Title:  Method for treating a demyelinating condition

United States Patent:  6,455,553

Issued:  September 24, 2002

Inventors:  Werner; Peter (New York, NY); Pitt; David (Bronx, NY)

Assignee:  Albert Einstein College of Medicine of Yeshiva University (Bronx, NY)

Appl. No.:  678686

Filed:  October 3, 2000

The present invention provides a method for treating a demyelinating condition in a subject in need of treatment, by administering to the subject an amount of a Ca²⁺ -channel blocker effective to treat the demyelinating condition. The present invention is also directed to a method for treating a demyelinating condition in a subject in need of treatment, by administering to the subject a Ca²⁺ -channel blocker in combination with a glutamate inhibitor, in amounts effective to treat the demyelinating condition. Also disclosed is a pharmaceutical composition comprising a Ca²⁺ -channel blocker, a glutamate inhibitor, and a pharmaceutically-acceptable carrier. Additionally, the present invention provides a method for treating a demyelinating condition in a subject in need of treatment, by administering to the subject a Ca²⁺ -channel blocker in combination with a hypertensive agent, in amounts effective to treat the demyelinating condition. Finally, the present invention discloses a pharmaceutical composition comprising a Ca²⁺ -channel blocker, a hypertensive agent, and a pharmaceutically-acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a method for treating a demyelinating condition in a subject in need of treatment. The subject may be any mammal (e.g., dog, human, monkey), but is preferably a human. The method of the present invention comprises administering to the subject an amount of a calcium-channel blocker (Ca²⁺ -channel blocker) effective to treat the demyelinating condition in the subject. As used herein, the term "demyelinating condition" refers to a disease, disorder, or condition characterized by loss of myelin. Examples include, without limitation, acute disseminated encephalomyelitis (ADEM), acute transverse myelitis, acute viral encephalitis, adrenoleukodystrophy (ALD), adrenomyeloneuropathy, AIDS-vacuolar myelopathy, experimental autoimmune encephalomyelitis (EAE), experimental autoimmune neuritis (EAN), HTLV-associated myelopathy, Leber's hereditary optic atrophy, multiple sclerosis (MS), progressive multifocal leukoencephalopathy (PML), subacute sclerosing panencephalitis, and tropical spastic paraparesis. Preferably, the demyelinating condition is MS. Additionally, as used herein, the term "calcium-channel blocker" or "Ca²⁺ -channel blocker" refers to one of a class of pharmacological agents, also known as calcium antagonists, which inhibit the transmembrane flux of calcium (Ca²⁺) ions.

As used herein, the term "agent" includes a protein, polypeptide, peptide, nucleic acid (including DNA or RNA), antibody, molecule, compound, antibiotic, drug, and any combinations thereof. Ca²⁺ -channel blockers are well-known in the art.

Examples of Ca²⁺ -channel blockers include, without limitation, amlodipine, bepridil, diltiazem, felodipine, flunarizine, isradipine, mibefradil, nicardipine, nifedipine, nimodipine, nisoldipine, nivaldipine, and verapamil. Preferably, the Ca²⁺ -channel blocker is amlodipine. As used herein, "amlodipine" refers to amlodipine and analogues thereof, including, for example, a functional variant of amlodipine which has amlodipine biological activity, as well as a fragment of amlodipine having amlodipine biological activity. As further used herein, the term "amlodipine biological activity" refers to amlodipine activity which ameliorates clinical impairment or symptoms of a demyelinating condition in a subject having a demyelinating condition.

Synthetic amlodipine is commercially available, and can be obtained from Pfizer Inc. (New York, N.Y.). Norvasc is the besylate salt of amlodipine. Norvasc tablets are formulated as white tablets, equivalent to 2.5, 5, and 10 mg of amlodipine, for oral administration. Amlodipine is an affordable compound; moreover, it provides a novel approach to treating demyelinating conditions based on pathophysiologic mechanisms [22]. As with other Ca²⁺ -channel blockers, though, amlodipine should be used with caution when treating subjects with heart failure [14].

The Ca²⁺ -channel blocker of the present invention is administered to a subject having a demyelinating condition in an amount which is effective to treat the demyelinating condition in the subject. As used herein, the phrase "effective to treat the demyelinating condition" means effective to ameliorate or minimize the clinical impairment or symptoms of the demyelinating condition. For example, where the demyelinating condition is MS, the amount of Ca²⁺ -channel blocker effective to treat the demyelinating condition is that which can ameliorate or minimize the symptoms of MS, including lack of co-ordination, paresthesias, speech and visual disturbances, and weakness. The amount of Ca²⁺ -channel blocker effective to treat a demyelinating condition in a subject will vary depending on the Ca²⁺ -channel blocker which is used. For example, the amount of amlodipine may range from about 5 mg/day to about 35 mg/day. Appropriate amounts of other Ca²⁺ -channel blockers effective to treat a demyelinating condition in a subject can be readily determined by the skilled artisan.

According to the method of the present invention, the Ca²⁺ -channel blocker may be administered to a human or animal subject by known procedures, including, but not limited to, oral administration, parenteral administration, transdermal administration, and administration through an osmotic mini-pump. Preferably, the Ca²⁺ -channel blocker is administered orally.

For oral administration, the formulation of the Ca²⁺ -channel blocker may be presented as capsules, tablets, powders, granules, or as a suspension. The formulation may have conventional additives, such as lactose, mannitol, corn starch, or potato starch. The formulation also may be presented with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch, or gelatins. Additionally, the formulation may be presented with disintegrators, such as corn starch, potato starch, or sodium carboxymethylcellulose. The formulation also may be presented with dibasic calcium phosphate anhydrous or sodium starch glycolate. Finally, the formulation may be presented with lubricants, such as talc or magnesium stearate.

For parenteral administration, the Ca²⁺ -channel blocker may be combined with a sterile aqueous solution which is preferably isotonic with the blood of the subject. Such a formulation may be prepared by dissolving a solid active ingredient in water containing physiologically-compatible substances, such as sodium chloride, glycine, and the like, and having a buffered pH compatible with physiological conditions, so as to produce an aqueous solution, then rendering said solution sterile. The formulations may be present in unit or multi-dose containers, such as sealed ampoules or vials. The formulation may be delivered by any mode of injection, including, without limitation, epifascial, intracapsular, intracutaneous, intramuscular, intraorbital, intraspinal, intrasternal, intravascular, intravenous, parenchymatous, or subcutaneous.

For transdermal administration, the Ca²⁺ -channel blocker may be combined with skin penetration enhancers, such as propylene glycol, polyethylene glycol, isopropanol, ethanol, oleic acid, N-methylpyrrolidone, and the like, which increase the permeability of the skin to the Ca²⁺ -channel blocker, and permit the Ca²⁺ -channel blocker to penetrate through the skin and into the bloodstream. The Ca²⁺ -channel blocker/enhancer compositions also may be further combined with a polymeric substance, such as ethylcellulose, hydroxypropyl cellulose, ethylene/vinylacetate, polyvinyl pyrrolidone, and the like, to provide the composition in gel form, which may be dissolved in solvent such as methylene chloride, evaporated to the desired viscosity, and then applied to backing material to provide a patch.

The Ca²⁺ -channel blocker of the present invention also may be released or delivered from an osmotic mini-pump. The release rate from an elementary osmotic mini-pump may be modulated with a microporous, fast-response gel disposed in the release orifice. An osmotic mini-pump would be useful for controlling release of, or targeting delivery of, a Ca²⁺ -channel blocker, particularly a short-acting Ca²⁺ -channel blocker.

The present invention is also directed to a method for treating a demyelinating condition in a subject in need of treatment, comprising administering to the subject a Ca²⁺ -channel blocker in combination with a glutamate inhibitor, in amounts effective to treat the demyelinating condition. The demyelinating condition may be any of those described above. The Ca²⁺ -channel blocker may be any of those described above. Additionally, as used herein, the term "glutamate inhibitor" refers to any of a class of pharmacological agents which prevent the binding and/or action of glutamate (or glutamatergic agonists) at ionotropic glutamate receptors, resulting in reduced or completely blocked ion-conductance of such receptors. Examples of appropriate glutamate inhibitors include, without limitation, carbidopa, levodopa, and sodium-channel blockers.

In the method of the present invention, administration of a Ca²⁺ -channel blocker "in combination with" a glutamate inhibitor refers to co-administration of the two agents. Co-administration may occur concurrently, sequentially, or alternately. Concurrent co-administration refers to administration of both a Ca²⁺ -channel blocker and a glutamate inhibitor at essentially the same time. For concurrent co-administration, the courses of treatment with a Ca²⁺ -channel blocker and with a glutamate inhibitor may be run simultaneously. For example, a single, combined formulation, containing both an amount of a Ca²⁺ -channel blocker and an amount of a glutamate inhibitor in physical association with one another, may be administered to the subject. The single, combined formulation may consist of an oral formulation, containing amounts of both a Ca²⁺ -channel blocker and a glutamate inhibitor, which may be orally administered to the subject, or a liquid mixture, containing amounts of both a Ca²⁺ -channel blocker and a glutamate inhibitor, which may be injected into the subject.

It is also within the confines of the present invention that a Ca²⁺ -channel blocker and a glutamate inhibitor may be administered concurrently to a subject, in separate, individual formulations. Accordingly, the method of the present invention is not limited to concurrent co-administration of a Ca²⁺ -channel blocker and a glutamate inhibitor in physical association with one another.

In the method of the present invention, a Ca²⁺ -channel blocker and a glutamate inhibitor also may be co-administered to a subject in separate, individual formulations that are spaced out over a period of time, so as to obtain the maximum efficacy of the combination. Administration of each agent may range in duration, from a brief, rapid administration to a continuous perfusion. When spaced out over a period of time, co-administration of a Ca²⁺ -channel blocker and a glutamate inhibitor may be sequential or alternate. For sequential co-administration, one of the agents is separately administered, followed by the other. For example, a full course of treatment with a Ca²⁺ -channel blocker may be completed, and then may be followed by a full course of treatment with a glutamate inhibitor. Alternatively, for sequential co-administration, a full course of treatment with a glutamate inhibitor may be completed, then followed by a full course of treatment with a Ca²⁺ -channel blocker. For alternate co-administration, partial courses of treatment with a Ca²⁺ -channel blocker may be alternated with partial courses of treatment with a glutamate inhibitor, until a full treatment of each agent has been administered.

The agents of the present invention (i.e., a Ca²⁺ -channel blocker and a glutamate inhibitor, either in separate, individual formulations, or in a single, combined formulation) may be administered to a human or animal subject by any known procedures, including all of the above-described methods. Preferably, however, the Ca²⁺ -channel blocker and the glutamate inhibitor are co-administered orally.

In the method of the present invention, a Ca²⁺ -channel blocker and a glutamate inhibitor are co-administered in amounts effective to treat the demyelinating condition in the subject. As described above, this means that an amount of Ca²⁺ -channel blocker in combination with an amount of glutamate inhibitor is effective to ameliorate or minimize the clinical impairment or symptoms of the demyelinating condition. Appropriate amounts of a Ca²⁺ -channel blocker and a glutamate inhibitor effective to treat a demyelinating condition in a subject can be readily determined by the skilled artisan. A Ca²⁺ -channel blocker and a glutamate inhibitor may be co-administered to a subject in order to achieve a synergistic effect in the treatment of a demyelinating condition.

It is within the confines of the present invention that the formulations of a Ca²⁺ -channel blocker and a glutamate inhibitor (whether individual or combined) may be further associated with a pharmaceutically-acceptable carrier, thereby comprising a pharmaceutical composition. Accordingly, the present invention also discloses a pharmaceutical composition, comprising a Ca²⁺ -channel blocker, a glutamate inhibitor, and a pharmaceutically-acceptable carrier. Such a pharmaceutical composition would be useful for treating a demyelinating condition in a subject in need of treatment. Where the pharmaceutical composition is administered to a subject to treat a demyelinating condition, a Ca²⁺ -channel blocker and a glutamate inhibitor are provided in amounts which are effective to treat the demyelinating condition.

The pharmaceutically-acceptable carrier of the present invention must be "acceptable" in the sense of being compatible with the other ingredients of the composition, and not deleterious to the recipient thereof. Examples of acceptable pharmaceutical carriers include carboxymethylcellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methyl cellulose, powders, saline, sodium alginate, sucrose, starch, talc, and water, among others. Formulations of the pharmaceutical composition may conveniently be presented in unit dosage.

The formulations of the present invention may be prepared by methods well-known in the pharmaceutical art. For example, the active compound may be brought into association with a carrier or diluent, as a suspension or solution. Optionally, one or more accessory ingredients (e.g., buffers, flavoring agents, surface active agents, and the like) also may be added. The choice of carrier will depend upon the route of administration. The pharmaceutical composition would be useful for administering the Ca²⁺ -channel blocker and the glutamate inhibitor of the present invention (either in separate, individual formulations, or in a single, combined formulation) to a subject to treat a demyelinating condition. The agents are provided in amounts that are effective to treat a demyelinating condition in the subject. These amounts may be readily determined by the skilled artisan.

The present invention also provides a method for treating a demyelinating condition in a subject in need of treatment, comprising administering to the subject a Ca²⁺ -channel blocker in combination with a hypertensive agent, in amounts effective to treat the demyelinating condition. The demyelinating condition may be any of those described above. The Ca²⁺ -channel blocker may be any of those described above. Additionally, as used herein, the term "hypertensive agent" refers to any of a class of pharmacological agents which increase blood pressure. As described above, an "agent" includes a protein, polypeptide, peptide, nucleic acid (including DNA or RNA), antibody, molecule, compound, antibiotic, drug, and any combinations thereof. Examples of appropriate hypertensive agents include, without limitation, phenylephrine (particularly phenylephrine that has been carefully titrated) and sodium chloride (NaCl).

In the method of the present invention, administration of a Ca²⁺ -channel blocker "in combination with" a hypertensive agent refers to co-administration of the two agents. As described above, co-administration may occur concurrently, sequentially, or alternately. A Ca²⁺ -channel blocker and a hypertensive agent may be co-administered by any of the above-described methods, and in any of the above-described formulations. For example, for concurrent co-administration, as described above, the courses of treatment with a Ca²⁺ -channel blocker and with a hypertensive agent may be run simultaneously, in a single, combined formulation containing both an amount of a Ca²⁺ -channel blocker and an amount of a hypertensive agent in physical association with one another. Alternatively, as described above, an amount of a Ca²⁺ -channel blocker and an amount of a hypertensive agent may be administered concurrently to a subject, in separate, individual formulations. Accordingly, the method of the present invention is not limited to concurrent co-administration of a Ca²⁺ -channel blocker and a hypertensive agent in physical association with one another.

In the method of the present invention, a Ca²⁺ -channel blocker and a hypertensive agent also may be co-administered to a subject in separate, individual formulations that are spaced out over a period of time, so as to obtain the maximum efficacy of the combination. Administration of each agent may range in duration, from a brief, rapid administration to a continuous perfusion. When spaced out over a period of time, co-administration of a Ca²⁺ -channel blocker and a hypertensive agent may be sequential or alternate, as described above.

The agents of the present invention (i.e., a Ca²⁺ -channel blocker and a hypertensive agent, either in separate, individual formulations, or in a single, combined formulation) may be administered to a human or animal subject by any known procedures, including all of the above-described methods. Preferably, however, the Ca²⁺ -channel blocker and the hypertensive agent are co-administered orally.

In the method of the present invention, a Ca²⁺ -channel blocker and a hypertensive agent are co-administered in amounts effective to treat the demyelinating condition in the subject. As described above, this means that an amount of Ca²⁺ -channel blocker in combination with an amount of hypertensive agent is effective to ameliorate or minimize the clinical impairment or symptoms of the demyelinating condition. Appropriate amounts of a Ca²⁺ -channel blocker and a hypertensive agent effective to treat a demyelinating condition in a subject can be readily determined by the skilled artisan. A Ca²⁺ -channel blocker and a hypertensive agent may be co-administered to a subject in order to achieve a synergistic effect in the treatment of a demyelinating condition.

It is within the confines of the present invention that the formulations of a Ca²⁺ -channel blocker and a hypertensive agent (whether individual or combined) may be further associated with a pharmaceutically-acceptable carrier, thereby comprising a pharmaceutical composition. Accordingly, the present invention also discloses a pharmaceutical composition comprising a Ca²⁺ -channel blocker, a hypertensive agent, and a pharmaceutically-acceptable carrier. Such a pharmaceutical composition would be useful for treating a demyelinating condition in a subject in need of treatment. Where the pharmaceutical composition is administered to a subject to treat a demyelinating condition, a Ca²⁺ -channel blocker and a hypertensive agent are provided in amounts which are effective to treat the demyelinating condition. The pharmaceutical composition of the present invention may be prepared in accordance with the methods, and in the formulations, described above.

Claim 1 of 6 Claims

What is claimed is:

1. A method for treating multiple sclerosis in a subject in need of treatment, comprising administering to the subject an amount of amlodipine effective to treat the multiple sclerosis in the subject.
 

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