Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-03
2001-09-11
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S039000
Reexamination Certificate
active
06288106
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention is in the fields of pharmacology and biochemistry. It relates to processes for the synthesis of certain complexes of &agr;-lipoic acid and the nutritional or therapeutic use of these and other related individual or complexed antioxidant, proglutathione molecules. Clinical uses for these molecules and complexes in the management of chronic open angle glaucoma, hearing loss, macular degeneration, lenticular cataract, insulin resistance, diabetic retinopathy, coronary artery disease, Parkinson's disease, Alzheimer's disease, various neurodegenerative diseases and vasoconstriction are described in particular.
I. Clinical Review
A. Chronic Glaucoma
The eye is maintained in a homeostatic shape by a relatively stable intraocular pressure (IOP), which varies within a reasonably narrow range so long as the intraocular production of aqueous fluid remains equal to its exit from the eye.
The optic nerve head can tolerate relatively high levels of IOP if the availability of oxygen from posterior ciliary arteries and optic nerve head arterioles remains adequate. However, if the intraocular (extravascular) pressure is higher than the perfusion (intravascular) pressure driving oxygen through the arteriole into the surrounding tissues, decreasing amounts of oxygen will reach the optic nerve head and nerve disability will result.
Similarly if nerve head arterioles are unable to provide sufficient volumes of blood to the optic nerve, dysfunction will follow. These arteriolar vascular flow deficiencies may occur because of: vasoconstriction secondary to generalized or localized microvascular dysregulation, arteriolar muscular hypertrophy (perhaps as a result of chronic spasm), atherosclerotic luminal reduction, changes in the viscosity or laminar flow patterns of the arterial blood or in either essential or iatrogenic systemic hypotension.
Glaucoma in various guises affects a large segment of the public. It is estimated that 2% to 2.5% of the population over the age of 40 has chronic open angle glaucoma (COAG). This is the most common form of glaucoma.
Because optic nerve damage occurs in patients with chronically elevated IOP, present treatments concentrate on reducing this single, objective finding by a variety of modalities: topical eye drops, oral medications, intravenous medications, surgical procedures, laser phototherapy, etc. All of these focus upon the reduction of pressure inside the eye and rely upon this pressure reduction to prevent optic nerve damage. For many patients this approach is effective. However, the effectiveness of each of these treatments runs from total ineffectiveness, progressive optic atrophy and eventual blindness, to an arrest of the disease, complete cessation or prevention of further optic nerve failure and preservation of vision.
Factors other than IOP levels influence the clinical outcome for many glaucoma patients. Attention is now focusing upon two alternatives: a) hypovascularity of the optic nerve head and loss of the vascular integrity of the optic nerve resulting in glial collapse, ganglion cell apoptosis and progressive neural atrophy with visual loss; b) hypoxia-induced free radical interference with retrograde axoplasmic flow within the optical neural axons.
(i) Ocular Microvascular Regulation
A balanced biochemistry of nitric oxide (NO) and endothelin-1 (ET-1) mediates local optical blood flow and many facets of systemic vascular autoregulation.
NO is a highly soluble gas formed within endothelial cells by the action of the constitutive enzyme nitric oxide synthetase (cNOS). NO activates guanylate cyclase and increases guanosine monophosphate (cGMP) within the vascular musculature. cGMP produces relaxation and dilatation of vessels. It also has more generalized smooth muscle relaxing abilities; in this regard it relaxes the contractile trabecular elements of the eye, increases aqueous outflow and reduces IOP. Levels of NO in the trabecular region of eyes of glaucoma patients are lower than in the eyes of non-glaucoma patients. Aging and atherosclerotic dysfunction of the vascular endothelium reduce its ability to produce NO because of reduced local levels of cNOS.
ET-1 is also formed within and secreted by endothelial cells. ET-1 reacts with local receptors on smooth muscle cells to produce a powerful and long-lasting vasoconstriction. ET-1 is particularly released by aged or unhealthy endothelial cells, e.g., in the presence of atherosclerosis, in the presence of local collections of endothelial leukocytes or platelets, and during periods of significantly reduced vascular flow and decreased blood fluidity, etc. The smooth muscle contraction produced by ET-1 strongly opposes the relaxation properties of NO and trabecular contraction is stimulated, resistance to aqueous outflow is increased and IOP increases. Aqueous levels of ET-1 are elevated in glaucomatous eyes. Experimentally-induced elevations of aqueous ET-1 levels produce optic nerve collapse.
This balance between NO and ET-1 mediates the autoregulation of blood flow within the optic nerve and throughout the peripheral circulation.
Exposure of some hypertensive glaucoma patients to therapeutic amounts of calcium channel blockers has resulted in a serendipitous improvement of their glaucomatous visual fields. Vascular endothelial production of ET-1 is dependent upon cytosolic calcium (Ca
2+
) influx via transmembrane calcium channels. Calcium channel blockade reduces this Ca
2+
influx and reduces the production of ET-1. A reduction of IOP has also been observed as a side effect in glaucoma patients using calcium channel blockers for systemic hypertension. However, prescribing therapeutic doses of calcium channel blockers to non-hypertensive glaucoma patients subjects the optic nerve to a risk of hypoxia secondary to iatrogenic hypotension and severely disrupts inherent transmembrane calcium modulation.
(ii) Ocular Vascular Disease
A balanced biochemistry of nitric oxide (NO) and endothelin-1 (ET-1) mediates local optical blood flow and many facets of systemic vascular autoregulation.
NO is a highly soluble gas formed within endothelial cells by the action of the constitutive enzyme nitric oxide synthetase (cNOS). NO activates guanylate cyclase and increases guanosine monophosphate (cGMP) within the vascular musculature. cGMP produces relaxation and dilatation of vessels. It also has more generalized smooth muscle relaxing abilities; in this regard it relaxes the contractile trabecular elements of the eye, increases aqueous outflow and reduces IOP. Levels of NO in the trabecular region of eyes of glaucoma patients are lower than in the eyes of non-glaucoma patients. Aging and atherosclerotic dysfunction of the vascular endothelium reduce its ability to produce NO because of reduced local levels of cNOS.
ET-1 is also formed within and secreted by endothelial cells. ET-1 reacts with local receptors on smooth muscle cells to produce a powerful and long-lasting vasoconstriction. ET-1 is particularly released by aged or unhealthy endothelial cells, e.g., in the presence of atherosclerosis, in the presence of local collections of endothelial leukocytes or platelets, and during periods of significantly reduced vascular flow and decreased blood fluidity, etc. The smooth muscle contraction produced by ET-1 strongly opposes the relaxation properties of NO and trabecular contraction is stimulated, resistance to aqueous outflow is increased and IOP increases. Aqueous levels of ET-1 are elevated in glaucomatous eyes. Experimentally-induced elevations of aqueous ET-1 levels produce optic nerve collapse.
This balance between NO and ET-1 mediates the autoregulation of blood flow within the optic nerve and throughout the peripheral circulation.
Exposure of some hypertensive glaucoma patients to therapeutic amounts of calcium channel blockers has resulted in a serendipitous improvement of their glaucomatous visual fields. Vascular endothelial production of ET-1 is dependent upon cytosolic calcium (Ca
2+
) influx via transmembrane calcium channel
Pearson Don C.
Richardson Kenneth T.
ChronoRX LLC
Lambkin Deborah C.
Townsend and Townsend / and Crew LLP
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