LitCovid-sentences  

PMC:7417114 / 77232-87873 JSONTXT 12 Projects

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Id Subject Object Predicate Lexical cue
T587 0-64 Sentence denotes Clinical trials: single agent and combination therapy approaches
T588 65-255 Sentence denotes Based on a query of www.ClinicalTrials.gov, which lists numerous ongoing trials for COVID-19, a number of studies were found that include testing of kinase inhibitors listed in this article.
T589 256-391 Sentence denotes There are currently several COVID-19 clinical studies investigating imatinib as a single agent (NCT04346147, NCT04357613, NCT04356495).
T590 392-691 Sentence denotes COVID-19 trials are ongoing that investigate ruxolitinib as a single agent and in combination with the lipid-lowering medication, simvastatin (NCT04348071, NCT04355793, NCT04354714, NCT04362137, NCT04334044, NCT04366232, NCT04338958, NCT04331665, NCT04337359, NCT04361903, NCT04348695, NCT04359290).
T591 692-1073 Sentence denotes Although there is no strong clinical evidence to date that statins are beneficial for COVID-19 patients and the limited evidence is mixed (156) (157), statins are still under consideration due to possible generation of a greater potent adaptive immune response and a decreased mortality rate associated with patients with influenza, pneumonia, and MERS-CoV (158) (159) (160) (161).
T592 1074-1324 Sentence denotes COVID-19 clinical studies are investigating baricitinib, both as a single agent and in combination with the antiviral drugs, lopinavir-ritonavir (NCT04340232, NCT04362943, NCT04346147, NCT04358614, NCT04320277, NCT04321993, NCT04345289, NCT04366206).
T593 1325-1481 Sentence denotes Baricitinib does not interact with antiviral agents due to its prevalent renal elimination, and so it is proposed to suitable for combination therapy (162).
T594 1482-1747 Sentence denotes There is one study investigating nintedanib, an FGFR (fibroblast growth factor receptor)/PDGFR/VEGFR inhibitor approved for idiopathic pulmonary fibrosis, as a single agent treatment for pulmonary fibrosis in patients with moderate to severe COVID-19 (NCT04338802).
T595 1748-1871 Sentence denotes A COVID-19 study is ongoing that investigates tofacitinib as a single agent at 10 mg twice a day for 14 days (NCT04332042).
T596 1872-2043 Sentence denotes Of note, this dose of tofacitinib administration has been associated with an increased risk of thrombosis and death and the FDA has issued a boxed warning (163) (Table 3).
T597 2044-2324 Sentence denotes In a clinical study investigating the predisposition of COVID-19 patients to venous and arterial thromboembolism, a 31% incidence of thrombotic complications, with pulmonary embolism being the most prevalent, was observed in intensive care unit SARS-CoV-2-infected patients (164).
T598 2325-2558 Sentence denotes The blood clotting risk reported for tofacitinib pertains to patients receiving the drug chronically, and while the increased risk reported for tofacitinib at 10 mg twice daily for 14 days is not known, it is anticipated to be small.
T599 2559-2732 Sentence denotes It is also general practice as a precaution to place hospital-admitted patients with COVID-19 on blood thinners as DVT/clot prophylaxis (most usually enoxaparin or heparin).
T600 2733-2816 Sentence denotes This would likely make the risk of blood clots minimal (although not zero percent).
T601 2817-3110 Sentence denotes Though not included on www.ClinicalTrials.gov as a COVID-19 trial, results of a clinical trial with Waldenstrom’s macroglobulinemia patients suggest that ibrutinib might confer protection against lung damage in hypoxic COVID-19 patients, and it may possibly improve respiratory function (165).
T602 3111-3289 Sentence denotes However, the study was small and involved 6 COVID-positive patients, 5 of whom received ibrutinib at 420 mg and presented with mild symptoms that did not require hospitalization.
T603 3290-3503 Sentence denotes The 6th patient on a lower dose of ibrutinib had progressive dyspnea and hypoxia and was placed on treatments in addition to ibrutinib at the lower dose, including hydroxychloroquine, azithromycin and tocilizumab.
T604 3504-3657 Sentence denotes Due to worsening hypoxia, the patient was eventually placed on the higher ibrutinib dose (420 mg) and this was followed by improvement of symptoms (165).
T605 3658-3994 Sentence denotes Kinase inhibitors with good safety profiles and desirable pharmacokinetics properties, including minimal association with drug transporters and CYP enzymes, warrant testing in combination with antiviral agents or other targeted agents, to more effectively decrease viral load and potentially more dramatically improve COVID-19 symptoms.
T606 3995-4152 Sentence denotes There are currently numerous direct antiviral agents that are under consideration for COVID-19 (several prominent investigational drugs are shown in Fig. 4).
T607 4153-4162 Sentence denotes Figure 4.
T608 4163-4211 Sentence denotes Drug therapies under investigation for COVID-19.
T609 4212-4463 Sentence denotes Although imatinib is, at the time of the writing of this article, under investigation in COVID-19 patients as a single agent, it may effectively combine with certain antiviral agents and this might be an approach worth considering for COVID-19 trials.
T610 4464-4566 Sentence denotes For instance, ribavirin has demonstrated synergy in vitro with imatinib against leukemia growth (166).
T611 4567-4808 Sentence denotes Despite proposed lack of efficacy of ribavirin as a single agent against SARS-CoV-2 (167), it is possible that it could synergize with imatinib against SARS-CoV-2 if the drugs are able to be administered at doses that are effective but safe.
T612 4809-4932 Sentence denotes The drug-drug interactions between imatinib and a wide variety of antiviral and other agents have been thoroughly assessed.
T613 4933-5072 Sentence denotes Imatinib displays variable drug-drug interactions and so its potential for effective combination needs to be taken on a case by case basis.
T614 5073-5231 Sentence denotes For instance, protease inhibitors ritonavir-lopinavir and darunavir increase imatinib exposure, and saquinavir and indinavir decrease imatinib exposure (168).
T615 5232-5437 Sentence denotes Contrarily, there is no interaction between imatinib and the antiviral/nucleoside analogs acyclovir and valaciclovir, although its intracellular exposure is reduced by ganciclovir and valganciclovir (168).
T616 5438-5522 Sentence denotes The antimalarial drug, chloroquine, decreases imatinib intracellular exposure (168).
T617 5523-5703 Sentence denotes The FDA-approved tapeworm medication, niclosamide, reported as having antiviral activity against SARS-CoV and MERS-CoV is presently under investigation as a SARS-CoV-2 agent (169).
T618 5704-5942 Sentence denotes Niclosamide has been reported (unpublished results; preprint) to be one of 24 FDA-approved drugs to show in vitro activity against SARS-CoV-2, with an IC50 of 0.28 μM (https://www.biorxiv.org/content/10.1101/2020.03.20.999730v3.full.pdf).
T619 5943-6156 Sentence denotes The inhibitory activity of niclosamide against SKP2, which diminishes MERS-CoV replication and augments autophagy (170), is proposed to be the potential mechanism through which niclosamide acts against SARS-CoV-2.
T620 6157-6295 Sentence denotes Niclosamide was demonstrated to synergize in preclinical studies with imatinib and other kinase inhibitors against different malignancies.
T621 6296-6444 Sentence denotes For instance, synergy between niclosamide and imatinib, as well as niclosamide and dasatinib or ponatinib, against CML cells was demonstrated (171).
T622 6445-6696 Sentence denotes Niclosamide was also found to potentiate the effects of erlotinib against head and neck cancer cells through STAT3 inhibition (172), with erlotinib against human colon cancer lines (173), and with sorafenib against human renal cell cancer cells (174).
T623 6697-6884 Sentence denotes EGFR-targeting kinase inhibitors are characterized by extensive tissue distribution, moderate to high plasma protein binding, and a relatively high volume of distribution (>1700 L) (175).
T624 6885-7141 Sentence denotes Although not currently under investigation for COVID-19 as of this writing, the non-small cell lung cancer drug and EGFR inhibitor, afatinib, has been shown to be able to be safely administered with various antiviral agents in clinical studies (176) (177).
T625 7142-7405 Sentence denotes In a phase I study in human papillomavirus (HPV)-associated head and neck squamous cell carcinoma, afatinib, with demonstrated anti-inflammatory and antifibrotic activity (116) (178) (179), was tested in combination with ribavirin and standard chemotherapy (176).
T626 7406-7574 Sentence denotes Afatinib was used because of its targeting of ErbB proteins associated with HPV infection, and ribavirin was chosen due to its targeting of oncogenic eIF4E (180) (176).
T627 7575-7780 Sentence denotes In this study, there were no dose-limiting toxicities, supporting the safe, clinical use of ribavirin with a kinase inhibitor having key virus-associated protein targets and those with respiratory benefit.
T628 7781-7972 Sentence denotes Another clinical study showed low potential for interaction between afatinib, a P-gp pump transporter substrate, and the protease inhibitor, ritonavir, a potent inhibitor of P-gp (181) (177).
T629 7973-8088 Sentence denotes This was partially attributed to the fact that afatinib is not a modulator of substrate of cytochrome P450 enzymes.
T630 8089-8298 Sentence denotes It is possible that the combination of afatinib and antiviral agents, such as ribavirin or ritonavir, which show little activity on their own against COVID-19, may be synergistic in the context of the disease.
T631 8299-8521 Sentence denotes Alternatively afatinib could potentially be combined with remdesivir, more recently shown to reduce the length of hospital stay for COVID-19 patients and thus exhibiting a degree of activity against SARS-CoV-2 in patients.
T632 8522-8658 Sentence denotes Or perhaps afatinib could be investigated as a treatment for COVID-19 in combination with several antiviral drugs as part of a cocktail.
T633 8659-8800 Sentence denotes Afatinib has also been tested in combination with nintedanib in a Phase I dose-escalation study in patients with advanced solid tumors (182).
T634 8801-8964 Sentence denotes It was determined that afatinib at 10 mg/day combined with nintedanib at 200 mg twice a day had a manageable safety profile, however the doses were subtherapeutic.
T635 8965-9193 Sentence denotes The antifibrotic and anti-inflammatory potential of afatinib and nintedanib, coupled with key virus-associated protein targets for each (Table 2, Fig. 3), warrant investigation of this drug combination for treatment of COVID-19.
T636 9194-9373 Sentence denotes Ritonavir is a strong inhibitor of CYP3A4 and it also inhibits ABCB1, and the multi-targeted inhibitor sunitinib is metabolized by CYP3A4 and is a substrate for ABCB1 (183) (184).
T637 9374-9470 Sentence denotes Consequently, this combination has the potential for reduced efficacy and/or increased toxicity.
T638 9471-9677 Sentence denotes Sunitinib was investigated in HIV-positive cancer patients treated with ritonavir, and due to toxicities was recommended to be dosed at 37.5mg/day on a 4 week on/2 week off schedule in these patients (185).
T639 9678-9803 Sentence denotes These results suggest that drug-drug interactions between sunitinib and ritonavir require dosing modifications for sunitinib.
T640 9804-10099 Sentence denotes Should sunitinib, with key virus-associated targets and anti-inflammatory, cytokine-suppressive and antifibrotic potential, be considered for co-administration with a protease inhibitor like ritonavir for COVID-19, this established dosing regimen would need to be considered to control toxicity.
T641 10100-10345 Sentence denotes Table 4 shows the chemical structures and molecular weights of a panel of the most promising kinase inhibitors in terms of their pharmacokinetics, potential antiviral targets and anti-inflammatory, cytokine suppressive, or antifibrotic activity.
T642 10346-10484 Sentence denotes Also included in Table 4 are those kinase inhibitors with potential to effectively synergize with other agents, including antiviral drugs.
T643 10485-10567 Sentence denotes Table 4 Chemical structures of kinase inhibitor candidates for COVID-19 treatment.
T644 10568-10641 Sentence denotes Chemical structures and molecular weights were obtained on chemspider.com