EGFR antagonist for the treatment of heart disease

a technology of epidermal growth factor and antagonist, which is applied in the direction of antibody medical ingredients, enzyme inhibitor ingredients, drug compositions, etc., can solve the problems of morbidity and mortality, morbidity and mortality, and the condition usually is fatal immediately

Inactive Publication Date: 2013-09-05
FENG QINGPING +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0076]The above disclosure generally describes the present invention. A more complete understanding can be obtained by reference to the following specific Examples. These Examples are described solely for purposes of illustration and are not intended to limit the scope of the invention. Changes in form and substitution of equivalents are contemplated as circumstances may suggest or render expedient. Although specific terms have been employed herein, such terms are intended in a descriptive sense and not for purposes of limitation.
[0077]The examples are described for the purposes of illustration and are not intended to limit the scope of the invention.

Problems solved by technology

Cardiovascular diseases account for 12 million deaths annually worldwide and myocardial infraction (MI) is a leading cause of morbidity and mortality.
Cardiac rupture, ventricular arrhythmia and heart failure are common causes of morbidity and mortality following MI.
Left untreated, the condition usually is fatal immediately or within a few days depending on the extent of the rupture.
An imbalance between the activities of MMPs and TIMPs can impair infarct healing and result in cardiac rupture [16, 30, 39].
Early post-infarct adaptation of the heart could be beneficial and promote survival, however, with deleterious long-term haemodynamic consequences.
Most drugs used to prevent LV remodeling after MI also impair infarct healing and collagen synthesis.
Until now, no method or drug has been designed to target the EGFR function as a treatment of MI.

Method used

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  • EGFR antagonist for the treatment of heart disease
  • EGFR antagonist for the treatment of heart disease
  • EGFR antagonist for the treatment of heart disease

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0078]The present study was designed to test the hypotheses that deficiency in TIMP-3 increases cardiac rupture post-MI via epidermal growth factor (EGF) / epidermal growth factor receptor (EGFR) signalling which downregulates TGF-β1 expression and collagen synthesis, and that treatment with cetuximab to inhibit EGFR signaling protects against cardiac rupture post-MI. Using a clinically relevant mouse model of MI, and cellular, molecular techniques, our study showed that incidence of cardiac rupture was increased in TIMP-3− / − mice post-MI via EGF / EGFR signalling which downregulated TGF-β1 expression and collagen synthesis in the infarct myocardium. Treatment with cetuximab decreased cardiac rupture and improved survival in TIMP-3− / − mice post-MI.

Materials and Methods

Animals

[0079]Wild-type (WT) mice of the genetic background C57BL / 6 were purchased from Charles River Laboratories (Wilmington, Mass.). TIMP3− / − mice were generated as described previously [22] and back-crossed more than 7 ...

example 2

[0108]As previously stated, most of the commonly drugs used to prevent left ventricular remodeling after MI (i.e. ACEI, ARB, aldosterone antagonists) impair healing and collagen synthesis. Accordingly, these drugs tend to prolong the time window of vulnerability for adverse cardiac remodeling during post-MI healing [53]. Accordingly, a new method for optimizing healing of the heart is needed.

[0109]It is proposed that cetuximab and other EGFR antagonists will have an added benefit in wild-type mice treated with an ACE inhibitor post-MI. As the incidence of cardiac rupture is low in WT mice, the combination of cetuximab and ACE inhibitor will show the beneficial effects of cetuximab on cardiac remodeling. Similar results are expected for the combination of cetuximab with beta blockers, angiotensin receptor antagonists (ARBs), and aldosterone antagonists, all of which are known to have beneficial effects on cardiac remodeling.

[0110]Adult male C57BL6 mice will be randomly assigned to ce...

example 3

[0113]Interestingly, the 129sv mice have been shown to have a significantly higher incidence of cardiac rupture compared to C57BL / 6 mice after MI (56, 57). The 129sv mice therefore represent an excellent model to study the effects of cetuximab on cardiac rupture induced by MI.

[0114]Adult male 129sv mice will be randomly assigned to vehicle control and cetuximab (10 mg / kg, iv) treatment groups (n=50 mice per group). Mice will be subjected to ligation of the left descending coronary artery to induce MI. Immediately after coronary artery ligation, mice will be treated with either vehicle or cetuximab (10 mg / kg, iv). This will be followed by IV injections at day 3 and 5 post-MI, respectively. Survival will be monitored for 30 days after MI. Hemodynamic measurements will be made at 5 and 30 days post-MI. To identify cardiac rupture, postmortem examinations will be performed in all mice died after MI. TGFβ expression, MMP activity and collagen synthesis in the infarct myocardium will also...

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Abstract

The present invention relates to the use of epidermal growth factor receptor (EGFR) antagonists in methods and compositions useful for the treatment of heart disease in a subject. In one embodiment, the methods of the present invention comprise: (a) administering to the subject an EGFR antagonist; and (b) inhibiting or substantially inhibiting the EGFR signal transduction cascade. In another embodiment the method of the present invention may be used in combination with another heart disease therapy.

Description

FIELD OF THE INVENTION[0001]The present invention relates to epidermal growth factor receptor antagonists. More particularly, the present invention relates to use of epidermal growth factor receptor antagonists in methods and compositions for treating heart disease, and for treating, preventing or minimizing conditions, diseases or disorders arising as a complication of heart disease.BACKGROUND OF THE INVENTION[0002]Cardiovascular diseases account for 12 million deaths annually worldwide and myocardial infraction (MI) is a leading cause of morbidity and mortality. Cardiac rupture, ventricular arrhythmia and heart failure are common causes of morbidity and mortality following MI. Cardiac rupture refers to a rupture of the left ventricle of the heart, generally following an acute myocardial infarction. Left untreated, the condition usually is fatal immediately or within a few days depending on the extent of the rupture. It is believed that such rupture occurs in approximately 10% of p...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A61K38/05
CPCA61K31/517A61K31/5377A61K31/7105A61K31/713A61K45/06A61K39/3955C07K16/2863C07K2317/24C07K2317/76A61K38/05A61K2039/505A61P17/02A61P9/00A61K9/127A61K38/005
Inventor FENG, QINGPINGLU, XIANGRU
Owner FENG QINGPING
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