Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-06-07
2001-07-24
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S026000, C514S027000, C424S563000, C424S565000
Reexamination Certificate
active
06265383
ABSTRACT:
BACKGROUND OF THE INVENTION
While heart attack and stroke now cause fewer deaths than previously, deaths due to heart failure (inability of the heart to deliver adequate blood supply to vital organs via the systemic circulation) have increased markedly (82.5%) between 1979 and 1992. In 1997, heart failure is expected to cause at least 250, 000 deaths in the United States. More than 400, 000 new cases of heart failure are expected to be diagnosed in 1997. In all, it is estimated that more than 4 million Americans are presently living with this dangerous condition.
Sixty to seventy percent of these cases of heart failure are due to ischemic causes, i.e., insufficient delivery of blood flow and vital oxygen via the coronary circulation to the cardiac muscle. This can be due to mechanical obstruction of the coronary arteries, for example by atherosclerotic deposits, to spasm (temporary occlusion) of the coronary arteries, or to restenosis of coronary arteries that have been previously opened by angioplasty (balloon catheter dilation).
Certain segments of the general population are particularly prone to heart failure. Heart attack survivors have a four to six times greater risk of having an additional heart attack. Patients with angina (ischemic coronary pain), diabetes mellitus, or uncontrolled high blood pressure have a two-fold risk of developing heart failure compared to the general population.
Current treatments of heart failure include agents which dilate, and thus, relax blood vessels reducing arterial resistance against which the heart must work. Converting enzyme inhibitors such as captopril, enalpril and lisinopril are examples of such arterial vasodilators. Side effects such as rash, persistent cough, excessive lowering of blood pressure and adverse effects on kidney function limit the use of these agents in therapy. Other drugs which work by directly dilating blood vessels (arteries), such as hydralazine, prazocin and doxazocin also reduce the resistance against which the failing heart must pump, but these drugs too can cause excessive lowering of blood pressure, as well as reflex tachycardia (increased heart rate) which increases cardiac work and oxygen demand by the heart muscle already deprived of an adequate oxygen supply in the case of ischemic heart failure.
Because of their positive inotropic effect, cardiac glycosides (e.g., digitalis, ouabain) have been considered unrivaled in value for the treatment of heart failure. Positive inotropic effect generally refers to the enhancement of the contractility of the cardiac cells in a dose-dependent manner. Cardiac glycosides are most frequently used therapeutically to increase the adequacy of the circulation in patients with congestive heart failure and to slow the ventricular rate in the presence of atrial fibrillation.
However, cardiac glycosides have narrow therapeutic indices and their use is frequently accompanied by toxic effects that can be severe or lethal. The most important toxic effects, in terms of risk to the patient, are those that involve the heart (e.g., abnormalities of cardiac rhythm and disturbances of atrio-ventricular conduction). Gastrointestinal disorders, neurological effects, anorexia, blurred vision, nausea and vomiting are other common cardiac glycoside-induced reactions.
In the case of ischemic heart disease, other classes of compounds have been used to improve blood flow to the failing myocardium through dilation of the coronary arteries. Examples of these agents include nitrates, such as isosorbide dinitrate, and calcium channel blockers such as diltiazem, nifedipine and verapamil.
Nitrates and calcium channel blockers do not have direct effects on the contractile mechanism of the cardiac muscle cells. That is, they are not positive inotropic agents. Digitalis and ouabain, on the other hand, are strong inotropes, but do not have vasoactive (dilatory) effects on the coronary circulation. Hypothalamic inhibitory factor (HIF) has also been shown to produce a positive inotropic effect on cardiac muscle cells (U.S. patent application Ser. No. 08/338,264, filed Nov. 10, 1994 and now U.S. Pat. No. 5,716,937). However, HIF was not shown to have vasoactive (dilatory) effects on the coronary circulation.
A single compound which has both inotropic effects and coronary vasodilatory effects would be highly desirable as an agent to treat ischemic heart failure since both abnormalities are present and each contributes to the morbidity of the condition. To this point, such a compound has not been identified or made available pharmaceutically for the treatment of ischemic heart failure.
SUMMARY OF THE INVENTION
The present invention relates to a method for increasing coronary perfusion in a mammalian host comprising administering to the host in need thereof an effective amount of hypothalamic inhibitory factor (HIF). The invention also relates to a method for producing an increased coronary vasodilatory effect in a mammalian host comprising administering to a mammalian host in need thereof an effective amount of HIF.
In a particular embodiment, the invention pertains to a method for preventing or treating ischemic cardiac malfunction comprising administering to a mammalian host in need thereof an effective amount of HIF. The invention also relates to a method for preventing or treating coronary artery restenosis comprising administering to a mammalian host in need thereof an effective amount of HIF. Also encompassed by the present invention is a method for treating stenosis of a coronary artery in a mammalian host comprising administering to the host in need thereof an effective amount of HIF. Stenosis of a coronary artery can be due to, for example, atherosclerosis and/or coronary artery restenosis following the intervention of mechanical dilitation or certain bypass graft operations.
HIF slows heart rate in spontaneously beating cardiac myocytes, further reducing cardiac work and thereby diminishing oxygen requirement. The invention provides a single compound, HIF, which has the combined properties of producing a positive inotropic effect and enhancing coronary flow, and which can be used prophylactically and/or therapeutically to treat the identified conditions associated with heart failure.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is based on the unexpected discoveries that hypothalamic inhibitory factor (HIF) has a positive inotropic effect in a whole organ preparation, such as an isolated perfused heart, and that HIF, to a greater extent than ouabain, dilates the coronary arteries in the isolated perfused heart as manifested in increased coronary flow in hearts treated with HIF. As defined herein “coronary flow” and/ or “coronary perfusion” refers to milliliters per minute of physiologic buffer perfusing the coronary arteries. As demonstrated herein HIF causes both enhanced contractility and simultaneous increase in coronary perfiision when administered to an intact heart. The present invention relates to methods for increasing coronary perfusion in a mammalian host comprising administering to the host in need thereof an effective amount of HIF. The present invention also relates to a method of producing a positive inotropic effect and an increased vasodilatory effect in a mammalian host comprising administering to the host in need thereof an effective amount of HIF. The mammalian host can be any mammal which is in need of increased coronary perfusion, and includes, for example, human, canine, feline, bovine and murine hosts.
HIF is an endogenous inhibitor of Na.
+
-K
+
-ATPase, which has been isolated from bovine hypothalamus and human plasma, and structurally characterized as an isomer of the plant cardiac glycoside, ouabain (Tymiak, A.A., et al.,
Proc. Natl. Acad. Sci., USA
, 90:8189-8193 (1993); Zhao, N., et al.,
Biochemistry
, 34:9893-9896 (1995)). HIF for use in the present invention can be obtained by purifying HIF from natural sources or chemically synthesizing HIF. In a preferred embodiment, purified HIF is used. Purified HIF refers to HIF which is substantiall
Hamilton Brook Smith & Reynolds P.C.
Krass Frederick
The General Hospital Corporation
LandOfFree
Treatment of ischemic cardiac malfunction does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Treatment of ischemic cardiac malfunction, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Treatment of ischemic cardiac malfunction will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2499023