Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-20
2002-10-22
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S557000
Reexamination Certificate
active
06469049
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a method of treating, preventing or inhibiting central nervous system (CNS) injuries and diseases. In particular, the invention relates to a method of treating, preventing or inhibiting a CNS injury or disease in a subject by the administration of at least one lipoic acid compound to the subject.
2. Description of the Related Art
Traumatic brain injury (TBI) can initiate a cascade of events which may lead to dramatic elevation of intracranial pressure (ICP), cerebral edema, ischemia, intracranial hemorrhage and dysfunction of cerebrovascular regulatory mechanisms essential for survival. Deficits in memory, attention, and perception, emotional disorders, social behavioral problems, seizures (including non-convulsive seizures), paralysis, aphasia, post-traumatic epilepsy (PTE), and oxidative stress-induced neurotoxicity may result from TBI.
In several studies of severely head-injured patients, over 80% had ischemic damage in the hippocampus. See McIntosh, T. K., et al., (1996) Laboratory Investigation 74(2):315-342. The hippocampal damage may explain the prevalence of memory defects in survivors of TBI. Generally, the two main stages in the development of TBI are (1) primary, including contusion, laceration, intracranial hemorrhage and diffuse axonal injury; and (2) secondary, including delayed effects such as seizures, ischemia, edema, and biochemical reactions, which lead to necrosis and apoptosis.
Penetrating brain injuries, associated with retained intracranial ferric metal fragments and inevitably associated with hemorrhage, are highly likely to produce posttraumatic epilepsy (PTE). See Salazar, A. M., et al., (1985) Neurology 35:1406-1414. Development of seizures following penetrating craniocerebral trauma has been associated with the presence of hematoma, total brain volume loss, presence of retained metal fragments, hemiparesis, aphasia, visual field loss, organic mental disorder, headache and a history of seizures during the first year post injury.
Initial events in TBI such as hemorrhage and ischemia can elicit activation of leukocytes and excessive release of the excitatory neurotransmitter glutamic acid with resulting excess influx of calcium. These events can trigger a number of interactive intermediate reactions which can lead ultimately to neurotoxicity. These include decompartmentalization of iron, and the activation of several enzymes including phospholipases, xanthine oxidase, intraneuronal nitric oxide synthase and poly[ADP-ribose]polymerase (PARP). Formation of neurotoxic reactive oxygen species (ROS) appears to be a result common to many of these “initiator” pathways and is a major “perpetrator” in mediating necrotic neuronal death. For example, it is well-known that glutamate, acting via both NMDA and non-NMDA receptors, leads to increased intraneuronal calcium, which in turn may activate (a) phospholipase A2, triggering arachidonic acid production, or (b) xanthine oxidase. Both pathways lead to the production of free radicals, such as superoxide. Additional pathways leading to free radical formation include liberation of “catalytic” iron from extravasated hemoglobin and decompartmentalization of iron or copper from damaged mitochondria. Thus, although the immediate mechanisms of pathologic responses to nervous system may vary, many forms of neurotoxicity are believed to share a common final pathway via formation of ROS, reactive nitrogen species, or both.
ROS are most aggressively damaging in the central nervous system (CNS) as ROS attack double bonds in the unsaturated fatty acids, which are abundant in CNS membranes, to form carbon-centered radicals (R) or (R—HC—R) wherein “R” generally refers to any carbon chain which length may vary. These radicals initiate a chain reaction of lipid peroxidation, which continues until arrested by the formation of a relatively non-reactive species such as oxidized vitamin E or vitamin C. Scavengers, such as vitamin E, also known as alpha-tocopherol, donate a hydrogen atom to a radical, thereby becoming a secondary radical. Since the tocopherol radical is rather stable, it breaks the chain reaction, hence these scavengers are known as “chain-breaking antioxidants”.
The several neurotoxic pathways can produce a variety of small, diffusible ROS, including superoxide, nitric oxide, peroxyl, perhydroxyl, peroxynitrite, hypochlorous and singlet oxygen. The antioxidant enzyme superoxide dismutase converts the superoxide radical to hydrogen peroxide, a non-radical oxidizing agent that can engage in a number of iron-catalyzed reactions producing the very toxic hydroxyl ion. For example, the ferrous ion can trigger the Fenton reaction with hydrogen peroxide to form hydroxyl ions plus a ferric ion. Iron ions can also catalyze the Haber-Weiss reaction, in which superoxide and hydrogen peroxide react to form hydroxyl ions and molecular oxygen. Superoxide can also react with nitric oxide to produce the intermediate peroxynitrite, which subsequently yields the hydroxyl radical.
Although a particular neurotoxic reaction might predominate initially, other pathways may rapidly be recruited, thereby exacerbating damage. For example, hemoglobin, a potential source of catalytic iron, potentiates excitatory amino acid-induced neurotoxic injury in cortical cell culture. Ischemia is a secondary effect of TBI and causes a metabolic imbalance wherein mitochondria increase production of ROS while decreasing production of energy required for neuronal homeostasis, engendering oxidative stress. Injury-induced activation of PARP can deplete NAD+, and consequently also deplete ATP. Depletion of energy sources such as ATP transforms glutamic acid from neurotransmitter to neurotoxin. Moreover, ROS exacerbate the excitotoxic pathways by increasing the release of glutamate and inhibiting its reuptake inactivation.
There are important endogenous antioxidant defenses in the central nervous system which are essential in providing cellular resilience in response to injury. These protective mechanisms include glutathione (GSH), alpha-lipoic acid (ALA), dihydrolipoic acid (DHLA), coenzyme Q, vitamin E, vitamin C, pyruvate, melatonin, and niacinamide. Some of these are synthesized endogenously and some are dietary requirements. The sulfhydryl group of GSH is particularly important in protecting cell membranes against peroxidative stress. GSH peroxidase, using GSH as a co-substrate and selenium as a metallic cofactor, reduces intracellular formation of hydrogen peroxide and free radicals.
Unfortunately, these endogenous antioxidant defenses in the central nervous system are not sufficient to prevent or inhibit TBI, PTE and other related CNS traumas. Consequently, various compounds and treatments have been developed.
Additionally, recent clinical trials of Tirilazad™ (Upjohn) and Peg-SOD (superoxide dimutase linked to polyethylene glycol) have been disappointing, their design has been controversial, and leaves the question of the value of antioxidants unresolved. See Marshall, S. B., et al., (1998) J. Neurosurg. 89(4):519-525. Tirilazad™ is an antioxidant aminosteroid which proved to be clinically unsuccessful against stroke because it did not readily cross the blood brain barrier and it failed to protect the hippocampus. Furthermore, a number of large clinical trials have failed to demonstrate a benefit of administering phenytoin, phenobarbital, carbamazepine or valproate as a way to prevent the onset of PTE.
Clearly, a need exists for effectively treating and preventing TBI, PTE and other CNS traumas.
SUMMARY OF THE INVENTION
In some embodiments, the present invention relates to a method of treating a subject suffering from a CNS injury or disease comprising administering to the subject a composition comprising a therapeutically effective amount of at least one lipoic acid compound.
In some embodiments, the present invention relates to a method of preventing or inhibiting a CNS injury or disease in a subject comprising administering to the subject a composition compris
Koenig Michael L.
Meyerhoff James L.
Yourick Debra L.
Arwine Elizabeth
Shah Mukund J.
The United States of America as represented by the Secretary of
Tucker Zachary C.
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