Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-04-24
2001-12-11
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S054000, C514S353000, C514S355000, C514S356000, C514S921000
Reexamination Certificate
active
06329349
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for administering compounds to protect the heart from ischemic injury. More specifically, the invention provides a novel combination of agents which act synergistically to potentiate their individual cardioprotective effects and thereby render the myocardium more resistant to ischemia.
BACKGROUND OF THE INVENTION
Several publications are referenced in this application by numerals in parentheses in order to more fully describe the state of the art to which this invention pertains. Full citations for these references are found at the end of the specification. The disclosure of each of these publications is incorporated by reference herein.
Ischemic preconditioning functions as an endogenous protective mechanism which enhances the ability of myocardium to withstand injury from prologed ischemia. Transient ischemic events, which are sufficiently brief to avoid irreversibly damaging myocardium, initiate unidentified biochemical events which limit infarct size and the occurrence of reperfusion arrhythmias following prolonged myocardial ischemias (5).
A series of studies have shown that it is possible to induce ischemic preconditioning with a variety of pharmacological agents. Adenosine is released in large amounts during myocardial ischemia and mediates potentially important protective functions in the cardiovascular system (1,4,5,7,9,14,17,18,19,25). Adenosine can precondition the heart with reduction in the size of myocardial infarction (4,5,9,14,17,18). Intracoronary administration of adenosine during reperfusion following prolonged no-flow ischemia can also limit infarct size in the intact heart (1, 19).
Previous studies have shown that adenosine A
1
and A
3
receptor agonists can precondition the heart when administered before the onset of ischemia (4, 5, 9, 14, 17, 18). Other studies have shown that adenosine A
2a
receptor antagonists also enhance the cardioprotective effect of preconditioning (23). These agents effectively 1) reduce infarct size; and 2) improve left ventricular function when given during reperfusion (1, 19) or during both low-flow ischemia and reperfusion in isolated perfused heart (6, 21, 22).
Monophosphoryl lipid A (MLA), a relatively non-toxic derivative of endotoxin, has also been found to provide cardioprotection in a variety of animal models (43-45) when administered prior to an ischemic event. The mechanism of myocardial protection mediated by MLA has not yet been definitively elucidated. Other effective pharmacological preconditioning agents include K
+
ATP channel openers and phorbol esters.
Intensive research efforts are currently focused on the development of agents and methods for treating and preventing cardiac diseases. The present invention is directed to such methods.
SUMMARY OF THE INVENTION
Methods are disclosed which may be used to advantage for preventing ischemic damage of the heart.
The methods of the invention entail the combined administration of a first cardioprotective agent and a second cardioprotective agent. The agents act synergistically to potentiate their individual cardioprotective effects. Agents suitable for use as a first cardioprotective agent are adenosine receptor agents, MLA or analogs or derivatives of MLA.
According to a preferred embodiment, the invention entails the administration of monophosphoryl lipid A (MLA), or a synthetic analog, or derivative thereof to a patient prior to a surgical treatment. Following MLA treatment, a second cardioprotective agent is administered that potentiates the cardioprotective effect of MLA. The second cardioprotective agent is delivered to the patient either before, during or after surgery. Alternatively, the second cardioprotective agent may be administered continuously throughout all of these periods. The protocols described above may be used for the treatment of patients at risk for ischemic damage from myocardial infarction, angina, or surgical complications.
Compounds suitable as second cardioprotective agents are adenosine, agonists at the A
1
and A
3
adenosine receptors, antagonists at the A
2a
adenosine receptor, and K
ATP
channel openers.
In an alternative embodiment, an adenosine receptor agonist is administered as the first cardioprotective agent and MLA or synthetic analogs thereof is administered as the second cardioprotective agent.
Methods of administration of the cardioprotective agents of the invention include direct perfusion of the organ during surgery and intravenous administration. Additionally, these agents may be administered to patients in solid form, e.g., tablets, in amounts effective to prevent or reduce ischemic damage to the heart.
REFERENCES:
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patent: 5286718 (1994-02-01), Elliott
patent: 5354764 (1994-10-01), Grover et al.
Kristyne Stambaugh, et al., “A novel cardioprotective function of adenosine A1and A3receptors during prolonged simulated ischemia”, Rapid Communication, H501-H505.
Jennifer Strickler, et al., Direct Preconditioning of Cultured Check Ventricular Myocytes—Novel Functions of Cardiac Adenosine A2aand A3Receptors, J. Clin. Invest., vol. 98, No. 8, Oct. 1996, 1773-1779.
Bruce T. Liang, “Direct preconditioning of cardiac ventricular myocytes via adenosine A1receptor and KATPcahnnel”, American Physiological Society, 1996, H1769-H1777.
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Kenneth A. Jacobson, et al., “8-(3-Chlorostyryl)caffeine (CSC) is a selective A2-adenosine Antagonist in vitro and in vivo”, FEBS Letters, May 1993, vol. 232, No. 1,2, pp. 141-144.
Kenneth A. Jacobson, “Structure-Activity Relationships of 8-Styrylzanthines as A2-Selective Adenosine Antagonists”, J. Med. Chem., 1993, vol. 36, pp. 1333-1342.
Kenneth A. Jacobson, et al., “A3-adenosine receptors: design of selective ligands and therapeutic prospects”, Drugs of the Future 1995, 20(7): 689-699.
Jacobson Kenneth A.
Liang Bruce T.
Dann Dorfman Herrell and Skillman
Trustees of the University of Pennsylvania
Weddington Kevin E.
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