Drug regimen for treatment of cerebral ischemia
Inventors
Kauvar, Lawrence M. • Janigro, Damir
Assignees
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Publication Number
US-11077188-B2
Publication Date
2021-08-03
Expiration Date
Abstract
Treatment of subjects experiencing cerebral ischemia is improved when the treatment employs a thrombolytic and an inhibitor against vascular endothelial growth factor receptor signal transduction (VEGF-RST) at a reduced, low dosage compared to that used to treat cancer patients. The treatment is also improved to permit point-of-care use by formulating protein drugs for long term stability at room temperature, providing doses appropriate for the method, and by combining the therapeutic agents with a point-of-care diagnostic for blood brain barrier integrity.
Core Innovation
The invention provides a method of treatment to reduce neuronal damage caused by a cerebral ischemic event in a human patient by administering an effective amount of a thrombolytic agent or a thrombolytic intervention together with an effective amount of an inhibitor of vascular endothelial growth factor (VEGF) receptor-mediated signal transduction (VEGF-RST). The effective amount of the inhibitor provides inhibition of >50% of VEGF-RST activity over 24 hours, while the serum concentration level of the inhibitor is reduced below the pharmacologically active level at least by 48 hours after administration.
In one implementation, the cerebral ischemic event is treated by using an effective amount of a thrombolytic agent selected from tissue plasminogen activator (tPA), urokinase, streptokinase, desmoteplase, or single chain urokinase-type plasminogen activator (uPA), or by applying a thrombolytic intervention characterized by mechanical disruption. In another implementation, neuronal damage reduction is achieved by mechanically removing a blood clot associated with the ischemic event, and administering in association with the removing a measured dose of the VEGF-RST inhibitor.
The inhibitor is antagonistic to VEGF or VEGF-R and is selected from specified antibodies or antigen-binding fragments, including ranibizumab, aflibercept, or bevacizumab, or from specified kinase inhibitors associated with VEGF-R signaling, including Tivozanib, Apatinib, Lenvatinib, Axitinib, Imtinib, Motesanib, Fruquitinib, Brivanib, Cediranib, Regorafenib, Sulfatinib, and Sunitinib.
Claims Coverage
The document provides two independent claims. Each independent claim includes a core combination of thrombolysis or clot removal with VEGF-RST inhibition, with the VEGF-RST inhibitor constrained by >50% inhibition over 24 hours and serum levels reduced below the pharmacologically active level by at least 48 hours after administration.
Thrombolytic agent with VEGF-RST inhibition with time-limited serum pharmacologically active level
A method of treatment to reduce neuronal damage caused by a cerebral ischemic event in a human patient comprising administering to the patient an effective amount of a thrombolytic agent or a thrombolytic intervention and an effective amount of an inhibitor of VEGF-RST, wherein the effective amount provides inhibition of >50% of VEGF-RST activity over 24 hours and wherein the serum concentration level of the inhibitor is reduced below the pharmacologically active level at least by 48 hours after administration, with the inhibitor selected as an antagonistic antibody or antigen-binding fragment binding VEGF or VEGF-R from ranibizumab, aflibercept, or bevacizumab, or as an inhibitor of a kinase associated with VEGF-R signaling from the recited list
Mechanical clot removal with measured VEGF-RST inhibitor dose with time-limited pharmacologically active serum level
A method of treatment to reduce neuronal damage caused by a cerebral ischemic event in a human patient comprising mechanically removing a blood clot associated with the ischemia event and administering in association with the removing a measured dose of an inhibitor of VEGF-RST effective to inhibit >50% of signal transduction over 24 hours and wherein the serum concentration level of the inhibitor is reduced below this pharmacologically active level at least by 48 hours after administration, with the inhibitor selected as an antagonistic antibody or antigen-binding fragment binding VEGF or VEGF-R from ranibizumab, aflibercept, or bevacizumab, or as an inhibitor of a kinase associated with VEGF-R signaling from the recited list
Both independent claims claim reducing neuronal damage from a cerebral ischemic event by combining thrombolytic therapy or mechanical clot removal with an inhibitor of VEGF-RST that achieves >50% VEGF-RST inhibition over 24 hours and whose serum level is reduced below the pharmacologically active level by at least 48 hours after administration, with VEGF-RST inhibition provided by either specified VEGF/VEGF-R antagonistic antibodies/antigen-binding fragments or specified VEGF-R-associated kinase inhibitors.
Stated Advantages
Reduces neuronal damage caused by a cerebral ischemic event in a human patient.
Documented Applications
Treatment of cerebral ischemia in a human patient using thrombolytic agent or thrombolytic intervention together with VEGF-RST inhibition.
Treatment of cerebral ischemia using mechanical removal of a blood clot associated with the ischemic event together with a measured dose of a VEGF-RST inhibitor.
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