Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-05
2003-04-08
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06545019
ABSTRACT:
FIELD OF THE INVENTION
The present invention comprises methods of treating various acute and chronic central nervous system disorders by the administration of FLAP or 5-lipoxygenase inhibitors.
BACKGROUND OF THE INVENTION
Acute and chronic brain injuries can activate resident microglia (resident macrophage-like cells found in the central nervous system) as well as recruit peripheral immune cells to injured brain regions that can exacerbate neuronal damage. Inflammatory processes can induce cell death by (a) the release of proteases and free radicals that induce lipid peroxidation, (b) direct cytotoxic effects or (c) by the phagocytosis of sublethally injured neurons. The attenuation of microglia and peripheral immune cell activation has been correlated with significant neuronal protection in pre-clinical studies of ischemia, traumatic brain injury, spinal cord injury and Alzheimer's disease.
Oxygenase enzymes like cycloxygenase and lipoxygenase can initiate the conversion of arachidonic acid to physiological important metabolites. Cycloxygenase (COX; prostaglandin H2 synthase) is responsible for the formation of prostaglandins and thomboxanes. See Versteeg, H. Van, van Bergen en Henegouwen, M. P. V., van Deventer, S. J. W. and Peppelenbosch, M. P. (1999). Cyclooxygenase-dependent signaling: :molecular events and consequences.
FEBS letters
445: 1-5. Lipoxygenase is responsible for the conversion of arachidonic acid to leukotrienes. Lipoxygenases and Their Metabolites, Plenum Press, N.Y. Eds. Nigam and Pace-Asciak. (1999). It is hypothesized that prostaglandins are an important step in transducing immune stimuli into CNS responses. There are two known isozymes of COX currently known COX-1 (constituitively expressed) and COX-2 (induction in response to immune stimuli). It has been established that COX-1 and COX-2 are found to be induced and constituitively expressed in peripheral immune cells as well as brain, with neuronal expression of COX-2 being enhanced following various CNS insults including cerebral ischemia. Tomimoto, H., Akiguchi, I. Watkita, H., Lin, J. X., Budka, H. Cyclooxygenase-2 is also induced in microglia during chronic cerebral ischemia in humans.
Acta Neuropathol
(Berl) 1: 26-30 (2000).
However, little is known about the role of lipoxygenases (or subsequent metabolites including hydroxyeicosatetraenoic acids (HETEs), leukotrienes, lipoxines, and hepoxilins) in regulating brain inflammation or neurodegeneration. There are currently four known human lipoxygenases (5, 8, 12, and 15-lipoxygenase). All isoforms share a common substrate as well as oxygenase activity but differ greatly in sequence. Although, the role of prostaglandins and COX-2 in modulating inflammation and pain has been well elucidated, the importance of LOX enzymes (specifically 5-LOX or 5-lipoxygenase) in brain following injury is still unresolved. Simon, L. S. Role and regulation of cyclooxygenase-2 during inflammation
American Journal of Medicine
106: 37S-42S (1999).
SUMMARY OF THE INVENTION
Thus, according to a first embodiment of a first aspect of the present invention is provided a method of modulating or inhibiting microglia activation comprising the administration to a human in need thereof a compound capable of inhibiting 5-LOX.
According to another embodiment of the first aspect of the present invention is provided a method of modulating or inhibiting microglia activation comprising the administration to a human in need thereof a compound capable of selectively inhibiting 5-LOX over COX-2.
According to another embodiment of the first aspect of the present invention is provided a method of modulating or inhibiting microglia activation comprising the administration to a human in need thereof a compound capable of inhibiting FLAP.
According to another embodiment of the first aspect of the present invention is provided a method of modulating or inhibiting microglia activation comprising the administration to a human in need thereof para-REV5901 (L-655,238), Bay-x-1005, ML-3000, NDGA or ZILEUTON®.
According to a first embodiment of a second aspect of the present invention is provided a method of inhibiting the release of pro-inflammatory substances from activated microglial cells comprising the administration to a human in need thereof a compound capable of inhibiting 5-LOX.
According to another embodiment of a second aspect of the present invention is provided a method of inhibiting the release of pro-inflammatory substances from activated microglial cells comprising the administration to a human in need thereof a compound capable of selectively inhibiting 5-LOX over COX-2.
According to another embodiment of a second aspect of the present invention is provided a method of inhibiting the release of pro-inflammatory substances from activated microglial cells comprising the administration to a human in need thereof a compound capable of inhibiting FLAP.
According to another embodiment of a second aspect of the present invention is provided a method of inhibiting the release of pro-inflammatory substances from activated microglial cells comprising the administration to a human in need thereof para-REV5901 (L-655,238), Bay-x-1005, ML-3000, NDGA or ZILEUTON®.
According to a first embodiment of a third aspect of the present invention is provided a method of treating Alzheimer's disease, brain ischemia, traumatic brain injury, Parkinson's Disease, Multiple Sclerosis, ALS, subarachnoid hemorrhage or other disorders associated with excessive production of inflammatory mediators in the brain comprising the administration to a human in need thereof a compound capable of inhibiting 5-LOX.
According to another embodiment of a third aspect of the present invention is provided a method of treating Alzheimer's disease, brain ischemia, traumatic brain injury, Parkinson's Disease, Multiple Sclerosis, ALS, subarachnoid hemorrhage or other disorders associated with excessive production of inflammatory mediators in the brain comprising the administration to a human in need thereof a compound capable of 5-LOX over COX-2.
According to another embodiment of a third aspect of the present invention is provided a method of treating Alzheimer's disease, brain ischemia, traumatic brain injury, Parkinson's Disease, Multiple Sclerosis, ALS, subarachnoid hemorrhage or other disorders associated with excessive production of inflammatory mediators in the brain comprising the administration to a human in need thereof a compound capable of inhibiting FLAP.
According to another embodiment of a third aspect of the present invention is provided a method of treating Alzheimer's disease, brain ischemia, traumatic brain injury, Parkinson's Disease, Multiple Sclerosis, ALS, subarachnoid hemorrhage or other disorders associated with excessive production of inflammatory mediators in the brain comprising the administration to a human in need thereof para-REV5901 (L-655,238), Bay-x-1005, ML-3000, NDGA or ZILEUTON®.
According to a first embodiment of a fourth aspect of the present invention is provided a method of attenuating degradation of I&kgr;B&agr; comprising the administration to a human in need thereof a compound capable of inhibiting 5-LOX.
According to another embodiment of a fourth aspect of the present invention is provided a method of attenuating degradation of I&kgr;B&agr; comprising the administration to a human in need thereof a compound capable of selectively inhibiting 5-LOX over COX-2.
According to another embodiment of a fourth aspect of the present invention is provided a method of attenuating degradation of I&kgr;B&agr; comprising the administration to a human in need thereof a compound capable of inhibiting FLAP.
According to another embodiment of a fourth aspect of the present invention is provided a method of attenuating degradation of I&kgr;B&agr; comprising the administration to a human in need thereof para-REV5901 (L-655,238), Bay-x-1005, ML-3000, NDGA or ZILEUTON®.
According to a first embodiment of a fifth aspect of the present invention is provided a method of
Parvathenani Lav Kumar
Posmantur Rand M.
Bristol--Myers Squibb Company
Criares Theodore J.
Kim Jennifer
Makujina Shah R.
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