Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-12-08
2002-04-16
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S046000
Reexamination Certificate
active
06372723
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to adenosine pharmacology and improved surgical procedures. More particularly, the invention relates to reducing or preventing restenosis following a revascularization procedure by selective activation of adenosine A
2A
receptors.
2. Related Art
Occlusion of blood vessels can be treated with revascularization procedures that attempt to either remove the occlusion or to reroute blood flow through a bypass graft. A variety of surgical approaches have been used, including percutaneous transluminal coronary angioplasty (PTCA), directional coronary atherectomy (DCA) and excimer laser angioplasty. In order to provide improved blood flow in the heart, for example, the insertion of coronary artery bypass grafts has become common practice. PTCA is an alternative procedure that is also conducted in patients whose coronary blood flow is severely impaired by the presence of atherosclerotic plaques within the coronary blood vessels. In this procedure, a balloon catheter is inserted into coronary blood vessels and inflated at the site of the stenosis in an attempt to disrupt the atherosclerotic plaque and/or distend the disease-free area of the vessel to restore coronary blood flow. This procedure is conducted in approximately 300,000 patients a year in the United States. Although the procedure is highly successful at relieving the stenosis and restoring coronary blood flow, the utility of the procedure is hampered by abrupt closure of the vessels in about 5% of patients (no re-flow phenomenon), and by restenosis in 30% to 40% of patients within three to six months of the procedure (Barry, W. L. and Sarembock, I. J.,
Anticoag Antiplatelet Ther
. 12:517-535 (1994)). Restenosis can be described as an exaggerated form of vascular repair following arterial injury. New devices and a variety of pharmacological strategies have not been successful at eliminating this problem.
Numerous studies have been conducted in an attempt to elucidate the mechanism of restenosis following angioplasty. A large body of evidence is available that suggests that a neutrophil/platelet interaction is involved. The angioplasty procedure produces brief periods of myocardial ischemia. Current evidence suggests that activation of neutrophils during ischemia results in injury by: (a) the release of oxygen free radicals, proteolytic enzymes, and leukotoxin, (b) aggregation and adherence of neutrophils to endothelial cells and subsequent capillary plugging and impairment of coronary blood flow, and (c) vasoconstriction that may result from leukotriene B
4
release by activated neutrophils. Platelets are activated by the release of oxygen free radicals, leukotrienes and platelet activating factor from activated neutrophils. Deposition of platelets and thrombus formation have been shown to contribute to restenosis following angioplasty. The activated platelets release vasoconstrictor substances including thromboxane, serotonin and adenine nucleotides. In addition, platelets release platelet-derived growth factor which causes proliferation of vascular smooth muscle cells.
A primary stimulus for restenosis appears to be the activation of neutrophils in response to ischemia during the angioplasty procedure. Numerous clinical studies have shown an increased expression of surface adhesion molecules on neutrophils in blood taken from the coronary sinus following angioplasty (Mickelson, J. K., et al.,
JACC
28:345-353 (1996); Ikeda, H., et al.,
Am. Heart J
. 128:1091-1098 (1994); Neumann et al.,
Circulation
92:748-755 (1995); Neumann et al.,
J. Am. Coll. Cardiol
. 27:819-824 (1996); Siminiak, T., et al.,
Br. Heart J
. 74:625-630 (1995); and Baj, Z., et al.,
Atherosclerosis
106:159-168 (1994)). In addition, neutrophils taken from the coronary sinus following angioplasty show an increased release of toxic oxygen products and elastase when tested ex vivo (Ikeda, H., et al.,
Am. Heart J
. 128:1091-1098 (1994)) and plasma from the coronary sinus causes an activation of normal neutrophils ex vivo (Neumann, F-J., et al.,
Br. Heart J
. 70:27-34 (1993)).
Adenosine is an endogenous signal molecule that is released into the circulation during periods of ischemia. Adenosine exerts its physiological actions by activation of four subtypes of adenosine receptors designated A
1
, A
2A
, A
2B
and A
3
. Adenosine A
2A
receptors are located on blood vessels where they mediate vasodilation (Ueeda, M., et al.,
J. Med. Chem
. 34:1334-1339 (1991); Ueeda, M., et al.,
J. Med. Chem
. 34:1340-1344 (1991); Niiya, K., et al.,
J. Med. Chem
. 35:4557-4561 (1992), Niiya, K., et al.,
J. Med. Chem
. 35:4562-4566 (1992); and Glover, D. K., et al.,
Circulation
94:1726-1732 (1996)), on platelets where they mediate an inhibition of aggregation (Cristalli, G., et al.,
Arch. Pharmacol
. 349:644-650 (1994); and Varani, K., et al.,
Biochem. Pharmacol
. 48:1658-1661 (1994)) and on neutrophils where they mediate inhibition of adherence to endothelial cells and release of toxic oxygen products (Cronstein, B. N., et al.,
J. Clin. Invest
. 85:1150-1157(1990), Cronstein, B. N., et al.,
J. Immunol
. 148:2201-2206 (1992); and Sullivan, G. W., et al.,
Int. J. Immunopharmac
. 17:793-803 (1995)). A compound that selectively activates only the A
2A
adenosine receptors is expected to have anti-inflammatory actions in ischemic tissue by virtue of these three properties. Activation of A
1
receptors on neutrophils promotes chemotaxis and thereby increases migration of neutrophils to the site of injury. In addition, activation of A
1
receptors increases adherence of neutrophils to the endothelium. Adenosine's actions at the A
1
receptor are therefore pro-inflammatory (Cronstein, B. N., et al.,
J. Clin. Invest
. 85:1150-1157 (1990), and Cronstein, B. N., et al.,
J. Immunol
. 148:2201-2206 (1992)). Stimulation of A
2A
-receptors and avoidance of A
1
-receptor activation are the basis of this invention.
In vitro studies using human neutrophils have shown that A
2A
selective agonists inhibit the release of oxygen free radicals and proteolytic enzymes from activated neutrophils and inhibit adherence of activated neutrophils to the endothelium (Cronstein, B. N., et al.,
J. Immunol
. 148:2201-2206 (1992), Cronstein, B. N., et al.,
J. Clin. Invest
. 85:1150-1157 (1990); and Sullivan, G. W., et al.,
Int. J. Immunopharmac
. 17:793-803 (1995)). An A
2A
selective agonist has also been shown to inhibit both the adhesion of activated canine neutrophils to canine cardiac myocytes and to reduce oxidative injury (Bullough, D. A., et al.,
J. Immunol
. 155:2579-2586 (1995)). Studies in pigs have shown that there is an increase in platelet deposition and neutrophil adhesion at the site of arterial injury produced by balloon inflation during angioplasty (Merhi, Y., et al.,
Circulation
90:997-1002 (1994); and Provost, P. and Merhi, Y.,
J. Pharmacol. Exp. Ther
. 277:17-21 (1996)).
Sollevi, in U.S. Pat. No. 5,449,655, discloses a method for percutaneous transluminal angioplasty comprising the concomitant continuous administration of adenosine to provide the beneficial properties of vasodilation, inhibition of platelet aggregation, and inhibition of presynaptic neural mechanisms regulating release of catecholamines.
Sollevi, in U.S. Pat. No. 5,534,504, discloses a method for coronary thrombolysis comprising the concomitant administration of adenosine with the thrombolytic agent to provide the above properties.
Bru-Magniez, et al., in U.S. Pat. No. 5,459,132, discloses certain N
6
-substituted adenosine derivatives that are claimed as analgesics, anti-hypertensives and anti-proliferative agents used to treat cancer, psoriasis, atherosclerosis and restenosis phenomena.
Impaired blood flow to organs in mammals commonly results from occlusion of blood vessels as a result of atherosclerosis. Insufficient blood flow causes tissue ischemia and can result in morbidity such as myocardial infarction, stroke, or renal failure. Treatment options include invasive surgical procedures, such as angioplas
Martin Pauline L.
McAfee Donald A.
Discovery Therapeutics Inc.
Sterne Kessler Goldstein & Fox PLLC
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