-23443 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 23444-23575 Sentence denotes Zhu et al. (317) also demonstrated the effects of arbidol by retrospectively analyzing the clinical data from 50 COVID-19 patients.
T443 23576-23950 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 23951-24165 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 24166-24393 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 24394-24600 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 24601-24811 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 24812-24909 Sentence denotes Nevertheless, China’s government (324) has recommended the use of ribavirin in COVID-19 patients.
T449 24910-25001 Sentence denotes Remdesivir (RDV) is also among the several potential drugs tested for SARS-CoV-2 treatment.
T450 25002-25176 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 25177-25254 Sentence denotes RDV showed an in vitro effective antiviral activity against SARS-CoV-2 (326).
T452 25255-25480 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 25481-25631 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 25632-25858 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 25859-26089 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 26090-26310 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 26311-26523 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 26524-26782 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 26783-26963 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 26964-27182 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 27183-27274 Sentence denotes However, the authors did not find any clinical improvement or significant antiviral effect.
T462 27275-27486 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 27487-27694 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 27695-27871 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 27872-27998 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 27999-28315 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 28316-28384 Sentence denotes Currently, 31 clinical trials using this medication are in progress.
T468 28385-28593 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 28594-28881 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 28882-29034 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 29035-29246 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 29247-29441 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 29442-29698 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 29699-30055 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 30056-30172 Sentence denotes However, late use of IFN-α2b increased mortality and delayed recovery of severe to critical COVID-19 patients (344).
T476 30173-30398 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 30399-30680 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 30681-31010 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 31011-31352 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 31353-31482 Sentence denotes Similarly, an open randomized clinical trial was carried out by Danoudi-Monfared et al. (345), analyzing treatment with IFN-β-1a.
T481 31483-31723 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 31724-31851 Sentence denotes The IFN-β-1a-treated patients showed a significantly increased discharge rate on day 14 and decreased mortality within 28 days.
T483 31852-31960 Sentence denotes A better survival rate was also observed when patients received IFN- β-1a in the early stage of the disease.
T484 31961-32057 Sentence denotes The COVID-19 treatment guidelines of many countries already recommend the use of IFNs α/β (335).
T485 32058-32184 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 32186-32220 Sentence denotes Chloroquine and Hydroxychloroquine
T487 32221-32374 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 32375-32713 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 32714-32900 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 32901-33156 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 33157-33285 Sentence denotes The action mechanism of these drugs has direct molecular effects on lysosomal activity, autophagy, and signaling pathways (347).
T492 33286-33484 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 33485-33781 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 33782-33911 Sentence denotes In addition to a potent antiviral inhibition, the immunomodulatory activity of these drugs is well established in the literature.
T495 33912-34366 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 34367-34522 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 34523-34629 Sentence denotes In addition, their association with azithromycin significantly inhibited viral replication (326, 360–362).
T498 34630-34882 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 34883-35125 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 35126-35275 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 35276-35440 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 35441-35600 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 35601-35759 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 35760-36014 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 36015-36234 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 36235-36338 Sentence denotes Arshad et al. (367) performed a multicenter observational study, which included 2541 COVID-19 patients.
T507 36339-36534 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 36535-36754 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 36755-36960 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 36961-37252 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 37253-37441 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 37442-37604 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 37605-37710 Sentence denotes However, it is worth mentioning that the study did not include a control group to establish a comparison.
T514 37711-37953 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 37954-38049 Sentence denotes The authors found that postexposure prophylaxis did not prevent the development of the disease.
T516 38050-38293 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 38294-38458 Sentence denotes In long-term treatments, effects such as retinopathy, vacuolar myopathy, neuropathy, restrictive cardiomyopathy, and cardiac conduction disorders are also reported.
T518 38459-38602 Sentence denotes Furthermore, its concomitant use with azithromycin may predispose patients to arrhythmias (213), which represents a major negative implication.
T519 38603-38748 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 38749-38952 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 38953-39292 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 39293-39505 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 39506-39573 Sentence denotes 181 patients were analyzed, 84 of whom received hydroxychloroquine.
T524 39574-39844 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 39845-40061 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 40062-40154 Sentence denotes The authors demonstrated that treatment does not contribute to the elimination of the virus.
T527 40155-40427 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 40428-40543 Sentence denotes The results did not evidence lower viral load in respiratory secretions, not even in combination with azithromycin.
T529 40544-40650 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 40651-40876 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 40877-40932 Sentence denotes Neither of the dosages was able to influence lethality.
T532 40933-41029 Sentence denotes The authors concluded that critically ill patients should not receive chloroquine at high doses.
T533 41030-41268 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 41269-41466 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 41467-41640 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 41641-41841 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 41843-41858 Sentence denotes Antihelminthics
T538 41859-42149 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 42150-42429 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 42430-42663 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 42664-42886 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 42887-43141 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 43142-43494 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 43495-43736 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 43737-43982 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 43983-44151 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 44152-44376 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 44377-44482 Sentence denotes This drug has shown to act in vitro by enhancing autophagy and efficiently reducing MERS-CoV replication.
T549 44483-44678 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 44679-44864 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 44865-45180 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 45181-45283 Sentence denotes These studies are yet to be published and preliminary results are expected in the second half of 2020.
T553 45285-45299 Sentence denotes Anticoagulants
T554 45300-45469 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 45470-45648 Sentence denotes Patients with sepsis and disseminated intravascular coagulation may develop thromboembolic complications or microvascular clot deposition, contributing to multiple organ failure.
T556 45649-45931 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 45932-46161 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 46162-46254 Sentence denotes Therefore, the use of anticoagulant therapy could be beneficial for COVID-19 patients (397).
T559 46255-46515 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 46516-46736 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 46737-46982 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 46983-47153 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 47154-47378 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 47379-47586 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 47588-47601 Sentence denotes Dexamethasone
T566 47602-47997 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 47998-48128 Sentence denotes This drug acts as a broad-spectrum immunosuppressor and has greater activity in inflammatory and autoimmune conditions (402, 403).
T568 48129-48347 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 48348-48462 Sentence denotes The trial accompanied a total of 2104 patients treated with dexamethasone and 4321 who received conventional care.
T570 48463-48714 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 48715-48904 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 48905-49113 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 49114-49451 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 49452-49565 Sentence denotes There are currently 29 clinical trials evaluating the therapeutic efficacy of dexamethasone in COVID-19 patients.
T575 49566-49861 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 49862-50046 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 50047-50265 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 50266-50431 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 50432-50569 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 50570-50676 Sentence denotes Thus, the two most promising treatment options selected were Remdesivir or Lopinavir/Ritonavir with IFN-β.
T581 50677-50734 Sentence denotes Other drugs can be added based on emerging evidence (13).