Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-01-04
2001-11-13
Carlson, Karen Cochrane (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S326000, C530S300000
Reexamination Certificate
active
06316411
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to compounds protective against ischemia and reperfusion injury, particularly in the myocardium, and their use.
BACKGROUND
Tissues deprived of blood and oxygen undergo ischemic necrosis or infarction with possible irreversible organ damage. In some circumstances, however, such as during cardiac surgery, it is desirable to interrupt the normal myocardial contractions (cardioplegia) and actually induce ischemia. Such elective or obligatory ischemia occurs in the presence of safeguards such as cardioplegia-induced cardiac arrest and hypothermia. While these safeguards provide considerable myocardial protection, alteration of myocardial energetics (stunning) and poor postoperative ventricular function still remain significant problems.
Once the flow of blood and oxygen is restored to the organ or tissue (reperfusion), the organ does not immediately return to the normal preischemic state. Reperfused postischemic non-necrotic myocardium is poorly contractile and has reduced concentrations of high energy nucleotides, depressed subcellular organelle function and membrane damage that resolves only slowly. Although reperfusion restores oxygen and reverses ischemia, repletion of high energy nucleotides such as adenosine triphosphate (ATP) and reversal of ischemic membrane damage is slow, and contractile function may be profoundly depressed for a long period. Just minutes of ischemia causes loss of myocardial systolic wall thickening for hours. Longer periods of reversible ischemia may depress contractility for days. Studies confirm that, despite restoration of myocardial flow and a quick recovery of myocardial oxygen consumption (MVO
2
) following ischemia, there is only very slow recovery of myocardial contractile function. The problems are exacerbated in high risk patients, such as those with poor preoperative ventricular function, recent myocardial infarction or left ventricular hypertrophy. These same problems also occur during organ storage for cardiac transplant, under which there are time constraints due to the limits of myocardial preservation.
Postischemic dysfunction may be due to a variety of factors. Oxygen free radicals may play a role, as generation of free radicals in stunned myocardium has been demonstrated and free radical scavengers have been shown to attenuate contractile dysfunction. Impaired intracellular calcium handling and calcium overload during early reperfusion may contribute to postischemic dysfunction; while calcium infusions enhance contractility in both normal and postischemic myocardium, ischemia as short as a few minutes produces an impairment in sarcoplasmic reticulum calcium transport and a shift of the calcium ATPase activity. Postischemic myocardium is also associated with reduced concentrations of myocardial high-energy phosphates and adenine nucleotides, as obligatory reduction in myocardial ATP content during ischemia occurs as myocytes utilize ATP for maintenance of cellular integrity. Since ATP is essential for myocardial contraction and relaxation, ATP depletion may have detrimental effects upon postischemic myocardial functional recovery.
The high volume of cardiac-related surgeries, both elective and emergency procedures and including cardiac transplants, lead to the above-described problems. Thus, methods and agents to provide protection against myocardial ischemia and to avoid post ischemic dysfunction are needed.
SUMMARY OF THE INVENTION
The invention is directed to an agent and a method of using the agent to reduce the injury associated with ischemia and reperfusion of organs such as the heart. The compound is Tyr-D-Leu-Phe-Ala-Asp-Val-Ala-Ser-Thr-Ile-Gly-Asp-Phe-Phe-His-Ser-Ile-NH
2
SEQ ID NO:1, hereinafter compound-D. Administration of compound-D SEQ ID NO:1, particularly prior to an ischemic event, reduces tissue necrosis and preserves organ function.
In one embodiment, a method of protecting against ischemia and reperfusion injury in a mammal is disclosed. An effective concentration of compound-D SEQ ID NO:1 is administered to the mammal in a pharmaceutically acceptable formulation prior to the onset of ischemia, for example, 24 hours prior to ischemia. In other embodiments, compound-D SEQ ID NO:1 is administered substantially concurrent with the onset of ischemia, during an ischemic episode, or post-ischemia. The formulation may be administered parenterally at a concentration in the range of about 1-20 mg/kg of body weight.
The invention is also directed to a method to prevent damage to an isolated organ, for example, a heart for transplant. The isolated organ is exposed to a preservative solution containing an effective amount of compound-D SEQ ID NO:1. The concentration of compound-D SEQ ID NO:1 in the preservative solution for a heart is about 100 &mgr;M.
The invention is additionally directed to a method for reducing effects of an ischemic episode in a mammal by administering an effective concentration of compound-D SEQ ID NO:1 in a pharmaceutically acceptable carrier. Administration is prior to or substantially concurrently with the onset of ischemia, or one hour post cerebral ischemia.
The invention is further directed to a composition that protects a mammalian organ from injury. The composition contains compound-D SEQ ID NO:1. Compound-D may be naturally occurring or may be synthesized.
The invention is also directed to an organ preservative solution that contains compound-D at a concentration effective to protect the organ, such as a heart, from ischemic injury.
These and other advantages of the invention will be apparent in light of the following drawings and detailed description.
REFERENCES:
Bolling et al., The use of hibernation induction triggers for cardiac transplant preservation, Transplantation 63: 326-329, 1997.
Bolling et al., Delta opioid agonist/antagonist activity and ischemic tolerance, American Heart Association Meeting, Atlanta, GA, Nov., 1999.
Bolling et al., Use of “natural” hibernation induction triggers for myocardial protection, Annals Thorac. Surg.: 623-627, 1997.
Chien et al., Two-day preservation of major organs with autoperfusion multiorgan preparation and hibernation induction trigger, J. Thorac. Cardiovasc. Surg., 102: 224-234, 1991.
Chien et al., Extension of tissue survival time in multiorgan block preparation with a delta opioid DADLE (D-Ala2, D-Leu5)-enkephalin), J. Thorac. Cardiovasc. Surg., 107: 965-967, 1994.
Stanley M. Crain and Ke-Fei Shen, Antagonists of excitatory opiod receptor functions enhance morphine's analgesic potency and attenuate opioid tolerance/dependence liability, Pain 82 (1999), 1-11.
Fryer et al., Opioid-induced cardioprotection against myocardial infarction and arrhythmias: Mitochondrial versus sarcolemmal ATP-sensitive potassium channels, JPET 294: 451-457, 2000.
Kevelaitis et al., Opening of potassium channels: The common cardioiprotective link between perconditioning and natural hibernation?, Circulation 99: 3079-3085, 1999.
Lishmanov et al., Activation of the &mgr;-opioid receptors as a factor increasing heart resistance against ischemic and reperfusion damages, Russian J. Physiol. 1998; 84 (11) (Russian w/ attached English translation).
L.N. Maslov and Yu. B. Lishmanov, Effects of &mgr;- and delta opioid receptor ligands on rhythm and contractility disorders of isolated rate heart in postischemic period, Kardiologya 1998; 12: 25-30 (Russian w/ English translation).
Oeltgen et al., The use of delta-2 opioid agonists for myocardial ischemia protection, Abstract, Experimental Biology 2000, submitted Nov., 1999.
P.R. Oeltgen et al., Extended lung preservation with the use of hibernation trigger factors, Ann. Thorac. Surg. 61: 1488-93, 1996.
Schultz et al., Evidence for involvement of opiod receptors in ischemic preconditioning in rat hearts, Am. J. Physiol. 268 (Heart Circ. Physiol. 3): H2157-H2161, 1995.
M.D. Schwartz et al., Delta opioid receptors and low temperature myocardial protection, Ann. Thorac. Surg. 68: 2089-92, 1999,
C.F. Toombs et al., Limitation of infarct size in the rabbit by ischaemic precondition
Bishop Paul D.
Kindy Mark S.
Oeltgen Peter R.
Sanchez Juan A.
Carlson Karen Cochrane
University of Kentucky Research Foundation
Wood, Herron & Evans, L
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