Glaucoma treatment

Details Glaucoma treatment Glaucoma treatment

1999-03-25

2002-11-19

Fay, Zohreh (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S912000

Reexamination Certificate

active

06482854

ABSTRACT:

This application relates to glaucoma treatment.
This application is a continuation and claims the benefit of priorty under 35 USC §120 of U.S. application Ser. No. 07/984,939, filed Dec. 4, 1992. This application is hereby incorporated by reference in it's entirety.
BACKGROUND OF THE INVENTION
Glaucoma affects approximately five percent of persons who are older than 65 years and fourteen percent of those older than 80 years. The visual loss which results from glaucoma conditions has been attributed to progressive damage of the optic nerve and consequent loss of retinal ganglion cells, mediated by elevated intraocular pressure (Quigley et al.,
Invest. Ophthalmol. Vis. Sci.
19:505, 1980). Consequently, therapeutic modalities have focused on the management of intraocular pressure.
Many compounds have been proposed to treat glaucoma. See generally, Horlington U.S. Pat. No. 4,425,346; Komuro et al. U.S. Pat. No. 4,396,625; Gubin et al. U.S. Pat. No. 5,017,579; Yamamori et al. U.S. Pat. No. 4,396,625; and Bodor et al. U.S. Pat. No. 4,158,005.
At the present time, medical control of intraocular pressure consists of topical or oral administration of a miotic (e.g., pilocarpine), epinephrine derivatives (e.g., dipivalyl epinephrine), or topical beta blockers (e.g., timolol). Abelson U.S. Pat. No. 4,981,871 discloses the use of a class I voltage-dependent Ca
++
channel blocking agent (a phenylalkylamine) to treat elevated ocular pressure (Specifically, Abelson '871 discloses the use of verapamil, which does not cross the blood brain barrier and does not reach retinal ganglion cells).
Miotics may reduce the patient's visual acuity, particularly in the presence of lenticular opacities. Topical beta blockers such as Timolo™ have been associated with systemic side effects such as fatigue, confusion, or asthma, and exacerbation of cardiac symptoms has been reported after rapid withdrawal of topical beta blockers. Oral administration of carbonic anhydrase inhibitors, such as acetazolamide, may also be used, but these agents can be associated with systemic side effects including chronic metabolic acidosis.
If current methods of treatment fail to reduce intraocular pressure, laser treatment or a drainage operation (e.g., trabeculectomy) is usually performed.
SUMMARY OF THE INVENTION
We have discovered that glaucoma is associated with elevated glutamate. We have further discovered that glaucoma management, particularly protection of retinal ganglion cells, can be achieved by administering to the patient a compound capable of reducing glutamate-induced excitotoxicity in a concentration effective to reduce such excitotoxicity, thereby reducing the loss of retinal ganglion cells resulting from such excitotoxicity.
By way of additional background underlying the invention, excessive influx of Ca
2+
due to glutamate-mediated receptor activation is thought to underlie excitotoxicity. Several types of calcium-permeable ion channels that can be involved in this excitotoxicity are mentioned below, including voltage-dependent Ca
2+
channels, the NMDA receptor channel complex, and other channels directly coupled to glutamate (or excitatory amino acid) receptors. Such channels are reviewed in Sommer, B. and Seeburg, P. H. Glutamate receptor channels: novel properties and new clones. Trends Pharmacological Sciences 13:291-296 (1992); Nakanishi, S. Molecular Diversity of glutamate receptors and implications for brain function. Science 248:597-603 (1992).
One aspect of the invention generally features administering antagonists of glutamate-induced excitotoxicity that are capable of crossing both the blood-brain brain barrier and the blood-retina barrier to human patients with non-vascular glaucoma—i.e., all types of glaucoma other than the type commonly termed “neo-vascular” glaucoma.
A second aspect of the invention features the use of antagonists that do not have a substantial direct effect on glutamate toxicity mediated by the L-type voltage dependent Ca
++
channel, but instead affect glutamate toxicity mediated by other mechanisms detailed below. We consider that a compound has a substantial direct effect on glutamate toxicity mediated by the L-type voltage dependent Ca
++
channel if it produces a statistically significant result in experiments measuring glutamate induced effects by the general method described in Karschian and Lipton,
J. Physiol.
418: 379-396 (1989) or by other techniques for measuring antagonism of the L-type Ca
++
channel known to those in the art. (We contrast the direct effect so measured with the secondary effects of excitoxicity mediated by other channels, which in turn causes flow through the voltage dependent Ca
++
channels.) In particular, this aspect of the invention features use of compounds which are not Class I voltage dependent Ca
++
channel antagonists, e.g., compounds that are not phenylalkylamines. Preferably, this second aspect of the invention features antagonists of the N-methyl-D-aspartate (NMDA) receptor channel complex and other glutamate receptor antagonists described in detail below. Other useful compounds according to the invention include antagonists of non-NMDA receptors—i.e. antagonists of glutamate induced excitotoxicity that do substantially affect excitotoxicity mediated via the NMDA receptor channel complex (e.g., excitoxicity caused by NMDA in experiments well known to those in the art), but instead operate by antagonizing excitoxicity mediated via other glutamate receptors. Also, antagonists of the second aspect are used in preferred embodiments of the first aspect of the invention.
According to both aspects, the invention preferably will be used to treat patients which have primary open-angle glaucoma, chronic closed-angle glaucoma, pseudoexfoliation, or other sub-types of glaucoma or ocular hypertension. Preferably, the agent is administered over an extended period (e.g., at least six months and preferably at least one year), regardless of changes in the patient's intraocular pressure over the period of administration.
Particularly preferred compounds used in both aspects of the invention are antagonists of the NMDA receptor-channel complex. The term “NMDA receptor antagonists” includes several sub-types of NMDA antagonists including: a) channel blockers—i.e., antagonists that operate uncompetitively to block the NMDA receptor channel; b) receptor antagonists—antagonists that compete with NMDA to act at the NMDA binding site; c) agents acting at either the glycine co-agonist site or any of several modulation sites such as the zinc site, the magnesium site, the redox modulatory site, or the polyamine site; d) agents which inhibit the downstream effects of NMDA receptor stimulation, such as agents that inhibit activation of protein kinase C activation by NMDA stimulation, antioxidants, and agents that decrease phosphatidylinositol metabolism.
Other compounds that are useful in the invention include voltage-dependent calcium channel antagonists which are described in greater detail below, particularly those which cross the blood-brain and blood-retina barriers and which can be administered chronically. Other preferred agents act as antagonists of non-NMDA receptors (glutamate receptor types other than the NMDA receptor complex discussed above), and include agents which block ionotropic glutamate receptors or interact with metabotropic glutamate receptors (Nakanishi, supra). Other preferred agents act to limit (reduce) release of glutamate from cells, thereby acting upstream from the glutamate receptors in the excitatory neurotoxicity process. Still other agents may act by blocking downstream effects of glutamate receptor stimulation, e.g., the intracellular consequences of glutamate interaction with a cell membrane glutamate receptor, such as agents (like dantrolene) that block the rise in intracellular calcium following stimulation of membrane glutamate receptors.
The most preferred compounds are those capable of crossing the blood-brain barrier or the b

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