LitCovid-sentences  

PMC:7127009 / 6516-14762 JSONTXT 15 Projects

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Id Subject Object Predicate Lexical cue
T41 0-96 Sentence denotes 2 Anti-rheumatic drugs as possible therapies: antimalarials, anti-IL6, anti-IL1 and baricitinib
T42 97-321 Sentence denotes Some drugs usually used in rheumatologic field and targeting the host and its immune response seem to have the potential to interfere with CoViD-19 infection and their potential benefit is being studied in patients (Fig. 1).
T43 322-487 Sentence denotes The pathogenesis of CoViD-19 remains unclear, but modelling assays revealed a high degree of homology in the receptor binding domains between SARS-CoV2 and SARS-CoV.
T44 488-797 Sentence denotes All coronaviruses express a surface glycoprotein termed a “spike” which bind to the host receptor for viral entry that has been identified as angiotensin-converting enzyme 2 receptors (ACE2r) [1], expressed by mature lung epithelial cells, enterocytes, kidney proximal tubular cells and endothelial cells [6].
T45 798-943 Sentence denotes After receptor binding, lysosomal proteases cleave the spike protein releasing the signal peptide that facilitates viral entry into the cell [7].
T46 944-1240 Sentence denotes These mechanisms may be targeted and interrupted by therapies such as chloroquine, an antimalarial drug, and preliminary data demonstrate that it may have clinical benefit in the management of CoViD-19 infected patients as determined by improved imaging and shortening of the diseases course [8].
T47 1241-1498 Sentence denotes We should note that hydroxychloroquine, which shares the same mechanism of action as chloroquine but has a better safety profile and is frequently used particularly in connective tissue disease, has a more potent anti-viral effect than chloroquine in vitro.
T48 1499-1802 Sentence denotes From the results of physiologically-based pharmacokinetic models, a loading dose of 800 mg orally followed by 400 mg daily for four days reaches three times the potency of chloroquine and is therefore a promising drug for both the prevention and the treatment of CoViD-19, with low risk of toxicity [9].
T49 1803-1951 Sentence denotes These findings have led to several clinical trials that are ongoing to study the efficacy of chloroquine or hydroxychloroquine in CoViD-19 patients.
T50 1952-2099 Sentence denotes Hydroxychloroquine is thus being used in Italy for the treatment of CoViD-19 patients despite the absence of efficacy data in the clinical setting.
T51 2100-2329 Sentence denotes In light of these data, the recommendation for rheumatic patients chronically taking antimalarial drugs is to not discontinue them, considering the antiviral efficacy and the immunomodulatory rather than immunosuppressive effect.
T52 2330-2434 Sentence denotes Fig. 1 Representation of possible mechanisms of action of anti-rheumatic drugs in coronavirus infection.
T53 2435-2516 Sentence denotes AAK1 = AP2-associated protein kinase 1; SARS = severe acute respiratory syndrome.
T54 2517-2653 Sentence denotes The pulmonary complications in human CoViD-19 patients are due to an exuberant local inflammatory response with diffuse alveolar damage.
T55 2654-2764 Sentence denotes Patients dying because of SARS have lung consolidation, edema and mucopurulent material in the bronchial tree.
T56 2765-2963 Sentence denotes At microscopic examination, alterations such as diffuse alveolar damage, hyaline membrane and fibrin formation, neutrophils and macrophages infiltrates were detected in the interstitium and alveoli.
T57 2964-3053 Sentence denotes Similar features were noted in the only human autopsy report available of MERS infection.
T58 3054-3240 Sentence denotes Cytokines and chemokines play a key role in the immune response against viral infections, and their altered production has been demonstrated in both SARS and MERS coronavirus infections.
T59 3241-3483 Sentence denotes Such altered levels have been shown to be likely due to the low synthesis of antiviral cytokines such as interferons (IFN)α or β and in concert increased levels of other pro-inflammatory cytokines/chemokines that have pathogenic consequences.
T60 3484-3684 Sentence denotes Among them, interleukin (IL)-1, IL-6 and other pro-inflammatory cytokines were shown to be significantly more elevated in patients with severe compared to uncomplicated SARS or MERS infection [10,11].
T61 3685-3906 Sentence denotes Recent preliminary data from China reported high plasma levels of cytokines including IL-6, related to the severity and the prognosis of the disease with a clear implication for the occurrence of “cytokine storm” and CRS.
T62 3907-4136 Sentence denotes Tocilizumab, an anti-IL-6 receptor antibody that has been used clinically to treat rheumatoid arthritis and other autoimmune diseases, has been used and approved for treatment of a variety of clinical conditions that include CRS.
T63 4137-4337 Sentence denotes These have included clinical conditions such as those associated with chimeric antigen receptor T-cell (CAR-T) therapy that appears to induce severe or life-threatening cytokine release syndrome [12].
T64 4338-4540 Sentence denotes A single dose of tocilizumab was used in 21 patients in China suffering from severe respiratory syndrome during CoViD-19 infection, at the dosage of 400 mg intravenously, in addition to routine therapy.
T65 4541-4735 Sentence denotes In a few days, 90% of patients recovered and lung opacities disappeared [13], suggesting that anti-IL-6 might be a powerful potential rescue therapy in respiratory distress syndrome of CoViD-19.
T66 4736-4893 Sentence denotes A potential role for anti-IL1 biologics could be hypothesized from data showing an activation of the NLRP3 inflammasome by SARS-CoV, with secretion of IL-1β.
T67 4894-5063 Sentence denotes Studies have demonstrated that inflammasome activation also occurs in SARS-CoV2 infection, especially within lymphoid cells and patients have increased serum IL-1β [14].
T68 5064-5382 Sentence denotes Another potential treatment under evaluation for SARS-CoV2 related acute respiratory disease is baricitinib, an oral drug used to treat rheumatoid arthritis patients that functions as a blocker of Janus Kinases (JAK) 1 and 2, enzymes associated with intracellular signaling, including Type I and type II IFN signaling.
T69 5383-5600 Sentence denotes One rationale for its use is based on the fact that viruses such as SARS-CoV2 utilize a protein expressed on its spike to bind to the ACE2 receptor and enter cells through a mechanism of receptor-mediated endocytosis.
T70 5601-5724 Sentence denotes One of the known regulators of receptor mediated endocytosis is a kinase termed the AP2-associated protein kinase 1 (AAK1).
T71 5725-5764 Sentence denotes Baricitinib has high affinity for AAK1.
T72 5765-5969 Sentence denotes Inhibition of AAK1 is reasoned to not only inhibit receptor mediated endocytosis (blocking intracellular entry of the virus) but it may also function in the intracellular assembly of virus particles [15].
T73 5970-6213 Sentence denotes The plasma concentration of baricitinib at its current therapeutic dosage (2 or 4 mg orally once daily) is sufficient to inhibit AAK1, thus it may be able to reduce both the viral entry and the inflammation characteristic of CoViD-19 patients.
T74 6214-6416 Sentence denotes Another important aspect in CoViD-19 is that patients are not able to initiate a valid and rapid type I IFN response [10], but the mechanisms underlying this defective response are not completely clear.
T75 6417-6631 Sentence denotes In SARS, macrophages and dendritic cells are only abortively infected and natural killer cells are not activated by the virus, thus suggesting a defective innate immune response with an altered virus clearance [6].
T76 6632-6920 Sentence denotes In a mouse model using the related coronavirus, delayed type-I IFN responses (with IFN levels peaking later in the immune response and remaining elevated) were associated with mortality from severe lung disease, due to recruitment of highly inflammatory macrophages into the lung [16,17].
T77 6921-7096 Sentence denotes Studies of human SARS-CoV infections also strongly suggest that dysregulated and persistently elevated type-I IFN responses are associated with severe human lung disease [18].
T78 7097-7226 Sentence denotes In the mouse model, absence of Type-I IFN signaling (achieved by knockout of the IFN-receptor) abolished lung mediated lethality.
T79 7227-7419 Sentence denotes These data also suggest a second possible explanation for a therapeutic effect of JAK inhibitors such as baricitinib, since they block the downstream signaling of alpha and beta IFN receptors.
T80 7420-7678 Sentence denotes The situation is complicated by the finding that very early administration of IFN-β in the mouse model also decreased lung disease, suggesting that timing and duration of type-I IFN responses is critical to whether the outcome is helpful or deleterious [16].
T81 7679-7739 Sentence denotes What does this imply for patients on JAK inhibition therapy?
T82 7740-7946 Sentence denotes They may have a decreased IFN response to the virus, which would cause excess virus replication, but they also might have less risk of severe lung disease due to downregulation of the IFN signaling pathway.
T83 7947-8128 Sentence denotes This illustrates the difficult balance between an adequate immune response to prevent viral replication and an over-exuberant immune response that causes severe lung pathology [17].
T84 8129-8246 Sentence denotes The role of type I IFN in SARS-CoV2 and the role of blocking IFN-I pathways therefore requires more detailed studies.