Composition and methods for preventing or reducing the incidence of transient ischemic attacks

A technique for transient ischemia, morbidity, applied in the fields of neurology and cardiology

Inactive Publication Date: 2021-06-01
MOREHOUSE SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] However, despite the risk of stroke in patients with AFIB a

Method used

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  • Composition and methods for preventing or reducing the incidence of transient ischemic attacks
  • Composition and methods for preventing or reducing the incidence of transient ischemic attacks
  • Composition and methods for preventing or reducing the incidence of transient ischemic attacks

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0152] Example 1: Neuroprotective effect of blocking calcium-permeable acid-sensitive ion channels on ischemia

[0153] This example describes experiments showing the role of ASIC1a in mediating ischemic injury and the ability of ASIC1a inhibitors to attenuate ischemic injury; see Figure 2 to Figure 1 0. Ca 2+ Toxicity may play a central role in ischemic brain injury. Cytotoxic Ca 2+ The mechanisms by which loading occurs in the ischemic brain have become less clear as multiple human trials of glutamate antagonists have failed to show potent neuroprotection against stroke. Acidosis is a common feature of ischemia and plays a key role in brain injury. This example shows that acidosis activates Ca 2+ Permeable acid-sensitive ion channels (ASICs), which induce Ca 2+ dependent (but not glutamate receptor dependent) neuronal injury. Thus, cells lacking endogenous ASICs are resistant to acid damage, while Ca 2+ Transfection of permeable ASIC1a establishes sensitivity. In...

example 2

[0205] Example 2: The time window of PcTX neuroprotection (Time Window)

[0206] This example describes exemplary experiments to measure the neuroprotective effects of PcTX venom at various times after the onset of stroke in rodents; see Figure 11 . Briefly, cerebral ischemia (stroke) was induced in rodents by middle cerebral artery occlusion (MCAO). At indicated times after induction, artificial cerebrospinal fluid (aCSF), PcTX venom (0.5 μl, 500 ng / ml total protein), or inactivated (boiled) venom was injected into the lateral ventricle of each rodent . Such as Figure 11As shown, administration of PcTX venom both 1 hour and 3 hours after stroke onset reduced stroke volume by 60%. Furthermore, a significant reduction in stroke volume was still achieved if treatment was discontinued 5 hours after the onset of MCAO. Thus, neuroprotection due to ASIC inhibition may have an extended treatment window after stroke onset, allowing stroke individuals to benefit from treatme...

example 3

[0207] Example 3: Exemplary Cystine Knot Peptides

[0208] This example describes exemplary cystine knot peptides, including full-length PcTxl and deletion derivatives of PcTx, which can be screened in cultured cells and tested in ischemic animals (e.g., rodents such as mice or rats) , and / or administered to an ischemic human subject.

[0209] Figure 12 The one-letter primary amino acid sequence (SEQ ID NO: 1 ) of an exemplary cystine knot peptide PcTxl (indicated at 50) is shown, with various exemplary peptide features shown relative to amino acid positions 1 to 40 . Peptide 50 may include six cysteine ​​residues that form cystine bonds 52 , 54 , 56 to create cystine knot motif 58 . The peptide may also include one or more beta sheet regions 60 and positively charged regions 62 . The N-terminal region 64 and the C-terminal region 66 may flank the cystine knot motif.

[0210] Figure 13 shown Figure 12 Comparison of the alignment of the PcTxl peptide 50 with various...

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Abstract

A composition and method for preventing or reducing the incidence of a transient ischemic attack in a subject at risk for developing a stroke comprises orally administering to the subject a prophylactically effective amount of a pharmaceutical composition comprising an ASIC la inhibitor capable of penetrating the blood-brain barrier. Preferred ASIC la inhibitors for use in the disclosed methods include amiloride and amiloride analogs.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Application Serial No. 16 / 114,815, filed August 28, 2018. All of the above applications are hereby incorporated by reference in their entirety. technical field [0003] This application relates to the fields of neurology and cardiology. In particular, the application relates to compositions comprising an ASICIa inhibitor for preventing or reducing the incidence of TIA and neurological damage in an individual. Background technique [0004] A transient ischemic attack ("transient ischemic attack; TIA" or "ministroke") is an acute onset of temporary neurological deficit, usually lasting less than 1 hour (sometimes as long as 24 hours). A TIA is caused by a brief interruption of oxygen flow to tissue or a transient disturbance in blood supply, usually by obstruction by a blood clot without infarction. When symptoms were prolonged and accompanied by infarction, the dysfunction was c...

Claims

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Application Information

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IPC IPC(8): A01N37/18A61K31/155A61K31/40A61K31/439A61K31/4418A61K31/4965
CPCA61K31/4965A61K45/06A61P9/10A61P9/06A61P7/02A61P9/14A61K2300/00A61K35/646A61K38/1767A61K31/40A61K31/155A61K9/0019A61K9/0085A61K47/02A61K47/26A61K47/18A61K9/0053
Inventor 熊志刚罗杰·赛门
Owner MOREHOUSE SCHOOL OF MEDICINE
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