Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2002-01-28
2003-11-11
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S567000, C514S573000, C514S619000, C514S913000
Reexamination Certificate
active
06646001
ABSTRACT:
FIELD OF THE INVENTION
This invention is directed to the use of non-steroidal anti-inflammatory agents, and especially certain non-steroidal cyclooxygenase inhibitors in combination with prostaglandin FP receptor agonists for treating glaucoma and/or ocular hypertension in an individual.
BACKGROUND OF THE INVENTION
The glaucomas are a heterogeneous group of optic neuropathies characterized by cupping of the optic nerve head, thinning of the retinal nerve fiber layer due to loss of retinal ganglion cells, and specific pathognomonic changes in visual fields. Elevated intraocular pressure (IOP) is a very important risk factor for the development of most common forms of glaucoma (Sommer A, et al., “Relationship Between Intraocular Pressure and Primary Open Angle Glaucoma Among White and Black Americans,”
Arch. Ophthalmol,
109:1090-1095 (1991)).
A family history of glaucoma also is an important risk factor for the development of glaucoma. It appears that a significant portion of glaucoma is inherited (or at least the risk for developing glaucoma is inherited) although it is often difficult to establish clear inheritance patterns for most of the glaucomas because of the disease onset late in life and the slowly progressive clinical manifestations of the disease. Despite these problems, a number of families with heritable forms of glaucoma have been identified and these families have been used to map a variety of glaucoma genes (Sheffield, et al., “Genetic Linkage of Familial Open Angle Glaucoma to Chromosome 1q21-q31,
” Nature Genetics,
4:47-50 (1993); Sarfarazi, et al., “Assignment of a Locus (GLC3A) for Primary Congenital Glaucoma (Buphthalmos) to 2p21 and Evidence for Genetic Heterogeneity,”
Genomics,
30:171-177 (1995); Akarsu, et al., “A Second Locus (GLC3B) for Primary Congenital Glaucoma (Buphthalmos) Maps to the 1p36 Region,”
Human Molecular Genetics,
5(8):1199-1203 (1996); Stoilova, et al., “Localization of a Locus (GLC1B) for Adult-Onset Primary Open Angle Glaucoma to the 2cen-q13 Region,”
Genomics,
36:142-150 (1996); Wirtz, et al., “Mapping a Gene for Adult-Onset Primary Open-Angle Glaucoma to Chromosome 3q,”
Am. J. Hum. Genet.,
60:296-304 (1997); Andersen, et al., “A Gene Responsible for the Pigment Dispersion Syndrome Maps to Chromosome 7q35-q36,
” Arch. Ophthalmol.,
115:384-388 (1997). The first glaucoma gene mapped (GLC1A) was in a large family with autosomal dominant inherited juvenile glaucoma (JG). This disease is characterized by an early disease onset (at the age of late teens to early 20s), relatively high IOPs, and general resistance to conventional pharmacological IOP lowering therapy. The GLC1A gene was mapped by positional cloning and linkage analysis to chromosome 1q22-q25 (Sheffield et al, Id., and a number of other groups have confirmed the 1q location of this juvenile glaucoma gene (Richards, et al., “Mapping of a Gene for Autosomal Dominant Juvenile-Onset Open-Angle Glaucoma to Chromosome 1q,”
Am. J. Hum. Genet.,
54:62-70 (1994); Morissette, et al., “A Common Gene for Juvenile and Adult-Onset Primary Open-Angle Glaucomas Confined on Chromosome 1q,”
Am. J. Hum. Genet.,
56:1431-1442 (1995); Wiggs, et al., “Genetic Linkage of Autosomal Dominant Juvenile Glaucoma to 1q21-q31 in Three Affected Pedigrees,”
Genomics,
21:299-303 (1994); Meyer, et al., “Age-Dependent Penetrance and Mapping of the Locus for Juvenile and Early-Onset Open-Angle Glaucoma on Chromosome 1q (GLC1A) in a French Family,”
Hum. Genet.,
98:567-571 (1996); Graff, et al., “Confirmation of Linkage to 1q21-31 in a Danish Autosomal Dominant Juvenile-Onset Glaucoma Family and Evidence of Genetic Heterogeneity,”
Hum. Genet.,
96:285-289 (1995). Glaucoma due to the GLC1A gene is hereinafter referred to as GLC1A glaucoma or 1q glaucoma.
The GLC1A gene was identified as encoding a 57 kD protein expressed in the trabecular meshwork (TM) (Stone, et al., “Identification of a Gene That Causes Primary Open Angle Glaucoma,”
Science,
275:668-670 (1997). The expression of the GLC1A gene, and the encoded TM protein, is up-regulated by glucocorticoids (Polansky, et al., “In Vitro Correlates of Glucocorticoid Effects on Intraocular Pressure,”
Glaucoma Update IV (
1991); and Polansky, et al., “Cellular Pharmacology and Molecular Biology of the Trabecular Meshwork Inducible Glucocorticoid Response Gene Product,”
Ophthalmologica,
211:126-139 (1997). This TM protein is also known as TIGR (trabecular meshwork inducible glucocorticoid response) (Polansky, Id.). The glucocorticoid-induction of this TM protein has been suggested to be involved in the generation of glucocorticoid-induced ocular hypertension and glaucoma (Polansky, Id.).
The GLC1A gene is expressed in other ocular tissues such as the ciliary epithelium (Ortego, et al., “Cloning and Characterization of Subtracted cDNAs from a Human Ciliary Body Library Encoding TIGR, a Protein Involved in Juvenile Open Angle Glaucoma with Homology to Myosin and Olfactomedin,”
FEBS Letters,
413:349-353 (1997) and the retina (Kubota, et al., “A Novel Myosin-like Protein (Myocilin) Expressed in the Connecting Cilium of the Photoreceptor: Molecular Cloning, Tissue Expression, and Chromosomal Mapping,”
Genomics,
41:360-369 (1997). The gene is referred to by several names including GLC1A (Sheffield, supra; Sunden, et al., “Fine Mapping of the Autosomal Dominant Juvenile Open Angle Glaucoma (GLC1A) Region and Evaluation of Candidate Genes,”
Genome Research,
6:862-869 (1996); Stone, et al., supra, TIGR (Polansky supra; Ortego, supra, and myocilin (Kubota, supra). Mutations inGLC1A are not only responsible for juvenile glaucoma, but also a significant subset of adult onset primary open angle glaucoma (Stone, et al., supra); Adam, et al., “Recurrent Mutations in a Single Exon Encoding the Evolutionarily Conserved Olfactomedin-Homology Domain of TIGR in Familial Open-Angle Glaucoma,”
Human Molecular Genetics,
6(12):2091-2097 (1997). The 1q glaucoma gene (GLC1A) is the subject of Nguyen, et al., U.S. Pat. No. 5,606,043, issued Feb. 25, 1997.
Ocular inflammation is a condition which generally affects the patient with scratchiness, itchiness and/or red eye. Ocular inflammation can be initiated by various insults. For example, ocular inflammation can result from allergic response to various allergens, trauma to the eye, dry eye and surgical complications. Various anti-inflammatory therapies are currently known for the treatment of inflammation, including the topical administration of non-steroidal anti-inflammatory agents such as diclofenac for ophthalmic inflammation. A number of these therapies, from aspirin to the recently commercialized COX II inhibitors, celocoxib and refocoxib, are believed to involve, at least in part, inhibition of prostaglandin synthesis. In addition to the treatment of inflammation, several patent applications have disclosed the use of non-steroidal cyclooxygenase inhibitors to treat intraocular pressure (WO 95/17178) through the action of the compounds on trabecular meshwork cells (WO 96/40103 and WO 96/40102). At least some of the beneficial effects of the non-steroidal cyclooxygenase inhibitors are attributed to the inhibition of the expression of myocilin (or TIGR) which is the gene product of GLC1A.
It is known that trabecular meshwork cells have glucocorticoid receptors and that glucocorticoid binding with these receptors causes a change in trabecular meshwork cell gene expression. Known manifestations of this change include a reorganization of the cytoskeleton (Wilson, et al., “Dexamethasone Induced Ultrastructural Changes in Cultured Human Trabecular Meshwork Cells,
Cur. Eye Res.,
12:783-793 (1993), and Clark, et al., “Glucocorticoid-Induced Formation of Cross-Linked Actin Networks in Cultured Human Trabecular Meshwork Cells,”
Invest. Ophthalmol. Vis. Sci.,
35:281-294 (1994) and increased deposition of the extracellular matrix material in trabecular meshwork cells. As a result, the trabecular meshwork becomes “clogged” and unable to perform one of its most critical functions, that is, serving as a gateway for aqueo
Hellberg Mark R.
Nixon Jon C.
Alcon Manufacturing Ltd.
Copeland Barry L.
Fay Zohreh
LandOfFree
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