Extended release of neuregulin for improved cardiac function

a neuregulin and cardiac function technology, applied in the direction of drug compositions, peptide/protein ingredients, metabolic disorders, etc., can solve the problems of ace inhibitor mortality reduction of 3%, lack of robust cell-cell interactions, size and accumulation of contractile proteins, etc., to enhance the production and/or function of said nrg, improve the effect of nrg, and reduce adverse side effects of nrg

Inactive Publication Date: 2007-08-16
ZENSUN (SHANGHAI) SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012] Extended release of NRG greatly improves the effect of NRG in the treatment of heart failure and cardiac hypertrophy compared to NRG administered by other methods. Extended release of NRG also has the benefit of reducing the adverse side effects of NRG compared to NRG administered by other methods. Thus, the present invention relates to compositions and methods for preventing, treating or delaying various cardiac diseases or disorders in mammals, particularly in humans, by extending the release of a NRG protein, or a functional fragment thereof, or a nucleic acid encoding a NRG protein, or a functional fragment thereof, or an agent that enhances production and / or function of said NRG.

Problems solved by technology

Thus, in pathological hypertrophy, the increased size and accumulation of contractile proteins are associated with disorganized assembly of sarcomeric structures and a lack of robust cell-cell interactions.
While the percent reduction in mortality has been significant, the actual reduction in mortality with ACE inhibitors has averaged only 3%-4%, and there are several potential side effects.
Additionally, diuretics can improve some symptoms of heart failure but it is not suitable as a sole treatment.
Additional limitations are associated with other options for preventing or treating heart failure.
For example, heart transplantation is clearly more expensive and invasive than drug treatment, and it is further limited by the availability of donor hearts.
Use of mechanical devices, such as biventricular pacemakers, are similarly invasive and expensive.
Targeted disruption of the NRG-1β or ErbB2 or ErbB4 led to embryonic lethality due to cardiac development defects.
More importantly, NRG-1β significantly prolongs survival of heart failure animals.

Method used

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  • Extended release of neuregulin for improved cardiac function
  • Extended release of neuregulin for improved cardiac function
  • Extended release of neuregulin for improved cardiac function

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0161] Phosphorylation of AKT and ERK in the Left Ventricle of Normal Rats after NRG is Infused by Different Methods.

[0162] To compare the effect of NRG with various treating methods on the signal transduction inside the cardiac myocytes in the left ventricle, we infused NRG by intravenous (hereinafter referred to as “IV”), intramuscular (hereinafter referred to as “IM”) and IV glucose tolerance test (hereinafter referred to as “IVGTT”).

[0163] Wistar male rats (Shanghai Animal Center of Chinese Academy of Science), which weighed 180±20 grams, were numbered, weighed, and divided into groups. Each group contained three rats. One group received IV injection of 4 ml / kg (volume / body weight) of vehicle (10 mM Na2HPO4-NaH2PO4, 150 mM NaCl, 0.2% human serum albumin (HSA), 5% mannitol, pH 6.0) as a control. Four other groups of rats received IM injection of 4 ml / kg (volume / body weight) of NRG (37.3 U / ml recombinant human NRG fragment (from the 177th to 237th amino acid sequence of human NR...

example 2

[0166] The Function of Left Ventricle Coronary Artery Ligated Rat Heart after Neuregulin Treatment by Different Methods

[0167] As osmotic pump is a way to deliver NRG constantly (as IVGTT), we examined whether NRG infused by osmotic pump was as effective as conventional IV injection in restoring the function of myocardial infarct (MI) heart.

A. Rat Left Ventricle Coronary Artery Ligation and Echocardiography

[0168] Wistar male rats (Shanghai Animal Center of Chinese Academy of Science), which weighed 200±20 g, were anesthetized by intraperitoneally injecting 100 mg / kg (drug / body weight) of ketamine. The neck and chest were depilated and sanitized. An incision was made in the middle front neck to expose the tracheae. An 18 G catheter overneedle was inserted into the tracheae between the 3rd and 5th cartilage of tracheae. After the needle was drawn out, a plastic cannula was pushed into the trachea 1-2 cm and fixed to connect the Rodent Ventilator (SAR-830 / P ventilator—Inspiratory fl...

example 3

[0182] Heart Function of Myocardial Infarcted Rats after Neuregulin was Constantly Intravenously Infused by Syringe Pump (Zhejiang University Medical Instrument Co. LTD, WZS 50-F2)

[0183] In this example, syringe pump is used for extended release of neuregulin in human patients. Syringe pump can pump the solution continuously at certain speed into the bloodstream through a needle injected into the vein in rat tail. For syringe pump, it's easy to control the infusion time and speed. Neuregulin was intravenously infused by syringe pump at different speed for different time per day into MI rats to better time period and speed for treatment.

[0184] Grouped MI rats was treated by intravenous injection of 4 ml / kg (volume / body weight) vehicle everyday for 10 days (group A); or intravenous injection of 10 μg / kg neuregulin (2.5 μg / ml) everyday for 10 days (group B); or intravenous syringe pump infusion of neuregulin (0.625 μg / ml) at 1.25 μg / kg / h with 4 hours per day for 10 days (group C); or...

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Abstract

The present invention provides extended release compositions comprising neuregulin for preventing, treating or delaying various diseases or disorders. The present invention also provides methods for preventing, treating or delaying various diseases or disorders by extended release of neuregulin.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority of U.S. provisional application Nos. 60 / 755,124, filed Dec. 30, 2005, and 60 / 758,626, filed Jan. 13, 2006.FIELD OF THE INVENTION [0002] This invention relates generally to compositions and methods for preventing, treating or delaying various cardiac diseases or disorders by extended release of neuregulin to a mammal. BACKGROUND OF THE INVENTION [0003] Cardiac (ventricular) hypertrophy is an important adaptive physiological response to increased stress or demands for cardiac work. One of the early cellular changes that occurs after a stimulus for hypertrophy is the synthesis of mitochondria and expansion of myofibrillar mass (wall thickening) with a proportional increase in the size of individual cells, but no (or minimal ) increase in the number of cells. [0004] When the ventricle is stressed, the initial response is an increase in sarcomere length. This is followed by an increase in the t...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/17A61K9/127A61K9/50
CPCA61K9/0019A61K9/127A61K38/1883A61K48/00A61K47/48215A61K47/60A61P21/00A61P21/04A61P25/00A61P25/18A61P25/28A61P27/02A61P27/16A61P3/10A61P35/00A61P43/00A61P9/00A61P9/04
Inventor ZHOU, MINGDONG
Owner ZENSUN (SHANGHAI) SCI & TECH CO LTD
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