Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1997-06-04
2001-10-23
Saound, Christine J. (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C530S399000
Reexamination Certificate
active
06306826
ABSTRACT:
BACKGROUND OF THE INVENTION
Heart failure occurs in three to four million individuals annually in the United States, and is a highly important cause of cardiac morbidity and mortality. In about 60% of the patients, the heart failure is secondary to late stage coronary disease, and in most of the remainder it is due to primary myocardial disease in the form of idiopathic dilated cardiomyopathy. Treatment for severe heart failure has improved with the addition of angiotensin converting enzyme (ACE) inhibitors to standard therapy, but despite such treatment the outlook remains poor in symptomatic patients (mortality about 10% per year), and limiting cardiac symptoms often persist. Cardiac transplantation is a definitive therapy for severe heart failure in some individuals, but there is a need for new adjunctive medical therapies to improve functional status and provide a more favorable prognosis. Previous findings in animal models, and a recent study in patients with heart failure, showing favorable effects of growth hormone (GH) suggest that GH treatment may offer such an adjunctive measure. Bunting et al., WO95/28173 disclosed treatment of congestive heart failure by administration of GH. Clark et al., U.S. Pat. No. 5,610,134 disclosed treatment of congestive heart failure by administration of GH and insulin-like growth factor 1 (“IGF1”), with or without an angiotensin II converting enzyme (ACE) inhibitor. However, our studies in animals with heart failure have shown that an ACE inhibitor in high dose may diminish the beneficial effects of GH, including its action to promote a physiologic form of hypertrophy.
SUMMARY OF THE INVENTION
We have now invented a new method for treating heart failure which follows myocardial infarction by administering an angiotensin II (AT
1
) receptor blocker for 8-12 weeks, followed thereafter by administration of a growth hormone for 1-3 weeks.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The term “cardiac ischaemia” as used herein refers to the interruption of oxygen supply to the cardiac muscle (which may be acute or chronic). Cardiac ischaemia caused by obstruction can lead to myocardial infarction. A large myocardial infarction, in turn, can lead to heart failure, a condition in which the function of the left ventricle is impaired and inadequate to meet the body's needs at rest or during stress. Heart failure can be due to other functions as well, or of unknown etiology (idiopathic).
The term “angiotensin II inhibitor” refers to a compound capable of inhibiting or reducing the activity or effect of angiotensin II (the active form of angiotensin). Angiotensin II inhibitors include compounds which bind, inhibit, or compete for AT
1
receptors (described by Fujisawa et al., U.S. Pat. No. 5,595,882, incorporated herein by reference). An exemplary, presently preferred AT
1
inhibitor is losartan. Other AT
1
inhibitors may be identified by determining their binding affinity to the AT
1
receptor as set forth in U.S. Pat. No. 5,595,882.
The term “ventricular remodeling” refers to the alteration in chamber size, wall thickness, and other dimensional changes which occur in response to myocardial damage.
The term “growth hormone” in general refers to a protein or polypeptide, whether natural, recombinant, or chemical in origin, which is capable of stimulating the growth or proliferation of normal cells under appropriate conditions. “GH” and “hGH” refer to human growth hormone and its variations, including Protropin® (Genentech Inc.), Nutropin® (Genentech, Inc.), placental GH (U.S. Pat. No. 4,670,393), and the variants described in WO90/04788 and WO92/09690, all incorporated herein by reference. GH may also be modified, for example by conjugation with polyoxyethylene (“PEG”) to form “PEGylated GH” as described in '134. Another growth factor which is endogenous and mediates some of the effects of growth hormone is insulin-like growth factor-1 (IGF-1). IGF-1 has been administered as an alternative for growth hormone in treating rats with heart failure, as described by R. Duerr et al.,
J Clin Invest
(1995) 95:619-27. IGF-1 may be used in conjunction with or in lieu of GH in the practice of the invention.
The terms “treating” and “treatment” as used herein refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, and improvement or remediation of damage.
The term “subject” as used herein refers to a mammal, particularly a mammal having heart failure, preferably a human.
We have now developed a method for maximizing the effect of GH treatment for heart failure following myocardial infarction. Angiotensin II effects were inhibited for 2½ months after myocardial infarction using a specific blocker of the angiotensin type 1 (AT
1
) receptor which is known to inhibit post-infarction hypertrophy and unfavorable remodeling of the left ventricle (LV), reduce myocardial fibrosis, and improve the cardiac output in this experimental model of heart failure. Such effects occurred in the present study and effects of remodeling after 2½ months of AT
1
treatment alone were detected at 2 weeks after the AT
1
blocker was discontinued compared to untreated animals. In another group of rats, following AT
1
receptor blockade with losartan for 2½ months after myocardial infarction, GH was then given alone for 2 weeks. In this setting, GH significantly improved myocardial contractility and LV performance, increased LV muscle mass and wall thickness, enhanced LV diastolic function, and increased the cardiac output and cardiac index (collectively “favorable remodeling”). “Favorable remodeling” is an improvement in any of the above-mentioned functions or parameters of at least 20% over post-infarction levels, preferably at least 25% or greater. Thus, following acute myocardial infarction an initial sustained inhibition of the unfavorable effects of angiotensin II on remodeling is followed by GH, in a sequential manner, and constitutes a new treatment for heart failure. This sequential treatment may be repeated cyclicly if desired.
Suitable angiotensin II inhibitors will reduce or eliminate unfavorable remodeling effects. Presently preferred angiotensin II inhibitors are AT
1
receptor blockers, for example losartan. Suitable growth hormones will improve cardiac function, improving one or more of myocardial contractility, LV performance, LV muscle mass, LV wall thickness, LV diastolic function, cardiac output and cardiac index. The presently preferred growth hormone is human growth hormone (hGH). Suitable therapeutics may also be examined using an animal model, for example as described in the Examples below. Animal models are well-developed, and fairly predictive of success in humans.
Following diagnosis of ischemic damage, an angiotensin II inhibitor is prescribed at a dosage determined in view of the patient's condition, weight, severity of symptoms, and the like. Angiotensin II inhibitors include ACE inhibitors, such as captopril or enalapril, and AT
1
receptor blockers such as losartan (others, such as valrantan and irbesartan are in clinical efficacy trials), prescribed at a dosage determined by the patient's condition. The typical starting dose ranges from about 2.5 mg/day to about 20 mg/day for ACE inhibitors such as enalapril, and about 12.5 mg/day to about 50 mg/day for AT
1
inhibitors such as losartan. Treatment with the angiotensin II inhibitor is continued until substantial beneficial remodeling of the heart occurs, or until the period for unfavorable remodeling has passed. Treatment is preferably continued until remodeling is complete (about 10 to about 12 weeks), or may be continued indefinitely, particularly if heart failure is present. The patient's recovery progress may be monitored using standard techniques, for example echocardiography. At this point, administration of the angiotensin II inhibitor can be discontinued (as it may also inhibit the effect of the growth hormone), or relatively low d
Chien Kenneth R.
Ross, Jr. John
Bozicevic, Field & Francis
Hall Kathleen S.
Saound Christine J.
The Regents of the University of California
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