Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-09-21
2003-07-01
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S422000, C424S423000, C424S468000, C424S456000
Reexamination Certificate
active
06585995
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to methods and products for treatment and/or prevention of platelet related thrombotic and other vaso-occlusive disorders.
BACKGROUND OF THE INVENTION
Conditions resulting from thrombotic or thromboembolic events are the leading causes of illness and death in adults in western civilization. A great deal of effort and monetary resources have been directed towards understanding the mechanisms involved in vascular occlusive diseases involving thrombotic and thromboembolic events. These efforts have yielded a number of promising therapeutic agents. Notwithstanding the effort and financial resources that have been invested, these conditions still account for the vast majority of illness and death in the adult populations of developed nations.
Platelets are an important cellular component of blood involved in hemostasis as well as thrombotic or thromboembolic events. Abnormally high platelet counts such as those that result from hematological proliferative disorders such as for example essential thrombocythemia have been recognized as an important risk factor in thrombus formation. Furthermore, it has long been accepted that aspirin, which is known to inhibit cyclooxygenase and thereby prevents production of thromboxane A
2
in platelets, lowers the incidence of thrombotic or thromboembolic events. For platelets, therapeutic regimens thus far reported have as their aim an inhibition of platelet function (e.g., inhibition of platelet adhesion, aggregation or factor release). An alternative modality is the reduction in platelet count in patients with abnormally high levels in certain hematological malignancies to levels approximating normal levels. Therapeutic intervention for reducing platelet count to low normal or below normal levels in subjects without myeloproliferative disorders has not been proposed primarily since normal platelet count has been thought to be critical to normal hemostasis.
SUMMARY OF THE INVENTION
The invention in a broad aspect involves the surprising discovery that subjects, including those with normal levels of circulating platelets, can unexpectedly derive medical benefit from a reduction in platelet count to below normal levels, without serious adverse consequences as a result of the platelet count reduction. The benefit may be proportional or correlative to the reduction in platelet count in a broad safety range. Thus in situations where it is desirable to inhibit a pathological condition or process mediated in part by normal levels of circulating platelets, subjects can be treated to lower platelet count preferably to a below normal level, thereby inhibiting the development, progression or propagation of the condition or accelerating or enhancing its regression. The methods of the invention are also useful for reducing the incidence of abnormal vessel growth induced by the presence of platelets.
A method is provided for treating a subject to reduce the risk of developing an adverse condition or to inhibit the progression and consequences of an adverse condition mediated at least in part by platelets. In some aspects, the subject is treated to reduce platelet count to low normal levels, while in other aspects the subject is treated to reduce platelet count to below normal levels. In one embodiment, the subject is treated with a pharmaceutical agent.
In one aspect, the invention provides a method for treating a subject to inhibit a vaso-occlusive event. Inhibiting a vaso-occlusive event means to prevent the formation of a vaso-occlusive event, to reduce progression and consequences of an already established vaso-occlusive event or to induce regression of a vaso-occlusive event. The invention also provides other methods aimed at reducing morbidity or mortality of subjects from vasoocclusive events such as but not limited to thrombotic events which may lead to total or partial vessel blockage by thrombus, or arterial stenosis due to excessive cell proliferation.
The methods of the invention comprise administering to a subject in need of such treatment an agent that reduces platelet count in the subject. The agent is administered in an amount effective to reduce platelet count in the subject to at least a low normal level. Such reductions in platelet count will reduce morbidity and/or mortality and thereby provide patient outcome benefit.
As used herein, a vaso-occlusive event includes a pathological partial occlusion (including a narrowing) or complete occlusion of a blood vessel, a stent or a vascular graft. A vaso-occlusive event intends to embrace thrombotic or thromboembolic events, and the vascular occlusion disorders or conditions to which they give rise. Thus, a vaso-occlusive event is intended to embrace all vascular occlusive disorders resulting in partial or total vessel occlusion from thrombotic or thromboembolic events, except those that are related to high platelet count due to a hematological proliferative disorder. A thrombotic event as used herein is meant to embrace both a local thrombotic event and a distal thrombotic event (e.g., a thromboembolic event such as for example an embolic stroke). A vaso-occlusive event also includes abnormal blood vessel growth induced by the presence of platelets and the factors they secrete. An example of this latter form of vaso-occlusive event is intimal hyperplasia which results in a narrowing of the blood vessels (i.e., reduction in the diameter of blood vessels either locally or throughout an extended segment of the vessel) due to a hyperproliferation of cells of the intimal layer of the blood vessel wall.
Preferably, the subject is otherwise free of symptoms calling for treatment with the agent. In some embodiments, the subject is preferably free of symptoms associated with a hematological proliferative disorder such as for example myeloproliferative disease. Preferably, the subject is a human subject, but is not so limited. In another embodiment, the subject is apparently healthy. In preferred embodiments, the subjects do not have abnormally elevated platelet levels (i.e., a platelet count that is higher than the normal range) that are caused by a hematological proliferative disorder. Thus preferably, the subjects do not have a hematological proliferative disorder. In an important embodiment, the subject has a normal platelet count prior to treatment. In some embodiments, the subject has a higher platelet count than the mean normal level but is still considered within the normal range. As an example, a subject with a platelet count of 450×10
3
platelets per &mgr;l is considered to be at the high end of the normal range and is intended to be treated by the methods of the invention. In some embodiments, the subject may have a platelet count above the usual range, but without any underlying hematological proliferative disorder. In another embodiment, the subject is not a post-menopausal female.
In some aspects, the invention intends to treat subjects who are at risk of a vaso-occlusive event. These subjects may or may not have had a previous vaso-occlusive event. The invention embraces the treatment of subjects prior to a vaso-occlusive event, at a time of a vaso-occlusive event and following a vaso-occlusive event. Thus, as used herein, the “treatment” of a subject is intended to embrace both prophylactic and therapeutic treatment, and can be used both to limit or to eliminate altogether the symptoms or the occurrence of a vaso-occlusive event. In one embodiment, the subject may exhibit symptoms of a vaso-occlusive event.
The invention also intends to embrace the treatment of a subject that has an abnormally elevated risk of a vaso-occlusive event such as a thrombotic event. The subject may have vascular disease. The vascular disease may be selected from the group consisting of arteriosclerosis, cardiovascular disease, cerebrovascular disease, renovascular disease, mesenteric vascular disease, pulmonary vascular disease, ocular vascular disease or peripheral vascular disease.
In another embodiment, the subject has had a primary vaso-occlusive event suc
Bennett Rachel M.
Page Thurman K.
Wolf Greenfield & Sacks P.C.
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