Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-09-30
1998-03-31
Jordan, Kimberly
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514263, 514266, 514267, 514352, A61K 3152, A61K 31505, A61K 3144
Patent
active
057339163
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US95/03702, filed Mar. 24, 1995 published as WO95/26728 Oct. 12, 1995.
FIELD OF INVENTION
Ischemia followed by reperfusion in an organ produces structural and functional abnormalities in the tissue of that organ and others. Neutrophil infiltration, hemorrhage, edema and necrosis are all observed in tissues following an ischemia-reperfusion injury. A.sub.1 and A.sub.2 adenosine receptors play an important role in the mechanisms behind this injury. P.sub.2X receptor activation also contributes to an increase in pulmonary vascular tone and pulmonary edema formation following ischemia-reperfusion injury. In the present invention a method is provided which prevents and treats ischemia-reperfusion related organ injury. It has now been found that administration of compositions comprising selective A.sub.1 adenosine receptor antagonists and/or P.sub.2X receptor antagonists can prevent injuries related to ischemia followed by reperfusion in an organ. Compositions of the present invention can be administered prior to, during or following harvesting a donor organ which will be transplanted, prior to or during a surgical procedure in which ischemia is expected, prior to angioplasty or thrombolytic therapy, or after transplantation or reperfusion of an ischemic organ following surgery, angioplasty or thrombolytic therapy. These compositions can also be used to prevent or treat ischemia-reperfusion injury in high risk patients.
BACKGROUND OF INVENTION
Nucleotides and nucleosides and their purinoceptors have been found to be important mediators in determining pulmonary vascular (PV) tone. Nucleotides are autacoids; that is, they are released locally, metabolized locally by stereoselective nucleotidases, and act on their own local receptors to bring about changes in vascular tone, and neutrophil and platelet function. The effects of nucleotides and nucleosides on PV tone were first described in 1929 by Drury and Szent-Gyorgi when they demonstrated that the nucleoside adenosine produced a fall in arterial pressure and a rise in pulmonary artery pressure in dogs and cats. Drury A. N., Szent-Gyorgi A, J. Physiol (Lond) 68:213-237, 1929. Since this discovery, much research has been performed to characterize the role of adenosine and its specific purinoceptors.
Based on pharmacological analysis in isolated systemic vessels, Burnstock originated the purinergic receptor hypothesis. Burnstock G, Handbook of Physiology-The Cardiovascular System II, 2nd Edition, Volume 2, Chapter 19, pp 567-612, 1979. Adenosine-sensitive receptors, referred to as P.sub.1 receptors, were characterized as having an agonist potency in the order of adenosine>AMP>ADP>ATP. These receptors were found to act via an adenylate cyclase system and were antagonized by methylxanthines. Since the original classification was made, P.sub.1 receptors have been subdivided into A.sub.1 and A.sub.2 receptors based upon their effect on adenylate cyclase, receptor affinity and radioligand binding.
A.sub.1 receptors inhibit adenylate cyclase activity. High affinity A.sub.1 receptors have been identified in brain, heart, lung, kidney, skin, pancreas, stomach, spinal cord, intestines, vas deferens, liver, spleen, testis, adrenergic nerve terminals, white blood cells and fat cells. These receptors preferentially bind the purine moiety of adenosine and the order of potency of adenosine analogues is R-phenylisopropyladenosine (R-PIA)>cyclohexyladenosine (CHA)>5'-N-ethylcarboxamidoadenosine (NECA)=2-chloroadenosine (2-CA)>S-phenylisopropyladenosine (S-PIA).
A.sub.2 receptors, on the other hand, stimulate adenylate cyclase activity. Low affinity A.sub.2 receptors have been identified in brain, heart, lung, liver, kidney, thymus, spleen, epididymis, vas deferens, adipose tissue, vascular smooth muscle cells, platelets, fibroblasts, lymphocytes, neutrophils and pheochromocytoma cells. They preferentially bind the ribose moiety of adenosine and follow a potency order NECA>2-CA>R-PIA=CHA>S-PIA. A.sub.2 receptors have
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Jordan Kimberly
The Trustees of the University of Pennsylvania
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