Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing
Reexamination Certificate
1999-11-15
2002-04-09
Leary, Louise N. (Department: 1623)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
C424S569000, C424S009200, C536S001110
Reexamination Certificate
active
06368573
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of 2-substituted adenosine carboxamide derivatives in the diagnosis of myocardial dysfunction by electrophysiologic analysis or by imaging the vasculature of the heart, especially under conditions that simulate stress.
BACKGROUND OF THE INVENTION
Adenosine has been known since the early 1920's to have potent vasodilator activity. It is a local hormone released from most tissues in the body during stress, especially hypoxic and ischemic stress (see Olsson et al., Physiological Reviews, 70(3), 761-845, 1990). As such, adenosine and adenosine-releasing agents are now commonly used to simulate the stress condition for diagnostic purposes (see The Medical Letter, 33(853), 1991).
Thallium-201 myocardial perfusion imaging is currently the most common approach in the use of stress-simulating agents as a means of imaging the coronary vessels to obtain a diagnosis of coronary artery disease. This is effected by injection of the stress agent such as adenesine at a dose of about 1 mg/kg body weight, followed by injection of the radionuclide, thallium-201, and scanning with a rotating gamma counter to image the heart and generate a scintigraph (see McNulty, Cardiovascular Nursing, 28(4), 24-29, 1992).
The mechanism underlying thallium-201 myocardial perfusion imaging is as follows: adenosine acting on coronary adenosine receptors causes relaxation of the coronary arterioles, thereby increasing blood flow throughout the heart. This effect is short-lasting and at a dose of 1 mg/kg, adenosine does not dilate other peripheral blood vessels to produce substantial systemic hypotension. Diseased or otherwise blocked coronary vessels will not further dilate in response to adenosine and the subsequent flow of thallium-201 through the heart will be less in these regions of hypoperfusion relative to other more normal areas of the heart. The resulting image allows the diagnostitian to quantitate the amount and severity of the coronary perfusion defect. This analysis is of paramount importance in selecting any further course of therapy and intervention by the physician [See U.S. Pat. No. 5,070,877 (Mohiuddin et al.) and U.S. Pat. No. 4,824,660 (Angello et al.)].
The use of adenosine and like-acting analogs is associated with certain side-effects. Adenosine acts on at least two subclasses of adenosine receptors, A
1
or A
2
, both of which are found in the heart. The A
1
receptor subtype, when activated by adenosine, among other actions, slows the frequency and conduction velocity of the electrical activity that initiates the heart beat. Sometimes adenosine, particularly at doses near 1 mg/kg, even blocks (stops) the heart beat during this diagnostic procedure—a highly undesirable action. The A
2
receptor subtype is found in blood vessels and is further divided into A
2a
and A
2b
receptor subtypes (see Martin et al., Journal of Pharmacology and Experimental Therapeutics, 265(1), 248-253, 1993). It is the A
2a
receptor that is specifically responsible for mediating coronary vasodilation—the desired action of adenosine in the diagnostic procedure. Thus, the side-effects of adenosine and adenosine releasing agents result substantially from non-selective stimulation of the various adenosine receptor subtypes. Clearly, a better procedure would be to use a substance as a stress agent that selectively activates only the A
2a
receptor, is short acting and works at doses substantially below 1 mg/kg body weight.
U.S. Pat. No. 5,477,857 to McAfee et al. discloses various diagnostic uses of hydrazinoadenosines. The compounds described in the McAfee patent are extremely effective for perfusion imaging, but suffer from a few limitations. Several of the compounds McAfee discloses as being useful are extremely labile, and prone to hydrolysis in vivo. For this reason, they have extremely short half-lives in vivo, and also must be stored in lyophilized form. Further, it is believed that one of the degradation processes for adenosine derivatives involves de-ribosylation of the derivative to form an adenine derivative, which can potentially be incorporated into genetic material of patients to whom they are administered. When using adenosine derivatives instead of adenosine, it would be advantageous to use compounds which are relatively more hydrophobic, and therefore, less likely to be absorbed by the cells, than adenosine derivatives which are commonly used.
It would be advantageous to provide perfusion imaging methods which overcome these limitations. The present invention provides such methods.
SUMMARY OF THE INVENTION
This invention is directed to the administration of 2-substituted adenosine carboxamide derivatives as a pharmacological stressor in conjunction with any one of several noninvasive diagnostic procedures available. For example, intravenous administration may be used in conjunction with thallium-201 myocardial perfusion imaging to assess the severity of myocardial ischemia.
Any one of several different radiopharmaceuticals may be substituted for thallium-201 (e.g., rubidium-82, technetium 99 m, derivatives of technetium 99 m, nitrogen-13, iodine 123, etc.). Similarly, the 2-substituted adenosine carboxamide derivatives may be administered as a pharmacological stressor in conjunction with radionuclide angiography to assess the severity of myocardial dysfunction. In this case, radionuclide angiographic studies may be first pass or gated equilibrium studies of the right and/or left ventricle. Similarly, the compounds may be administered as a pharmacological stressor in conjunction with echocardiography to assess the presence of regional wall motion abnormalities. Similarly, the 2-substituted adenosine carboxamide derivatives may be administered as a pharmacological stressor in conjunction with invasive measurements of coronary blood flow such as by intracardiac catheter to assess the functional significance of stenotic coronary vessels.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The methods described herein use specific compounds having activity as A
2
adenosine receptor agonists, namely 2-substituted adenosine carboxamide derivatives. The method involves using one or more of the compounds described herein as a substitute for exercise in conjunction with imaging to detect the presence and/or assess the severity of ischemic ventricular dysfunction in humans wherein ischemic ventricular dysfunction is measured by any one of several imaging techniques including echocardiography, contrast ventriculography, or radionuclide angiography.
It is essential that the compounds herein be capable of binding selectively to A
2
adenosine receptors, e.g., in a human. Methods for determining whether compounds bind selectively to A
2
adenosine receptors, e.g., in a human, are well known to those of skill in the art, and include, for example, competitive binding studies. Suitable competitive binding studies are disclosed in the Examples section.
The following definitions will be useful in understanding the compounds and methods described herein.
Definitions
As used herein, a compound is selective for the A
2
receptors if the ratio of A
2
/A
1
and A
2
/A
3
activity is greater than about 20, preferably between 50 and 100, and more preferably, greater than about 100.
As used herein, the term “lower” referred to above and hereinafter in connection with organic radicals or compounds respectively defines such with up to and including 7, preferably up to and including 4 and advantageously one or two carbon atoms.
As used herein, the term “alkyl” refers to monovalent straight, branched or cyclic alkyl groups preferably having from 1 to 20 carbon atoms (“alkyl”). A lower alkyl group is straight chain or branched and preferably contains 1 to 4 carbon atoms, and represents for example ethyl, propyl, butyl, and advantageously methyl.
This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, -butyl, iso-butyl, n-hexyl, and the like. The terms “alkylene” and “lower alkylene” refer to divalent radicals of the corresponding alkane. Fur
King Pharmaceuticals Research and Development, Inc.
Leary Louise N.
Roberts Abokhair & Mardula LLC
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