Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-05-18
2004-03-16
Weber, Jon P. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600
Reexamination Certificate
active
06706689
ABSTRACT:
BACKGROUND OF THE INVENTION
Heart disease is a major health problem throughout the world. Myocardial infarctions are a significant source of mortality among those individuals with heart disease.
Acute coronary syndrome (“ACS”) denotes patients who have or are at high risk of developing an acute myocardial infarction (MI). This complex includes unstable angina (UA), non-Q-wave cardiac necrosis (NQCN) and Q-wave MI (QMI). Thompson et al.,
M.J.A.
171; 153 (1999). Typically, ACS is diagnosed when a patient has acute (i.e., sudden onset) chest pain of a cardiac origin that is either new or clearly different from pre-existing, chronic, stable angina; that is, ACS chest pain is more severe, more frequent, occurs at rest, or is longer than 15 minutes in duration. After ACS has been diagnosed, the patient is stratified into UA, NQCN, and QMI, using criteria that are described elsewhere in this application. UA, NQCN, and QMI are believed to represent different stages of plaque rupture and thrombosis. Zaacks et al.,
J. Am. College Cardiol.
33; 107 (1999). With UA, there typically is no myocardial necrosis. Id. UA, NQCN, and QMI all are characterized by varying degrees of ischemia. Id. Additionally, Q-wave MI generally is understood to result from total occlusion of a coronary artery, whereas UA is caused by a subtotal occlusion. Thompson et al.
M.J.A.
171; 153 (1999).
During normal, aerobic metabolism, cardiac tissue uses free fatty acids (FFA) to generate energy. During ischemia induced by UA, NQCN, or Q-wave MI, the heart switches to anaerobic metabolism, using glucose as its primary energy source.
Many other detrimental metabolic changes occur during ischemia in cardiac tissue, including accumulation of excess unoxidized FFA products, inhibition of Ca
2+
and Na
+
/K
+
pumps, and increased levels of cAMP. Additionally, there is decreased secretion of insulin by pancreatic &bgr;-cells and excess secretion of glucagon by pancreatic &agr;-cells.
Excess glucagon can lead to myocardial tissue damage; glucagon is also an insulin antagonist and mediates lipolysis in adipose tissue, with release of FFAs. Excess FFAs can lead to free radical formation and consequent tissue damage. Glucagon is one of the so-called counter-regulatory hormones, a group that includes cortisol, growth hormone, and catechlolamines, which are released during “stress” conditions, such as ACS, UA, NQCN, fasting, starvation, infection, disease, internal injury, and trauma. The role of such hormones is to counter-regulate the effects of insulin, thereby raising blood glucose and fatty acid levels and producing a generally insulin-antagonistic state. Glucose is a mediator of stress responses and a component of systemic inflammatory reactions.
A variety of therapeutic agents is known for treating Q-wave MI. These include thrombolytic therapy and angiotensin-converting enzyme (ACE) inhibitors. Thompson et al.,
M.J.A.
171; 153 (1999). PCT Application WO 98/08531 relates to treatment with GLP-1 of a patient suffering from Q-wave MI who is also incapable of auto-regulation of blood glucose.
Agents known for treatment of a subtotal coronary occlusion, which results in UA, include heparin, low-molecular-weight heparin, and nitroglycerine. Thompson et al.,
M.J.A.
171; 153 (1999). &bgr;-blockers can be used to combat myocardial ischemia and left ventricular dysfunction that result from acute MI and UA. Id. Prior to the formation of a fibrin thrombus, which leads to partial or total coronary artery occlusion, it is known that that there is plaque erosion or fissure, followed by platelet aggregation. This aggregation can be treated with aspirin, glycoprotein IIb/IIIa antagonists or clopidogrel. Thompson et al.,
M.J.A.
171; 153 (1999).
Most therapies for the treatment of UA work by (1) stabilizing or reducing the occlusion, such as the anti-thrombin agents heparin and low-molecular-weight heparin, and the anti-platelet agents aspirin, glycoprotein IIb/IIIa antagonists, or clopidogrel, (2) reducing preload, such as nitroglycerine, (3) reducing afterload, such as ACE inhibitors, or (4) reducing myocardial oxygen demand, such as &bgr;-blockers. These therapies do not treat directly the disturbed energy metabolism that results from ischemia and that induces tissue damage. Also, dosages of drugs such as heparin must be controlled carefully to avoid toxic effects of overdose.
As a result, there is a need for therapeutic treatments that can be used preferably beginning at the earliest stages of ACS, and during UA or NQCN, and that will prevent and/or reduce the damage resulting from ACS, including any subsequent Q-wave MI.
SUMMARY OF THE INVENTION
Objects of the present invention include the following:
(1) A method of treating a patient suffering from acute coronary syndrome, comprising administering to the patient a therapeutically effective amount of a GLP-1 molecule, wherein the patient is not suffering from a Q-wave MI. The above method, wherein the patient is suffering from unstable angina. The above method, wherein the patient is suffering from non-Q-wave cardiac necrosis. The above method, wherein the patient has a blood troponin I level of no more than 0.4 ng/ml. The above method, wherein the patient has a blood troponin T level of no more than 0.1 ng/ml. The above method, wherein the patient does not have elevated blood creatine kinase. The above method, wherein the patient does not have ST-segment elevation. The above method, wherein the patient does not exhibit a pathological Q-wave. The above method, wherein the patient exhibits one or more of the following symptoms: chest pain greater than 15 minutes in duration, chest pain at rest, or chest pain following minimal exertion that is poorly responsive to sublingual nitrates. The above method, wherein the patient has stable angina. The above method, wherein the patient administers the GLP-1 to himself. The above method, wherein the GLP-1 is administered in the form of a GLP-1-stick. The above method, wherein the GLP-1 is administered in a single dose. The above method, wherein the GLP-1 is administered in more than one dose. The above method, wherein the GLP-1 is administered continuously. The above method, wherein glucose, or a potassium salt, or a combination thereof, is co-administered with the GLP-1.
(2) A method for treatment of a patient, comprising administering to the individual a therapeutically effective amount of a GLP-1 molecule, wherein the administration is after the onset of one or more of the following symptoms: chest pain lasting longer than 15 minutes, chest pain at rest, chest pain following minimal exertion, nausea, shortness of breath, palpitations, or dizziness. The above method, wherein the patient has not suffered a Q-wave MI prior to the onset of the symptom or symptoms. The above method, wherein the patient is suffering from unstable angina. The above method, wherein the patient is suffering from non-Q-wave cardiac necrosis. The above method, wherein the patient has a blood troponin I level of no more than 0.4 ng/ml. The above method, wherein the patient has a blood troponin T level of no more than 0.1 ng/ml. The above method, wherein the patient does not have elevated blood creatine kinase myocardial isoenzyme. The above method, wherein the patient does not have ST-segment elevation. The above method, wherein the patient does not exhibit a pathological Q-wave. The above method, wherein the administration occurs between the time of onset of the one or more symptoms, and the time the patient suffers a Q-wave MI. The above method, further comprising the step of continuing the administration of a GLP-1 molecule during the time that the patient suffers a Q-wave MI. The above method, further comprising the step of continuing the administration of a GLP-1 molecule after the time the patient suffers a Q-wave MI. The above method, wherein the patient has ischemic heart disease, or is at risk for developing ischemic heart disease. The above method, wherein the patient has one or more of the following cardiac abnormalities: congestive he
Coolidge Thomas R.
Ehlers Mario
Amylin Pharmaceuticals Inc.
Arnold & Porter
Holman Molly A.
Kim Mi K.
Weber Jon P.
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