Diagnosis, evaluation and treatment of coronary artery disease by exercise simulation using closed loop drug delivery of an exercise simulating agent beta agonist

• US 5,108,363 A
• Filed: 02/09/1989
• Issued: 04/28/1992
• Est. Priority Date: 02/19/1988
• Status: Expired due to Fees

• Current Assignee: Gensia Pharmaceuticals, Inc. (Teva Pharmaceutical Industries Limited)
• Original Assignee: Gensia Pharmaceuticals, Inc. (Teva Pharmaceutical Industries Limited)
• Inventors: Tuttle, Ronald R., Browne, Clinton E.
• Primary Examiner(s): Pellegrino, Stephen C.
• Assistant Examiner(s): Rafa, Michael
• Application Number:
  US07/308,683
• Time in Patent Office: 1,174 Days
• Field of Search: 564/165, 564/374, 560/23, 560/28, 604/20, 128/668, 128/670-672, 128/695
• US Class Current: 604/20
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61N 1/044 Shape of the electrode
• CPC Class Codes: A61N 1/0448 Drug reservoir
• CPC Class Codes: A61N 1/30 Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
• CPC Class Codes: A61N 1/325 for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body electrodes for external use A61N1/0428
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 215/60 the chain having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
• CPC Class Codes: C07C 217/62 linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
• CPC Class Codes: C07C 237/30 having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 45/305 with halogenochromate reagents, e.g. pyridinium chlorochromate
• CPC Class Codes: C07C 47/277 containing ether groups, groups, groups, or groups
• CPC Class Codes: Y10S 128/13 Infusion monitoring

Abstract

Methods and devices for the diagnosis, evaluation and treatment of coronary artery disease (CAD) by means of a closed-loop drug delivery system that delivers an exercise simulating agent, including novel exercise simulating agents which elicit both acute and adaptive cardiovascular responses similar to those elicited by aerobic activity are provided. The acute responses to the exercise simulating agent are used to diagnose and evaluate CAD in lieu of the acute responses to aerobic exercise. Due to their adaptive responses these compounds may be used to treat CAD in lieu of the adaptive responses caused by aerobic exercise training or to treat other conditions where the adaptive responses caused by aerobic exercise are desirable.

Claims

1. A method of eliciting in a mammal immediate physical responses similar to those physical responses elicited by aerobic activity comprising the steps of:

administering an exercise simulating agent by a closed loop drug delivery device;

controlling the rate of infusion of said exercise simulating agent into the bloodstream of said mammal by a power source operatively connected to said delivery device, said device carrying said exercise simulating agent and being operatively connected to said mammal, wherein said power source is regulated by a microprocessor operatively connected to both said power source and an electrocardiographic heart rate monitoring device operatively connected to said mammal;

said exercise simulating agent being introduced in sufficient amount to induce reversible myocardial ischemia when coronary artery disease is present; and

said exercise simulating agent having the chemical formula;

##STR9## wherein X₁ and X₂ are independently hydrogen, hydroxy, methoxy or carbamoyl, provided that X₁ and X₂ are not both hydrogen or carbamoyl;

one of Y₁ and Y₂ is hydrogen and the other is hydrogen or methyl, provided that if Y₁ is methyl, then X₁ is not carbamoyl;

Z is hydrogen or hydroxy; and

n is 2 or 3;

or a pharmaceutically acceptable acid addition salt thereof.

2. The method of claim 1 wherein said drug delivery device comprises a transdermal iontophoretic device.

3. The method of claim 1 wherein said drug delivery device comprises an intravenous drug delivery device.

4. The method of claim 1 wherein X₁ is hydrogen, X₂ is hydroxy, Y₁ and Y₂ are hydrogen, Z is hydroxy and n is 3.

5. The method of claim 1 wherein X₁ is hydrogen, X₂ is methoxy, Y₁ and Y₂ are hydrogen, Z is hydroxy and n is 2.

6. A method of eliciting in a mammal immediate cardiovascular responses similar to those cardiovascular responses elicited by aerobic activity for diagnostic purposes, comprising the administration of an exercise simulating agent with beta adrenergic activity which elicits immediate cardiovascular responses similar to those cardiovascular responses elicited by aerobic activity by closed loop drug delivery device wherein said exercise simulating agent is administered for diagnostic purposes by transdermal iontophoretic infusion and comprises a catecholamine which induces reversible myocardial ischemia when coronary artery disease is present.

7. The method of claim 6 wherein said catecholamine has the formula:

##STR10## wherein X₁ and X₂ are independently hydrogen, hydroxyl, methoxy, or carbamoyl, provided that X₁ and X₂ are not both hydrogen or carbamoyl;

one of Y₁ and Y₂ is hydrogen and the other is hydrogen or methyl, provided that if Y₁ is methyl, then X₁ is not carbamoyl;

Z is hydrogen or hydroxy; and

n is 2 or 3 or a pharmaceutically acceptable acid addition salt thereof.

8. The method of claim 7 wherein X₁ is hydrogen, X₂ is hydroxy, Y₁ and Y₂ are hydrogen, Z is hydroxyl and n is 3.

9. The method of claim 8 (wherein X₁ is hydrogen, X₂ is methoxy, Y₁ and Y₂ are hydrogen, Z is hydroxy and n is 2.

10. The method of claim 6 wherein the rate of administration of said exercise simulating agent is controlled by a power source operatively connected to a transdermal iontophoretic device, said device containing said exercise simulating agent in gel-solution or polymer and operatively connected to said mammal, and said power source being regulated by a microprocessor operatively connected both to said power source and an electrocardiographic heart rate monitoring device operatively connected to said mammal.

11. The method of claim 10 wherein the flow of electrical current from said power source is discontinued when a predetermined heart rate of said mammal is achieved.

12. The method of claim 10 wherein the flow of electrical current from said power source is discontinued when myocardial ischemia is achieved.

13. The method of claim 10 wherein said flow of electrical current from said power source discontinues when non-sinus or premature beats of a preprogrammed origin and frequency are electrocardiographically detected.

14. The method of claim 10 wherein the directional flow of electrical current from said power source is reversed upon the occurrence of an event pre-programmed in said microprocessor.

15. The method of claim 14 wherein said pre-programmed event is a predetermined maximal heart rate for said mammal.

16. The method of claim 11 wherein said microprocessor terminates the flow of said electrical current through said electrode of said transdermal delivery device and activates an air-activated tourniquet located proximally to said electrode.

17. A method of simulating the cardiovascular responses of a mammal to an exercise stress test wherein the heart of said mammal is exercised or stressed at a selected level without body motion which comprises:

(a) administering to said mammal an exercise simulating agent having beta adrenergic activity by a closed loop drug delivery device wherein said exercise simulating agent induces reversible myocardial ischemia in said mammal and is administered in an amount effective to obtain a preselected range of physical responses in said mammal;

(b) controlling infusion of said exercise simulating agent into said mammal'"'"'s bloodstream so as to maintain said preselected range of responses for a preselected time period; and

(c) discontinuing infusion of said exercise simulating agent when said preselected time period has expired, or when said physical responses are outside said preselected range.

18. The method of claim 17 wherein said exercise simulating agent comprises a compound of the formula:

##STR11## wherein X₁ and X₂ are independently hydrogen, hydroxy, methoxy or carbamoyl, provided that X₁ and X₂ are not both hydrogen or carbamoyl;

one of Y₁ and Y₂ is hydrogen and the other is hydrogen or methyl, provided that if Y₁ is methyl, then X₁ is not carbamoyl;

Z is hydrogen or hydroxy; and

n is 2 or 3;

or a pharmaceutically acceptable acid addition salt thereof.

19. The method of claim 18 wherein said exercise simulating agent is a compound wherein Z is hydroxy.

20. The method of claim 19 wherein said exercise simulating agent is a compound wherein X₁, Y₁ and Y₂ are hydrogen.

21. The method of claim 20 wherein X₂ is hydroxy and n is 3.

22. The method of claim 20 wherein X₂ is methoxy and n is 2.

23. The method of claim 18 wherein said closed loop drug delivery device comprises a transdermal iontophoretic device.

24. The method of claim 18 wherein said closed loop drug delivery device comprises an intravenous drug delivery device.

25. The method according to claim 23 wherein infusion of said exercise simulating agent is controlled by a power source operatively connected to said mammal wherein said power source is regulated by a microprocessor operatively connected to both said power source and to an electrocardiographic heart rate monitoring device operatively connected to said mammal, whereby infusion of said exercise simulating agent is feedback controlled by said microprocessor in response to changes in heart rate.

26. The method according to claim 17 wherein infusion of said exercise simulating agent is controlled by a power source operatively connected to said mammal wherein said power source is regulated by a microprocessor operatively connected to both said power source and to an electrocardiographic heart rate monitoring device operatively connected to said mammal, whereby infusion of said exercise simulating agent is feedback controlled by said microprocessor in response to changes in heart rate.

27. The method according to claim 26 further comprising (d) upon discontinuing infusion of said exercise simulating agent, simultaneously administering an antagonizing agent which comprises a beta adrenergic blocking agent in an amount effective to counteract the physical responses to said exercise simulating agent.

28. A method of diagnosing and evaluating coronary artery disease in a mammal by eliciting in said mammal immediate cardiovascular responses similar to those cardiovascular responses elicited by aerobic activity which comprises:

(a) administering an exercise simulating agent to said mammal by closed loop drug delivery device;

(b) controlling infusion of said exercise simulating agent into the blood stream of said mammal so that a predetermined range of cardiovascular responses of said mammal is obtained;

(c) monitoring the range of responses of said mammal;

(d) changing infusion of said exercise simulating agent as required to maintain said range of responses in said mammal; and

(e) evaluating said responses.

29. A method according to claim 28 wherein said exercise simulating agent comprises a compound of the formula:

##STR12## wherein X₁ and X₂ are independently hydrogen, hydroxy, methoxy or carbamoyl, provided that X₁ and X₂ are not both hydrogen or carbamoyl;

one of Y₁ and Y₂ is hydrogen and the other is hydrogen or methyl, provided that if Y₁ is methyl, then X₁ is not carbamoyl;

Z is hydrogen or hydroxy; and

n is 2 or 3;

or a pharmaceutically acceptable acid addition salt thereof.

30. A method according to claim 29 wherein Z is --OH.

31. A method according to claim 30 wherein X₁ is hydrogen, X₂ is hydroxy, Y₁ and Y₂ are hydrogen and n is 3.

32. A method according to claim 30 wherein X₁ is hydrogen, X₂ is methoxy, Y₁ and Y₂ are hydrogen and n is 2.

33. A method according to claim 28 wherein said drug delivery device comprises a transdermal iontophoretic drug delivery device.

34. A method of diagnosing and evaluating coronary artery disease by simulating the cardiovascular responses of a mammal to an exercise stress test wherein the heart of said mammal is exercised or stressed at a selected level without body motion which comprises:

(a) administering to said mammal an exercise simulating agent by a closed loop drug delivery device wherein said exercise simulating agent induces reversible myocardial ischemia if coronary artery disease is present in said mammal and is administered in an amount effective to obtain a preselected range of physical responses in said mammal;

(b) controlling infusion of said exercise simulating agent into said mammal'"'"'s bloodstream so as to maintain said preselected range of responses for a preselected time period;

(c) discontinuing infusion of said exercise simulating agent when said preselected time period has expired or when said physical responses are outside said preselected range; and

(d) evaluating said physical responses.

35. A method according to claim 34 further comprising:

(e) upon discontinuing infusion of the exercise simulating agent, simultaneously administering an antagonizing agent having beta adrenergic blocking activity in an amount effective to counteract the physical responses elicited by the exercise simulating agent.

36. A method according to claim 35 wherein said drug delivery device comprises a transdermal iontophoretic drug delivery device.

37. A method according to claim 34 wherein said drug delivery device comprises a transdermal iontophoretic drug delivery device.

38. A method according to claim 34 wherein said exercise simulating agent comprises a compound of the formula:

##STR13## wherein X₁ and X₂ are independently hydrogen, hydroxy, methoxy or carbamoyl, provided that X₁ and X₂ are not both hydrogen or carbamoyl;

one of Y₁ and Y₂ is hydrogen and the other is hydrogen or methyl, provided that if Y₁ is methyl, then X₁ is not carbamoyl;

Z is hydrogen or hydroxy; and

n is 2 or 3;

or a pharmaceutically acceptable acid addition salt thereof.

39. A method according to claim 38 wherein Z is --OH.

40. A method according to claim 39 wherein X₁ is hydrogen, X₂ is hydroxy, Y₁ and Y₂ are hydrogen and n is 3.

41. A method according to claim 39 wherein X₁ is hydrogen, X₂ is methoxy, Y₁ and Y₂ are hydrogen and n is 2.

42. A method according to claim 38 wherein said drug delivery device comprises a transdermal iontophoretic drug delivery device.

43. A method according to claim 38 wherein said physical responses are monitored using echocardiography.

44. A method according to claim 38 wherein said physical responses are monitored using radionucleotide imaging.