Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-04-30
2002-08-06
Low, Christopher S. F. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S003100, C514S012200, C530S303000, C530S308000, C530S324000, C530S350000, C424S185100
Reexamination Certificate
active
06429197
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to an/effective treatment to improve the function of the ischemic and reperfused brain.
BACKGROUND OF THE INVENTION
Strokes, or cerebrovascular accidents, are the result of an acute obstruction of cerebral blood flow to a region of the brain. There are approximately 500,000 cases each year in the United States, of which 30% are fatal, and hence stroke is the third leading cause of death in the United States. Approximately 80% of strokes are “ischemic” and result from an acute occlusion of a cerebral artery (usually a clot or thrombus), with resultant reduction in blood flow. The remainder are “hemorrhagic”, which are due to rupture of a cerebral artery with hemorrhage into brain tissue and consequent obstruction of blood flow due to local tissue compression, creating ischemia.
Stroke commonly affects individuals older than 65 years, and the most powerful risk factor is hypertension. However, there are additional strong risk factors, of which the most important is diabetes mellitus, which confers a two to three-fold increased risk and is associated with increased mortality and morbidity after stroke. Moreover, there is strong evidence that hyperglycemia per se, whether associated with diabetes or not, correlates with increased stroke-related mortality and morbidity, although the causal relationship and underlying mechanisms remain controversial.
Until recently, there was no approved therapy for acute stroke, which was treated by general medical support only, followed by rehabilitation from the observed damage. In 1996, the FDA approved the use of tissue plasminogen activator (tPA) as therapy for acute ischemic stroke, based on a limited number of controlled trials. Some, but not all, of the trials revealed a 30-55% improvement in clinical outcome, with an overall reduction in mortality and morbidity. This overall benefit was achieved despite a markedly enhanced risk of intracranial hemorrhage (6.4% in tPA-treated vs. 0.64% in placebo-treated groups), half of which were fatal. Because of concerns about safety and variable efficacy, thrombolytic therapy with tPA has not been universally adopted by clinicians treating acute ischemic stroke. At present, thrombolytic therapy is effectively restricted to major centers with specialized expertise in the management of acute stroke, and it is limited to patients who on CT scanning do not have evidence of major infarction, are less than 70 years old, and are free of major medical conditions including diabetes. As a result, only approximately 1.5% of patients who might be candidates for tPA therapy actually receive it. This situation is likely to improve as clinical experience with its use accumulates and the subset of patients most likely to benefit is more clearly defined. Moreover, there is increasing evidence that spontaneous reperfusion after ischemic stroke improves outcome, which supports the logic of implementing reperfusion therapy.
From these considerations it is evident that there is an enormous unmet need for new, effective therapies for acute stroke. This has stimulated intense research in identifying strategies that can provide neuroprotection during the period of ischemia (whether due to ischemic or hemorrhagic strokes), and therapies that block reperfusion injury following revascularization in ischemic strokes. The goal is to salvage neurons in the so-called ischemic penumbra that surrounds the infarcted core. Candidate agents fall into three major groups: excitotoxicity inhibitors; leukocyte adhesion inhibitors; and neurotrophic factors. In the first group, most efforts are aimed at blocking the action of the excitotoxic neurotransmitter glutamate, mostly by blocking. the NMDA class of glutamate receptor. Other strategies include blocking Na
+
and Ca
2+
channels and scavenging nitrous oxide.
The second strategy, blocking leukocyte adhesion, is based on the premise that neutrophils and monocytes contribute significantly to reperfusion injury and infarct zone by administering inhibitors of relevant adhesion molecules and inflammatory cytokines (Jean et al., 1998. Reperfusion injury after focal cerebral ischemia: the role of inflammation and the therapeutic horizon. Neurosurgery 43, 1382-96.)
The third strategy involves the administration of neurotrophic factors that can protect neurons by providing general trophic support during both the ischemic and reperfusion periods. Included in this group of agents are basic fibroblast growth factor and insulin. Numerous studies have shown that insulin can exert potent neuroprotective effects in a variety of stroke models. However, the use of insulin is complicated by the uncertainty surrounding the neurotoxic effects of hyperglycemia, the potential benefits of mild-to-modest hypoglycemia, and the potentially lethal effects of severe hypoglycemia.
In accordance with this invention it can be seen that there is a real and continuing need for an effective treatment to improve the function of the ischemic and reperfused brain. This invention has as its primary object the fulfillment of this need.
Another object of the present invention is to treat the ischemic or reperfused brain with GLP-1 or its biologically active analogues after acute stroke or hemorrhage to optimize insulin secretion, to enhance insulin effectiveness by suppressing glucagon antagonism, and to maintain euglycemia or mild hypoglycemia with no risk of severe hypoglycemia.
Another objective of the present invention is to accomplish the above objectives with a composition that provides no risk of severe hypoglycemia, and can correct hyperglycemia.
A still further objective of the present invention is to provide a treatment with a biologically active compound that offers no side effect risk, whatsoever.
The means and manner of accomplishing each of the above objectives will become apparent from the detailed description of the invention which follows hereinafter.
SUMMARY OF THE INVENTION
It has now been discovered that GLP-1 treatment after acute stroke or hemorrhage, preferably intravenous administration, dan be an ideal treatment because it provides a means for optimizing insulin secretion, increasing brain anabolism, enhancing insulin effectiveness by suppressing glucagon, and maintaining euglycemia or mild hypoglycemia with no risk of severe hypoglycemia or other adverse side effects.
DETAILED DESCRIPTION OF THE INVENTION
Numerous animal and human studies have revealed a strong correlation between hyperglycemia and the severity of stroke-related morbidity and mortality. However, there is considerable disagreement about whether high blood glucose levels actually contribute to neuronal injury during ischemia, or whether hyperglycemia is merely a secondary stress response to neuronal injury. A recent retrospective follow-up study of 811 patients with acute stroke in the U.K. concluded that hyperglycemia predicts higher mortality and morbidity independently of other adverse prognostic factors and thus may be causally related to neuronal damage. However, this conclusion has been challenged by some on statistical grounds, and there is a consensus in some quarters that hyperglycemia in stroke patients is reactive to cerebral damage rather than causative. Nevertheless, it is remarkable that 20% to 43% of acute stroke patients are hyperglycemic at presentation. This can be accounted for, in part, by preexisting diabetes (25% to 50% of hyperglycemic patients), but in the majority this appears to be a reflection of an acute stress response with an increased production of cortisol, glucagon, and catecholamines. Whether the resultant hyperglycemia is in fact causally related to neuronal injury in human stroke patients cannot be answered definitively at present.
Attempts to clarify the role of hyperglycemia in producing neuronal damage have focused on appropriate animal models of acute stroke. These studies have revealed that in rat models of transient focal cerebral ischemia followed by reperfusion—a model relevant to the clinical situation of ischemic stroke treated by tPA re
Coolidge Thomas R.
Ehlers Mario R. W.
Bionebraska, Inc.
Low Christopher S. F.
McKee Voorhees & Sease, P.L.C.
Mohamed Abdel A.
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