Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-20
2001-11-06
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S223500
Reexamination Certificate
active
06313112
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to potassium adenosine triphosphate (“K
ATP
”) channel openers and their use. According to the present invention, diazoxide (7-chloro-3-methyl-2H-1,2,4-benzo-thiadiazine 1,1-dioxide) or aprikalim, or the combination, may be utilized as a selective K
ATP
channel opener for neuronal channels. The present also relates to therapeutic methods for protecting neuronal function utilizing K
ATP
channel openers. Methods of the present invention may be advantageous for protecting neuronal function, prior to medical procedure, after stroke-like events or other events associated with reductions in blood flow, and/or for preserving tissues or organs against cellular injury and death during removal, storage, transplantation or reattachment.
BACKGROUND
Strokes and other events associated with reductions in blood flow to the brain continue to result in serious and costly neurological sequelae such as: 1) loss of normal neurological function such as movement or memory; 2) altered neurological function (i.e., seizure type activity); and/or 3) death of the affected individual. Examples of disruptions in the cerebral blood flow include, but are not limited to, cardiac failure, hypotensive shock, occlusion of carotid arteries for endarterectomy, occlusion of cerebral arteries for aneurysm surgery, and lodging of microvascular emboli during cardiopulmonary bypass. Further, such events account for considerable costs to society in terms of the medical care and loss of productivity.
A number of putative neuroprotective agents have been developed over the last several decades, but the results of these agents in clinical trials and practice have been disappointing at best. For example, non-selective stimulators of potassium channels such as aprikalim and NS1619 have been shown to protect the brain under a wide range of ischemic conditions. However, two basic limitations typically occur with these compounds. First, these potassium channel stimulators are not selective for cellular localization, so that it is impossible to determine the situs of their function. This is important because the effects of these agents at locations distinct from mitochondria may counteract or interfere with protective functions. Second, mechanisms of action for these non-selective stimulators have yet to be determined, and thus results have been difficult to interpret. There, thus, remains a need to develop neuroprotective agents that can improve neuronal cell function and recovery and prevent cell death after stroke-like events or events associated with reductions of cerebral blood flow (ischemia).
SUMMARY OF THE INVENTION
The present invention is generally directed to potassium adenosine triphosphate (“K
ATP
”) channel opening compositions. The present invention also relates to the use of K
ATP
channel openers in therapeutic applications.
The K
ATP
channel opening compositions of the present invention include diazoxide (7-chloro-3-methyl-2H-1,2,4-benzo-thiadiazine 1,1-dioxide) and aprikalim. According to the present invention, diazoxide and aprikalim can be used independently, or in combination.
In methods of the present invention, diazoxide may be utilized as a selective K
ATP
channel opener, particularly in neuronal channels and/or mitochondria. The present invention includes therapeutic applications of diazoxide as a neuroprotective agent. Alternate methods and therapeutic methods of the present invention comprise the use of aprikalim, a K
ATP
channel opener with vasodilation.
In a first aspect the present invention relates to a therapeutic application of a K
ATP
channel opener to provide protection to an individual's brain against neurological events. Examples of neurological events include, but are not limited to, stroke, reduction of cerebral blood flow (ischemia); events resulting from trauma, for example trauma to the head; and/or similar events that are generally an initial and unplanned event.
In another aspect the present invention relates to a therapeutic application of K
ATP
channel opener to provide protection to an individual's brain prior to scheduled, or unscheduled, procedures that may affect the cerebral circulation and brain. In general, the methods of the present invention may be utilized with any medical procedure that may affect neuronal function. Examples of procedures include, but are not limited to, surgical procedures, for example endarterectomy or cardiopulmonary bypass; cardiac catherization; angioplasty; and other medical procedures that may affect cerebral circulation. A procedure may also comprise the administration of pharmaceutical compositions that may affect cerebral circulation.
In a further aspect, the present invention relates to a therapeutic application of a K
ATP
channel opener to provide protection to tissues and organs against cellular damage associated with transplantation and reattachment procedures.
The K
ATP
channel opener may comprise diazoxide, or may comprise aprikalim, or may comprise a combination of diazoxide and aprikalim.
In a still further aspect, the present invention relates to the use of diazoxide as a selective mitochondrial K
ATP
channel opener.
Diazoxide is a selective stimulator of ATP-sensitive potassium channels in mitochondria, and provides several advantages over non-selective stimulators of potassium channels. The methods of the present invention may be utilized to target the mitochondria to preserve function of the cellular components and to improve the survival of the affected cells. By targeting a specific mechanism, it is possible to minimize unwanted effects that could interfere with cellular protection. In contrast to non-selective potassium channel stimulators, which by their mode of action increase general blood flow to various cellular locations, diazoxide may be utilized to protect mitochondria without substantial effects on blood flow or blood vessel responsiveness.
In a therapeutic method of the present invention, a K
ATP
channel opener is administered in a therapeutically effective dosage to mammals in need of such treatment. The term “therapeutically effective dosage” as used in the present invention is defined as the dosage which provides effective protection or preservation of neuronal function for mammals, in particular humans, for the medical conditions described herein. As described in detail below, in general, a therapeutically effective dosage in a method of the present invention may comprise a dosage ranging between approximately, 0.1 &mgr;M to 150 &mgr;M, preferably 0.5 &mgr;M to 100 &mgr;M, more preferably, 1 &mgr;M to 50 &mgr;M, and still more preferably 1 &mgr;M to about 10 &mgr;M. It is further contemplated that the therapeutic applications for K
ATP
channel openers described herein are by no means limited to the disclosed medical conditions, but instead include other conditions that will be apparent to those skilled in the art.
In an embodiment of the present invention, diazoxide, or a mammalian metabolic conjugate thereof, is administered to the brain at varying dosages ranging between approximately, 0.1 &mgr;M to 150 &mgr;M, preferably 0. 5 &mgr;M to 100 &mgr;M, more preferably, 1 &mgr;M to 50 &mgr;M, and still more preferably 1 &mgr;M to about 10 &mgr;M. The diazoxide may be administered into a mammals circulatory system or into a mammal's brain ventriculocistemal (fluid circulation) system prior to planned, or unplanned, surgical procedures that may affect the cerebral circulation and brain.
Alternatively, diazoxide may be administered into a mammal's circulatory system or into the brain following a neurological event such as stroke or general circulatory failure in order to protect the brain against reperfusion injury or to prevent damage during secondary insults.
Further, neuroprotective K
ATP
channel opener agents like diazoxide may be administered to a mammal, for example through the circulatory system, immediately prior to the removal of tissue or organs in order to protect the tissues during removal, transport, and then subs
Chalkins Charles W.
Henley III Raymond
Kennedy Pat Winston
Kilpatrick & Stockton LLP
Wake Forest University
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