Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-06-11
2003-03-11
Solola, Taofiq (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C556S045000, C556S110000, C556S118000, C562S557000
Reexamination Certificate
active
06531608
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention is in the fields of pharmacology and biochemistry. It relates to the synthesis of certain complexes of L-cysteine, N-acetyl L-cysteine, N-(2-mercapto-propionyl)glycine, L-2-oxothiazolidine-4-carboxylate and the nutritional or clinical use of these and other related individual or complexed thiol contributing, glutathione predecessors. The use of these molecules and complexes in clinical presentations of chronic glaucoma, diabetes mellitus, macular degeneration, 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) that 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 global intraocular pressure is higher than the perfusion 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 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 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. This invention is focused 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.
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 or in the presence of local collections of endothelial leukocytes or platelets, 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. 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 patients to calcium channel blockers has resulted in an improvement of some 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 serendipitous reduction of IOP has 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.
Ocular Vascular Disease
In the optic nerve two tissues are particularly vulnerable to hypoxia:
a. The microglial ganglion cells.
b. The transiting axonic neurons.
A reduction in optic nerve oxygen delivery may follow acute or chronic, segmental or widespread, vascular spasm or prolonged constriction secondary to a physical reduction in the vascular lumen. This luminal reduction (vasoconstriction) may be caused by or associated with hypertrophy of the vascular muscle wall (the media), the accumulation of atherosclerotic plaque, platelet agglutination and/or local inflammatory swelling and leukocytic accumulation. Any and all of these findings may occur with aging and with systemic disease: diabetes, hypertension, dyslipogenesis, arteriosclerosis, thyroid disease, etc. Although vascular insufficiency at specific tissue sites is widely variable and not predictable with certainty, the fact that most glaucoma patients are over 50 years old makes the frequency of these risk factors and the frequency of vascular insufficiency high in this clinical group.
If a reduction of optic nerve vascular risk factors is united with a reduction in outflow resistance, the combined effects of a more pressure resistant nerve head and lower IOP will beneficially decrease the potential for optic atrophy and blindness.
Glaucoma—Present Treatment
Current non-surgical treatments of COAG are based upon a limited number of biochemical approaches and focus exclusively upon reducing IOP:
a. Enzyme poisons—these are most frequently tablets of carbonic anhydrase inhibitors that inhibit the production of aqueous humor. Besides the development of renal stones, potassium loss is a constant clinical concern. Topical forms of this group have appeared as eye drops. However, because carbonic anhydrase activity is also present in the cytoplasm of corneal endothelial cells the long-term corneal effects of this form of these medications are unknown. To avoid systemic reactions, patients with sulfonamide allergies should not use these drugs.
b. Parasympathomimetics—pilocarpine-containing eye drops are widely prescribed and act by causing pupillary constriction. Miosis causes lacunae in the trabeculum to enlarge; thus, mechanical resistance to aqueous outflow is reduced. Frequent side effects include headache from iris spasm, decreased night vision from miosis and blurred vision, especially in myopes.
c. Beta blocking agents—these drugs block the beta-adrenergic
Pearson Don C.
Richardson Kenneth T.
Chronorx, LLC.
Solola Taofiq
Townsend and Townsend / and Crew LLP
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