Use of adenosine antagonists in the treatment of bradyarrhythmias and mechanical dysfunction associated with cardiopulmonary resuscitation

• US 4,904,472 A
• Filed: 04/10/1987
• Issued: 02/27/1990
• Est. Priority Date: 04/10/1987
• Status: Expired due to Term

• Current Assignee: University of Virginia Patent Foundation (University of Virginia)
• Original Assignee: University of Virginia Patent Foundation (University of Virginia)
• Inventors: Belardinelli, Luiz, Wesley, Robert C. Jr.
• Primary Examiner(s): Killos, Paul J.
• Application Number:
  US07/037,050
• Time in Patent Office: 1,054 Days
• Field of Search: 424/263, 424/9, 424/213, 424/265
• US Class Current: 514/263.1
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine

Abstract

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.

Claims

1. A method of enhancing the efficacy of cardiopulmonary resuscitation, comprising:

applying an electrical defibrillatory shock to a human or animal in cardiac arrest to resuscitate the human or animal;

administering to said human or animal an amount of adenosine antagonist sufficient to alleviate asystole and cardiac arrhythmia associated with said resuscitation, wherein said antagonist is selected from the group consisting of methylxanthines, imidazopyrimidine, pyrazolopyridine, etazolate, pyrazoloquinoline and triazoloquinazoline and wherein said antagonist competitively inhibits adenosine or reduces the level of adenosine present in myocardial tissue and associated fluids.

2. The method of claim 1, wherein said antagonist is a methylxanthine.

3. The method of claim 2, wherein said methylxanthine is selected from the group consisting of 1,3,7-trimethylxanthine;

3,7-dimethylxanthine;

1,3-dimethylxanthine;

aminophylline; and

8-(p-sulfophenyl)theophylline.

4. The method of claim 1, wherein said antagonist is a non-xanthine derivative.

5. The method of claim 4, wherein said non-xanthine derivative is selected from the group consisting of imidazopyrimidine, pyrazolopyridine, etazolate, pyrazoloquinoline and triazoloquinazoline.

6. The method of claim 1, wherein said antagonist is administered in a dose of about 0.1-20 mg/kg.

7. The method of claim 6, wherein said antagonist is administered in a dosage of from about 0.45-10 mg/kg.

8. The method of claim 6, wherein said antagonist is administered in a dosage of about 3-5 mg/kg.

9. The method of claim 1, wherein said administration is selected from the group consisting of intravenous injection, oral ingestion, local release and insertion of a suppository.

10. The method of claim 9, wherein said administration is by intravenous injection.

11. The method of claim 10, wherein said intravenous injection is a continuous intravenous injection.

12. The method of claim 11, wherein said continuous intravenous injection is at a rate of about 0.45 mg/kg/hr.

13. The method of claim 1, wherein said administering occurs concurrently with an α

-adrenergic, β

-adrenergic or dopaminergic agent.

14. The method of claim 13, wherein said adrenergic or dopaminergic agent is administered in a ratio of about 0.01:

1.0 to 1.0;

0.01 relative to said antagonist.

15. The method of claim 1, wherein said enhancing comprises enhancing the effectiveness of cardioversion, defibrillation, and cardiac pacing within the setting of resuscitation.

16. A method for the treatment of post-resuscitation asystole, bradyarrhythmias, electro-mechanical dissociation, and hemodynamic collapse, comprising:

applying an electrical difibrillatory shock to a human or animal in cardiac arrest to resuscitate the human or animal;

administering to said human or animal an amount of adenosine antagonist sufficient to alleviate asystole, bradyarrhythmias, electromechanical dissociation and hemodynamic collapse associated with said resuscitation wherein said antagonist competitively inhibits adenosine or reduces the level of adenosine present in myocardial tissue and associated fluids.

17. The method of claim 16, wherein said antagonist is a methylxanthine.

18. The method of claim 16, wherein said methylxanthine is selected from the group consisting of 1,3,7-trimethylxanthine;

3,7-dimethylxanthine;

1,3-dimethylxanthine;

aminophylline; and

8-(p-sulfophenyl)theophylline.

19. The method of claim 16, wherein said antagonist is a non-xanthine derivative.

20. The method of claim 19, wherein said non-xanthine is selected from the group consisting of imidazopyrimidine, pyrazolopyridine, etazolate, pyrazoloquinoline and triazoloquinazoline.

21. The method of claim 16, wherein said antagonist is administered in a dose of about 0.1-20 mg/Kg.

22. The method of claim 21, wherein said antagonist is administered in a dose of from about 0.45-10 mg/Kg.

23. The method of claim 21, wherein said antagonist is administered in a dose of about 3-5 mg/Kg.

24. The method of claim 16, wherein said administration is selected from the group consisting of intravenous injection, oral ingestion, local release and insertion of a suppository.

25. The method of claim 24, wherein said administration is by intravenous injection.

26. The method of claim 25, wherein said intravenous injection is a continuous intravenous injection.

27. The method of claim 26, wherein said continuous intravenous injection is at a rate of about 0.45 mg/Kg/hr.

28. The method of claim 16, wherein said administering occurs concurrently with an α

-adrenergic, β

-adrenergic or dopaminergic agent.

29. The method of claim 28, wherein said adrenergic or dopaminergic agent is administered in a ratio of about 0.01:

1.0 to about 1.0-0.01 relative to said antagonist.