Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-03-09
2003-02-11
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S054000
Reexamination Certificate
active
06518244
ABSTRACT:
TECHNICAL FIELD
The present application relates to combinations of a heparin cofactor II agonist and a platelet glycoprotein IIb/IIIa receptor (GPIIb/IIIa) antagonist that are useful in inhibiting both platelet aggregation and thrombin generation resulting from disease, or injury responses to wound repairs. The present application particularly relates to the use of subtherapeutic amounts of a heparin cofactor II agonist and subtherapeutic amounts of a platelet GPIIb/IIIa receptor antagonist that, in combination, are therapeutically effective in inhibiting both platelet aggregation and thrombin generation.
BACKGROUND OF THE INVENTION
Cardiovascular disease is the primary cause of death in the USA. According to the American Heart Association, 2.5 million individuals suffer from venous thrombosis and 600,000 suffer from pulmonary embolism each year. In 1996, approximately 830,000 cardiac surgeries and 700,000 cardiac catheterization procedures were performed in the USA as a result of arterial and venous thromboses. Usually, anticoagulant therapy is implemented either alone or in combination with anti-platelet and/or anti-fibrinolytic therapies, particularly in acute care settings where the immediate reopening of a blocked vessel becomes imperative. The drugs used in these therapies, however, have certain dose-limiting side effects, the foremost being hemorrhagic (i.e., prolonged bleeding) and when used in combination, these side effects can become potentiated, further limiting effective dosing and duration of the needed drug treatment. See Fareed, “Drug Interactions with Antiplatelet Agents”
IBC
3
rd
Annual Mini
-
Symposium on Advances in Antiplatelet Therapies
(Waltham, Mass. 2000).
With current anticoagulants, the bleeding effects are due to an action on one or more of the enzymes that regulate hemostasis in the global circulation, versus their action in a more specific and limited sense on enzymes of the hemostatic mechanism that promote the disease process at the vascular wall, e.g., low selectivity. Likewise, antiplatelet drugs exhibit strong interactions with the anticoagulants (such as heparin), antithrombin drugs and thrombolytic agents, and safety considerations, for example, preclude their administration to patients at high risk for intracranial hemorrhage, particularly elderly patients with poorly controlled hypertension and previous manifestations of cerebrovascular disease.
Central to this problem is control of thrombin generation and activity. This enzyme plays a key role in the formation of venous and arterial occlusions and in the causation of platelet emboli. Also key to this problem is achieving the sustained inhibition of thrombin at the diseased site which otherwise perpetuates its continued generation in an unabated fashion through a thrombin feedback mechanism that drives clot growth and platelet activation. A more targeted inhibition of thrombin at the disease site and the platelet surface using agents or drugs of higher selectivity would cause fewer side effects on the blood coagulation properties of the peripheral circulation and thus potentially allow safer and more effective dosing regimens in combination therapies.
Processes that compromise the integrity of the vascular wall result in the activation of the hemostatic mechanism affecting the blood coagulation cascade and platelet activation pathways. See Furie et al., “Molecular and Cellular Biology of Blood Coagulation,”
N. Eng. J Med
(1992) 326: 800-806. This response to wound repair results in the growth of a thrombus forming an occlusion that impedes the flow of blood and thus oxygen and needed nutrients to the vital tissues. For example, atherosclerosis is a disease process affecting the coronary arteries and major arterioles of the heart in which both inflammatory reactions (leukocytes, neutrophils, complement activation) and the accumulation of lipids (e.g., cholesterol, cholesterol esters, saturated fats, oxidized lipids and foam cells) occur. These events are toxic to the endothelial cells that line the blood vessel wall, the purpose of these cells being to form a protective non-thrombogenic surface or barrier separating blood from tissue. The exfoliation of the endothelial cells exposes blood to the subendothelial surface which has a high thrombogenic potential. This results in the activation of the blood coagulation cascade and the generation of active thrombin. This active thrombin becomes bound to the disease site and promotes the formation of the clot. Contact of blood with foreign surfaces such as those of extracorporeal circuits and vascular devices (stents, guidewires, etc.) also induces thrombin generation.
Thrombin converts soluble fibrinogen into insoluble fibrin at the vascular injury site where it is stabilized by enzymatic crosslinking reactions and platelet interactions. Thrombin is a potent platelet agonist and can interact on the platelet surface with receptors that lead to activation. See Furman et al, “The Cleaved Peptide of the Thrombin Receptor Is a Strong Platelet Agonist,”
Proc. Natl. Acad Sci.
(1998) 95(6):3082-3087; Zucker et al,
Platelet Activation Arteriosclerosis
(1985) 5(1):2-18. This leads to a thrombus rich in fibrin and platelets that may then become occlusive to the flow of blood to the heart and other organs such as the brain, resulting in serious life-threatening illnesses such as myocardial infarction and stroke.
There are many variations of vessel disease of the arterial and venous circulations. Clots of the arterial side tend to be enriched in platelets whereas those on the venous side contain fewer platelets and are enriched in fibrin. Thrombo-embolic diseases involving thrombus formation of the arterial and venous circulations include acute coronary syndromes (ACS), myocardial infarction (MI), deep vein thrombosis (DVT), pulmonary embolism (PE) and stroke to name a few. Procedures involving clamping of arteries such as carotid endarterectomy and peripheral vascular surgery also induce vascular damage, thrombin formation and platelet activation. Invasive cardiovascular procedures such as coronary artery bypass grafts (CABG), percutaneous transluminal coronary angioplasty (PTCA), cardiac catheterizations and the use of extracorporeal interventions, including cardiopulmonary bypass surgery (CPB), end-stage renal dialysis (ESRD) and extracorporeal membrane oxygenation (ECMO), potently activate the clotting system and affect platelet function.
Heparin-induced thrombocytopenia (HIT) is a special class of platelet thrombosis that occurs as an immune response to heparin, the anticoagulant drug most often employed first in the prevention and treatment of thrombo-embolic diseases. HIT leads to a precipitous drop in platelet count, an increase in platelet-induced thrombin generation and potentially to a fatal thrombosis. Standard treatment of HIT involves the discontinuation of heparin and use of an alternative anticoagulant such as a thrombin inhibitor, followed by close patient monitoring for the recovery of platelet counts. Despite the use of these alternatives, the morbidity and mortality of HIT patients remains high. Recently, a standard dose of GPIIb/IIIa antagonist, combined with a lowered dose of thrombin inhibitor to minimize hemorrhagic events, was used to treat HIT thrombosis. See Walenga et al, “Clinical Experience with Combined Treatment of Thrombin Inhibitors and GPIIb/IIIa Inhibitors in Patients with HIT,”
Semin. Thromb. Hemost.
(1999) 25 (suppl. 1):77-81. While initial thrombosis of the coronary arteries tends to be susceptible to first treatment with fibrin-dissolving agents (e.g., tissue plasminogen activator or streptokinase), a fibrinolytic-resistant re-thrombosis often occurs that is platelet-rich. This most often requires the use of fast-acting antiplatelet drugs such as GPIIb/IIIa antagonists combined with thrombin inhibitors to control the local generation of active thrombin. However, more effective combinations of improved anticoagulants in combination with the GPIIb/IIIa antagonists are needed in the treatment of HIT and other
Cardin Alan D.
Van Gorp Cornelius L.
Guttag Eric W.
Hasse Guttag & Nesbitt LLC
IntimaX Corporation
O'Sullivan Peter
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