Title: Inhibition of noninactivating Na channels of mammalian optic nerve as a means of preventing optic nerve degeneration associated with glaucoma

United States Patent:  6,326,389

Assignee:  Allergan Sales, Inc. (Irvine, CA)

Filed:  March 22, 1999

A method an composition for altering a plausible sequence of pathological events in retinal ganglion cells associated with glaucoma, the sequence including membrane depolarization, influx of millimolar amounts of Na⁺ via non-inactivating Na⁺ channels, and the lethal elevation of cell Ca²⁺ due to reversal of the Na⁺ /Ca²⁺ exchanger. The method includes blocking, by administration of a selected composition, of associated, non-inactivating Na⁺ channels in retinal ganglion cells in order to limit Na⁺ /Ca³⁰ exchange in the retinal ganglion cells and prevent buildup of the Ca²⁺ level in the retinal ganglion cells to a lethal level. The results in a method of preventing retinal ganglion cell death, associated with glaucoma, by administering to the optic nerve of a mammal, a compound which blocks the non-inactivating sodium ion channels of the optic nerve. Alternately, said invention relates to a method of preventing optic retinal ganglion cell death in a human by administering to the retinal ganglion cells of said human a compound which blocks the non-inactivating sodium ion channel of the retinal ganglion cells.

SUMMARY OF THE INVENTION

Surprisingly, it has been discovered in accordance with the present invention, that sodium channel blockers which block the non-inactivating sodium ion channel of the optic nerve of a mammal may be effective for preventing the loss of retinal ganglion cells when such sodium channel blockers are administered and applied in a pharmaceutical composition. Accordingly, the present invention relates to a method of preventing loss of retinal ganglion cells and their associated axons (optic nerve) function, associated with glaucoma, by systemically or directly administering to the eye of a mammals an ophthalmic composition which includes an amount of a sodium channel blocker which is effective to block the non-inactivating sodium ion channel of the ganglion cells of said mammal.

More specifically, the present invention is directed to a method for altering a possible sequence of pathological events in retinal ganglion cells that may be associated with glaucomatous optic neuropathy. The sequence includes the pathological depolarization of retinal ganglion cells, an influx of millimolar amounts of sodium via non-inactivating sodium channels and a subsequent reversal of the sodium/calcium exchanger. Reversal of the sodium/calcium exchanger mediated by both membrane depolarization and increased intracellular sodium causes a toxic buildup of intracellular calcium. The method for altering this sequence includes a step of blocking associated non-inactivating sodium channels in retinal ganglion cells in order to prevent reversal of sodium/calcium ion exchange and subsequent buildup of the calcium ion concentration in the retinal ganglion cells to a lethal level.

Specifically, this blocking is achieved by administering to the retinal ganglion cells a pharmaceutical composition having an active ingredient with non-inactivating sodium channel blocking activity.

Specific examples of sodium channel blockers which are used as the active effective ingredients in the ophthalmic compositions of the present invention are described as benzothialzole, phenyl benzothialzole, disopyramide, propafenone, flecainide, lorcainide, aprindine, encainide, GEA-968, azure A, pancuronium, N-methylstrychnine, CNS 1237, BW1003C87, BW619C89, U54494A, PD85639, ralitoline, C1953, lifarizine, zonisamide and riluzole.

The composition may comprise an ophthalmic solution adapted for administration to the eye of a mammal in the form of intracameral injection.

A direct effect on retinal ganglion cells is an important discovery in accordance with the method of the present invention. However, normal electrical excitability of ganglion cells, crucial for vision, will not be compromised.

Further, a pharmaceutical composition provided in accordance with the present invention useful for preventing retinal ganglion cell death associated with glaucoma with the composition comprising with its active ingredient one or more compounds having non-inactivating sodium channel blocking activity.

More specifically, the present invention provides a method for preventing retinal ganglion cell death associated with glaucoma in an animal of the mammalian species, including humans, which includes the step of administering to the retinal ganglion cells of the mammal a pharmaceutical composition which comprises as its active ingredient one or more compounds having non-inactivating sodium channel blocking activity.

Claim 1 of 4 Claims

What is claimed is:

1. A method for preventing retinal ganglion cell death, associated with glaucoma, in an animal of the mammalian species, including humans, comprising the step of administering to the ganglion optic nerve of said mammal a pharmaceutical composition which comprises as its active ingredient one or more compounds having non-inactivating sodium channel blocking activity.

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