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Claims for Patent: 5,108,363

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Claims for Patent: 5,108,363

Title: Diagnosis, evaluation and treatment of coronary artery disease by exercise simulation using closed loop drug delivery of an exercise simulating agent beta agonist
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.
Inventor(s): Tuttle; Ronald R. (Escondido, CA), Browne; Clinton E. (Oceanside, CA)
Assignee: Gensia Pharmaceuticals, Inc. (San Diego, CA)
Application Number:07/308,683
Patent 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 X.sub.1 and X.sub.2 are independently hydrogen, hydroxy, methoxy or carbamoyl, provided that X.sub.1 and X.sub.2 are not both hydrogen or carbamoyl; one of Y.sub.1 and Y.sub.2 is hydrogen and the other is hydrogen or methyl, provided that if Y.sub.1 is methyl, then X.sub.1 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 X.sub.1 is hydrogen, X.sub.2 is hydroxy, Y.sub.1 and Y.sub.2 are hydrogen, Z is hydroxy and n is 3.

5. The method of claim 1 wherein X.sub.1 is hydrogen, X.sub.2 is methoxy, Y.sub.1 and Y.sub.2 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 X.sub.1 and X.sub.2 are independently hydrogen, hydroxyl, methoxy, or carbamoyl, provided that X.sub.1 and X.sub.2 are not both hydrogen or carbamoyl; one of Y.sub.1 and Y.sub.2 is hydrogen and the other is hydrogen or methyl, provided that if Y.sub.1 is methyl, then X.sub.1 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 X.sub.1 is hydrogen, X.sub.2 is hydroxy, Y.sub.1 and Y.sub.2 are hydrogen, Z is hydroxyl and n is 3.

9. The method of claim 8 (wherein X.sub.1 is hydrogen, X.sub.2 is methoxy, Y.sub.1 and Y.sub.2 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 X.sub.1 and X.sub.2 are independently hydrogen, hydroxy, methoxy or carbamoyl, provided that X.sub.1 and X.sub.2 are not both hydrogen or carbamoyl; one of Y.sub.1 and Y.sub.2 is hydrogen and the other is hydrogen or methyl, provided that if Y.sub.1 is methyl, then X.sub.1 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 X.sub.1, Y.sub.1 and Y.sub.2 are hydrogen.

21. The method of claim 20 wherein X.sub.2 is hydroxy and n is 3.

22. The method of claim 20 wherein X.sub.2 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 X.sub.1 and X.sub.2 are independently hydrogen, hydroxy, methoxy or carbamoyl, provided that X.sub.1 and X.sub.2 are not both hydrogen or carbamoyl; one of Y.sub.1 and Y.sub.2 is hydrogen and the other is hydrogen or methyl, provided that if Y.sub.1 is methyl, then X.sub.1 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 X.sub.1 is hydrogen, X.sub.2 is hydroxy, Y.sub.1 and Y.sub.2 are hydrogen and n is 3.

32. A method according to claim 30 wherein X.sub.1 is hydrogen, X.sub.2 is methoxy, Y.sub.1 and Y.sub.2 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 X.sub.1 and X.sub.2 are independently hydrogen, hydroxy, methoxy or carbamoyl, provided that X.sub.1 and X.sub.2 are not both hydrogen or carbamoyl; one of Y.sub.1 and Y.sub.2 is hydrogen and the other is hydrogen or methyl, provided that if Y.sub.1 is methyl, then X.sub.1 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 X.sub.1 is hydrogen, X.sub.2 is hydroxy, Y.sub.1 and Y.sub.2 are hydrogen and n is 3.

41. A method according to claim 39 wherein X.sub.1 is hydrogen, X.sub.2 is methoxy, Y.sub.1 and Y.sub.2 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.
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