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

• US 5,286,252 A
• Filed: 12/11/1990
• Issued: 02/15/1994
• 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): Rosenbaum, C. Fred
• Assistant Examiner(s): Rafa, Michael
• Application Number:
  US07/625,362
• Time in Patent Office: 1,162 Days
• Field of Search: 604/20, 604/64-67, 128/898, 128/802, 128/803
• 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 transdermal iontophoretic device for closed loop delivery of a drug to a mammal comprising:

at least one cardiovascular sensing device being operatively connected to said mammal;

said device simultaneously being operatively connected to a device for receiving and processing a signal from said sensing device;

said receiving and processing device simultaneously being operatively connected to a power source;

said power source simultaneously being operatively connected to a transdermal iontophoretic drug delivery device; and

said drug delivery device simultaneously being operatively connected to said mammal;

wherein an air-activated tourniquet is operatively connected to said receiving and processing device.

2. A transdermal iontophoretic device for closed loop delivery of a drug to a mammal comprising:

at least one cardiovascular sensing device being operatively connected to said mammal;

said device simultaneously being operatively connected to a device for receiving and processing a signal from said sensing device;

said receiving and processing device simultaneously being operatively connected to a power source;

said power source simultaneously being operatively connected to a transdermal iontophoretic drug delivery device; and

said drug delivery device simultaneously being operatively connected to said mammal;

wherein said drug has the chemical structure;

##STR9## wherein X₁ and X₂ ar 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.

3. The drug delivery device of claim 2 wherein X₁ is hydrogen, X₂ is hydroxy, Y₁ and Y₂ are hydrogen, Z is hydroxy and n is 3.

4. The drug delivery device of claim 2 wherein X₁ is hydrogen, X₂ is methoxy, Y₁ and Y₂ are hydrogen, Z is hydroxy and n is 2.

5. A closed loop transdermal iontophoretic delivery system for controlling the delivery of a drug to a mammal comprising:

means for monitoring at least one cardiovascular variable of said mammal, and means for producing a signal from said monitoring means;

means for receiving and processing said signal; and

means for controlling delivery of a drug to said mammal through a transdermal iontophoretic delivery device in response to said signal, wherein said drug is an ionized catecholamine and wherein said drug has the chemical structure;

##STR10## wherein X₁ and X₂ ar 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.

6. The system of claim 5 wherein X₁ is hydrogen, X₂ is hydroxy, Y₁ and Y₂ are hydrogen, Z is hydroxy and n is 3.

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

8. A closed loop transdermal iontophoretic delivery system for controlling the delivery of a drug to a mammal comprising:

means for monitoring at least one cardiovascular variable of said mammal, and means for producing a signal from said monitoring means;

means for receiving and processing said signal;

means for controlling delivery of a drug to said mammal through a transdermal iontophoretic delivery device in response to said signal; and

an air activated tourniquet operatively connected to said receiving and processing means and said mammal.

9. A device for eliciting cardiovascular responses in a mammal similar to cardiovascular responses elicited by aerobic exercise which comprises:

(a) a drug delivery system for administering an exercise simulating agent into said mammals blood stream;

(b) an infusion control system for controlling infusion of said exercise simulating agent into the blood stream of said mammal which is operatively connected to said delivery system, said infusion control system including a discontinuing system for discontinuing infusion of exercise simulating agent into said mammal'"'"'s blood stream when a preselected time period has expired or when said cardiovascular responses are outside said preselected range and which is operatively connected to said drug delivery system, said control system further including a second drug delivery system for administering a β

-adrenergic blocking agent controlled by said discontinuing system which is activated simultaneously with the discontinuing system and which administers said blocking agent when said discontinuing system is activated; and

(c) a monitoring system connected to said mammal to measure response levels of said mammal to said exercise simulating agent which is operatively connected to said drug delivery system and infusion control system such that infusion of exercise simulating agent may be feedback-controlled to obtain and maintain a preselected range of responses of said mammal to said exercise simulating agent.

10. A device for eliciting cardiovascular responses in a mammal similar to cardiovascular responses elicited by aerobic exercise which comprises:

(a) a drug delivery system for administering an exercise simulating agent into said mammal'"'"'s blood stream;

(b) an infusion control system for controlling infusion of said exercise simulating agent into the blood stream of said mammal which is operatively connected to said delivery system, said infusion control system including a discontinuing system for discontinuing infusion of exercise simulating agent into said mammal'"'"'s blood stream when a preselected time period has expired or when said cardiovascular responses are outside said preselected range and which is operatively connected to said drug delivery system, said control system further including an air activated tourniquet for terminating absorption of said exercise simulating agent into said mammal'"'"'s blood stream when said discontinuing system is activated; and

(c) a monitoring system connected to said mammal to measure response levels of said mammal to said exercise simulating agent which is operatively connected to said drug delivery system and infusion control system such that infusion of exercise simulating agent may be feedback-controlled to obtain and maintain a preselected range of responses of said mammal to said exercise simulating agent.