CN-121987622-A - Cerebral apoplexy treatment time window extender, application thereof and cerebral apoplexy thrombolysis kit

Abstract

The invention relates to a cerebral apoplexy treatment time window extender, application thereof and a cerebral apoplexy thrombolysis kit, wherein the cerebral apoplexy treatment time window extender comprises a protein PAI-1 targeted inhibitor and is used for specifically combining with a plasminogen activator inhibitor PAI-1 released by activated platelets in a cerebral thrombosis area to inhibit fibrinolysis inhibition activity of PAI-1. The method has the advantages that endogenous fibrinolysis is activated in a safe and effective mode, the sharp contradiction between timeliness and safety in the prior art is directly solved, the method is hopeful to be used as a safe early intervention drug, and a large number of patients missing initial treatment occasions are provided with new treatment possibilities. The exquisite 'unlocking' mechanism delays the cerebral apoplexy treatment time window to 6 hours, and precious time is gained for cerebral apoplexy treatment subsequently.

Inventors

• HUANG MINGDONG
• XU YANYAN
• YUAN CAI
• JIANG LONGGUANG
• XU PI
• ZHAO WANFU

Assignees

• 福州大学

Dates

Publication Date

20260508

Application Date

20260213

Claims (10)

1. 1. A stroke treatment time window extender comprising a protein PAI-1 targeted inhibitor for specifically binding to the plasminogen activator inhibitor PAI-1 of activated platelet release in the thrombotic region of stroke to inhibit the fibrinolytic inhibitory activity of PAI-1.
2. 2. The stroke therapeutic time window extender of claim 1, wherein the protein PAI-1 targeted inhibitor is PAItrap4, PAItrap4 is modified with platelet targeting peptide cRGD to specifically bind PAI-1 released by activated platelets in the thrombotic region of the stroke.
3. 3. Application of protein PAI-1 targeted inhibitor in preparing pharmaceutical composition or kit for prolonging ischemic cerebral apoplexy thrombolysis treatment time window.
4. 4. The use according to claim 3, wherein the pharmaceutical composition or kit is administered by intravenous injection.
5. 5. The use according to claim 4, wherein the pharmaceutical composition or kit is in a dosage form for intravenous injection.
6. 6. The use according to claim 3, wherein the protein PAI-1 targeting inhibitor is PAItrap4.
7. 7. The use according to claim 3 or 6, wherein the protein PAI-1 targeting inhibitor is further modified with a platelet targeting peptide cRGD.
8. 8. A kit for thrombolysis in ischemic stroke comprising a first formulation and a second formulation, wherein the first formulation comprises PAItrap a 4 and the second formulation comprises a plasminogen activator, and wherein the first formulation and the second formulation are packaged separately.
9. 9. The kit of claim 8, wherein, the plasminogen is activated the agent is alteplase.
10. Use of a pharmaceutical kit of paitrapp 4 and alteplase for the preparation of a thrombolytic agent for ischemic stroke.

Description

Cerebral apoplexy treatment time window extender, application thereof and cerebral apoplexy thrombolysis kit Technical Field The invention relates to the technical field of biological medicines, in particular to a cerebral apoplexy treatment time window extender, application thereof and a cerebral apoplexy thrombolysis kit. Background Cerebral stroke is a high-mortality and high-disability disease, with acute ischemic stroke (Acute Ischemic Stroke, AIS) being the predominant disease. For AIS, early implementation of occlusive vascular reperfusion is critical to improving prognosis. In the clinical treatment of cerebral apoplexy, intravenous thrombolytic drugs (such as recombinant tissue plasminogen activator rt-PA, trade name of alteplase) are widely adopted, but thrombolytic drugs are limited by strict administration time window, risk of bleeding complications such as intracranial hemorrhage and the like, so that the proportion of patients who can benefit is limited. In addition, in newly formed thrombi, endogenous plasmin inhibitor PAI-1 (Plasminogen Activator Inhibitor-1) can rapidly inhibit the activity of plasminogen activator tPA (tissue-type plasminogen activator) and uPA (urokinase-type plasminogen activator), and the concentration can be remarkably increased in the local and platelet-activating environments of the thrombi, thus leading to thrombolysis resistance and reduction of the recanalization rate, and clinically, higher doses of thrombolytic drugs are often required to counter the inhibition effect, however, the bleeding risk is further increased. Studies in the prior art show that the treatment dosage of the alteplase can be effectively reduced by specifically inhibiting the PAI-1, so that the cerebral hemorrhage risk （Xu Y. et al., "Specific inhibition on PAI-1 reduces the dose of Alteplase for ischemic stroke treatment",International Journal of Biological Macromolecules, 2024, 257: 128618）. is obviously reduced while the thrombolytic effect is ensured, but due to the limitation of the thrombolytic drug administration time window, the pre-hospital transfer delay or the non-hospital arrival of a patient suffering from acute ischemic cerebral apoplexy directly leads to the missing or obvious compression of the intravenous thrombolysis treatment time window, which deprives the patient of the opportunity of receiving the most effective early reperfusion therapy, accelerates the transformation of ischemic penumbra to irreversible infarction, obviously increases the disability rate and the mortality rate, and aggravates medical and social burden. Disclosure of Invention First, the technical problem to be solved In view of the above-mentioned shortcomings and disadvantages of the prior art, the invention provides a cerebral apoplexy treatment time window extender and application thereof, and a cerebral apoplexy thrombolysis kit, which solves the technical problem that the cerebral apoplexy treatment time window period is limited, thereby influencing the subsequent cerebral apoplexy treatment effect. (II) technical scheme In order to achieve the above purpose, the main technical scheme adopted by the invention comprises the following steps: in a first aspect, embodiments of the present invention provide a stroke treatment time window extender comprising a protein PAI-1 targeted inhibitor for specifically binding to the plasminogen activator inhibitor PAI-1 released by activated platelets in the thrombotic region of stroke to inhibit the fibrinolytic inhibitory activity of PAI-1. The cerebral apoplexy treatment time window extender is used for administering the cerebral apoplexy suspected cases in the emergency treatment stage so as to prolong the treatment time window of the cerebral apoplexy diagnosis cases, wherein the treatment time window is the time period from cerebral apoplexy occurrence to thrombolysis administration treatment after diagnosis. As a preferred embodiment of the invention, the protein PAI-1 targeting inhibitor is PAItrap4, PAItrap4 is modified with platelet targeting peptide cRGD to specifically bind PAI-1 released by activated platelets in the thrombotic region of stroke. In a second aspect, embodiments of the present invention provide for the use of a protein PAI-1 targeted inhibitor in the preparation of a pharmaceutical composition or kit for extending the time window of thrombolytic therapy of ischemic stroke. As a preferred embodiment of the invention, the use, the route of administration of the pharmaceutical composition or kit is intravenous injection. As a preferred embodiment of the invention, the pharmaceutical composition or kit is in a dosage form for intravenous injection. As a preferred embodiment of the invention, the protein PAI-1 targeted inhibitor is PAItrap4 for the use. As a preferred embodiment of the invention, the protein PAI-1 targeting inhibitor is further modified with a platelet targeting peptide cRGD for the use. In a third aspect, embodiments of t