LitCovid-sentences  

PMC:7796052 / 941-6254 JSONTXT 3 Projects

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Id Subject Object Predicate Lexical cue
T8 0-2 Sentence denotes 1.
T9 3-15 Sentence denotes Introduction
T10 16-312 Sentence denotes About 20% of patients infected with SARS-Cov-2 develop respiratory complications, including pneumonia, that may evolve to severe hypoxemia, acute respiratory distress syndrome (ARDS), pulmonary edema, shock, metabolic acidosis, coagulation dysfunction and multiple organ functional failure [1,2].
T11 313-497 Sentence denotes Covid-19 patients with severe symptoms exhibit an immune response characterized by elevated serum levels of diverse proinflammatory molecules, including interleukin-6 (IL-6) [3,4,5,6].
T12 498-832 Sentence denotes Presently, these patients are treated with anti-inflammatory drugs like dexamethasone [7] or cytokine inhibitors, combined with antibiotics to treat secondary infections, sometimes combined with remdesivir, an antiviral originally developed to treat hepatitis C and tested against the Ebola virus disease to reduce the viral load [8].
T13 833-1066 Sentence denotes Treatment of Covid-19 urges a deeper understanding of the underlying molecular mechanisms involved in disease progression to provide a prompt therapeutical response with an adequate use of available drugs, including drug repurposing.
T14 1067-1188 Sentence denotes Indeed, there is a number of ongoing clinical trials to test the efficacy of diverse FDA-approved drugs against Covid-19.
T15 1189-1335 Sentence denotes Among them, a few involve assessment of the therapeutic efficacy of IL-6 inhibition, unfortunately without reporting conclusive results [9,10,11].
T16 1336-1505 Sentence denotes Recently, it was proposed that dysregulated bradykinin (BK) signaling could be the trigger of the cytokine storm observed in patients with severe Covid-19 [12,13,14,15].
T17 1506-1741 Sentence denotes The rational for this hypothesis relies on the increased availability of BK and its metabolite des-Arg9-BK in Covid-19 patients, due to the downregulation of angiotensin converting enzyme 2 (ACE2), the entry protein of SARS-Cov-2 [16].
T18 1742-1923 Sentence denotes Indeed, ACE2 downregulation increases the amount of angiotensin I processed by the angiotensin-converting enzyme (ACE) with a concomitant decrease of its degradation activity on BK.
T19 1924-2060 Sentence denotes Moreover, levels of des-Arg9-BK are also increased due to the diminished degradative activity of ACE2 caused by its downregulation [12].
T20 2061-2161 Sentence denotes The BK hypothesis is consistent with the observed elevated levels of IL-6 in Covid-19 patients [17].
T21 2162-2299 Sentence denotes This new perspective suggests that inhibition of BK signaling may be a suitable therapy to avoid the cytokine storm and its consequences.
T22 2300-2512 Sentence denotes Indeed, as a proof of principle, preliminary results from a limited study suggests that inhibition of the BK signaling is associated with a decrease of the oxygen supplementation needed by Covid-19 patients [18].
T23 2513-2718 Sentence denotes Nowadays, icatibant is the only BK antagonist approved as therapeutic agent for the treatment of hereditary angioedema [19], in spite of the number of selective BK ligands described in the literature [20].
T24 2719-2891 Sentence denotes The discovery of the bradykinin hypothesis prompted the launch of an ongoing clinical trial to assess the benefits of icatibant for the treatment of covid-19 patients [21].
T25 2892-3082 Sentence denotes In other to swiftly test the efficacy of alternative BK antagonists with diverse pharmacological profiles for the treatment of Covid-19, drug repurposing represents a valuable strategy [22].
T26 3083-3253 Sentence denotes To this aim, we recently carried out a virtual screening study on the DrugBank database [23] aimed at identifying BK ligands among drugs already approved by the FDA [24].
T27 3254-3444 Sentence denotes The study was carried out using four points common to the pharmacophores derived for the B1 and B2 bradykinin receptors recently reported that were used as queries for the search [25,26,27].
T28 3445-3569 Sentence denotes Hits identified were subsequently subjected to a docking study using the Molecular Operating Environment (MOE) program [28].
T29 3570-3721 Sentence denotes The virtual screening process permitted the identification of a small set of drugs as prospective nonselective BK ligands, as described elsewhere [24].
T30 3722-3890 Sentence denotes Specifically, the DrugBank database, containing a total of 1703 molecules, was screened for compounds that fulfilled a common pharmacophore for the B1 and B2 receptors.
T31 3891-4028 Sentence denotes The study identified eight drugs including raloxifene, sildenafil, cefepime, cefpirome, imatinib, ponatinib, abemaciclib and entrectinib.
T32 4029-4211 Sentence denotes Subsequently, the eight compounds were purchased and tested for their capacity to displace a reference ligand in any of the two bradykinin receptors B1 and B2, respectively at 20 µM.
T33 4212-4390 Sentence denotes Three of the compounds including raloxifene, sildenafil and cefepime displaced the reference ligand from B2, which represents a 40% success rate as found in similar studies [29].
T34 4391-4483 Sentence denotes However, none of the compounds exhibited affinity for the B1 receptor at this concentration.
T35 4484-4589 Sentence denotes This might be due to the steric hindrance that was not properly included in the virtual screening search.
T36 4590-4726 Sentence denotes Raloxifene, the most potent antagonist identified was further investigated in a functional study in vitro, exhibiting an IC50 of ~16 µM.
T37 4727-4820 Sentence denotes Moreover, the compound showed a weak partial agonist profile with a maximal activity of ~20%.
T38 4821-4986 Sentence denotes Ralixofene is a selective estrogen receptor modulator, exerting estrogen agonist action in some target tissues while acting as an estrogen antagonist in others [30].
T39 4987-5126 Sentence denotes The compound was approved a few years ago for the treatment of osteoporosis in postmenopausal women, as well as for cancer chemoprotection.
T40 5127-5313 Sentence denotes The discovery of a new pharmacodynamic profile of relixofene as a BK partial agonist opens an opportunity for its repurposing as a therapeutic agent for the treatment of severe Covid-19.