Drug regimen for treatment of cerebral ischemia
Inventors
Kauvar, Lawrence M. • Janigro, Damir
Assignees
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Publication Number
US-12109265-B2
Publication Date
2024-10-08
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. The method administers an effective amount of a thrombolytic agent and an effective amount of an inhibitor of vascular endothelial growth factor (VEGF) receptor-mediated signal transduction (VEGF-RST), with the inhibitor selected from ranibizumab and bevacizumab.
The effective amount of the inhibitor is 0.1-2.5 mg in a 70 kg patient with adjustments for patients of different weights. The effective amount provides inhibition of >50% of VEGF-RST activity over 24 hours, while the serum concentration level is reduced below the pharmacologically active level at least by 48 hours after administration.
The disclosed approach also includes treating cerebral ischemia by mechanically removing a blood clot associated with the ischemic event. In that embodiment, a measured dose of an inhibitor of VEGF-RST is administered in association with mechanical clot removal, with the inhibitor selected from ranibizumab and bevacizumab and the same temporal constraints on pathway inhibition and serum concentration reduction.
Claims Coverage
The partial content contains two independent claims, each requiring a VEGF-RST inhibitor combined with an intervention for cerebral ischemia. Across the claims, the inventive features center on combining a thrombolytic agent with a VEGF-RST inhibitor, or pairing mechanical clot removal with a measured VEGF-RST inhibitor dose, while ensuring transient VEGF-RST suppression and clearance below pharmacologically active levels by at least 48 hours.
Thrombolytic plus VEGF-RST inhibitor for neuronal damage reduction
A method of treatment to reduce neuronal damage caused by a cerebral ischemic event in a human patient comprising administering an effective amount of a thrombolytic agent and an effective amount of an inhibitor of vascular endothelial growth factor (VEGF) receptor-mediated signal transduction (VEGF-RST).
Ranibizumab or bevacizumab with weight-adjusted dosing
The inhibitor is selected from ranibizumab and bevacizumab, and the effective amount of the inhibitor is 0.1-2.5 mg in a 70 kg patient with adjustments for patients of different weights.
Transient inhibition of VEGF-RST activity over 24 hours
The effective amount of said inhibitor provides inhibition of >50% of said VEGF-RST activity over 24 hours.
Serum concentration reduced below pharmacologically active level by 48 hours
The serum concentration level of said inhibitor is reduced below this pharmacologically active level at least by 48 hours after administration.
Mechanical clot removal with measured VEGF-RST inhibitor dose
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 said ischemia event and administering in association with said removing a measured dose of an inhibitor of VEGF-RST.
Ranibizumab or bevacizumab for mechanical clot-removal associated dosing
The inhibitor is selected from ranibizumab and bevacizumab, and the effective amount is 0.1-2.5 mg in a 70 kg patient with adjustments for patients of different weights.
Across the independent claims, claim coverage centers on reducing neuronal damage in a human patient with cerebral ischemia by administering either a thrombolytic agent together with a VEGF-RST inhibitor or a measured VEGF-RST inhibitor dose in association with mechanical clot removal, while selecting ranibizumab or bevacizumab and enforcing transient pathway inhibition and serum clearance below pharmacologically active levels by at least 48 hours.
Stated Advantages
Reduces neuronal damage caused by a cerebral ischemic event in a human patient.
Reduces hemorrhagic transformation risk.
Documented Applications
Treatment of cerebral ischemia / embolic stroke by combining thrombolytic agent administration with transient VEGF-RST inhibition.
Treatment of cerebral ischemia by mechanically removing a blood clot and administering a measured VEGF-RST inhibitor dose in association with clot removal.
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