University of Connecticut

The United States of America, as Represented by the Secretary, Department of Health and Human Services

Other

University of Pennsylvania

Mayo Foundation for Medical Education and Research

Bruce T Liang

Kenneth Alan Jacobson

Bhalchandra V Joshi

Jian-Bing Shen

Christopher C Pickett

Achilles Pappano

Michael Azrin

Allan S Jaffe

Rajkumar Verma

Heiko Schmitt

Thatikonda Santhosh Kumar

Described herein are methods for the treatment of a human subject who has had a stroke by administering to the subject a pharmaceutical composition including an antagonist of the P2X4 receptor. The antagonist of the P2X4 receptor can be administered in the acute phase of stroke, optionally in combination with a thrombolytic therapeutic or a procedure on the subject involving a clot-removal device.

Methods for pharmacologic treatment of stroke

Phosphonate and phosphinate N-methanocarba derivatives of AMP including their prodrug analogs are described. MRS2339, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) ring system in place of ribose, activates P2X receptors, ligand-gated ion channels. Phosphonate analogues of MRS2339 were synthesized using Michaelis-Arbuzov and Wittig reactions, based on the expectation of increased half-life in vivo due to the stability of the C&#x2014;P bond. When administered to calsequestrin-overexpressing mice (a genetic model of heart failure) via a mini-osmotic pump (Alzet), some analogues significantly increased intact heart contractile function in vivo, as assessed by echocardiography-derived fractional shortening (FS) as compared to vehicle-infused mice. The range of carbocyclic nucleotide analogues for treatment of heart failure has been expanded.

Compositions and methods to treat cardiac diseases

Phosphonate and phosphinate N-methanocarba derivatives of AMP including their prodrug analogs are described. MRS2339, a 2-chloro-AMP derivative containing a (N)-methanocarba(bicyclo[3.1.0]hexane) ring system in place of ribose, activates P2X receptors, ligand-gated ion channels. Phosphonate analogues of MRS2339 were synthesized using Michaelis-Arbuzov and Wittig reactions, based on the expectation of increased half-life in vivo due to the stability of the C&#x2014;P bond. When administered to calsequestrin-overexpressing mice (a genetic model of heart failure) via a mini-osmotic pump (Alzet), some analogues significantly increased intact heart contractile function in vivo, as assessed by echocardiography-derived fractional shortening (FS) as compared to vehicle-infused mice. The range of carbocyclic nucleotide analogues for treatment of heart failure has been expanded.

Disclosed herein are methods of detecting and/or prognosing myocardial infarction by detecting a proteolytic fragment of caspase-3 such as the p17 fragment or the p12 fragment. The myocardial infarction can be STEMI or NSTEMI.

Methods for the detection and monitoring of acute myocardial infarction

Phosphonate and phosphinate N-methanocarba derivatives of AMP including their prodrug analogs are described. MRS2339, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) ring system in place of ribose, activates P2X receptors, ligand-gated ion channels. Phosphonate analogs of MRS2339 were synthesized using Michaelis-Arbuzov and Wittig reactions, based on the expectation of increased half-life in vivo due to the stability of the C&#x2014;P bond. When administered to calsequestrin-overexpressing mice (a genetic model of heart failure) via a mini-osmotic pump (Alzet), some analogs significantly increased intact heart contractile function in vivo, as assessed by echocardiography-derived fractional shortening (FS) as compared to vehicle-infused mice. The range of carbocyclic nucleotide analogs for treatment of heart failure has been expanded.

Disclosed herein are N-methanocarba derivatives of AMP and their use in the treatment of cardiac and vascular diseases and conditions responsive to activation of the cardiac P2X receptor. In one embodiment, the N-methanocarba derivative of AMP is the N-methanocarba derivative of 2-chloro-AMP. Diseases and conditions responsive to activation of the cardiac P2X receptor include, for example, cardiac hypertrophy, cardiac failure resulting from any cause of abnormal Cahomeostasis or from myocardial injuries, vascular insufficiency leading to myocardial infarction, post-myocardial infarction conditions, post-myocardial infarction conditions within the short-term post-infarction period, and diastolic heart failure.

Composition and methods to treat cardiac diseases

Disclosed herein are methods of using an adenosine analog or derivative for treating heart failure, increasing cardiac muscle contractility, increasing cardiac diastolic relaxation, and increasing vasodilation. Exemplary adenosine analogs/derivatives include compounds of the following formula wherein

Methods of treating heart failure with modified ATP, ADP and AMP compounds

Compositions and methods for reducing or preventing ischemic damage of the heart are disclosed. A preferred embodiment of the invention comprises the simultaneous administration of specific A3/A1 receptor agonists, to patients suffering from ischemic damage or at risk for the same. In yet another embodiment of the invention, a binary conjugate which acts as an agonist for the A3 receptor and an antagonist at the A2 receptor, is administered to reduce or prevent ischemic damage to the heart.

Methods and compositions for reducing ischemic injury of the heart by administering adenosine receptor agonists and antagonists

Materials and methods for reducing or preventing ischemic damage of the heart are disclosed. A preferred embodiment of the invention comprises methods of sequential administration of a plurality of cardioprotective agents to patients suffering from ischernic damage or at risk for the same.

Methods for reducing ischemic injury of the heart via the sequential administration of monophosphoryl lipid A and adenosine receptor agents

The specification discloses purine nucleotide analogues which modulate cardiac muscle contractility and possess vasodilator activity. In addition, related methods of administration and the identity of receptors that bind these compounds are disclosed.

Purine nucleotide analogues, pharmaceutical compositions thereof, and methods of improving cardiac functions

Compositions and methods for reducing or preventing ischemic damage of the heart are disclosed. A preferred embodiment of the invention comprises the simultaneous administration of specific A3/A1 receptor agonists, to patients suffering from ischemic damage or at risk for the same. In yet another embodiment of the invention, a binary conjugate which acts as an agonist for the A3 receptor and an antagonist at the A2a receptor, is administered to reduce or prevent ischemic damage to the heart.

Methods for reducing or preventing ischemic damage of the heart are disclosed. A preferred embodiment of the invention comprises the administration of a specific A.sub.2a receptor antagonist, 8-(3-chlorostyryl) caffeine, to patients suffering from ischemic damage or at risk for the same.

Methods for protecting against cardiac ischemia by administering

Purine-containing compounds that modulate cardiac muscle contractility are provided, as well as methods for modulating cardiac muscle contractility and receptors that bind the compounds.

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Merion Station, PA, United States of America

Bruce T Liang