MXPA99008771A - Use of sodium channel blocker in the manufacture of a medicament for preventing optic nerve degeneration associated with glaucoma - Google Patents

Abstract

A method and 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+ 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+/Ca2+ 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.

Description

INHIBITION OF NON-INACTIVATING SODIUM CHANNELS OF THE OPTICAL NERVE OF A MAMMALIAN AS A MEANS OF PREVENTING THE DEGENERATION OF THE OPTICAL NERVE ASSOCIATED WITH GLAUCOMA BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to a method of preventing the death of retinal ganglion cells, associated with glaucoma, by administering to the retinal ganglion cells of a mammal, a compound which blocks the putative non-inactivating sodium ion channels of the cell type. previous.

Brief description of the technique Glaucoma is an optic neuropathy associated with high intraocular pressures, which are too high for normal eye function, and results in an irreversible loss of visual function. (See, for example, Dreyer et al. "Elevated glutamate levéis in the vitreous body of human and monkeys with glaucoma", Arch. Ophthalmology 114: 229-305, 1996). It is estimated in medical science that glaucoma concerns approximately 2 percent of the population over 40 years of age, and is therefore a serious health problem. The Ref. 031233 l ^ iM HÉßM ________ ^^^^^ IIMßU ^^ Miiáíil ^ liittM «__.

Ocular hypertension, that is, the condition of elevated intraocular pressure, which has not yet caused irreversible damage, is thought to represent the first phase of glaucoma. Many therapeutic agents have been invented and discovered in the prior art for the treatment or improvement of glaucoma and the condition of increased intraocular pressure, which precedes glaucoma.

Primary open-angle glaucoma (POAG) is associated with an increase in intraocular pressure (IOP). This increase in IOP is thought to contribute to the loss of optic nerve function, which eventually leads to blindness. The reduction of the IOP is therefore a crucial component in the management of the POAG. However, in many individuals the decrease in IOP is not sufficient or is ineffective in preventing the loss of vision associated with POAG.

It is observed that a new class of sodium channels that are inside the optic nerve of the rat is responsible for the damage to the optic nerve of the rat, after the anoxia or hypoxia. However, in glaucoma, the sequence of pathological events that lead to loss of optic nerve function is not known.

Drugs currently used in the treatment of glaucoma include miotics (eg, pilocarpine, carbacol, and acetylcholinesterase inhibitors), sympathomimetics (eg, epinephrine and dipivalypinephrine), beta blockers (eg, betaxolol, levobunolol, and tmololol). ), alpha-2 agonists (for example, para-amino clonidine) and carbon-anhydrase inhibitors (for example, acetazolamide, methozolamide and ethoxzolamide). The miotics and sympathomimetics are believed to reduce intraocular pressure by increasing the flow of aqueous humor, while beta-blockers, alpha-2 agonists and carbon-anhydrase inhibitors are thought to reduce intraocular pressure by decreasing aqueous humor formation. All five types of drugs have potential side effects. Myotics, such as pilocarpine, can cause vision blurring and other visual side effects, which may either decrease patient flexibility or require termination of miotic drug therapy. Carbonic anhydrase inhibitors can also cause serious side effects, which affect the patient's flexibility and / or require the withdrawal of drug therapy. At least one beta-blocker, timolol, has become increasingly associated with serious pulmonary side effects attributable to its effect on the beta-2 receptors in lung tissue.

As a result, additional antiglaucoma drugs are being developed, for example, prostaglandin derivatives, muscarinic antagonists, etc. However, none of the above drugs is intended to directly interact with the retinal ganglion cells and their associated neuroejuves.

Thus, it would be desirable to prevent the loss of ganglion cell function and neuroaxis, which can be associated with glaucoma by a biological mechanism, which does not modulate the dynamics of aqueous humor and therefore intraocular pressure. In addition, it would be desirable to treat the retinal and neuraxial ganglionic body of a mammal directly to prevent destruction thereof by the glaucomatous condition.

BRIEF DESCRIPTION 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 can be effective in preventing the loss of retinal ganglion cells when said blockers of sodium channel are administered and applied in a pharmaceutical composition. Therefore, the present «A ufe- .... invention relates to a method of preventing the loss of retinal ganglion cells and their associated neuroaxis (optic nerve), associated with glaucoma, systematically or directly by administering to the eye of a mammal an ophthalmic composition, which includes an amount of a blocker of sodium channel, which is effective to block the non-inactivating sodium ion channel of the ganglion cells of the mammal.

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

Specifically, this block is achieved by administering to the retinal ganglion cells a pharmaceutical composition having an active ingredient with a non-inactivating sodium channel blocking activity. The composition may comprise antiarrhythmic agents or compounds such as benzothiazole riluzole, lubelezol, RS6685, phenylbenzene acetamide, such as PD 85, 689. Laryarizine (RS-87476) and diphenylpiperazine, anticonvulsants such as phenytoin and carbamezepine. . Lamotrigine and its derivatives.

The composition may comprise an ophthalmic solution adapted for administration to the eye of a mammal in the intracameral injection form and the active ingredient, such as antiarrhythmic agents, may be present between 0.001 to about 1% weight per volume.

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

In addition, a pharmaceutical composition is 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-sodium channel blocking activity. inactivating.

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 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.

BRIEF DESCRIPTION OF THE DRAWINGS The advantages and features of the present invention would be better understood by the following description when considered in conjunction with the accompanying drawings.

Figure 1 is a diagram of the relevant transport mechanisms assumed for a retinal ganglion cell under normal conditions; Y ^^^^^^^^^^^^^^^^^^^ ____ ^^^^ _, ^ _ «^ í; & ^ ftk_i_.

Figure 2 is a diagram of a retinal ganglion cell under ischemic conditions ^.

DETAILED DESCRIPTION OF THE INVENTION While not wishing to be bound by theory, it is believed that the death or loss of neuroaxis and associated cell bodies comprising the optic nerve is the result of a lethal increase in the intracellular calcium ion (Ca + 2) concentration that results from an influx of sodium ion (Na +) through a non-inactivating sodium ion channel. While studies have been carried out on segments of the rat optic nerve (Stys et al., 1995; Waxman, 1995), no application has been made to the ganglion cells. There is no expectation of altering a similar sequence of pathological events in the retinal cells to prevent their death after anoxia based on the first experiments in the rat optic nerves, because it is unclear if (1) a sequence Similar events occur during glaucoma or (2) if non-inactivating Na channels are present in mammalian retinal ganglion cells, and, if present, the role of these channels plays in the destruction of ganglion cells retinal accompanying loss of vision associated with glaucoma.

The procedure in the rat retinal ganglion cell is as follows: After depolarization, the excitable voltage dependent Na channels open for approximately one millisecond and then close. As long as the cell membrane remains depolarized, the channels will not open again until the membrane becomes biased close to its dormant state. In addition to normal excitable Na channels, non-inactivating Na channels can be opened in normal latent membrane potentials and can remain open in depolarized potentials. Under pathophysiological conditions, such as decreased adenosine triphosphate (ATP) or sustained depolarization, the influx of Na through the non-inactivating Na channels can substantially increase the intracellular Na. This increase in intracellular Na causes the electrogenic Na / Ca2 + exchanger (Ransom et al., 1993; Stys, 1995, Waxman et al., 1992), which normally operates to promote the Ca2 + flow of the cell, reverse the operation with a large increase resulting in the concentration of intracellular Ca2 +. The Ca2 + concentration of the cell can increase from nanomolar to micromolar levels with the resulting death of the neuronal cell. (Large increases in intracellular Ca2 + have been associated with neuronal cell death and the prevention of increased intracellular Ca2 + concentration has been shown to protect the neurons of the central nervous system, and the optic nerve of the rat). In the preparation of the optic nerve, intracellular Ca2 + is not measured, however, the Ca2 + of the normal cell in most cell types, including * neurons, is approximately 100-200 nanomolar. When Ca2 + increases to micromolar levels it becomes toxic. Exactly what level of Ca2 + in the optic nerve causes cell destruction is not known or at least has not been reported.

Thus, the compounds used according to the method of the present invention and in the compositions of the present invention are the sodium channel blockers, which block the non-inactivating sodium ion channels of the retinal ganglion cells. The sodium channel blockers of the present invention prevent the influx of sodium ions into the neuronal cell through the non-inactivating sodium channel. Preferably, the sodium channel blockers of the present invention will selectively block the non-inactivating sodium channels as opposed to the sodium ion channels cyclically disconnected from the voltage which become rapidly inactive.

The pharmaceutically acceptable salts of the sodium channel blockers can also be used in accordance with the present invention. A pharmaceutically acceptable salt can be any salt, which retains the activity of the main compound and does not impart any adverse or unfavorable effect on the subject to which it is administered and in the context in which it is administered.

Such salt can be derived from any organic or inorganic acid or base. The salt can be a mono or polyvalent ion. Of particular interest, where the acid function is related, are inorganic ions, such as alkali ions, for example, sodium, potassium, etc. The organic amine salts can be made with amines, particularly ammonium salts, such as mono-, di- and trialkyl amines, for example, alkyl amines, wherein each alkyl group can comprise up to six carbon atoms, or amines of ethanol. The salts can also be formed with caffeine, tromethamine and similar molecules. It is only important that the cation of any salt of a sodium channel blocker used in the compositions or methods of this invention be capable of blocking the non-inactivating sodium channels of the retinal ganglion cells.

To protect against the loss of retinal ganglion cells in a mammalian eye, and particularly for the prevention of retinal ganglion cell loss in humans exposed to a condition causing loss of optic neurons, the active compounds (or mixtures or salts thereof) same) are administered, according to the present invention, to the eye mixed with an ophthalmically acceptable carrier. Any ophthalmically acceptable, conventional, suitable carrier, for example, may be employed. A carrier is ophthalmically acceptable if it substantially does not have a long term or permanent detrimental effect on the eye to which it is administered. Examples of ophthalmically acceptable carriers include water (distilled or deionized water), saline and other aqueous medium. According to the invention, the active compounds are preferably soluble in the carrier, which is used for administration, so that the active compounds are administered to the eye in the form of a solution. Alternatively, a suspension of the active compound (s) (or salts thereof) in a suitable carrier can also be employed.

According to the invention, the active compounds (or mixtures or salts thereof) are administered in an ophthalmically acceptable carrier in a sufficient concentration to deliver an effective amount of the compound or compounds Flto? G £ & tt ^ assets to the site of the optic nerve of the eye. Preferably, Therapeutic, ophthalmic solutions contain one or more of the active compounds in a concentration range of about 0.0001% up to about 1% (weight per volume) and more preferably about 0.0005% up to about 0.1% (weight per volume).

Any method of administering drugs to the retinal ganglion cell site of a mammalian eye can be employed to administer, in accordance with the present invention, the compound or compounds active to the eye to be treated. The term "administration" means that it includes those general systemic drug administration modes, for example, injection directly into the patient's blood vessels, oral administration and the like, which results in the compound or compounds being commercially available. Also, intercameral injection can be used to deliver the sodium channel blocker to the site of the retinal ganglion cell. The primary effect in the mammal resulting from the direct administration of the active compound or compounds to the eye of the mammal is the prevention of the loss of the optic nerve. Preferably, the active useful compound or compounds are applied topically to the eye or are injected directly into the eye.

The injection of ophthalmic preparations, for example eye drops, gels or creams can be used because of their ease of application, ease of delivery of doses and few systemic side effects, such as cardiovascular hypotension. An exemplary topical ophthalmic formulation is shown below in Table I. The abbreviation q.s. means enough to produce the result or complete the volume.

TABLE I Ingredient Quantity (% P / v) Active Compound according to approximately 0.0001 the invention up to approximately 1 Conservative 0 - 0.10 Vehicle 0 - 40 Tonicity Adjuster 1 - 10 Buffer 0.01 - 10 pH Adjuster q.s. pH 4.5 - 7.5 Antioxidant as necessary Purified water as necessary to complete 100% ^ jH | Various preservatives can be used in the ophthalmic preparation described in Table I above. Preferred preservatives include, but are not limited to, benzalkonium potassium, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate. Likewise, several preferred vehicles can be used in such ophthalmic preparation. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamers, carboxymethylcellulose and hydroxyethylcellulose.

Tonicity adjusters can be added as necessary or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, etc., mannitol and glycerin, or any other ophthalmically acceptable tonicity adjuster.

Various buffers and means for adjusting the pH can be used as long as the resulting preparation is ophthalmically acceptable. Accordingly, dampers include but are not limited to acetate buffers, citrate buffers, phosphate buffers, and borate buffers. The acids or bases can be used to adjust the pH of these formulations as necessary.

In a similar manner, ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

Those skilled in the art will recognize that the frequency of administration depends on the precise nature of the active ingredient and its concentration in the ophthalmic formulation. The compounds that are blockers of the non-inactivating Na channels are Class I antiarrhythmic agents, such as phenytoin, lidocaine, lamotrigine, mexiletine, prajmaline, tocainide, QX-314, QX-222 and other functionally referred compounds. These agents preferably block the non-inactivating Na channels when compared to the Na channels cyclically disconnected from the normal voltage.

Specific examples of sodium channel blockers, which are used as the effective active ingredients in the ophthalmic compositions of the present invention are described as quinidine, ajmaline, prajmal, procainamide, disopyramide, propafenone, lidocaine, tocainide, mexiletine, phenytoin , flecainide, lorcainide, aprindine, encainide, QX-314, procaine, QX-222, tetracaine, Benzocaine, GEA-968, azure A, pancuronium, N-methylstricnin, fosphenytoin, CNS 1237, B 1003C87, BW619C89, U54494A, PD85639, ralitolin, C1953, lifarizine, zonisamide and riluzole.

A sodium channel blocker, according to the present invention, can be identified by the methods described in "The Extracellular Patch Clamp: A Method for Resolving Currents Through Individual Open Channels in Biological Membranes", Neher et al., Pflugers Archiv V375 pp. 219-228 (1978) and "Improved Patch-Clamp Techniques for Higher Resolution Current Recording from Cells and Cell-Free Membrane Patches", Hamill et al., Pflugers Archiv V391 pp. 85-100 (1981). These references are incorporated herein fully to provide a method for identifying sodium channel blockers useful in accordance with the present invention.

EXAMPLE Figure 1 shows a representation of a retinal ganglion cell 10, under normal conditions and relevant transport mechanisms assumed 12, 14, 16, 18 responsible for maintaining the gradients of sodium (Na +), potassium (K +) and calcium (Ca2 +) and the electrical activity of the cell. As shown under normal conditions, the ATP levels are adequate and provide the fuel needed to drive the Na + / K + 14 pump that maintains the K + and Na + gradients, maintains the intracellular concentrations of K + high and Na + low in relation to its particular extracellular concentrations. The Na + and K + channels disconnected cyclically from the voltage 12, 16 provide the currents that complete the action potential. The electrogenic Na + / Ca2 + exchanger 18 maintains cellular Ca2 + levels within the physiological range (nanomolar).

However, if the ATP levels fall, due to some pathophysiological trauma, the neuroaxis will depolarize and the Na + / K + gradients will fall over time as a result of the inhibition of the Na + / K + 14 pump as shown in the Figure 2 for a cell 20 under ischemic conditions. The increase in cellular Na + is mediated by a subset of Na + channels cyclically disconnected from the voltage that do not become inactive over time. These Na + channels become "non-inactivating". The combination of membrane depolarization and intracellular Na + increase is sufficient to drive the Na + / Ca2 + exchanger in the opposite direction (see Figure 2), such that the ganglion cells are loaded with lethal levels of Ca2 +. It is assumed that this scenario occurs in the retinal ganglion cell in glaucoma. ^ a SÉHÉit. Accordingly, according to the present invention, the following sequence is expected in the presence of a therapeutic concentration of a selective Na + channel blocker for the non-inactivating type. First, the Na + channel blocker would have little or no effect on the normal action potential. This is crucial for the normal function of the ganglion cell. Second, it will block the noxious increase in Na + of the cell and the subsequent lethal increase in Ca2 + in the cell. In this way, normal lymph node cell dysfunction will be minimized and therefore help prevent the loss of visual field associated with glaucoma. In addition, blockers of non-inactivating Na + channels can produce an additional benefit. This is because the Na + channels are thought to help prevent the release of excitotoxic glutamate, which occurs in neuronal tissue during ischemia, hypoxia and other pathological conditions. Excessive extracellular glutamate levels are neurodestructive and thus can also be understood in glaucomatous optic neuropathy. Thus, the overload of Na + and excitotoxic increase in extracellular glutamate according to the present invention can be prevented by a therapeutic concentration of a drug, a blocker of the non-inactivating Na + channels.

In view of the foregoing, it is clear that the scope of the present invention should be interpreted only on the basis of the following claims, since such claims are read in the clarity of the disclosure.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (10)

1. The use of a sodium blocker in the manufacture of a medicament for maintaining normal intracellular Na and Ca in the ganglion cells after a period of anoxia, the sodium blocker comprises a composition for the blocking of calcium channel activity not inactivating in retinal ganglion neuronal cells.

2. The use according to claim 1, wherein the composition for blocking non-inactivating sodium channels is selected from the group consisting of benzothiazole riluzole, lubelezol, phenyl benzothiozole and lifarizine.

3. The use according to claim 2, wherein the composition having non-inactivating sodium channel blocking activity comprises an antiarrhythmic agent.

4. The use according to claim 1, wherein the composition comprises an ophthalmic solution adapted for administration to the eye of a mammal in the form of intracameral injection.

5. The use of a sodium blocker in the manufacture of a pharmaceutical composition useful for preventing the death of retinal ganglion cells, associated with glaucoma, in the eye of a mammal, the composition comprises as its active ingredient one or more compounds having activity of blockade of the non-inactivating sodium channel.

6. The use according to claim 5, wherein the compound having non-inactivating sodium channel blocking activity is selected from the group consisting of benzothiazole riluzole, lubelezol, phenyl benzothiozole and lifarizine.

7. The use according to claim 5, wherein the composition is an ophthalmic solution, adapted for administration to the eye of a mammal in the form of an intracameral injection.

* ~ «« * - - «- 8. The use of a sodium blocker in the manufacture of a drug to prevent the death of retinal ganglion cells, associated with glaucoma, in an animal of the species of mammals, including humans , the pharmaceutical composition of the sodium blocker, which comprises as its active ingredient one or more compounds having non-inactivating sodium channel blocking activity.

9. The use of a sodium blocker in the manufacture of a medicament to provide a neuroprotective effect to retinal ganglion cells in a human eye, the sodium blocker comprises a pharmaceutical composition, which comprises as its active ingredient one or more compounds which have non-inactivating sodium channel blocking activity.

10. The use according to claim 9, wherein the compound having non-inactivating sodium channel blocking activity is selected from the group consisting of benzothiazole riluzole, lubelezol, phenyl benzothiozole and lifarizine.