Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-02-22
2002-10-15
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S912000
Reexamination Certificate
active
06465464
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for the protection of nerve cells, including the retina, optic nerve and spinal cord of mammals from noxious provocations including damage from compressive or mechanical effects or trauma or stress factors, including but not limited to impaired blood flow to the nerves, and with respect to the retina and optic nerve, glaucoma, retinitis pigmentosa, and age-related macular degeneration.
BACKGROUND OF THE INVENTION
Glaucoma is a disease of the eye characterized at least initially by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. Primary glaucoma is an independent syndrome in adults may be classified as either chronic open-angle or chronic angle-closure. Primary open angle glaucoma is the most commonly occurring form of glaucoma where there is no other attributable underlying cause. Angle-closure glaucoma usually afflicts those persons having “shallow” angles in the anterior chamber and results from the sides (or angels) of the chamber coming together and blocking aqueous outflow through the trabecular meshwork. Secondary glaucoma, as the name suggests, results from pre-existing ocular diseases such as uveitis, intraocular tumor or enlarged cataract.
The underlying causes of primary glaucoma are not yet well known. Increased intraocular pressure can be a result of obstruction of aqueous humor outflow. In chronic open-angle glaucoma, the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impeded. In acute and chronic angle-closure glaucoma, the anterior chamber is shallow, the filtration angle is narrowed and the iris may obstruct the trabecular meshwork at the entrance to the canal of Schlemm. Dilation of the pupil may push the root of the iris forward against the angle or may produce pupillary block and thus precipitate an acute attack of elevated intraocular pressure. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of varying degrees of severity.
Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and, subsequently, into the canal of Schlemm. Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior synechia in iris bombe, and may plug the drainage channel with exudates. Other common causes are intraocular tumors, enlarged cataracts, ventral retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.
Considering all types together, glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptomatic for years before progressing to rapid loss of vision. It is not clear whether glaucomatous nerve damage is the end result of one pathological process or whether there are several mechanisms by which the final disease is manifest.
There is growing evidence that more than one pathomechanism may be involved early in the glaucomatous process. See for example: Ruben, S. T., Hitchings, et al., Eye 8 (5) pp 516-20 (1994). Among those risk factors are elevated intraocular pressure, family history of glaucoma, age and the vertical cup-to-disk ratio of the internal structures in the posterior chamber of the eye. One study found that in hypertensive eyes without visual field loss, the most important factors in predicting the likelihood of glaucoma-induced loss were the cup-to-disk ratio and age. Johnson, C. A., Brandt, J. D., et al., Arch. Ophthalmol. 113(1) pp. 70-76 (1995). These studies implicitly assume that there are persons who have elevated intraocular pressure (ocular hypertension) without nerve damage to the optic disk or the retina. See also: Pfeiffer N., Bach, M. Ger. J. Ophthalmol. 1(1) pp. 35-40 (1992). Glaucomatous field damage is also known to occur in the eyes of individuals with normotensive intraocular pressure. One theory is that the size of the optic disk determines the susceptibility of the nerve head to glaucomatous visual field damage at statistically normal intraocular pressure. Burk, R. O., Rohrschneider, K., Noack, H., et al. Graefes Arch. Clin. Exp. Ophthalmol. 230 (6) pp. 552-60 (1992). Another explains visual field damage at normotensive pressure as occurring by a different, as yet unidentified, pathologic mechanism. Trick, G. L., Doc. Ophthalmol. 85 (2) pp. 125-33 (1993). Regardless of the theory, glaucomatous visual field damage at statistically normal intraocular pressure is a clinically recognized condition.
Elevated intraocular pressure, while being generally acknowledged as a risk factor for the possible onset of glaucoma, is not a necessary condition for glaucomatous field damage. Nerve cell damage can occur with or without elevated intraocular pressure and nerve cell damage does not necessarily occur in individuals who experience elevated intraocular pressure. Two studies have suggested that increased choroidal perfusion (circulation) may help to prevent glaucomatous optic nerve damage in patients with ocular hypertension. Schmidt, K. G., von Ruckmann, A., et al., Ophthalmologica, 212 (1) pp. 5-10 (1998) and Kerr J.; Nelson P.; O'Brien C., Am, J Ophthalmol., 126 (1) pp. 42-51 (1998). Thus, modernly it appears that glaucoma is characterized as a complex syndrome that manifests itself as optic nerve damage with or without elevated intraocular pressure. It further appears that each symptom, either elevated intraocular pressure or glaucomatous damage to nerve cells, can occur independently of the other. The present invention provides methods to protect retinal ganglion cells and the optic nerve that are damaged or lost despite a therapeutic lowering of intraocular pressure to within normal levels; to protect such cells from damage in the case of so-called normotensive glaucoma; and to protect such cells in glaucomatous eyes that do not respond adequately to treatment modalities intended to lower intraocular pressure.
In cases where surgery is not indicated, topical beta-adrenoceptor antagonists have been the drugs of choice for treating glaucoma. However, alpha adrenergic agonists have more recently been approved for use in the treatment of elevated intraocular pressure and are probably becoming mainstays in the treatment of the disease. Among this class of drugs are various quinoxaline derivatives having alpha
2
agonist activity which were originally suggested as therapeutic agents by Danielewicz, et al. in U.S. Pat. Nos. 3,890,319 and 4,029,792. These patents disclose compounds as regulators of the cardiovascular system which have the following formula:
where the 2-imidazolin-2-ylamino group may be in any of the 5-, 6-, 7- or 8-position of the quinoxaline nucleus; x, y and z may be in any of the remaining 5-, 6-, 7- or 8-positions and may be selected from hydrogen, halogen, lower alkyl, lower alkoxy or trifluoromethyl; and R is an optional substituent in either the 2- or 3-position of the quinoxaline nucleus and may be hydrogen, lower alkyl or lower alkoxy. The presently useful compounds may be prepared in accordance with the procedures outlined by Danielewicz, et al. The contents of both U.S. Pat. Nos. 3,890,319 and 4,029,792 are hereby incorporated by reference in their entirety.
In “Ocular Effects of a Relatively Selective Alpha-2 Agonist (UK-14,304-18) in Cats, Rabbits and Monkeys” [A. Burke, et al.,
Current Eye Rsrch.,
5, (9), pp. 665-676 (1986)] the quinoxaline derivative shown below and having the generic name brimonidine was shown to be effective in reducing intraocular pressure in rabbits, cats and monkeys. Compounds in this study were administered topically to the corneas of the study animals.
It has long been known that one of the sequelae of glaucoma is damage to the optic nerve head. The optic nerve head or optic disk is where, along with the retinal vasculature, the axons of the retinal ganglion cell (RGC) bodies that are distributed along the upper layer of the retina converge and are bundled together to transmit signals to the l
Lai Ronald K.
Wheeler Larry A.
Woldemussie Elizabeth
Allergan Inc.
Baran Robert J.
Fay Zohreh
Fisher Carlos A.
Voet Martin A.
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