University of Virginia Patent Foundation

University of Florida Research Foundation, Incorporated

Whitby Research, Inc.

Luiz Belardinelli

Peter J Scammells

Ray Olsson

Stephen Baker

Peter G Milner

Jurg R Pfister

Robert C Wesley, Jr

George Frederic Schreiner

Donald A McAfee

Rafael Rubio

Robert M Berne

Thomas C Skalak

Marc D Feldman

J Urg Pfister

Larry J Findley

Adenosine and xanthine deriviatives, and compositions comprising those compounds, are potent selective agonists of adenosine receptors. The derivatives and compositions are used to treat conditions, including certain cardiac arrhythmias.

Method for using A.sub.1 adenosine receptor agonists

N.sup.6 -(epoxynorborn-2-yl)adenosines are Al adenosine receptor agonists that are useful for controlling atrial fibrillation, ventricular rate in atrial flutter, supraventricular tachyarrhythmia, inhibiting A--V- nodal transmission in supraventricular tachycardia, and for normalizing ventricular rhythm and hemodynamics.

N.sup.6 -(epoxynorborn-2-yl) adenosines as A.sub.1 adenosine receptor

Adenosine and xanthine derivatives, and compositions comprising those compounds, are potent selective agonists and antagonists of adenosine receptors. The derivatives and compositions are used to treat conditions, including certain cardiac arrhythmias.

A1 adenosine receptor agonists and antagonists

Xanthine derivatives, and compositions comprising those compounds, are potent selective antagonists of adenosine receptors. The derivatives and compositions are used to treat conditions, including certain cardiac arrhythmias. The compounds, specifically, are C-8 epoxide derivatives of xanthine having the general formulae of: ##STR1## wherein R.sub.1 and R.sub.2 are the same or different, and can be H or an alkyl group of 1-4 carbons, and n=0-4; and ##STR2## wherein R.sub.1 and R.sub.2 are the same or different, and can be H or an alkyl group of 1-4 carbons, R.sub.3 is either O or (CH.sub.2).sub.1-4, and n=0-4.

Xanthine epoxides as A.sub.1 adenosine receptor agonists and antagonists

Adenosine and xanthine derivatives, and compositions comprising those compounds, are potent selective agonists and antagonists of adenosine receptors. The derivatives and composition are used to treat conditions, including certain cardiac arrhythmias.

A1 adenosine receptor agonists and antagonists as diuretics

A method and composition of determining the viability of tissue in a region of an organism having a vascular circulatory system that supplies blood to said region is disclosed. The composition includes the combination of adenosine or an adenosine antagonist in combination with an A.sub.1 adenosine receptor which may be: ##STR1## wherein R.sub.1 is hydrogen or R.sub.2 ; R.sub.2 is selected from the group consisting of endo-2-norbornyl or cyclopentyl; R.sub.3 is selected from the group consisting of hydrogen, halogen, amine, carboxy, alkyl radicals having 1 to 10 carbon atoms, cycloalkyl radicals having from 3 to 8 ring carbon atoms, thio sulfonate, sulfonamide, sulfone, sulfoxamide, phenyl, alkyl-substituted amine, and cycloalkyl substituted amine; R.sub.4 is selected from the group consisting of benzyl, phenyl, alkyl groups comprising from 1 to 4 carbon atoms, wherein said alkyl group can be substituted with oxygen, for instance ethers and alcohols; and R.sub.5 is selected from the group consisting of hydrogen, hydroxy, sulfonate, halogen, alkoxy and cycloalkoxy groups comprising 1 to 6 carbon atoms.

Composition for determining viability of tissue

A method and composition for determining the viability of tissue in a region of an organism having a vascular circulatory system that supplies blood to said region including the steps of dilating said vascular circulation system by introducing adenosine or an adenosine agonist into said vascular circulation system in order to increase the flow of blood into said region; introducing a blood flow marking medium into said region; alleviating the non-dilating effects of adenosine or said adenosine agonist by introducing an A.sub.1 adenosine receptor antagonist into said vascular circulatory system; and determining the amount of marking medium in said region. A composition is disclosed which includes the combination of adenosine or an adenosine agonist in combination with an A.sub.1 adenosine receptor which may be: ##STR1## wherein R.sub.1 is hydrogen or R.sub.2 ; R.sub.2 is selected from the group consisting of endo-2-norbornyl or cyclopentyl; R.sub.3 is selected from the group consisting of hydrogen, halogen, amine, carboxy, alkyl radicals having 1 to 10 carbon atoms, cycloalkyl radicals having from 3 to 8, preferably 5 to 6, ring carbon atoms, thio, sulfonate, sulfonamide, sulfon, sulfoxamide, phenyl, alkyl-substituted amine, and cycloalkyl substituted amine; R.sub.4 is selected from the group consisting of benzyl, phenyl, and alkyl groups comprising from 1 to 4 carbon atoms, wherein said alkyl group can be substituted with oxygen, for instance ethers and alcohols; and R.sub.5 is selected from the group consisting of hydrogen; hydroxy; sulfonate; halogen; alkoxy and cycloalkoxy groups comprising 1 to 6 carbon atoms.

Method of determining viability of tissue

Infusion of adenosine, adenoside analogs and nucleoside uptake blockers, e.g. dipyridamole, will decrease the number of apneas and associated oxyhemoglobin desaturation during sleep in patients with obstructuve sleep apnea.

Use of adenosine, adenosine analogs or nucleoside uptake blockers, e.g.

A metabolic catheter and method which allows the simultaneous removal of body fluids from organs and immediate addition of stop solution to the body fluid at the catheter tip to prevent degradation of the metabolite to be measured.

Metabolic catheter

A method to enhance the efficacy of cardioversion, defibrillation, cardiac pacing, and cardiopulmonary resuscitation and to treat post-resuscitation asystole, bradyarrhythmias, electromechanical dissociation, and hemodynamic collapse by administering to a human or animal an effective amount of an adenosine antagonist that competitively inhibits adenosine or that reduces the level of adenosine present in myocardial and vascular tissues and associated fluids.

Use of adenosine antagonists in the treatment of bradyarrhythmias and

A method of diagnosing and treating arrhythmias caused by re-entry in the A-V node by administering to a human or animal an effective amount of adenosine that restores normal sinus rhythm.

Adenosine in the treatment of supraventricular tachycardia

A method of relieving atrioventricular conduction block by administering to a human or animal an effective amount of an adenosine antagonist that competitively inhibits adenosine or that reduces the level of adenosine present in myocardial tissue and associated fluids. A method of diagnosing atrioventricular conduction block caused by ischemia of the heart by measuring the time delay between atrial and ventricular excitation before and after the administration of an adenosine antagonist. Specific antagonists disclosed include methylxanthines.

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Gainesville, FL, United States of America

Luiz Belardinelli