PMC:7417114 / 77232-87873 JSONTXT

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There are currently several COVID-19 clinical studies investigating imatinib as a single agent (NCT04346147, NCT04357613, NCT04356495). 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). 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). 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). Baricitinib does not interact with antiviral agents due to its prevalent renal elimination, and so it is proposed to suitable for combination therapy (162). 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).\nA COVID-19 study is ongoing that investigates tofacitinib as a single agent at 10 mg twice a day for 14 days (NCT04332042). 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). 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). 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. 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). This would likely make the risk of blood clots minimal (although not zero percent).\nThough 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). 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. 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. 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).\nKinase 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. There are currently numerous direct antiviral agents that are under consideration for COVID-19 (several prominent investigational drugs are shown in Fig. 4).\nFigure 4. Drug therapies under investigation for COVID-19.\nAlthough 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. For instance, ribavirin has demonstrated synergy in vitro with imatinib against leukemia growth (166). 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.\nThe drug-drug interactions between imatinib and a wide variety of antiviral and other agents have been thoroughly assessed. Imatinib displays variable drug-drug interactions and so its potential for effective combination needs to be taken on a case by case basis. For instance, protease inhibitors ritonavir-lopinavir and darunavir increase imatinib exposure, and saquinavir and indinavir decrease imatinib exposure (168). 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). The antimalarial drug, chloroquine, decreases imatinib intracellular exposure (168).\nThe 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). 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). 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. Niclosamide was demonstrated to synergize in preclinical studies with imatinib and other kinase inhibitors against different malignancies. For instance, synergy between niclosamide and imatinib, as well as niclosamide and dasatinib or ponatinib, against CML cells was demonstrated (171). 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).\nEGFR-targeting kinase inhibitors are characterized by extensive tissue distribution, moderate to high plasma protein binding, and a relatively high volume of distribution (\u003e1700 L) (175). 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). 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). 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). 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. 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). This was partially attributed to the fact that afatinib is not a modulator of substrate of cytochrome P450 enzymes. 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. 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. Or perhaps afatinib could be investigated as a treatment for COVID-19 in combination with several antiviral drugs as part of a cocktail.\nAfatinib has also been tested in combination with nintedanib in a Phase I dose-escalation study in patients with advanced solid tumors (182). 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. 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.\nRitonavir 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). Consequently, this combination has the potential for reduced efficacy and/or increased toxicity. 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). These results suggest that drug-drug interactions between sunitinib and ritonavir require dosing modifications for sunitinib. 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.\nTable 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. Also included in Table 4 are those kinase inhibitors with potential to effectively synergize with other agents, including antiviral drugs.\nTable 4 Chemical structures of kinase inhibitor candidates for COVID-19 treatment. Chemical structures and molecular weights were obtained on chemspider.com"}

{"project":"LitCovid-PD-UBERON","denotations":[{"id":"T128","span":{"begin":2329,"end":2334},"obj":"Body_part"},{"id":"T129","span":{"begin":2656,"end":2661},"obj":"Body_part"},{"id":"T130","span":{"begin":2768,"end":2779},"obj":"Body_part"},{"id":"T131","span":{"begin":2768,"end":2773},"obj":"Body_part"},{"id":"T132","span":{"begin":3013,"end":3017},"obj":"Body_part"},{"id":"T133","span":{"begin":6519,"end":6523},"obj":"Body_part"},{"id":"T134","span":{"begin":6528,"end":6532},"obj":"Body_part"},{"id":"T135","span":{"begin":6607,"end":6612},"obj":"Body_part"},{"id":"T136","span":{"begin":6761,"end":6767},"obj":"Body_part"},{"id":"T137","span":{"begin":6980,"end":6984},"obj":"Body_part"},{"id":"T138","span":{"begin":7202,"end":7206},"obj":"Body_part"},{"id":"T139","span":{"begin":7211,"end":7215},"obj":"Body_part"}],"attributes":[{"id":"A128","pred":"uberon_id","subj":"T128","obj":"http://purl.obolibrary.org/obo/UBERON_0000178"},{"id":"A129","pred":"uberon_id","subj":"T129","obj":"http://purl.obolibrary.org/obo/UBERON_0000178"},{"id":"A130","pred":"uberon_id","subj":"T130","obj":"http://purl.obolibrary.org/obo/UBERON_0010210"},{"id":"A131","pred":"uberon_id","subj":"T131","obj":"http://purl.obolibrary.org/obo/UBERON_0000178"},{"id":"A132","pred":"uberon_id","subj":"T132","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A133","pred":"uberon_id","subj":"T133","obj":"http://purl.obolibrary.org/obo/UBERON_0000033"},{"id":"A134","pred":"uberon_id","subj":"T134","obj":"http://purl.obolibrary.org/obo/UBERON_0000974"},{"id":"A135","pred":"uberon_id","subj":"T135","obj":"http://purl.obolibrary.org/obo/UBERON_0001155"},{"id":"A136","pred":"uberon_id","subj":"T136","obj":"http://purl.obolibrary.org/obo/UBERON_0000479"},{"id":"A137","pred":"uberon_id","subj":"T137","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A138","pred":"uberon_id","subj":"T138","obj":"http://purl.obolibrary.org/obo/UBERON_0000033"},{"id":"A139","pred":"uberon_id","subj":"T139","obj":"http://purl.obolibrary.org/obo/UBERON_0000974"}],"text":"Clinical trials: single agent and combination therapy approaches\nBased 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. There are currently several COVID-19 clinical studies investigating imatinib as a single agent (NCT04346147, NCT04357613, NCT04356495). 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). 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). 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). Baricitinib does not interact with antiviral agents due to its prevalent renal elimination, and so it is proposed to suitable for combination therapy (162). 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).\nA COVID-19 study is ongoing that investigates tofacitinib as a single agent at 10 mg twice a day for 14 days (NCT04332042). 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). 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). 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. 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). This would likely make the risk of blood clots minimal (although not zero percent).\nThough 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). 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. 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. 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).\nKinase 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. There are currently numerous direct antiviral agents that are under consideration for COVID-19 (several prominent investigational drugs are shown in Fig. 4).\nFigure 4. Drug therapies under investigation for COVID-19.\nAlthough 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. For instance, ribavirin has demonstrated synergy in vitro with imatinib against leukemia growth (166). 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.\nThe drug-drug interactions between imatinib and a wide variety of antiviral and other agents have been thoroughly assessed. Imatinib displays variable drug-drug interactions and so its potential for effective combination needs to be taken on a case by case basis. For instance, protease inhibitors ritonavir-lopinavir and darunavir increase imatinib exposure, and saquinavir and indinavir decrease imatinib exposure (168). 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). The antimalarial drug, chloroquine, decreases imatinib intracellular exposure (168).\nThe 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). 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). 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. Niclosamide was demonstrated to synergize in preclinical studies with imatinib and other kinase inhibitors against different malignancies. For instance, synergy between niclosamide and imatinib, as well as niclosamide and dasatinib or ponatinib, against CML cells was demonstrated (171). 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).\nEGFR-targeting kinase inhibitors are characterized by extensive tissue distribution, moderate to high plasma protein binding, and a relatively high volume of distribution (\u003e1700 L) (175). 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). 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). 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). 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. 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). This was partially attributed to the fact that afatinib is not a modulator of substrate of cytochrome P450 enzymes. 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. 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. Or perhaps afatinib could be investigated as a treatment for COVID-19 in combination with several antiviral drugs as part of a cocktail.\nAfatinib has also been tested in combination with nintedanib in a Phase I dose-escalation study in patients with advanced solid tumors (182). 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. 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.\nRitonavir 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). Consequently, this combination has the potential for reduced efficacy and/or increased toxicity. 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). These results suggest that drug-drug interactions between sunitinib and ritonavir require dosing modifications for sunitinib. 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.\nTable 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. Also included in Table 4 are those kinase inhibitors with potential to effectively synergize with other agents, including antiviral drugs.\nTable 4 Chemical structures of kinase inhibitor candidates for COVID-19 treatment. Chemical structures and molecular weights were obtained on chemspider.com"}

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trials: single agent and combination therapy approaches\nBased 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. There are currently several COVID-19 clinical studies investigating imatinib as a single agent (NCT04346147, NCT04357613, NCT04356495). 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). 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). 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). Baricitinib does not interact with antiviral agents due to its prevalent renal elimination, and so it is proposed to suitable for combination therapy (162). 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).\nA COVID-19 study is ongoing that investigates tofacitinib as a single agent at 10 mg twice a day for 14 days (NCT04332042). 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). 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). 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. 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). This would likely make the risk of blood clots minimal (although not zero percent).\nThough 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). 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. 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. 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).\nKinase 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. There are currently numerous direct antiviral agents that are under consideration for COVID-19 (several prominent investigational drugs are shown in Fig. 4).\nFigure 4. Drug therapies under investigation for COVID-19.\nAlthough 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. For instance, ribavirin has demonstrated synergy in vitro with imatinib against leukemia growth (166). 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.\nThe drug-drug interactions between imatinib and a wide variety of antiviral and other agents have been thoroughly assessed. Imatinib displays variable drug-drug interactions and so its potential for effective combination needs to be taken on a case by case basis. For instance, protease inhibitors ritonavir-lopinavir and darunavir increase imatinib exposure, and saquinavir and indinavir decrease imatinib exposure (168). 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). The antimalarial drug, chloroquine, decreases imatinib intracellular exposure (168).\nThe 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). 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). 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. Niclosamide was demonstrated to synergize in preclinical studies with imatinib and other kinase inhibitors against different malignancies. For instance, synergy between niclosamide and imatinib, as well as niclosamide and dasatinib or ponatinib, against CML cells was demonstrated (171). 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).\nEGFR-targeting kinase inhibitors are characterized by extensive tissue distribution, moderate to high plasma protein binding, and a relatively high volume of distribution (\u003e1700 L) (175). 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). 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). 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). 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. 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). This was partially attributed to the fact that afatinib is not a modulator of substrate of cytochrome P450 enzymes. 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. 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. Or perhaps afatinib could be investigated as a treatment for COVID-19 in combination with several antiviral drugs as part of a cocktail.\nAfatinib has also been tested in combination with nintedanib in a Phase I dose-escalation study in patients with advanced solid tumors (182). 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. 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.\nRitonavir 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). Consequently, this combination has the potential for reduced efficacy and/or increased toxicity. 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). These results suggest that drug-drug interactions between sunitinib and ritonavir require dosing modifications for sunitinib. 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.\nTable 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. Also included in Table 4 are those kinase inhibitors with potential to effectively synergize with other agents, including antiviral drugs.\nTable 4 Chemical structures of kinase inhibitor candidates for COVID-19 treatment. Chemical structures and molecular weights were obtained on chemspider.com"}

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trials: single agent and combination therapy approaches\nBased 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. There are currently several COVID-19 clinical studies investigating imatinib as a single agent (NCT04346147, NCT04357613, NCT04356495). 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). 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). 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). Baricitinib does not interact with antiviral agents due to its prevalent renal elimination, and so it is proposed to suitable for combination therapy (162). 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).\nA COVID-19 study is ongoing that investigates tofacitinib as a single agent at 10 mg twice a day for 14 days (NCT04332042). 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). 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). 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. 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). This would likely make the risk of blood clots minimal (although not zero percent).\nThough 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). 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. 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. 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).\nKinase 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. There are currently numerous direct antiviral agents that are under consideration for COVID-19 (several prominent investigational drugs are shown in Fig. 4).\nFigure 4. Drug therapies under investigation for COVID-19.\nAlthough 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. For instance, ribavirin has demonstrated synergy in vitro with imatinib against leukemia growth (166). 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.\nThe drug-drug interactions between imatinib and a wide variety of antiviral and other agents have been thoroughly assessed. Imatinib displays variable drug-drug interactions and so its potential for effective combination needs to be taken on a case by case basis. For instance, protease inhibitors ritonavir-lopinavir and darunavir increase imatinib exposure, and saquinavir and indinavir decrease imatinib exposure (168). 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). The antimalarial drug, chloroquine, decreases imatinib intracellular exposure (168).\nThe 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). 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). 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. Niclosamide was demonstrated to synergize in preclinical studies with imatinib and other kinase inhibitors against different malignancies. For instance, synergy between niclosamide and imatinib, as well as niclosamide and dasatinib or ponatinib, against CML cells was demonstrated (171). 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).\nEGFR-targeting kinase inhibitors are characterized by extensive tissue distribution, moderate to high plasma protein binding, and a relatively high volume of distribution (\u003e1700 L) (175). 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). 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). 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). 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. 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). This was partially attributed to the fact that afatinib is not a modulator of substrate of cytochrome P450 enzymes. 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. 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. Or perhaps afatinib could be investigated as a treatment for COVID-19 in combination with several antiviral drugs as part of a cocktail.\nAfatinib has also been tested in combination with nintedanib in a Phase I dose-escalation study in patients with advanced solid tumors (182). 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. 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.\nRitonavir 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). Consequently, this combination has the potential for reduced efficacy and/or increased toxicity. 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). These results suggest that drug-drug interactions between sunitinib and ritonavir require dosing modifications for sunitinib. 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.\nTable 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. Also included in Table 4 are those kinase inhibitors with potential to effectively synergize with other agents, including antiviral drugs.\nTable 4 Chemical structures of kinase inhibitor candidates for COVID-19 treatment. Chemical structures and molecular weights were obtained on chemspider.com"}

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trials: single agent and combination therapy approaches\nBased 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. There are currently several COVID-19 clinical studies investigating imatinib as a single agent (NCT04346147, NCT04357613, NCT04356495). 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). 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). 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). Baricitinib does not interact with antiviral agents due to its prevalent renal elimination, and so it is proposed to suitable for combination therapy (162). 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).\nA COVID-19 study is ongoing that investigates tofacitinib as a single agent at 10 mg twice a day for 14 days (NCT04332042). 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). 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). 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. 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). This would likely make the risk of blood clots minimal (although not zero percent).\nThough 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). 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. 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. 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).\nKinase 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. There are currently numerous direct antiviral agents that are under consideration for COVID-19 (several prominent investigational drugs are shown in Fig. 4).\nFigure 4. Drug therapies under investigation for COVID-19.\nAlthough 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. For instance, ribavirin has demonstrated synergy in vitro with imatinib against leukemia growth (166). 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.\nThe drug-drug interactions between imatinib and a wide variety of antiviral and other agents have been thoroughly assessed. Imatinib displays variable drug-drug interactions and so its potential for effective combination needs to be taken on a case by case basis. For instance, protease inhibitors ritonavir-lopinavir and darunavir increase imatinib exposure, and saquinavir and indinavir decrease imatinib exposure (168). 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). The antimalarial drug, chloroquine, decreases imatinib intracellular exposure (168).\nThe 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). 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). 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. Niclosamide was demonstrated to synergize in preclinical studies with imatinib and other kinase inhibitors against different malignancies. For instance, synergy between niclosamide and imatinib, as well as niclosamide and dasatinib or ponatinib, against CML cells was demonstrated (171). 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).\nEGFR-targeting kinase inhibitors are characterized by extensive tissue distribution, moderate to high plasma protein binding, and a relatively high volume of distribution (\u003e1700 L) (175). 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). 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). 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). 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. 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). This was partially attributed to the fact that afatinib is not a modulator of substrate of cytochrome P450 enzymes. 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. 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. Or perhaps afatinib could be investigated as a treatment for COVID-19 in combination with several antiviral drugs as part of a cocktail.\nAfatinib has also been tested in combination with nintedanib in a Phase I dose-escalation study in patients with advanced solid tumors (182). 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. 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.\nRitonavir 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). Consequently, this combination has the potential for reduced efficacy and/or increased toxicity. 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). These results suggest that drug-drug interactions between sunitinib and ritonavir require dosing modifications for sunitinib. 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.\nTable 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. Also included in Table 4 are those kinase inhibitors with potential to effectively synergize with other agents, including antiviral drugs.\nTable 4 Chemical structures of kinase inhibitor candidates for COVID-19 treatment. Chemical structures and molecular weights were obtained on chemspider.com"}

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trials: single agent and combination therapy approaches\nBased 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. There are currently several COVID-19 clinical studies investigating imatinib as a single agent (NCT04346147, NCT04357613, NCT04356495). 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). 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). 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). Baricitinib does not interact with antiviral agents due to its prevalent renal elimination, and so it is proposed to suitable for combination therapy (162). 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).\nA COVID-19 study is ongoing that investigates tofacitinib as a single agent at 10 mg twice a day for 14 days (NCT04332042). 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). 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). 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. 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). This would likely make the risk of blood clots minimal (although not zero percent).\nThough 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). 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. 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. 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).\nKinase 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. There are currently numerous direct antiviral agents that are under consideration for COVID-19 (several prominent investigational drugs are shown in Fig. 4).\nFigure 4. Drug therapies under investigation for COVID-19.\nAlthough 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. For instance, ribavirin has demonstrated synergy in vitro with imatinib against leukemia growth (166). 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.\nThe drug-drug interactions between imatinib and a wide variety of antiviral and other agents have been thoroughly assessed. Imatinib displays variable drug-drug interactions and so its potential for effective combination needs to be taken on a case by case basis. For instance, protease inhibitors ritonavir-lopinavir and darunavir increase imatinib exposure, and saquinavir and indinavir decrease imatinib exposure (168). 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). The antimalarial drug, chloroquine, decreases imatinib intracellular exposure (168).\nThe 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). 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). 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. Niclosamide was demonstrated to synergize in preclinical studies with imatinib and other kinase inhibitors against different malignancies. For instance, synergy between niclosamide and imatinib, as well as niclosamide and dasatinib or ponatinib, against CML cells was demonstrated (171). 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).\nEGFR-targeting kinase inhibitors are characterized by extensive tissue distribution, moderate to high plasma protein binding, and a relatively high volume of distribution (\u003e1700 L) (175). 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). 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). 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). 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. 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). This was partially attributed to the fact that afatinib is not a modulator of substrate of cytochrome P450 enzymes. 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. 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. Or perhaps afatinib could be investigated as a treatment for COVID-19 in combination with several antiviral drugs as part of a cocktail.\nAfatinib has also been tested in combination with nintedanib in a Phase I dose-escalation study in patients with advanced solid tumors (182). 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. 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.\nRitonavir 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). Consequently, this combination has the potential for reduced efficacy and/or increased toxicity. 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). These results suggest that drug-drug interactions between sunitinib and ritonavir require dosing modifications for sunitinib. 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.\nTable 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. Also included in Table 4 are those kinase inhibitors with potential to effectively synergize with other agents, including antiviral drugs.\nTable 4 Chemical structures of kinase inhibitor candidates for COVID-19 treatment. Chemical structures and molecular weights were obtained on chemspider.com"}

{"project":"LitCovid-PD-HP","denotations":[{"id":"T235","span":{"begin":1025,"end":1034},"obj":"Phenotype"},{"id":"T236","span":{"begin":1617,"end":1635},"obj":"Phenotype"},{"id":"T237","span":{"begin":1669,"end":1687},"obj":"Phenotype"},{"id":"T238","span":{"begin":2141,"end":2156},"obj":"Phenotype"},{"id":"T239","span":{"begin":2208,"end":2226},"obj":"Phenotype"},{"id":"T240","span":{"begin":2917,"end":2948},"obj":"Phenotype"},{"id":"T241","span":{"begin":3351,"end":3358},"obj":"Phenotype"},{"id":"T242","span":{"begin":3363,"end":3370},"obj":"Phenotype"},{"id":"T243","span":{"begin":3521,"end":3528},"obj":"Phenotype"},{"id":"T244","span":{"begin":4544,"end":4552},"obj":"Phenotype"},{"id":"T245","span":{"begin":6519,"end":6539},"obj":"Phenotype"},{"id":"T246","span":{"begin":6607,"end":6619},"obj":"Phenotype"},{"id":"T247","span":{"begin":6677,"end":6683},"obj":"Phenotype"},{"id":"T248","span":{"begin":6965,"end":6991},"obj":"Phenotype"},{"id":"T249","span":{"begin":7216,"end":7239},"obj":"Phenotype"},{"id":"T250","span":{"begin":9514,"end":9520},"obj":"Phenotype"}],"attributes":[{"id":"A235","pred":"hp_id","subj":"T235","obj":"http://purl.obolibrary.org/obo/HP_0002090"},{"id":"A236","pred":"hp_id","subj":"T236","obj":"http://purl.obolibrary.org/obo/HP_0002206"},{"id":"A237","pred":"hp_id","subj":"T237","obj":"http://purl.obolibrary.org/obo/HP_0002206"},{"id":"A238","pred":"hp_id","subj":"T238","obj":"http://purl.obolibrary.org/obo/HP_0001907"},{"id":"A239","pred":"hp_id","subj":"T239","obj":"http://purl.obolibrary.org/obo/HP_0002204"},{"id":"A240","pred":"hp_id","subj":"T240","obj":"http://purl.obolibrary.org/obo/HP_0005508"},{"id":"A241","pred":"hp_id","subj":"T241","obj":"http://purl.obolibrary.org/obo/HP_0002094"},{"id":"A242","pred":"hp_id","subj":"T242","obj":"http://purl.obolibrary.org/obo/HP_0012418"},{"id":"A243","pred":"hp_id","subj":"T243","obj":"http://purl.obolibrary.org/obo/HP_0012418"},{"id":"A244","pred":"hp_id","subj":"T244","obj":"http://purl.obolibrary.org/obo/HP_0001909"},{"id":"A245","pred":"hp_id","subj":"T245","obj":"http://purl.obolibrary.org/obo/HP_0012288"},{"id":"A246","pred":"hp_id","subj":"T246","obj":"http://purl.obolibrary.org/obo/HP_0003003"},{"id":"A247","pred":"hp_id","subj":"T247","obj":"http://purl.obolibrary.org/obo/HP_0002664"},{"id":"A248","pred":"hp_id","subj":"T248","obj":"http://purl.obolibrary.org/obo/HP_0030358"},{"id":"A249","pred":"hp_id","subj":"T249","obj":"http://purl.obolibrary.org/obo/HP_0002860"},{"id":"A250","pred":"hp_id","subj":"T250","obj":"http://purl.obolibrary.org/obo/HP_0002664"}],"text":"Clinical trials: single agent and combination therapy approaches\nBased 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. There are currently several COVID-19 clinical studies investigating imatinib as a single agent (NCT04346147, NCT04357613, NCT04356495). 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). 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). 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). Baricitinib does not interact with antiviral agents due to its prevalent renal elimination, and so it is proposed to suitable for combination therapy (162). 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).\nA COVID-19 study is ongoing that investigates tofacitinib as a single agent at 10 mg twice a day for 14 days (NCT04332042). 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). 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). 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. 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). This would likely make the risk of blood clots minimal (although not zero percent).\nThough 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). 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. 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. 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).\nKinase 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. There are currently numerous direct antiviral agents that are under consideration for COVID-19 (several prominent investigational drugs are shown in Fig. 4).\nFigure 4. Drug therapies under investigation for COVID-19.\nAlthough 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. For instance, ribavirin has demonstrated synergy in vitro with imatinib against leukemia growth (166). 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.\nThe drug-drug interactions between imatinib and a wide variety of antiviral and other agents have been thoroughly assessed. Imatinib displays variable drug-drug interactions and so its potential for effective combination needs to be taken on a case by case basis. For instance, protease inhibitors ritonavir-lopinavir and darunavir increase imatinib exposure, and saquinavir and indinavir decrease imatinib exposure (168). 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). The antimalarial drug, chloroquine, decreases imatinib intracellular exposure (168).\nThe 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). 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). 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. Niclosamide was demonstrated to synergize in preclinical studies with imatinib and other kinase inhibitors against different malignancies. For instance, synergy between niclosamide and imatinib, as well as niclosamide and dasatinib or ponatinib, against CML cells was demonstrated (171). 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).\nEGFR-targeting kinase inhibitors are characterized by extensive tissue distribution, moderate to high plasma protein binding, and a relatively high volume of distribution (\u003e1700 L) (175). 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). 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). 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). 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. 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). This was partially attributed to the fact that afatinib is not a modulator of substrate of cytochrome P450 enzymes. 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. 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. Or perhaps afatinib could be investigated as a treatment for COVID-19 in combination with several antiviral drugs as part of a cocktail.\nAfatinib has also been tested in combination with nintedanib in a Phase I dose-escalation study in patients with advanced solid tumors (182). 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. 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.\nRitonavir 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). Consequently, this combination has the potential for reduced efficacy and/or increased toxicity. 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). These results suggest that drug-drug interactions between sunitinib and ritonavir require dosing modifications for sunitinib. 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.\nTable 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. Also included in Table 4 are those kinase inhibitors with potential to effectively synergize with other agents, including antiviral drugs.\nTable 4 Chemical structures of kinase inhibitor candidates for COVID-19 treatment. Chemical structures and molecular weights were obtained on chemspider.com"}

{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T227","span":{"begin":214,"end":231},"obj":"http://purl.obolibrary.org/obo/GO_0033673"},{"id":"T228","span":{"begin":928,"end":952},"obj":"http://purl.obolibrary.org/obo/GO_0002250"},{"id":"T229","span":{"begin":937,"end":952},"obj":"http://purl.obolibrary.org/obo/GO_0006955"},{"id":"T230","span":{"begin":1530,"end":1534},"obj":"http://purl.obolibrary.org/obo/GO_0005007"},{"id":"T231","span":{"begin":1547,"end":1553},"obj":"http://purl.obolibrary.org/obo/GO_0040007"},{"id":"T232","span":{"begin":2329,"end":2343},"obj":"http://purl.obolibrary.org/obo/GO_0007596"},{"id":"T233","span":{"begin":2335,"end":2343},"obj":"http://purl.obolibrary.org/obo/GO_0050817"},{"id":"T234","span":{"begin":3658,"end":3675},"obj":"http://purl.obolibrary.org/obo/GO_0033673"},{"id":"T235","span":{"begin":3780,"end":3797},"obj":"http://purl.obolibrary.org/obo/GO_0015893"},{"id":"T236","span":{"begin":4553,"end":4559},"obj":"http://purl.obolibrary.org/obo/GO_0040007"},{"id":"T237","span":{"begin":6047,"end":6056},"obj":"http://purl.obolibrary.org/obo/GO_0016236"},{"id":"T238","span":{"begin":6047,"end":6056},"obj":"http://purl.obolibrary.org/obo/GO_0006914"},{"id":"T239","span":{"begin":6246,"end":6263},"obj":"http://purl.obolibrary.org/obo/GO_0033673"},{"id":"T240","span":{"begin":6697,"end":6701},"obj":"http://purl.obolibrary.org/obo/GO_0005006"},{"id":"T241","span":{"begin":6712,"end":6729},"obj":"http://purl.obolibrary.org/obo/GO_0033673"},{"id":"T242","span":{"begin":7001,"end":7005},"obj":"http://purl.obolibrary.org/obo/GO_0005006"},{"id":"T243","span":{"begin":7684,"end":7700},"obj":"http://purl.obolibrary.org/obo/GO_0033673"},{"id":"T244","span":{"begin":7729,"end":7744},"obj":"http://purl.obolibrary.org/obo/GO_0006605"},{"id":"T245","span":{"begin":7871,"end":7882},"obj":"http://purl.obolibrary.org/obo/GO_0006810"},{"id":"T246","span":{"begin":8064,"end":8074},"obj":"http://purl.obolibrary.org/obo/GO_0045158"},{"id":"T247","span":{"begin":8064,"end":8074},"obj":"http://purl.obolibrary.org/obo/GO_0045157"},{"id":"T248","span":{"begin":8064,"end":8074},"obj":"http://purl.obolibrary.org/obo/GO_0045156"},{"id":"T249","span":{"begin":8064,"end":8074},"obj":"http://purl.obolibrary.org/obo/GO_0008121"},{"id":"T250","span":{"begin":9076,"end":9091},"obj":"http://purl.obolibrary.org/obo/GO_0006605"},{"id":"T251","span":{"begin":10193,"end":10210},"obj":"http://purl.obolibrary.org/obo/GO_0033673"},{"id":"T252","span":{"begin":10381,"end":10398},"obj":"http://purl.obolibrary.org/obo/GO_0033673"},{"id":"T253","span":{"begin":10516,"end":10532},"obj":"http://purl.obolibrary.org/obo/GO_0033673"}],"text":"Clinical trials: single agent and combination therapy approaches\nBased 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. There are currently several COVID-19 clinical studies investigating imatinib as a single agent (NCT04346147, NCT04357613, NCT04356495). 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). 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). 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). Baricitinib does not interact with antiviral agents due to its prevalent renal elimination, and so it is proposed to suitable for combination therapy (162). 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).\nA COVID-19 study is ongoing that investigates tofacitinib as a single agent at 10 mg twice a day for 14 days (NCT04332042). 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). 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). 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. 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). This would likely make the risk of blood clots minimal (although not zero percent).\nThough 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). 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. 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. 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).\nKinase 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. There are currently numerous direct antiviral agents that are under consideration for COVID-19 (several prominent investigational drugs are shown in Fig. 4).\nFigure 4. Drug therapies under investigation for COVID-19.\nAlthough 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. For instance, ribavirin has demonstrated synergy in vitro with imatinib against leukemia growth (166). 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.\nThe drug-drug interactions between imatinib and a wide variety of antiviral and other agents have been thoroughly assessed. Imatinib displays variable drug-drug interactions and so its potential for effective combination needs to be taken on a case by case basis. For instance, protease inhibitors ritonavir-lopinavir and darunavir increase imatinib exposure, and saquinavir and indinavir decrease imatinib exposure (168). 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). The antimalarial drug, chloroquine, decreases imatinib intracellular exposure (168).\nThe 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). 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). 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. Niclosamide was demonstrated to synergize in preclinical studies with imatinib and other kinase inhibitors against different malignancies. For instance, synergy between niclosamide and imatinib, as well as niclosamide and dasatinib or ponatinib, against CML cells was demonstrated (171). 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).\nEGFR-targeting kinase inhibitors are characterized by extensive tissue distribution, moderate to high plasma protein binding, and a relatively high volume of distribution (\u003e1700 L) (175). 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). 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). 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). 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. 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). This was partially attributed to the fact that afatinib is not a modulator of substrate of cytochrome P450 enzymes. 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. 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. Or perhaps afatinib could be investigated as a treatment for COVID-19 in combination with several antiviral drugs as part of a cocktail.\nAfatinib has also been tested in combination with nintedanib in a Phase I dose-escalation study in patients with advanced solid tumors (182). 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. 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.\nRitonavir 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). Consequently, this combination has the potential for reduced efficacy and/or increased toxicity. 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). These results suggest that drug-drug interactions between sunitinib and ritonavir require dosing modifications for sunitinib. 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.\nTable 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. Also included in Table 4 are those kinase inhibitors with potential to effectively synergize with other agents, including antiviral drugs.\nTable 4 Chemical structures of kinase inhibitor candidates for COVID-19 treatment. Chemical structures and molecular weights were obtained on chemspider.com"}

{"project":"LitCovid-sentences","denotations":[{"id":"T587","span":{"begin":0,"end":64},"obj":"Sentence"},{"id":"T588","span":{"begin":65,"end":255},"obj":"Sentence"},{"id":"T589","span":{"begin":256,"end":391},"obj":"Sentence"},{"id":"T590","span":{"begin":392,"end":691},"obj":"Sentence"},{"id":"T591","span":{"begin":692,"end":1073},"obj":"Sentence"},{"id":"T592","span":{"begin":1074,"end":1324},"obj":"Sentence"},{"id":"T593","span":{"begin":1325,"end":1481},"obj":"Sentence"},{"id":"T594","span":{"begin":1482,"end":1747},"obj":"Sentence"},{"id":"T595","span":{"begin":1748,"end":1871},"obj":"Sentence"},{"id":"T596","span":{"begin":1872,"end":2043},"obj":"Sentence"},{"id":"T597","span":{"begin":2044,"end":2324},"obj":"Sentence"},{"id":"T598","span":{"begin":2325,"end":2558},"obj":"Sentence"},{"id":"T599","span":{"begin":2559,"end":2732},"obj":"Sentence"},{"id":"T600","span":{"begin":2733,"end":2816},"obj":"Sentence"},{"id":"T601","span":{"begin":2817,"end":3110},"obj":"Sentence"},{"id":"T602","span":{"begin":3111,"end":3289},"obj":"Sentence"},{"id":"T603","span":{"begin":3290,"end":3503},"obj":"Sentence"},{"id":"T604","span":{"begin":3504,"end":3657},"obj":"Sentence"},{"id":"T605","span":{"begin":3658,"end":3994},"obj":"Sentence"},{"id":"T606","span":{"begin":3995,"end":4152},"obj":"Sentence"},{"id":"T607","span":{"begin":4153,"end":4162},"obj":"Sentence"},{"id":"T608","span":{"begin":4163,"end":4211},"obj":"Sentence"},{"id":"T609","span":{"begin":4212,"end":4463},"obj":"Sentence"},{"id":"T610","span":{"begin":4464,"end":4566},"obj":"Sentence"},{"id":"T611","span":{"begin":4567,"end":4808},"obj":"Sentence"},{"id":"T612","span":{"begin":4809,"end":4932},"obj":"Sentence"},{"id":"T613","span":{"begin":4933,"end":5072},"obj":"Sentence"},{"id":"T614","span":{"begin":5073,"end":5231},"obj":"Sentence"},{"id":"T615","span":{"begin":5232,"end":5437},"obj":"Sentence"},{"id":"T616","span":{"begin":5438,"end":5522},"obj":"Sentence"},{"id":"T617","span":{"begin":5523,"end":5703},"obj":"Sentence"},{"id":"T618","span":{"begin":5704,"end":5942},"obj":"Sentence"},{"id":"T619","span":{"begin":5943,"end":6156},"obj":"Sentence"},{"id":"T620","span":{"begin":6157,"end":6295},"obj":"Sentence"},{"id":"T621","span":{"begin":6296,"end":6444},"obj":"Sentence"},{"id":"T622","span":{"begin":6445,"end":6696},"obj":"Sentence"},{"id":"T623","span":{"begin":6697,"end":6884},"obj":"Sentence"},{"id":"T624","span":{"begin":6885,"end":7141},"obj":"Sentence"},{"id":"T625","span":{"begin":7142,"end":7405},"obj":"Sentence"},{"id":"T626","span":{"begin":7406,"end":7574},"obj":"Sentence"},{"id":"T627","span":{"begin":7575,"end":7780},"obj":"Sentence"},{"id":"T628","span":{"begin":7781,"end":7972},"obj":"Sentence"},{"id":"T629","span":{"begin":7973,"end":8088},"obj":"Sentence"},{"id":"T630","span":{"begin":8089,"end":8298},"obj":"Sentence"},{"id":"T631","span":{"begin":8299,"end":8521},"obj":"Sentence"},{"id":"T632","span":{"begin":8522,"end":8658},"obj":"Sentence"},{"id":"T633","span":{"begin":8659,"end":8800},"obj":"Sentence"},{"id":"T634","span":{"begin":8801,"end":8964},"obj":"Sentence"},{"id":"T635","span":{"begin":8965,"end":9193},"obj":"Sentence"},{"id":"T636","span":{"begin":9194,"end":9373},"obj":"Sentence"},{"id":"T637","span":{"begin":9374,"end":9470},"obj":"Sentence"},{"id":"T638","span":{"begin":9471,"end":9677},"obj":"Sentence"},{"id":"T639","span":{"begin":9678,"end":9803},"obj":"Sentence"},{"id":"T640","span":{"begin":9804,"end":10099},"obj":"Sentence"},{"id":"T641","span":{"begin":10100,"end":10345},"obj":"Sentence"},{"id":"T642","span":{"begin":10346,"end":10484},"obj":"Sentence"},{"id":"T643","span":{"begin":10485,"end":10567},"obj":"Sentence"},{"id":"T644","span":{"begin":10568,"end":10641},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"Clinical trials: single agent and combination therapy approaches\nBased 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. There are currently several COVID-19 clinical studies investigating imatinib as a single agent (NCT04346147, NCT04357613, NCT04356495). 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). 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). 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). Baricitinib does not interact with antiviral agents due to its prevalent renal elimination, and so it is proposed to suitable for combination therapy (162). 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).\nA COVID-19 study is ongoing that investigates tofacitinib as a single agent at 10 mg twice a day for 14 days (NCT04332042). 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). 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). 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. 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). This would likely make the risk of blood clots minimal (although not zero percent).\nThough 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). 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. 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. 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).\nKinase 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. There are currently numerous direct antiviral agents that are under consideration for COVID-19 (several prominent investigational drugs are shown in Fig. 4).\nFigure 4. Drug therapies under investigation for COVID-19.\nAlthough 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. For instance, ribavirin has demonstrated synergy in vitro with imatinib against leukemia growth (166). 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.\nThe drug-drug interactions between imatinib and a wide variety of antiviral and other agents have been thoroughly assessed. Imatinib displays variable drug-drug interactions and so its potential for effective combination needs to be taken on a case by case basis. For instance, protease inhibitors ritonavir-lopinavir and darunavir increase imatinib exposure, and saquinavir and indinavir decrease imatinib exposure (168). 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). The antimalarial drug, chloroquine, decreases imatinib intracellular exposure (168).\nThe 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). 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). 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. Niclosamide was demonstrated to synergize in preclinical studies with imatinib and other kinase inhibitors against different malignancies. For instance, synergy between niclosamide and imatinib, as well as niclosamide and dasatinib or ponatinib, against CML cells was demonstrated (171). 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).\nEGFR-targeting kinase inhibitors are characterized by extensive tissue distribution, moderate to high plasma protein binding, and a relatively high volume of distribution (\u003e1700 L) (175). 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). 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). 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). 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. 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). This was partially attributed to the fact that afatinib is not a modulator of substrate of cytochrome P450 enzymes. 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. 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. Or perhaps afatinib could be investigated as a treatment for COVID-19 in combination with several antiviral drugs as part of a cocktail.\nAfatinib has also been tested in combination with nintedanib in a Phase I dose-escalation study in patients with advanced solid tumors (182). 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. 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.\nRitonavir 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). Consequently, this combination has the potential for reduced efficacy and/or increased toxicity. 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). These results suggest that drug-drug interactions between sunitinib and ritonavir require dosing modifications for sunitinib. 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.\nTable 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. Also included in Table 4 are those kinase inhibitors with potential to effectively synergize with other agents, including antiviral drugs.\nTable 4 Chemical structures of kinase inhibitor candidates for COVID-19 treatment. Chemical structures and molecular weights were obtained on chemspider.com"}

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There are currently several COVID-19 clinical studies investigating imatinib as a single agent (NCT04346147, NCT04357613, NCT04356495). 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). 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). 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). Baricitinib does not interact with antiviral agents due to its prevalent renal elimination, and so it is proposed to suitable for combination therapy (162). 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).\nA COVID-19 study is ongoing that investigates tofacitinib as a single agent at 10 mg twice a day for 14 days (NCT04332042). 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). 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). 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. 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). This would likely make the risk of blood clots minimal (although not zero percent).\nThough 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). 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. 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. 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).\nKinase 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. There are currently numerous direct antiviral agents that are under consideration for COVID-19 (several prominent investigational drugs are shown in Fig. 4).\nFigure 4. Drug therapies under investigation for COVID-19.\nAlthough 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. For instance, ribavirin has demonstrated synergy in vitro with imatinib against leukemia growth (166). 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.\nThe drug-drug interactions between imatinib and a wide variety of antiviral and other agents have been thoroughly assessed. Imatinib displays variable drug-drug interactions and so its potential for effective combination needs to be taken on a case by case basis. For instance, protease inhibitors ritonavir-lopinavir and darunavir increase imatinib exposure, and saquinavir and indinavir decrease imatinib exposure (168). 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). The antimalarial drug, chloroquine, decreases imatinib intracellular exposure (168).\nThe 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). 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). 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. Niclosamide was demonstrated to synergize in preclinical studies with imatinib and other kinase inhibitors against different malignancies. For instance, synergy between niclosamide and imatinib, as well as niclosamide and dasatinib or ponatinib, against CML cells was demonstrated (171). 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).\nEGFR-targeting kinase inhibitors are characterized by extensive tissue distribution, moderate to high plasma protein binding, and a relatively high volume of distribution (\u003e1700 L) (175). 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). 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). 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). 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. 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). This was partially attributed to the fact that afatinib is not a modulator of substrate of cytochrome P450 enzymes. 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. 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. Or perhaps afatinib could be investigated as a treatment for COVID-19 in combination with several antiviral drugs as part of a cocktail.\nAfatinib has also been tested in combination with nintedanib in a Phase I dose-escalation study in patients with advanced solid tumors (182). 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. 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.\nRitonavir 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). Consequently, this combination has the potential for reduced efficacy and/or increased toxicity. 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). These results suggest that drug-drug interactions between sunitinib and ritonavir require dosing modifications for sunitinib. 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.\nTable 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. Also included in Table 4 are those kinase inhibitors with potential to effectively synergize with other agents, including antiviral drugs.\nTable 4 Chemical structures of kinase inhibitor candidates for COVID-19 treatment. Chemical structures and molecular weights were obtained on chemspider.com"}

{"project":"LitCovid-PMC-OGER-BB","denotations":[{"id":"T2158","span":{"begin":8203,"end":8213},"obj":"DG_28"},{"id":"T2159","span":{"begin":8276,"end":8284},"obj":"SP_7"},{"id":"T2160","span":{"begin":8343,"end":8353},"obj":"SP_7"},{"id":"T2161","span":{"begin":8378,"end":8386},"obj":"CHEBI:61390;CHEBI:61390"},{"id":"T2162","span":{"begin":8429,"end":8437},"obj":"SP_7"},{"id":"T2163","span":{"begin":8466,"end":8475},"obj":"CHEBI:67079;CHEBI:67079"},{"id":"T2164","span":{"begin":8476,"end":8481},"obj":"CHEBI:36044;CHEBI:36044"},{"id":"T2165","span":{"begin":8495,"end":8503},"obj":"CHEBI:60004;CHEBI:60004"},{"id":"T2166","span":{"begin":8505,"end":8513},"obj":"CHEBI:61390;CHEBI:61390"},{"id":"T2167","span":{"begin":8555,"end":8565},"obj":"CHEBI:85164;CHEBI:85164"},{"id":"T2168","span":{"begin":8670,"end":8678},"obj":"CHEBI:61390;CHEBI:61390"},{"id":"T2169","span":{"begin":8706,"end":8716},"obj":"CHEBI:85164;CHEBI:85164"},{"id":"T2170","span":{"begin":8863,"end":8871},"obj":"CHEBI:61390;CHEBI:61390"},{"id":"T2171","span":{"begin":8876,"end":8886},"obj":"CHEBI:85164;CHEBI:85164"},{"id":"T2172","span":{"begin":8888,"end":8895},"obj":"MOP:0000779"},{"id":"T2173","span":{"begin":8905,"end":8910},"obj":"NCBITaxon:10239"},{"id":"T2174","span":{"begin":8996,"end":9000},"obj":"CHEBI:23888;CHEBI:23888"},{"id":"T2175","span":{"begin":9030,"end":9038},"obj":"SP_7"},{"id":"T2176","span":{"begin":9040,"end":9049},"obj":"DG_30"},{"id":"T2177","span":{"begin":9062,"end":9071},"obj":"CHEBI:35222;CHEBI:35222"},{"id":"T2178","span":{"begin":9075,"end":9081},"obj":"PR:000006130"},{"id":"T2179","span":{"begin":9103,"end":9108},"obj":"PR:000001891"},{"id":"T2180","span":{"begin":9132,"end":9141},"obj":"CHEBI:35222;CHEBI:35222"},{"id":"T2181","span":{"begin":9142,"end":9151},"obj":"CHEBI:38940;CHEBI:38940"},{"id":"T2182","span":{"begin":9155,"end":9164},"obj":"GO:0008152"},{"id":"T2183","span":{"begin":9168,"end":9174},"obj":"PR:000006130"},{"id":"T2184","span":{"begin":9198,"end":9203},"obj":"PR:000001891"},{"id":"T2185","span":{"begin":9388,"end":9397},"obj":"CHEBI:45409;DG_30;CHEBI:45409"},{"id":"T2186","span":{"begin":9550,"end":9554},"obj":"CHEBI:23888;CHEBI:23888"},{"id":"T2187","span":{"begin":9555,"end":9559},"obj":"CHEBI:23888;CHEBI:23888"},{"id":"T2188","span":{"begin":9582,"end":9591},"obj":"CHEBI:38940;CHEBI:38940"},{"id":"T2189","span":{"begin":9596,"end":9605},"obj":"CHEBI:45409;CHEBI:45409;DG_30"},{"id":"T2190","span":{"begin":9639,"end":9648},"obj":"CHEBI:38940;CHEBI:38940"},{"id":"T2191","span":{"begin":9677,"end":9682},"obj":"NCBITaxon:10239"},{"id":"T69885","span":{"begin":9826,"end":9835},"obj":"CHEBI:37670;CHEBI:37670"},{"id":"T33890","span":{"begin":9841,"end":9850},"obj":"DG_30"},{"id":"T25248","span":{"begin":9855,"end":9863},"obj":"SP_7"},{"id":"T55669","span":{"begin":9928,"end":9935},"obj":"GO:0065007"},{"id":"T37960","span":{"begin":10045,"end":10055},"obj":"CHEBI:35222;CHEBI:35222"},{"id":"T16837","span":{"begin":10074,"end":10090},"obj":"CHEBI:52217;CHEBI:52217"},{"id":"T80607","span":{"begin":10234,"end":10244},"obj":"CHEBI:35222;CHEBI:35222"},{"id":"T87435","span":{"begin":10296,"end":10302},"obj":"CHEBI:23888;CHEBI:23888"},{"id":"T76445","span":{"begin":10314,"end":10323},"obj":"CHEBI:67079;CHEBI:67079"},{"id":"T42551","span":{"begin":10324,"end":10329},"obj":"CHEBI:36044;CHEBI:36044"},{"id":"T62224","span":{"begin":10367,"end":10376},"obj":"CHEBI:35222;CHEBI:35222"},{"id":"T85240","span":{"begin":10392,"end":10400},"obj":"SP_7"},{"id":"T6700","span":{"begin":10523,"end":10532},"obj":"CHEBI:35222;CHEBI:35222"},{"id":"T35698","span":{"begin":10548,"end":10556},"obj":"SP_7"}],"text":"Clinical trials: single agent and combination therapy approaches\nBased 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. There are currently several COVID-19 clinical studies investigating imatinib as a single agent (NCT04346147, NCT04357613, NCT04356495). 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). 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). 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). Baricitinib does not interact with antiviral agents due to its prevalent renal elimination, and so it is proposed to suitable for combination therapy (162). 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).\nA COVID-19 study is ongoing that investigates tofacitinib as a single agent at 10 mg twice a day for 14 days (NCT04332042). 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). 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). 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. 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). This would likely make the risk of blood clots minimal (although not zero percent).\nThough 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). 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. 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. 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).\nKinase 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. There are currently numerous direct antiviral agents that are under consideration for COVID-19 (several prominent investigational drugs are shown in Fig. 4).\nFigure 4. Drug therapies under investigation for COVID-19.\nAlthough 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. For instance, ribavirin has demonstrated synergy in vitro with imatinib against leukemia growth (166). 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.\nThe drug-drug interactions between imatinib and a wide variety of antiviral and other agents have been thoroughly assessed. Imatinib displays variable drug-drug interactions and so its potential for effective combination needs to be taken on a case by case basis. For instance, protease inhibitors ritonavir-lopinavir and darunavir increase imatinib exposure, and saquinavir and indinavir decrease imatinib exposure (168). 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). The antimalarial drug, chloroquine, decreases imatinib intracellular exposure (168).\nThe 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). 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). 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. Niclosamide was demonstrated to synergize in preclinical studies with imatinib and other kinase inhibitors against different malignancies. For instance, synergy between niclosamide and imatinib, as well as niclosamide and dasatinib or ponatinib, against CML cells was demonstrated (171). 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).\nEGFR-targeting kinase inhibitors are characterized by extensive tissue distribution, moderate to high plasma protein binding, and a relatively high volume of distribution (\u003e1700 L) (175). 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). 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). 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). 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. 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). This was partially attributed to the fact that afatinib is not a modulator of substrate of cytochrome P450 enzymes. 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. 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. Or perhaps afatinib could be investigated as a treatment for COVID-19 in combination with several antiviral drugs as part of a cocktail.\nAfatinib has also been tested in combination with nintedanib in a Phase I dose-escalation study in patients with advanced solid tumors (182). 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. 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.\nRitonavir 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). Consequently, this combination has the potential for reduced efficacy and/or increased toxicity. 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). These results suggest that drug-drug interactions between sunitinib and ritonavir require dosing modifications for sunitinib. 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.\nTable 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. Also included in Table 4 are those kinase inhibitors with potential to effectively synergize with other agents, including antiviral drugs.\nTable 4 Chemical structures of kinase inhibitor candidates for COVID-19 treatment. Chemical structures and molecular weights were obtained on chemspider.com"}