Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-10-07
2002-08-27
Richter, Johann (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S046000, C514S056000, C514S059000, C514S062000
Reexamination Certificate
active
06440947
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compositions and methods for treatment of occlusive peripheral vascular disease and coronary diseases, in particular, the occlusion of coronary vessels. More particularly, the invention relates to the promotion of the growth of new blood vessels (angiogenesis), especially coronary blood vessels, and/or the recruitment of collateral blood vessels, after myocardial infarction.
BACKGROUND OF THE INVENTION
It is estimated that five million people are afflicted with chronic stable angina in the United States. Each year 200,000 people under the age of 65 die with what is termed “premature ischemic heart disease.” Despite medical therapy, many go on to suffer myocardial infarction and debilitating symptoms prompting the need for revascularization with either percutaneous transluminal coronary angioplasty or coronary artery bypass surgery. Medical researchers have postulated that one way of relieving myocardial ischemia would be to enhance coronary collateral circulation.
Fujita et. al. (Fujita et al.,
Am. Heart Journal
., 122:453 (1991), Fujita et al.,
Int. J. Cardiol
., 40:51 (1993)) demonstrated that heparin in combination with short term exercise training improved exercise tolerance as measured by dynamic exercise testing. The researchers, believing this effect was mediated through increased collateral vascular development, examined the effects of heparin in combination with a brief concomitant exercise training protocol on coronary collateral flow. Thallium-201 myocardial perfusion images obtained in association with the same work-load both before and late after combined heparin exercise treatment, which indicated that coronary collateral circulation was enhanced. Such dramatic changes over a short term do not occur naturally, and suggest that angiogenesis has taken place. These investigators carried out further studies which demonstrated that exercise alone or heparin alone were insufficient stimuli for collateral development (Fujita et al.,
Am. Heart Journal
, 122:453 (1991)). That is, only when exercise and heparin were combined were they able to elicit this apparent angiogenic response. Other studies have suggested that exercise-induced ischemia combined with heparin increases coronary collateral flow.
More recently Quyyumi et. al. (Quyyumi et al.,
J. Am. Coll. Cardiol
., 22:635 (1993)) studied the anti-ischemic effects of combined treatment with low molecular weight heparin and exercise-induced ischemia. Twenty three patients received either heparin or placebo in combination with an exercise protocol for 4 weeks. Eighty percent of the low molecular weight heparin (LMWH) group compared with 31% of placebo group had a significant increase in rate-pressure product at the onset of 1 mm of ST segment depression. Further, the time to ischemia increased in 100% of the LMWH group compared with 62% in the placebo group. In this same population, the incidence and duration of ST segment depression, measured using an ambulatory holter monitor, decreased by 30 and 35% respectively compared with 0% in controls.
These authors concluded that exercise and LMWH lessens myocardial ischemia and that the improvement is likely to be mediated by enhanced collateral function. Similar findings resulted from another double-blind, randomized, placebo-controlled trial, involving 29 patients with stable exercise-induced angina pectoris who received a single daily subcutaneous injection of LMWH Pamaparin (trademark for a brand of heparin)
Correlations have now been made between the anatomic appearance of coronary collateral vessels (“collaterals”) visualized at the time of intracoronary thrombolitic therapy during the acute phase of myocardial infarction and the creatine kinase time-activity curve, infarct size, and aneurysm formation. These studies demonstrate a protective role of collaterals in hearts with coronary obstructive disease, showing smaller infarcts, less aneurysm formation, and improved ventricular function compared with patients in whom collaterals were not visualized.
When the cardiac myocyte is rendered ischemic, collaterals develop actively by growth with DNA replication and mitosis of endothelial and smooth muscle cells. One hypothesis suggests that heparin-binding growth factors are present in the heart, or that biological activity is quiescent under normal physiological conditions. Once ischemia develops, these factors are activated and become available for receptor occupation, which may initiate angiogenesis after exposure to exogenous heparin. Unfortunately, the “natural” process by which angiogenesis occurs is inadequate to reverse the ischemia in almost all patients with coronary artery disease.
The etiology of the benefit of combined heparin-exercise treatment is unknown with certainty (Norrby and Sorbo,
Int. J. Exp. Pathol
. 73: 147 (1992), Sasayama and Fujita,
Circulation
, 85: 1197 (1992)). One possibility is that ischemia stimulates the release or expression of some angiogenic substance which in combination with heparin stimulates collateral development. However, a definitive link between an angiogenic substance and heparin to promote angiogenesis has not been established.
During ischemia, adenosine is released through the breakdown of ATP. Adenosine participates in many cardio-protective biological events. Adenosine has a role in hemodynamic changes such as bradycardia and vasodilation, and adenosine has been suggested to have a role in such unrelated phenomena as preconditioning and possibly the reduction in reperfusion injury (Ely and Beme,
Circulation
, 85: 893 (1992)).
Intrinsic adenosine may facilitate the coronary flow response to increased myocardial oxygen demands and so modulate the coronary flow reserve. Ethier et. al. (Ethier et al.,
Am. J. Physiol
., H131 (1993)) demonstrated that the addition of physiological concentrations of adenosine to human umbilical vein endothelial cell cultures stimulates proliferation, possibly via a surface receptor. They suggested that adenosine may be a factor for human endothelial cell growth and possibly angiogenesis. Angiogenesis appears to be protective for patients with CAD, but the rate at which blood vessels grow naturally is inadequate to reverse the disease. Thus, strategies to enhance and accelerate the body's natural angiogenesis potential should be beneficial in patients with CAD.
Combinations of thrombolytic agents such as streptokinase, urokinase and tissue plasminogen activator with adenosine have been proposed for use in providing coronary thrombolysis (see, for example, U.S. Pat. No. 5,534,504 to Sollevi). Sollevi does not teach that these agents, in combination with adenosine, provided any angiogenic benefit. Sollevi further teaches that administration of heparin is unsafe, and instead teaches administering adenosine in lieu of heparin.
There remains a need for an effective therapy for promotion of coronary angiogenesis with minimum side effects. Such a therapy would be particularly useful for patients who have myocardial infarctions and could be used prophylactically in patients who have poor coronary circulation which places them at high risk of ischemia and myocardial infarctions.
SUMMARY OF THE INVENTION
Compositions and methods for treatment of occlusive peripheral vascular disease and coronary diseases, in particular, the occlusion of coronary vessels, and disorders associated with the occlusion of the peripheral vasculature and/or coronary blood vessels, are disclosed. Also disclosed are compositions and methods for promoting angiogenesis and/or recruiting collateral blood vessels in a patient in need thereof. The compositions include an effective amount of heparin or a heparin-like substance and an effective amount of an adenosine A
2
receptor agonist. The compositions can be in the form of a sterile, injectable, pharmaceutical formulation that includes an angiogenically effective amount of heparin or a heparin-like substance and an adenosine A
2
receptor agonist in a physiologically and pharmaceutically acceptable carrier, optionally w
Barron Hal V.
Botvinick Elias
Owens Howard
Richter Johann
The Regents of the University of California
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