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

• US 5,234,404 A
• Filed: 10/11/1991
• Issued: 08/10/1993
• 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. III
• Primary Examiner(s): Pellegrino, Stephen C.
• Assistant Examiner(s): Rafa, Michael
• Application Number:
  US07/775,735
• Time in Patent Office: 669 Days
• Field of Search: 128/798, 128/802, 128/803, 128/668, 128/670-672, 128/695, 604/20, 564/165, 564/379, 560/23, 560/28
• 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 1/325 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: 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

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 cardiovascular responses similar to those cardiovascular responses elicited by aerobic activity 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.

2. A method of eliciting in a mammal adaptive cardiovascular and metabolic responses similar to the adaptive cardiovascular and metabolic responses elicited by aerobic activity comprising the administration of an exercise simulating agent with beta adrenergic activity which elicits adaptive cardiovascular and metabolic responses similar to the adaptive cardiovascular and metabolic responses elicited by aerobic activity to a mammal by means of closed loop transdermal iontophoretic infusion for 0.5 to 4.0 hours daily, for a period of from 1 to 30 days.

3. The method of claim 2 wherein said exercise simulating agent has 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.

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

5. The method of claim 3 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 exercise which comprises

(a) administering an exercise simulating agent with beta adrenergic activity which elicits immediate cardiovascular responses similar to those cardiovascular responses elicited by aerobic exercise to said mammal by a closed loop drug delivery device;

(b) controlling infusion of said exercise simulating agent into the bloodstream 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; and

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

7. A method of eliciting in a mammal immediate cardiovascular responses similar to those cardiovascular responses elicited by aerobic exercise which comprises

(a) administering an exercise simulating agent with beta adrenergic activity which elicits immediate cardiovascular responses similar to those cardiovascular responses elicited by aerobic exercise to said mammal by a closed loop drug delivery device;

(b) controlling infusion of said exercise simulating agent into the bloodstream 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; and

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

wherein said exercise simulating agent comprises a compound of the formula;

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.

8. The method of claim 7 wherein said predetermined level of response comprises reversible myocardial ischemia when coronary artery disease is present.

9. The method of claim 8 wherein said closed loop drug delivery device comprises an intravenous drug delivery device.

10. The method of claim 8 wherein said closed loop drug delivery device comprises a transdermal iontophoretic device.

11. The method of claim 8 wherein said exercise simulating agent is a compound wherein Z is hydroxy.

12. The method of claim 11 wherein said exercise simulating agent is a compound wherein X₁ is hydrogen, X₂ is hydroxy, Y₁ and Y₂ are both hydrogen and n is 3.

13. The method of claim 11 wherein said exercise simulating agent is a compound wherein X₁ is hydrogen, X₂ is methoxy, Y₁ and Y₂ are hydrogen and n is 2.

14. A method for increasing cardiac contractility in a mammal having depressed cardiac contractility which comprises administering to said mammal an effective amount of a compound of the formula:

##STR10## 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; and

n is 2 or 3;

or a pharmaceutically acceptable addition salt thereof.

15. The method according to claim 14 wherein X₁ is hydrogen, X₂ is carbamoyl, Y₁ is methyl, Y₂ is hydrogen and n is 2.

16. A method for causing adaptive effects in a mammal which are similar to adaptive responses of said mammal (caused by aerobic exercise over a period of time which comprises administering to said mammal an effective amount of a compound of the formula:

##STR11## wherein X₁ and Y₂ 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; and

n is 2 or 3;

or a pharmaceutically acceptable acid addition salt thereof.

17. The method of claim 16 wherein X₁ is hydrogen, X₂ is hydroxy, Y₁ and Y₂ are hydrogen and n is 3.

18. The method of claim 16 wherein X₁ is hydrogen, X₂ is methoxy, Y₁ and Y₂ are hydrogen and n is 2.

19. The method of claim 16 wherein X₁ is hydrogen, X₂ is carbamoyl, Y₁ is methyl, Y₂ is hydrogen and n is 2.