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Modulation hypoxia associated with stroke

An effective dose, ischemic attack technology, applied in non-active ingredient medical formulations, active ingredient-containing medical formulations, resistance to vector-borne diseases, etc., can solve the problem of successful or partial reperfusion, selective Neuron loss, penumbra loss, etc.

Inactive Publication Date: 2018-12-21
OMNIOX
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, not all patients will benefit from recanalization and the penumbra remains lost to the infarct before recanalization can occur
Regardless of successful or partial reperfusion, secondary hypoxic events within the penumbra of rescue can lead to selective neuronal loss (SNL), which may be responsible for suboptimal clinical recovery

Method used

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  • Modulation hypoxia associated with stroke
  • Modulation hypoxia associated with stroke
  • Modulation hypoxia associated with stroke

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0318] Example 1. Animal model of hypoxia

[0319] Myocardial hypoxia in lambs

[0320] Neonatal sheep were anesthetized with ketamine hydrochloride (-1 mg / kg), intubated with a 4.5-mm OD endotracheal tube and mechanically ventilated with a Healthdyne pediatric time-cycled, pressure-limiting ventilator (Healthdyne, Marietta, GA). Chlorosuccinylcholine (2 mg / kg) was administered intermittently for muscle relaxation. Regulates ventilation using 21% oxygen, thereby reducing systemic arterial PCO 2 Maintain between 35 and 45 torr. Through a median sternotomy, polyethylene catheters were placed to measure systemic, pulmonary, right and left atrial pressures. Admittance catheters were placed in the right and left ventricle for pressure-volume loop analysis, and a flow probe was placed in the left pulmonary artery to measure blood flow. Then, close the sternum with forceps. After 45 min of recovery with steady ventilation, hemodynamic variables, systemic arterial blood gases and...

Embodiment 2

[0327] Example 2. Pharmacokinetics and distribution of H-NOX

[0328] Trimeric H-NOX L144F and PEGylated trimeric H-NOXL144F were expressed in Escherichia coli (E.coli) and purified by 3-step chromatography and buffer exchange procedures to obtain >99% purity, Products with endotoxin levels image 3). Plasma levels of trimeric H-NOX L144F were quantified using an ELISA assay specific for H-NOX protein and the volume of distribution at steady state (Vss) was determined (Table 2). Circulatory half-lives were calculated by fitting the data points using a 5-parameter non-linear fitting model, resulting in a circulatory half-life of 1 hour for trimer H-NOX L144F and 20 hours for PEGylated trimer H-NOX L144F significantly longer circulating half-life. The distribution of PEGylated trimeric H-NOX L144F to normal tissues was shown to be restricted in rats by a small steady-state volume of distribution, which was only slightly greater than the value in plasma volume in rats (31.2 mL / ...

Embodiment 3

[0332] Example 3. Functional H-NOX-mediated delivery of oxygen to hypoxic tissues

[0333] Real-time detection of oxygen in hypoxic tissue (OxyLite Probe).

[0334] Subcutaneously implant 3 × 10 6 H460 human lung cancer cells were monitored until the tumor reached ~600mm 3 The average size of (9-18 days after tumor cell implantation). Use isoflurane mixed with 20% oxygen to make a 500-700mm 3 Mice xenografted with H460 tumors were anesthetized and OxyLite TM Oxygen-detecting nanofiber devices (Oxford Optronix, UK) were implanted into H460 subcutaneous xenograft tumors. OxyLite TM Consists of a ruthenium chloride dye held in a 230 μm diameter polymer matrix at the tip. After ~20-30 minutes of equilibration, measure pO using an optical fluorescence sensor and a four-channel unit 2 . Confirm low starting pO 2 Into hypoxic tissue (~0.2-1 mmHg) away from adjacent blood vessels. After probe implantation, keep the probe for ~30min to allow the pO 2 The measurement is stabl...

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Abstract

The invention provides H-NOX proteins for the delivery of oxygen to hypoxic tissue following stroke. H-NOX proteins extravasate into hypoxic penumbra associated with stroke and preferentially accumulate for sustained delivery of oxygen to the hypoxic tissue to ameliorate adverse affects of stroke related hypoxia. In some embodiments, the H-NOX comprises PEGylated H-NOX and non-PEGylated H-NOX.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 296,009, filed February 16, 2016, the disclosure of which is incorporated herein by reference in its entirety for all purposes. [0003] Submission of Sequence Listing as ASCII Text File [0004] The following submission on the ASCII text file is hereby incorporated by reference in its entirety: Computer Readable Form of the Sequence Listing (CRF) (File Name: 627042001040SeqList.txt, Date of Record: February 16, 2017, Size: 9KB) . [0005] Statement Regarding Federally Sponsored Research or Development [0006] This work was supported by 1R43NS076272-01Al. The US Government is entitled to any patent granting this invention. technical field [0007] The present application pertains to methods of using H-NOX proteins to regulate hypoxia associated with organ damage. Background technique [0008] H-NOX proteins (named for the heme-nitri...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/16A61P9/10
CPCA61K38/164A61P25/00A61P9/10Y02A50/30A61K47/60A61K45/06A01H1/06C12N9/0006C12N9/1085C12N15/8218C12N15/8243C12P17/12C12Y101/01247C12Y205/01059
Inventor N·勒摩恩A·克尔托利察菲尔伯塔·梁S·P·L·卡里
Owner OMNIOX