{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T14:23:45Z","timestamp":1791901425512,"version":"4.3.4"},"reference-count":47,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,2,28]],"date-time":"2023-02-28T00:00:00Z","timestamp":1677542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Alteplase is the only FDA-approved drug for thrombolysis in acute ischemic stroke (AIS). Meanwhile, several thrombolytic drugs are deemed to be promising candidates to substitute alteplase. This paper evaluates the efficacy and safety of urokinase, ateplase, tenecteplase, and reteplase for intravenous AIS therapy by computational simulations of the pharmacokinetics and pharmacodynamics combined with a local fibrinolysis model. The performances of the drugs are evaluated by comparing clot lysis time, plasminogen activator inhibitor (PAI) inhibition resistance, intracranial hemorrhage (ICH) risk, and activation time from drug administration to clot lysis. Our results reveal that urokinase has the quickest lysis completion but the highest ICH risk due to excess fibrinogen depletion in systemic plasma. While tenecteplase and alteplase have very similar thrombolysis efficacy, tenecteplase has a lower risk of ICH and better resistance to PAI-1. Among the four simulated drugs, reteplase has the slowest fibrinolysis rate, but fibrinogen concentration in systemic plasma is unaffected during thrombolysis.<\/jats:p>","DOI":"10.3390\/pharmaceutics15030797","type":"journal-article","created":{"date-parts":[[2023,2,28]],"date-time":"2023-02-28T06:55:16Z","timestamp":1677567316000},"page":"797","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["In Silico Study of Different Thrombolytic Agents for Fibrinolysis in Acute Ischemic Stroke"],"prefix":"10.3390","volume":"15","author":[{"given":"Yilin","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boram","family":"Gu","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 61186, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8267-621X","authenticated-orcid":false,"given":"Xiao Yun","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2370","DOI":"10.1161\/ATVBAHA.120.315754","article-title":"Thrombus Structural Composition in Cardiovascular Disease","volume":"41","author":"Alkarithi","year":"2021","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_2","unstructured":"Chou, E.L., and Kabutey, N.K. (2022). Vascular Surgery: Principles and Practice, CRC Press. [4th ed.]."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1080\/21655979.2016.1229718","article-title":"The evolution of recombinant thrombolytics: Current status and future directions","volume":"8","author":"Adivitiya","year":"2016","journal-title":"Bioengineered"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1161\/01.STR.7.2.135","article-title":"A pilot study of urokinase therapy in cerebral infarction","volume":"7","author":"Fletcher","year":"1976","journal-title":"Stroke"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1001\/jama.1996.03540120039031","article-title":"Streptokinase for Acute Ischemic Stroke with Relationship to Time of Administration","volume":"276","author":"Donnan","year":"1996","journal-title":"JAMA"},{"key":"ref_6","unstructured":"Shahar, E., Mcgovern, P.G., Hommel, M., and Boissel, J.P. Letters to the Editor."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Multicenter Acute Stroke Trial\u2014Europe Study Group (1996). Thrombolytic Therapy with Streptokinase in Acute Ischemic Stroke. N. Engl. J. Med., 335, 145\u2013150.","DOI":"10.1056\/NEJM199607183350301"},{"key":"ref_8","unstructured":"FDA, and CDER (1996). Center for Drug Evaluation and Research Approval Package for Ivermectin, CDER."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"19","DOI":"10.4103\/abr.abr_169_18","article-title":"Reteplase: Structure, Function, and Production","volume":"8","author":"Sadeghi","year":"2019","journal-title":"Adv. Biomed. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"12","DOI":"10.5853\/jos.2020.03349","article-title":"Development and Testing of Thrombolytics in Stroke","volume":"23","author":"Nikitin","year":"2021","journal-title":"J. Stroke"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.1161\/STROKEAHA.120.029749","article-title":"Tenecteplase Thrombolysis for Acute Ischemic Stroke","volume":"51","author":"Warach","year":"2020","journal-title":"Stroke"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"265","DOI":"10.2165\/00129784-200606040-00007","article-title":"Reteplase: A review of its use in the management of thrombotic occlusive disorders","volume":"6","author":"Simpson","year":"2006","journal-title":"Am. J. Cardiovasc. Drugs"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"249","DOI":"10.2147\/VHRM.S3848","article-title":"Review of tenecteplase (TNKase) in the treatment of acute myocardial infarction","volume":"5","author":"Melandri","year":"2009","journal-title":"Vasc. Health Risk Manag."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/S0140-6736(22)01054-6","article-title":"Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada (AcT): A pragmatic, multicentre, open-label, registry-linked, randomised, controlled, non-inferiority trial","volume":"400","author":"Menon","year":"2022","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"52","DOI":"10.4068\/cmj.2012.48.1.52","article-title":"Outcome Evaluation of Intravenous Infusion of Urokinase for Acute Ischemic Stroke","volume":"48","author":"Lee","year":"2012","journal-title":"Chonnam Med. J."},{"key":"ref_16","first-page":"189","article-title":"Safety and Effect of Continuous Intravenous Urokinase Therapy in Acute Ischemic Stroke (Open Clinical Trial)","volume":"17","author":"Doh","year":"1999","journal-title":"J. Korean Neurol. Assoc."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhang, R., Wei, H., Wu, Y., Luo, Y., Zhang, L., Zheng, P., Wang, T., and Qin, X. (2018). Outcomes and Treatment Complications of Intravenous Urokinase Thrombolysis in Acute Ischemic Stroke: A Retrospective Cohort Study. SSRN Electron. J.","DOI":"10.2139\/ssrn.3304297"},{"key":"ref_18","first-page":"6702965","article-title":"Comparison of Efficacy and Safety of Recombinant Human Prourokinase and Alteplase in the Treatment of STEMI and Analysis of Influencing Factors of Efficacy","volume":"2021","author":"Liu","year":"2021","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"S9","DOI":"10.1016\/j.wneu.2011.05.048","article-title":"Medical Therapy for Ischemic Stroke: Review of Intravenous and Intra-Arterial Treatment Options","volume":"76","author":"Taussky","year":"2011","journal-title":"World Neurosurg."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1136\/svn-2020-000640","article-title":"Effectiveness of intravenous r-tPA versus UK for acute ischaemic stroke: A nationwide prospective Chinese registry study","volume":"6","author":"Wang","year":"2021","journal-title":"Stroke Vasc. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"15810","DOI":"10.1038\/s41598-018-34082-7","article-title":"Computational Simulations of Thrombolytic Therapy in Acute Ischaemic Stroke","volume":"8","author":"Piebalgs","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Gu, B., Piebalgs, A., Huang, Y., Longstaff, C., Hughes, A.D., Chen, R., Thom, S.A., and Xu, X.Y. (2019). Mathematical Modelling of Intravenous Thrombolysis in Acute Ischaemic stroke: Effects of Dose Regimens on Levels of Fibrinolytic Proteins and Clot Lysis Time. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11030111"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"685454","DOI":"10.3389\/fneur.2021.685454","article-title":"Outcomes and Treatment Complications of Intravenous Urokinase Thrombolysis in Acute Ischemic Stroke in China","volume":"12","author":"Zhang","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"(1995). The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue Plasminogen Act. Acute Ischemic Stroke, 333, 1581\u20131588.","DOI":"10.1056\/NEJM199512143332401"},{"key":"ref_25","unstructured":"(2022, October 03). Thrombolytic Agents\u2014ClinicalKey. Available online: https:\/\/www.clinicalkey.com\/#!\/content\/book\/3-s2.0-B9780323427913000414."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1016\/S0021-9258(17)36084-2","article-title":"Activation of plasminogen by pro-urokinase. II. Kinetics","volume":"261","author":"Collen","year":"1986","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"10112","DOI":"10.1074\/jbc.275.14.10112","article-title":"Identification of the Mechanism Responsible for the Increased Fibrin Specificity of TNK-Tissue Plasminogen Activator Relative to Tissue Plasminogen Activator","volume":"275","author":"Stewart","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/0268-9499(93)90060-9","article-title":"A variant of tissue plasminogen activator (t-PA) comprised of the Kringle 2 and the protease domain shows a significant difference in the in vitro rate of plasmin formation as compared to the recombinant human t-PA from transformed chinese hamster ovary cells","volume":"7","author":"Kohnert","year":"1993","journal-title":"Fibrinolysis"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/0003-9861(88)90182-8","article-title":"Kinetic analysis of the interactions between plasminogen activator inhibitor 1 and both urokinase and tissue plasminogen activator","volume":"262","author":"Hekman","year":"1988","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3670","DOI":"10.1073\/pnas.91.9.3670","article-title":"A faster-acting and more potent form of tissue plasminogen activator","volume":"91","author":"Keyt","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/BF00133082","article-title":"Comparison of the pharmacokinetics and effects on the hemostatic system of saruplase and urokinase in patients with acute myocardial infarction","volume":"3","author":"Poeppelmeier","year":"1996","journal-title":"J. Thromb. Thrombolysis"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1177\/00912700022009125","article-title":"Pharmacokinetics and Pharmacodynamics of Tenecteplase: Results from a Phase II Study in Patients with Acute Myocardial Infarction","volume":"40","author":"Modi","year":"2000","journal-title":"J. Clin. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"265","DOI":"10.2165\/00003088-199936040-00002","article-title":"Current Clinical Use of Reteplase for Thrombolysis A Pharmacokinetic-Pharmacodynamic Perspective","volume":"36","author":"Martin","year":"1999","journal-title":"Clin. Pharmacokinet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.2165\/00003088-200241150-00001","article-title":"Pharmacokinetics and Pharmacodynamics of Tenecteplase in Fibrinolytic Therapy of Acute Myocardial Infarction","volume":"41","author":"Tanswell","year":"2002","journal-title":"Clin. Pharmacokinet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12639","DOI":"10.1016\/S0021-9258(18)99924-2","article-title":"The specific roles of finger and kringle 2 domains of tissue-type plasminogen activator during in vitro fibrinolysis","volume":"269","author":"Horrevoets","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"12171","DOI":"10.1016\/S0021-9258(17)44152-4","article-title":"The effects of fibrinogen and its cleavage products on the kinetics of plasminogen activation by urokinase and subsequent plasmin activity","volume":"258","author":"Lucas","year":"1983","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/clpt.1991.160","article-title":"Dose-ranging study of the novel recombinant plasminogen activator BM 06.022 in healthy volunteers","volume":"50","author":"Martin","year":"1991","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2805","DOI":"10.1161\/01.CIR.98.25.2805","article-title":"TNK\u2013Tissue Plasminogen Activator Compared with Front-Loaded Alteplase in Acute Myocardial Infarction","volume":"98","author":"Cannon","year":"1998","journal-title":"Circulation"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"105073","DOI":"10.1016\/j.jstrokecerebrovasdis.2020.105073","article-title":"Comparative analysis of fibrinolytic properties of Alteplase, Tenecteplase and Urokinase in an in vitro clot model of intracerebral haemorrhage","volume":"29","author":"Keric","year":"2020","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.medj.2022.07.006","article-title":"IV tenecteplase: A non-inferior alternative to alteplase?","volume":"3","author":"Zubair","year":"2022","journal-title":"Med"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s11936-022-00973-2","article-title":"Intravenous Thrombolytics in the Treatment of Acute Ischemic Stroke","volume":"25","author":"Alhadid","year":"2023","journal-title":"Curr. Treat. Options Cardiovasc. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1212\/WNL.0000000000004062","article-title":"Tenecteplase in ischemic stroke offers improved recanalization","volume":"89","author":"Bivard","year":"2017","journal-title":"Neurology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S0268-9499(97)80057-4","article-title":"Major mechanistic differences explain the higher clot lysis potency of reteplase over alteplase: Lack of fibrin binding is an advantage for bolus application of fibrin-specific thrombolytics","volume":"11","author":"Fischer","year":"1997","journal-title":"Fibrinolysis Proteolysis"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"BSR20170730","DOI":"10.1042\/BSR20170730","article-title":"Evaluation of efficacy and safety of Reteplase and Alteplase in the treatment of hyper-acute cerebral infarction","volume":"38","author":"Lin","year":"2018","journal-title":"Biosci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/0268-9499(89)90033-7","article-title":"The sequential, complementary and synergistic activation of fibrin-bound plasminogen by tissue plasminogen activator and pro-urokinase","volume":"3","author":"Gurewich","year":"1989","journal-title":"Fibrinolysis"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1186\/s13063-022-06596-z","article-title":"Dual thrombolytic therapy with mutant pro-urokinase and small bolus alteplase for ischemic stroke (DUMAS): Study protocol for a multicenter randomized controlled phase II trial","volume":"23","author":"Roozenbeek","year":"2022","journal-title":"Trials"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1159\/000469151","article-title":"Activation of Fibrin-Bound Plasminogen by Pro-Urokinase and Its Complementariness with That by Tissue Plasminogen Activator","volume":"40","author":"Guremch","year":"1988","journal-title":"Enzyme"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/3\/797\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:44:13Z","timestamp":1760121853000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/3\/797"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,28]]},"references-count":47,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["pharmaceutics15030797"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15030797","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,28]]}}}