WO2017120298A1

WO2017120298A1 - Treatment of radiculopathies with 4-aminopyridine or derivatives thereof

Info

Publication number: WO2017120298A1
Application number: PCT/US2017/012281
Authority: WO
Inventors: Mark Noble
Original assignee: University Of Rochester
Priority date: 2016-01-05
Filing date: 2017-01-05
Publication date: 2017-07-13

Abstract

Compositions and methods of treating a subject with radiculopathy are disclosed. The methods include administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising 4-aminopyridine, a 4-aminopyridine derivative, or a combination thereof. In some embodiments, the pharmaceutical composition can include a therapeutically effective amount of the 4-aminopyridine, a 4-aminopyridine derivative, or a combination thereof dispersed in a release matrix, including for example, a composition that can be formulated into a continuous, sustained-release oral dosage formulation or topical formulation. The pharmaceutical composition, when administered to a patient, can provide a therapeutically effective plasma level of the 4-aminopyridine, a 4-aminopyridine derivative, or a combination thereof for a period of at least 4 hours. In some embodiments, the pharmaceutical composition can be administered with an additional therapeutic agent such as an anticonvulsant.

Description

TREATMENT OF RADICULOPATHIES WITH 4-AMINOPYRIDINE OR

DERIVATIVES THEREOF

FIELD

This disclosure relates generally to methods and compositions for treating radiculopathies in a subject.

BACKGROUND

Radiculopathies represent afflictions with the common feature of a pinching of the nerves of the spinal cord. They present with a range of symptoms, including numbness, weakness and pain that may affect different parts of the body. They can also be caused by different types of pathological changes in bone, cartilage, muscle or tendons.

Some of the major causes of radiculopathies are herniated spinal discs and narrowing of vertebral space. When the outer rim of a spinal disc weakens or tears, this can exert pressure on a nearby spinal nerve or on the spinal cord itself. Similar symptoms can also be caused by the growth of bone spurs, which can narrow the space where the spinal cord or nerves connected to the cord are located.

Regardless of the cause of a radiculopathy, treatment choices currently consist of analgesics, non-steroidal anti-inflammatory agents, muscle relaxants, oral corticosteroids, prescription opiods, spinal corticosteroid injections or surgery.

Spinal stenosis is a critical radiculopathy which is caused by compression of the spinal cord and/or spinal nerve roots due to a reduction in size of the space in which these tissues reside. Spinal stenosis occurs mostly in people older than 50, although younger people with a spine injury or a narrow spinal canal are also at risk. For example, spinal stenosis can occur in people with Paget' s disease, disk herniation, thickened ligaments, tumors that grow inside the spinal cord, or spinal trauma. Swelling of adjacent tissue immediately following back surgery can also put pressure on the spinal cord or nerves.

Treatment options for spinal stenosis are limited and the development of new treatments have been lacking. For example, in the absence of severe or progressive nerve involvement, a doctor typically prescribe one or more conservative treatments including nonsteroidal antiinflammatory drugs to reduce inflammation and relieve pain, analgesics to relieve pain, corticosteroid injections to reduce inflammation and treat acute pain, anesthetic injections to temporarily relieve pain, restricted activity, prescribed exercises and/or physical therapy to maintain motion of the spine, strengthen abdominal and back muscles, and build endurance, and/or a lumbar brace or corset to provide some support and help the patient regain mobility. Surgical interventions are used if more conservative treatments haven't helped, the symptoms are disabling and/or the patient is otherwise in good health. However, while surgery may help reduce spinal stenosis symptoms, some people's symptoms stay the same or get worse after surgery. In addition, surgical risks include infection, a tear in the membrane that covers the spinal cord, a blood clot in a leg vein, and neurological deterioration. Thus, surgery is not considered an attractive treatment strategy unless it is absolutely necessary.

Radiculopathies caused by disc herniation will present with different MRI findings, or other imaging findings, and may be managed with differing approaches to physical therapy and generally require very different kinds of surgery. The pharmaceutical approaches employed for trying to alleviate the symptoms caused by spinal stenosis or disc herniation or other causes of radiculopathy are similar, however.

It is important to note that none of the therapies recommended for treatment of other neurological conditions such as multiple sclerosis, spinal cord injury, Lambert-Eaton syndrome or nystagmus are considered of value in the treatment of radiculopathies like spinal stenosis and herniated discs. In particular, the nature of the damage in such radiculopathies is very different from these neurological conditions. For example, multiple sclerosis and spinal cord injury are demyelinating diseases or traumatic insults, respectively, to the central nervous system that results in damage to the protective covering (myelin sheath) that surrounds nerve fibers in the brain and spinal cord. When the myelin sheath is damaged, nerve impulses slow or even stop, causing neurological problems. Potassium channel blockers are a class of compounds that have been found to improve the conduction of nerve impulses. As a result, they have become the focus of attention in the symptomatic treatment of spinal cord injury, multiple sclerosis, and

Alzheimer's disease.

In contrast, changes in conduction are considered to be a counter-indication for a diagnosis of radiculopathies. For example, Dr. Patrick Kortebein in the New England Journal of Medicine, 2008, 358:2647-2648, discloses that electromyography is not routinely necessary in the diagnostic workup of spinal stenosis. However, a complete electrodiagnostic examination (i.e., nerve-conduction studies and electromyography) can often be quite helpful in

differentiating symptoms related to radiculopathies from those due to a peripheral neuropathy. In general, a patient with clinically significant spinal stenosis will have electromyographic evidence of multilevel lumbosacral radiculopathies with essentially normal nerve-conduction studies, whereas a patient with clinically significant peripheral neuropathy will have just the opposite findings (i.e., abnormal nerve-conduction studies and normal electromyography). Even when both disorders are present, it is frequently possible to identify the one that is more symptomatic, since electrodiagnostic testing can also delineate the severity of each process.

There is a need for improved compositions and methods for treating radiculopathies, and particularly those caused by spinal stenosis or herniated discs. The compositions and methods disclosed herein address these and other needs.

SUMMARY

Compositions and methods for treating or improving neurological function in a subject with radiculopathy, caused by spinal stenosis, disc herniation or other causes, are provided herein. The method can include administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising 4- aminopyridine, a derivative thereof, or a

combination thereof. In certain embodiments, 4-aminopyridine or a derivative thereof can be represented by a structure according to Formula I:

Formula I,

wherein R¹, R², R³, R⁴, and R⁵ are each independently selected from hydrogen, halogen, amine, hydroxyl, alkoxy, carboxyl, or Ci-C₆ alkyl.

In some examples, the pharmaceutical composition can contain 4-aminopyridine and a pharmaceutically acceptable carrier. In some examples, the pharmaceutical composition can contain a derivative of 4-aminopyridine, such as 3,4-diaminopyridine, 3-hydroxy-4- aminopyridine, or a combination thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition can be formulated to provide sustained release of 4-aminopyridine, 4-aminopyridine derivative, or a combination thereof.

The pharmaceutical composition can be formulated for continuous, sustained release of 4-aminopyridine, or a 4-aminopyridine derivative, or a combination thereof. For example, the pharmaceutical composition can include a matrix suitable for controlling the release rate of 4- aminopyridine, 4-aminopyridine derivative, or a combination thereof. The 4-aminopyridine, 4- aminopyridine derivative, or a combination thereof can be dispersed in or coated with the matrix. The matrix can include a polymer. In some embodiments, the method include administering a continuous, sustained release pharmaceutical composition.

The subject can be administered the pharmaceutical composition in an amount such that the dose of 4-aminopyridine, or a 4-aminopyridine derivative, or a combination thereof is about 15 mg or less or about 10 mg or less of 4-aminopyridine, a 4-aminopyridine derivative, or a combination thereof. The composition can be administered twice daily, such as about every 12 hours.

In some cases, the pharmaceutical composition can provide a release profile to obtain a concentration of the active agent at steady state (C_avss) of about 15 ng/ml to about 35 ng/ml. In some examples, the pharmaceutical composition can provide a release profile to obtain a time to maximum plasma concentration (T_max) of about 2 hours to about 6 hours after administration of the pharmaceutical composition. For example, the composition can provide a T_max of about 2 hours to about 5.2 hours after administration of the pharmaceutical composition. In some embodiments, the pharmaceutical composition, after administration to the subject, can provide a release profile of the 4-aminopyridine, or a 4-aminopyridine derivative, or a combination thereof extending over at least 6 hours.

In some embodiments, the pharmaceutical composition can be administered repeatedly for at least 2 weeks (e.g., from about 2 to about 12 weeks). The same dose of the pharmaceutical composition can be repeatedly administered over at least a 2 week period. Any suitable method can be used to administer the pharmaceutical composition to the subject. In some embodiments, the composition can be administered orally to the subject (for e.g., in the form of a tablet). In some embodiments the pharmaceutical composition can be administered transdermally to the subject.

The pharmaceutical compositions described herein can be used in treating or improving neurological function in a subject with radiculopathy caused by spinal stenosis, including cervical spinal stenosis, thoracic spinal stenosis, relapsing lumbar spinal stenosis, and combinations thereof. In some embodiments, the compositions can be in an amount to improve lower extremity function such as increasing the speed of walking of the subject; reduce pain in the neck and/or back; reduce pain going down the leg; or decrease numbness, improve sensation, and/or decrease aberrant sensations in the foot. The pharmaceutical compositions described herein also can be used in treating or improving neurological function in a subject with radiculopathy caused by a herniated disc or other causes.

The pharmaceutical composition can be administered in combination with an additional therapeutic agent. The additional therapeutic agent can include an anticonvulsant.

Additional advantages will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the aspects described below. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive.

DETAILED DESCRIPTION

Compositions and methods for treating radiculopathy, caused by spinal stenosis, spinal disc herniation or other causes, in a subject are provided. In some aspects, the compositions and methods can be used to treat a subject with cervical radiculopathy, thoracic radiculopathy, lumbar radiculopathy, cervical spinal stenosis, thoracic spinal stenosis, lumbar spinal stenosis, and combinations thereof.

General Definitions

Before the present compositions and methods are described, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

As used in the specification and the appended claims, the singular forms "a," "an," and

"the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an aminopyridine derivative" includes mixtures of various aminopyridine derivatives, and reference to "the active compound" includes one or more active compounds, and the like.

Ranges can be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as "about" that particular value in addition to the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed.

"Pharmaceutically acceptable," as used herein, refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio, in accordance with the guidelines of agencies such as the Food and Drug Administration.

A "subject" refers to any individual who is the target of administration or treatment. The subject can be a vertebrate, for example, a mammal. Thus, the subject can be a human or veterinary patient. The term "patient" refers to a subject under the treatment of a clinician, e.g., physician.

"Treating" refers to the administration of a therapeutically effective amount of a therapeutic agent (e.g., 4-aminopyridine or a derivative thereof) to a subject known or suspected to be afflicted with radiculopathy, which can be caused by spinal stenosis, disc herniation or other causes. The term "treatment" refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. It also includes preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of damage that can be caused by surgical interventions; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the durable improvement of the associated disease, pathological condition, or disorder.

A "therapeutically effective amount" refers to that amount of an active agent that will have a clear beneficial effect. The beneficial effect can include a decrease or prevention of the symptoms associated with a medical condition, for example spinal stenosis, normalization of body functions in disease or disorders that result in impairment of specific bodily functions, or improvement in one or more of the clinically measured parameters of the disease. The beneficial effect can be curative on the health and well-being of the subject with regard to a disease or condition with which the subject is known or suspected to be afflicted. The beneficial effect on the health and well-being of a subject can also include, but is not limited to: (1) curing the condition; (2) slowing the progress of the condition; (3) decreasing the severity of adverse effects of the condition' or (4) causing the condition to retrogress. In some embodiments, a

"therapeutically effective amount" is an amount sufficient to improve symptoms associated with spinal stenosis.

"Pharmaceutically acceptable excipient" refers to an excipient that is conventionally useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for veterinary use as well as for human

pharmaceutical use. Such excipients can be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous.

A "pharmaceutically acceptable carrier" is a carrier, such as a solvent, suspending agent or vehicle, for delivering the disclosed compounds to the patient. The carrier can be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutical carrier. As used herein, "carrier" includes any and all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.

The term "pharmaceutically acceptable salts, esters, amides, and prodrugs" as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.

The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compounds of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

The term "salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like. These can include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, tetramethylammonium, tetramethylammonium, methlyamine, dimethlyamine, trimethlyamine, triethlyamine, ethylamine, and the like. (See, for example, S. M. Barge et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19 which is incorporated herein by reference).

In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present disclosure.

Chemical Definitions

Terms used herein will have their customary meaning in the art unless specified otherwise. The organic moieties mentioned when defining variable positions within the general formulae described herein (e.g., the term "halogen") are collective terms for the individual substituents encompassed by the organic moiety. The prefix C_n-C_m indicates in each case the possible number of carbon atoms in the group.

The term "alkyl," as used herein, refers to saturated straight, branched, primary, secondary or tertiary hydrocarbons, including those having 1 to 20 atoms. In some examples, alkyl groups will include Ci-C₆, C1-C5, C1-C4, C1-C3, or C1-C2 alkyl groups. Examples of C1-C10 alkyl groups include, but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl, 1- methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1 -methylbutyl, 2-methylbutyl, 3- methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2- dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1- ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1 -ethyl- 1-methylpropyl, 1- ethyl-2-methylpropyl, heptyl, octyl, 2-ethylhexyl, nonyl and decyl groups, as well as their isomers. Examples of Cl-C4-alkyl groups include, for example, methyl, ethyl, propyl, 1- methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, and 1,1-dimethylethyl groups.

The alkyl group can be unsubstituted or substituted with one or more moieties chosen from alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, alkyl- or dialkylamino, amido, arylamino, alkoxy, aryloxy, nitro, cyano, azido, thiol, imino, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphoric acid, phosphate, phosphonate, or any other viable functional group that does not inhibit the biological activity of the compounds of the invention, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as described in Greene, et al, Protective Groups in Organic Synthesis, John Wiley and Sons, Third Edition, 1999, hereby incorporated by reference.

The term "alkoxy," as used herein, refers to alkyl-O-, wherein alkyl refers to an alkyl group, as defined above. Similarly, the terms "alkenyloxy," "alkynyloxy," and "cycloalkoxy," refer to the groups alkenyl-O-, alkynyl-O-, and cycloalkyl-O-, respectively, wherein alkenyl, alkynyl, and cycloalkyl are as defined above. Examples of Ci-C6-alkoxy groups include, but are not limited to, methoxy, ethoxy, C2H5-CH2O-, (CH₃)2CHO-, n-butoxy, C₂H₅-CH(CH₃)0-, (CH3)2CH-CH20-, (CH3)3CO-, n-pentoxy, 1 methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2 dimethylpropoxy, 2,2-dimethyl-propoxy, 1-ethylpropoxy, n-hexoxy, 1 methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1 dimethylbutoxy, 1,2- dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3 dimethylbutoxy, 3,3- dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2 trimethylpropoxy, 1,2,2-trimethylpropoxy, 1 -ethyl- 1-methylpropoxy, and l-ethyl-2-methylpropoxy.

The term "halogen," as used herein, refers to the atoms fluorine, chlorine, bromine and iodine. The prefix halo- (e.g., as illustrated by the term haloalkyl) refers to all degrees of halogen substitution, from a single substitution to a perhalo substitution (e.g., as illustrated with methyl as chloromethyl (-CH2CI), dichloromethyl (-CHCI2), trichloromethyl (-CCI3)).

As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms "substitution" or "substituted with" include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

Reference will now be made in detail to specific aspects of the disclosed materials, compounds, compositions, articles, and methods, examples of which are illustrated in the accompanying Examples.

Compositions

The compositions described herein can be used in methods to treat spinal stenosis in a subject. In some aspects, the composition can comprise 4-aminopyridine, a derivative thereof, or a combination thereof. In certain embodiments, 4-aminopyridine or the 4-aminopyridine derivative can have a chemical structure according to Formula I:

Formula I,

wherein R¹, R², R³, R⁴, and R⁵ can each be independently selected from hydrogen, halogen, alkoxy, carboxyl, thiol, Ci-C₆ alkyl, cycloalkyl, or aryl. In some examples, R¹, R², R³, R⁴, and R⁵ can each be independently selected from hydrogen, halogen, amine, hydroxyl, alkoxy, carboxyl, or Ci-C₆ alkyl.

In some examples, R¹, R², R³, R⁴, and R⁵ can all be hydrogen. In some embodiments, the composition can include a pharmaceutically acceptable salt, solvate, or prodrug of 4- aminopyridine or a 4-aminopyridine derivative.

In some examples, the compositions described herein can include 4-aminopyridine. In some examples, the composition can include a derivative of 4-aminopyridine. Representative examples of 4-aminopyridine derivatives include, but are not limited to, 3,4-diaminopyridine, 3- hydroxy-4-aminopyridine, N-(4-pyridyl)-t-butyl carbamate, N-(4-pyridyl) ethyl carbamate, N-(4- pyridyl) methyl carbamate, N-(4-pyridyl) isopropyl carbamate, salts thereof, solvates thereof, or prodrugs thereof.

The compositions disclosed herein can be used therapeutically in combination with a pharmaceutically acceptable carrier. In another aspect, the compositions disclosed herein can be used prophylactically, i.e., as a preventative agent, with a pharmaceutically acceptable carrier. The compositions disclosed herein can be conveniently formulated into pharmaceutical compositions composed of one or more of the compositions disclosed herein in association with a pharmaceutically acceptable carrier. See, e.g., Remington's Pharmaceutical Sciences, latest edition, by E.W. Martin Mack Pub. Co., Easton, Pa., which discloses typical carriers and conventional methods of preparing pharmaceutical compositions that can be used in conjunction with the preparation of formulations of the compositions disclosed herein and which is incorporated by reference herein. Such pharmaceutical carriers, most typically, would be standard carriers for administration of compositions to humans and non-humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH. Other compounds will be administered according to standard procedures used by those skilled in the art.

Depending on the intended mode of administration, the pharmaceutical composition can be in the form of, for example, solids, semi-solids, liquids, solutions, suspensions (e.g., incorporated into microparticles, liposomes, etc.), emulsions, gels, or the like. The

pharmaceutical compositions can include, as noted above, an effective amount of the 4- aminopyridine compound, a derivative thereof, or a combination thereof, in combination with a pharmaceutically acceptable carrier and, in addition, can include other adjuvants such as diluents, thickeners, buffers, preservatives, surfactants, glidants, dissolution agents, binders including low temperature melting binders, disintegrants, solubilizing agents, or lubricants. The composition can also include excipients such as microcrystalline cellulose, colloidal silicon dioxide, lactose, starch, sorbitol, cyclodextrin, antioxidants, film-formers, pigments, anti-adhesive agents, politicizes, and combinations of these. In some embodiments, an antioxidant such as sodium metabisulfite, tocopherols, ascorbic acid or a pharmaceutically acceptable salt thereof, ascorbyl palmitate, alkyl gallates such as propyl gallate, Tenox PG, Tenox s-1, sulfites or a

pharmaceutically acceptable salt thereof, BHA, BHT, or monothioglycerol can be included in the pharmaceutical compositions. The film-former can contain fast-dissolving constituents, such as low-viscosity hydroxypropyl-methylcelluose, for example, Methocel E5 or D14, or Pharmacoat 606 (Shin-Etsu). The film coating can also contain excipients or enteric coatings customary in film-coating procedures, such as, for example, light protective pigments, for example, iron oxide, or titanium dioxide, anti-adhesive agents, for example, talc, and also suitable plasticizers such as, for example, PEG 400, PEG 6000, diethyl phthalate or triethyl citrate.

In some embodiments, the pharmaceutical compositions described herein can be formulated as a sustained release formulation. As used herein, the term "sustained-release" includes the release of the active compound from the dosage pharmaceutical composition at a sustained rate such that a therapeutically beneficial blood level below toxic levels of the active compound is maintained over a period of at least about 12 hours, such as about 24 hours or more. In some embodiments, the amount of the active compound in the composition can establish a therapeutically useful plasma concentration through BID (twice daily) administration of the pharmaceutical composition.

The sustained release composition can include a matrix that can provide sustained release of the 4-aminopyridine, a 4-amino pyridine derivative, or a combination thereof. In some examples, the matrix can include a fibrin glue, a biocompatible polymer, or hydrogel or a combination thereof. In some examples, the 4-aminopyridine, a 4-amino pyridine derivative, or a combination thereof can be encapsulated in the polymer or hydrogel such that the active agent is slowly released in the body. Optionally, the 4-aminopyridine, a 4-amino pyridine derivative, or a combination thereof can be dispersed throughout the polymer or hydrogel in such a manner to result in continuous, sustained release of the active agent as the polymer or hydrogel degrades inside the body. In some examples, the composition can comprise a biodegradable biocompatible polymer such as polyglycolide or polyglycolic acid (PGA), polylactide or polylactic acid (PLA), poly-L-lactic acid (PLLA), poly-D/L-lactic acid with polyglycolic acid (PDLLA-co-PGA), poly- L-lactic acid-co-glycolic acid (PLGA), PDLLA with bioactive glass, PLGA with bioactive glass, poly-L-lactic acid with β-tricalcium phosphate (PLLA- TCP), poly-L-lactic acid with hydroxyapatite (PLLAHA), polydioxanone (PDS), polyethylene glycol (PEG), poly(8- caprolactone) (PCL), polycaprolactone (PCL) with alginate, polyhydroxybutyrate (PHB), polycarbonate (PC), N-vinyl pyrrolidone copolymers, polyorthoester, chitosan, poly(2- hydroxyethyl-methacrylate) (PHEMA), hyaluronic acid and hydrogels. In some examples, the sustained release pharmaceutical composition can comprise hydroxypropylmethylcellulose. In other examples, the sustained release can be obtained by using transdermal administration of 4- AP in conjunction with methods known in the art that provide sustained release of therapeutic agents in the context of transdermal delivery.

The pharmaceutical composition can be in any suitable dosage unit form. In some examples, the pharmaceutical composition can be in the form of beads, films, or some other shape, as would be understood by a person of ordinary skill in the art. Optionally, the beads can be implanted, ingested, or otherwise placed inside the body in some way, such that the agent is administered locally or systemically in a sustained-release manner. In some embodiments, the composition can be in the form of tablets, granules, capsules, sustained release microcapsules, spheroids, or any other means that allow for oral administration. In some embodiments, the composition can be in the form of a transdermal delivery system for 4-aminopyridine, a 4- aminopyridine derivative, or combinations thereof.

The rate of release of the active compound (4-aminopyridine, a 4-aminopyridine derivative, or combinations thereof) from the pharmaceutical composition can be controlled by the erosion mechanism. In some embodiments, the release of the active compound from the matrix of the pharmaceutical composition can be relatively linear over time. In some embodiments, the sustained release pharmaceutical composition can be formulated to exhibit a specific, desired release profile that maximizes the therapeutic effect of the active compound while minimizing adverse side effects. In some embodiments, the pharmaceutical composition can be formulated such that 4-aminopyridine, a 4-aminopyridine derivative, or a combination thereof is delivered continuously over the course of about 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, or 24 hours.

The release profile of the pharmaceutical composition can be described in terms of the maximum plasma concentration of the drug or active agent (C_max) and the plasma concentration of the drug or active agent at a specific dosing interval (Cr). A ratio of C_max to Cr(C_max:Cr) can be calculated from the observed C_max and Cr. A dosing interval (r) is the time since the last administration of the drug or active agent. In the present application, the dosing interval (r) can be twelve (12) hours, therefore Crcan be the concentration of the drug or active agent at twelve (12) hours from the last administration.

In some embodiments, the sustained release pharmaceutical composition can be formulated to exhibit a release profile that can be described in terms of the maximum plasma concentration of the drug or active agent at steady state (Cmaxss) and the minimum plasma concentration of the drug or active agent at steady state (Cminss). Steady state is observed when the rate of administration (absorption) is equal to the rate of elimination of the drug or active agent. A ratio of Cmaxss to Cminss (C_maxss: Cminss) can be calculated from the observed Cmaxss and Cminss- The pharmaceutical compositions described herein can exhibit a desired release profile that can also be described in terms of the average maximum plasma concentration of the drug or active agent at steady state (C_avss).

In certain embodiments, the pharmaceutical composition can exhibit a release profile to obtain a C_max:Cr ratio in vivo of from about 1.0 to 3.5, such as from about 1.5 to about 3.0 or from about 2.0 to about 3.0. In certain embodiments, the pharmaceutical composition can exhibit a release profile to obtain a C_avss of about 15 ng/ml to about 35 ng/ml. In some examples, the pharmaceutical composition can be in the form of a tablet and can exhibit a sustained release profile of aminopyridine, or a derivative thereof, to obtain a C_max:Cr ratio in vivo of from 1.0 to 3.5 (such as from about 1.5 to about 3.0 or from about 2.0 to about 3.0) and a C_avss of about 15 ng/ml to about 35 ng/ml. In some examples, the pharmaceutical composition can provide a Cmiixss of about 20 ng/ml to about 35 ng/ml. The pharmacokinetic characteristics of sustained release 4- aminopyridine compositions and methods of using the compositions are described in International Application Publication No. WO2004082684 (PCT/US2004/008101) filed April 17, 2004 and U.S. Patent No. 8,007,826 filed December 13, 2004, the contents of which are incorporated herein by reference in their entireties.

Optionally, liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., a composition as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example see Remington 's Pharmaceutical Sciences, referenced above.

Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions which can also contain buffers, diluents and other suitable additives. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives, such as antimicrobials, anti-oxidants, chelating agents, and inert gases and the like, can also be present.

Parenteral administration, if used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. A more recently revised approach for parenteral administration involves use of a slow release or sustained release system such that a constant dosage is maintained.

Transdermal formulations can also be prepared in the form of creams, ointments, salves, sprays, gels, lotions, emulsions, and transdermal patches. Such compositions can contain one or more chemical penetration enhancers, membrane permeability agents, membrane transport agents, emollients, surfactants, stabilizers, and combination thereof.

In some aspects, the pharmaceutical composition can contain from about 0.01 to about 99 percent of active compound(s), together with the carriers and/or excipients. However, one of ordinary skill in the art knows that the amount of the active compound present in the composition can vary, depending on various factors, including, for example, the aminopyridine,

aminopyridine derivative, or combinations thereof used, the desired dosage level, the type and amount of rate-controlling polymer matrix if used, and the presence, types and amounts of additional materials included in the composition. In some embodiments, for example in compositions formulated for oral administration, the composition can include from about 0.1 to about 13% w/w (e.g., from about 0.5 to about 6.25% w/w or from about 0.5 to 4.75% w/w) of 4- aminopyridine, a 4-aminopyridine derivative, or combinations thereof.

In some embodiments, the actual amount of active agent in the pharmaceutical composition can vary depending on the patient's age, weight, sex, medical condition, disease or any other medical criteria. However, the actual amount of active compound can be determined according to the intended medical use by techniques known in the art. In some embodiments, the pharmaceutical composition can include about 30 mg or less of the active compound. For example, the pharmaceutical composition can include about 25 mg or less, about 20 mg or less, about 15 mg or less, about 14 mg or less, about 13 mg or less, about 12 mg or less, about 11 mg or less, about 10 mg or less, about 9 mg or less, about 8 mg or less, about 7 mg or less, about 6 mg or less, or about 5 mg or less of the active compound. In some examples, the pharmaceutical composition can include about 5 mg or greater, about 7 mg or greater, about 10 mg or greater, about 12 mg or greater, about 15 mg or greater, about 20 mg or greater, or about 25 mg or greater of the active compound. In some examples, the pharmaceutical composition can include from about 1 mg to about 25 mg, about 2 mg to about 25 mg, about 5 mg to about 25 mg, about 5 mg to about 20 mg, about 5 mg to about 15 mg, or about 5 mg to about 10 mg of the active compound.

The amount of the pharmaceutical composition administered, such as the tablet weight, can vary in accordance with, among other things, the active compound dosage, the type and amount of rate-controlling matrix used, and the presence, types, and amounts of additional materials. In some embodiments, the pharmaceutical composition can have a weight of from 250 to 500 mg, such as from about 400 mg.

Methods

Methods of making the pharmaceutical compositions described herein are provided. The pharmaceutical compositions can be prepared using methods known in the art. For example, sustained release compositions can be prepared using dry or wet methods. In certain

embodiments, tablets can be prepared by wet granulation in the presence of either water or an aqueous solution of a hydrophilic polymer or using another binder as a granulating fluid.

Alternately, an organic solvent such as isopropyl alcohol, ethanol and the like, can be employed with or without water. The active compound and the polymer can be granulated alone or in combination.

In certain embodiments, tablets can be prepared from an active compound-polymer dispersion in organic solvents in the presence or absence of water. Where the active compound, such as 4-aminopyridine or its derivative, has very low solubility in water it can be advantageous to reduce the particle size, for example, by milling it into fine powder and in this way to control the release kinetics of the drug and enhance its solubility.

The hardness of the composition (e.g., tablets) can vary depending on a variety of factors, including, for example, the relative amounts and specific types of ingredients used, the tableting equipment employed, and the selected processing parameters. The pressure used to prepare the compositions can influence the release profile of the active compound into the patient. The pressure used to prepare tablets can vary depending upon their surface area and the amount and particle size of the active compound, additive, excipients, or binders included in the tablet. The degree of hydration and solvation of the components in the composition can affect the hardness of the tablets. In some embodiments, the formed tablets can have a hardness of from 80-400 N, such as from 150 to 300N.

The effects of various matrices, concentrations of active compound, as well as various excipients and additives to the composition on the concentration of the active compound or its dissolution rate can be monitored for example using a type H dissolution apparatus according to U.S. Pharmacopoeia ΧΧΠ, or USP Apparatus II (Paddle Method). Clinical evaluations can be used to study the effects on plasma levels of various release matrices, concentrations of the active compound, as well as various excipients and additives. Plasma concentrations of the active compound can be used to calculate the pharmacokinetic data (release profiles) including apparent absorption and elimination rates, area-under-the curve (AUC), maximum plasma concentration (Cmax), time to maximum plasma concentration (T_m_x), absorption half-life

and elimination half-life (Ti/₂(_eum)). Pharmacodynamic effects can be assessed based upon response tests, such as muscle strength improvement or reduction in spasticity for patients with spinal stenosis or other tests as would be known to those skilled in the art. The plasma concentration of the active compound in blood plasma or cerebral spinal fluid can be monitored using liquid chromatography/MS/MS assay methods.

Methods of using the compounds and pharmaceutical compositions described herein are also provided. The compounds and compositions can be used to treat radiculopathy in a subject, which can be caused spinal stenosis, disc herniation or other causes. In certain embodiments, the compounds and compositions can be used to treat cervical radiculopathy, thoracic radiculopathy, lumbar radiculopathy, cervical spinal stenosis, thoracic spinal stenosis, or lumbar spinal stenosis (such as relapsing lumbar spinal stenosis) in the subject.

The method of treating radiculopathy in a subject can include administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising 4-aminopyridine, a 4-aminopyridine derivative, or a combination thereof. The pharmaceutical composition can be administered by any suitable method depending on whether local or systemic treatment is desired, and on the area to be treated. For example, the pharmaceutical composition can be administered to a subject topically, intranasally, orally, or parenterally. In some examples, the pharmaceutical composition can be administered by intradermal, implantation, subcutaneous, transdermal, intramuscular, intraperitoneal, intrarectal, intraarterial, intralymphatic, intravenous, intrathecal, and intratracheal routes.

In certain embodiments, the pharmaceutical composition can be delivered orally. For example, the pharmaceutical composition can be administered as a continuous, sustained release formulation, such as in the form of a tablet. In certain embodiments, the pharmaceutical composition can be administered transmucosally, transepithelially, transendothelially, or transdermally. In some examples, the pharmaceutical composition can be administered transdermally. For example, the pharmaceutical compositions can be topically applied to the skin in the vicinity of the area to be treated.

The pharmaceutical compositions described herein are used in a "therapeutically effective amount" of 4-aminopyridine, a 4-aminopyridine derivative, or a combination thereof. The selected amount of 4-aminopyridine, a 4-aminopyridine derivative, or a combination thereof will depend upon a variety of factors including the activity of 4-aminopyridine or the particular derivative, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the duration of the treatment, other drugs and/or materials used in combination with the particular antioxidant employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, the possibility of co-usage with other therapeutic treatments including use of other therapeutic agents, and like factors well-known in the medical arts. In some embodiments, 4-aminopyridine, a 4-aminopyridine derivative, or a combination thereof can be administered to a subject at a dose and for a period sufficient to allow the subject to tolerate the dose without showing any adverse effects and thereafter increasing the dose at selected intervals of time until a therapeutic dose is achieved. In some embodiments, the pharmaceutical composition can be administered to a subject at a dose and for a period sufficient to allow the subject to tolerate the dose without showing any adverse effects and thereafter increasing the dose of the active compound at selected intervals of time until a therapeutic dose is achieved.

A broad range of disclosed composition dosages are believed to be both safe and effective. In some examples, effective amounts of 4-aminopyridine, a 4-aminopyridine derivative, or a combination thereof for treating a mammalian subject can include about 5 mg to about 40 mg per day (e.g., from about 10 mg to about 40 mg per day; from about 5 mg to about 30 mg per day; or from about 5 mg to about 20 mg per day). In some embodiments, at the commencement of treatment, the active compound can be administered at a dose of less than 15 mg/day until a tolerable state is reached. Suitably when the tolerable state is reached, the dose administered can be increased by amounts of at least 5-15 mg/day until a therapeutic dose is reached. In some examples, the therapeutically effective amount of 4-aminopyridine, a derivative thereof, or a combination thereof is about 10 mg per day. However, a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the composition and increase or decrease the levels as required in order to achieve the desired therapeutic effect. This is considered to be within the skill of the artisan and one can review the existing literature on a specific compound or similar compounds to determine optimal dosing.

The pharmaceutical composition can be administered in periodic doses over a given period. For example, the composition can be administered in separate administrations of 2, 3, 4, or 6 equal doses. Alternatively, the pharmaceutical composition is administered as a sustained release formulation where the active compound is continuously released to the subject over a given period (e.g., a tablet, an implant, or transdermal patch). The method can include scheduling administration of the pharmaceutical composition such that the concentration of the active compound in the subject is at about the minimum therapeutically effective level to ameliorate the neurological condition, yet relatively lower compared to the maximum concentration in order to enhance restful periods for the subject during the day or night, depending on desired results or dosage schedule. In some embodiments, a sustained release pharmaceutical composition can be administered twice daily at a dose of about 5-15 mg of the active compound (i.e., about 10-30 mg/day), depending upon the condition or symptoms being treated. Alternatively, the sustained release formulation can be administered once daily at a dose of about 10-30 mg of the active compound.

In some embodiments, the pharmaceutical compositions can be administered at a dose such that the concentration of the active compound, such as 4-aminopyridine in the patient's plasma over time (release profile) can extend over a period of at least 6 hours, such as over at least 8 hours or over about 12 hours. In some embodiments, the composition can provide in a single dose a mean maximum plasma concentration of the active compound in the patient of from about 15 to about 180 ng/ml; a mean T_max from about 1 to about 6 hours, such as about 2 to about 5.2 hours after administration of the composition to the patient. In some embodiments, the pharmaceutical composition can include from about 0.0001 mole to about 0.0013 mole of the active compound and can provide a mean maximum plasma concentration of the active compound from about 15 to about 180 ng/ml, a mean T_max of about 2 to about 5 hours after administration, and a mean minimum plasma concentration of from about 10 to 60 ng/ml at about 8-24 hours after administration.

The compositions described herein are suitable for short term and long term use. "Short- term use", as used herein, can generally refer to the administration to a patient of no more than about 150 doses of the compositions disclosed. Accordingly, the term "long-term use", as used herein, can refer to the administration to a patient of more than about 150 doses of the compounds or compositions disclosed. In certain embodiments, the composition can be repeatedly administered for about 2 weeks or greater, about 3 weeks or greater, about 4 weeks or greater, about 5 weeks or greater, about 6 weeks or greater, about 7 weeks or greater, or about 8 weeks or greater. For example, the composition can be repeatedly administered for about 2 weeks to about 12 weeks or greater.

The compounds and compositions described can be administered alone or in combination with one or more additional therapeutic agents. In some embodiments, the pharmaceutical compositions can be administered with one or more additional active ingredients such as other medicinal agents, pharmaceutical agents, antimicrobial agents, anti-inflammatory agents, anesthetics, anticonvulsants, and the like. In some examples, the compositions can be administered with an anticonvulsant or a therapeutic agent used to treat acute traumatic injury to the central nervous system. The one or more additional therapeutic agent may or may not produce a therapeutic effect when administered on its own, but results in such an effect (e.g. , pain reduction) when administered with any of the compound or composition disclosed.

The one or more additional therapeutic agents and the compounds and compositions described herein can be administered in any order, including simultaneous administration, as well as temporally spaced order of up to several days apart. The administration of the one or more additional agents and the compounds and compositions described herein can be by the same or different routes. In some examples, the one or more additional agents can be combined with the compounds and compositions described herein.

In some examples, the one or more additional therapeutic agents can include an anticonvulsant. Representative anticonvulsant can include, without limitation, lamotrigine, gabapentin, valproic acid, topiramate, famotodine, phenobarbital, diphenylhydantoin, phenytoin, mephenytoin, ethotoin, mephobarbital, primidone, carbamazepine, ethosuximide, methsuximide, phensuximide, trimethadione, benzodiazepine, phenacemide, acetazolamide, progabide, clonazepam, divalproex sodium, magnesium sulfate injection, metharbital, paramethadione, phenytoin sodium, valproate sodium, clobazam, sulthiame, dilantin, diphenylan and L-5- hydroxytrytophan, and a combination thereof.

When 4-aminopyridine, a derivative thereof, or a combination thereof is administered with an additional therapeutic agent, the dose can be increased or decreased, depending on the therapeutic agent. For example, when 4-aminopyridine, a derivative thereof, or a combination thereof is administered with an anticonvulsant, the dose can be increased. In some embodiments, the dose of 4-aminopyridine, a derivative thereof, or a combination thereof can be from about 10 mg to about 200 mg per day (e.g., from about 30 mg to about 100 mg per day; from about 40 mg to about 200 mg per day; or from about 40 mg to about 150 mg per day), when administered with an anti-convulsant.

Radiculopathy, caused by spinal stenosis, disc herniation or other causes can result in dramatic impairment of sensory and/or motor function. In some embodiments, the methods described herein can result in improvement of specific bodily functions, and/or provide improvement in one or more of the clinically measured parameters of the disease. For example, the methods of treating spinal stenosis can result in improvement in symptoms associated with spinal stenosis, improved lower extremity muscle strength or improved lower extremity muscle tone, increased walking speed, decreased pain in the neck or back, decreased numbness, weakness or cramping, decreased pain going down the leg, or decreased foot problems as typified by numbness, decreases in sensation and/or the presence of aberrant sensations. The methods used in treating spinal stenosis, disc herniation or other classes of radiculopathy can be used to cause more rapid recovery. In some embodiments, the method include administering a therapeutically effective amount of the active agent that is sufficient to reduce the pain or spasticity associated with the neurological disorder being treated, or an amount sufficient to result in improvement of sexual, bladder or bowel function in subjects having a neurological disorder which impairs nerve conduction, which hinders normal sexual, bladder or bowel functions.

Methods for selecting individuals based on responsiveness to a treatment using the compositions described are also provided. The method can include identifying a plurality of individuals, administering a test to each individual prior to a treatment period, administering a treatment, including, but not limited to administering a pharmaceutical composition described herein, to one or more of the individuals during the treatment period, administering the test a plurality of times to each individual during the treatment period, and selecting one or more individuals, wherein the selected individuals exhibit an improved performance during a majority of the tests administered during the treatment period as compared to the test administered prior to the treatment period. In certain embodiments, the method can further comprise administering the test to each individual after the treatment period, wherein the selected individuals further exhibit an improved performance during a majority of the tests administered during the treatment period as compared to the test administered after the treatment period. Subjects who show a pattern of change that is consistent with a treatment response, but does not define the full characteristics of that response can be selected. The criterion itself does not specify the amount of improvement nor does it specify that the improvement must be stable over time. For example, a progressive decline in effect during the course of the study period, even one resulting in speeds slower than the maximum non-treatment value, would not be excluded by the criterion; as a specific example, changes from the maximum non-treatment value of, respectively, +20%, +5%, +1% and -30% during the double blind treatment period would qualify as a response under the criterion, but would actually show a net negative average change for the entire period, poor stability and a negative endpoint.

Further, the similarities between the current understanding of the pathological underpinnings of the radiculopathies of herniated discs and spinal stenosis are particularly emphasized by the similarities in their pharmacological treatment. For example, the medical advice website of the Mayo clinic lists the following pharmacological treatments for these two types of radiculopathy:

Herniated discs may be treated with over-the-counter pain medications, "such as ibuprofen (Advil, Motrin IB, others) or naproxen (Aleve, others)." Spinal stenosis may be treated with nonsteroidal anti -inflammatory drugs (NSAIDs) to help relieve pain and reduce

inflammation, such as "ibuprofen (Advil, Motrin IB, others) and naproxen (Aleve)."

Herniated discs may be treated with narcotics if pain is not responsive to over-the-counter medications. Such drugs may include "codeine or an oxycodone-acetaminophen combination (Percocet, Oxycontin, others ).^" Spinal stenosis may be treated with drugs "that contain codeine- related drugs such as oxycodone (Percocet, OxyContin, others) and hydroeodone (Norco, Zohydro, others)."

Herniated discs may be treated with muscle relaxants to control muscle spasms. Spinal stenosis may be treated with muscle relaxants to "calm the muscle spasms that occasionally occur with spinal stenosis.^"

Herniated disc may be treated with cortisone injections to control inflammation in the area around the spinal nerves. Spinal stenosis may be treated by injecting a corticosteroid into the space around the area of constriction to help reduce the inflammation and relieve some of the pressure.

Herniated discs may be treated with drugs "such as gabapentin (Neurontin, Gralise, Hori/ant). pregabalin (Lyrica), duloxetine (Cymbalta), tramadol (Ultram) and amitriptyline^" to help relieve nerve-damage pain. Spinal stenosis may be treated with tricyclic antidepressants ("such as amitripiyline^") to help ease chronic pain. In addition, some anti-seizure drugs "such as gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica)" are used to reduce pain caused by damaged nerves.

EXAMPLES

The following examples are set forth below to illustrate the compositions, methods, and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods, compositions, and results. These examples are not intended to exclude equivalents and variations of the present invention, which are apparent to one skilled in the art.

Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts) but some errors and deviations should be accounted for. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, temperatures, pressures, and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions.

Example 1:

An 80 year old woman had been experiencing lower back pain, bilateral loss of sensation in her legs, feelings of numbness, abnormal foot sensations, disrupted ability to feel the floor to the soles of her feet, decreased walking ability, and decreased sensation needed for maintaining proper balance. Based on the bilateral nature of these sensations, the specific constellation of symptoms, and the gradual progression of symptoms, she was diagnosed with spinal stenosis.

The 80 year old woman was treated with 4-aminopyridine in oral sustained release formulation provided by a local compounding pharmacist, at a dosage of 5 mg given twice per day.

Within several days, the patient reported beneficial changes including improved walking ability, decreased numbness, a decrease in abnormal foot sensations, and an increase in sensation needed for maintaining proper balance. At the end of the first month of treatment, the 80 year old woman stopped drug usage for several days. During this period, her symptoms returned.

Restarting treatment was associated with a return of benefits. In this case, benefits were increased, and included also the ability to feel the floor through the soles of the feet. The individual also has seen improvements in balance.

Prophetic example:

In a patient that presents with numbness, tingling and pain in their legs, or when a radiological examination reveals the presence of a herniated disc in the lower back presents in the clinic, they are treated by administering 4-AP in an amount to cause a reduction in symptoms.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from

consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

CLAIMS What is claimed is:

1. A method of treating a subject with a radiculopathy, comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising 4-aminopyridine, or a 4-aminopyridine derivative, or a combination thereof.

2. The method of claim 1 , wherein the pharmaceutical composition provides a

continuous, sustained release of the 4-aminopyridine, or a 4-aminopyridine derivative, or a combination thereof.

3. The method of claim 1 or 2, wherein the pharmaceutical composition comprises a matrix, in which the 4-aminopyridine, or a 4-aminopyridine derivative, or a combination thereof is dispersed, that is suitable for controlling the release rate of the 4-aminopyridine, or a 4-aminopyridine derivative, or a combination thereof.

4. The method of any one of claims 1-3, wherein the pharmaceutical composition comprises a polymer.

5. The method of any one of claims 1-4, wherein the subject is administered the

pharmaceutical composition at a dose of about 15 mg or less of 4-aminopyridine, or a 4-aminopyridine derivative, or a combination thereof.

6. The method of any one of claims 1-5, wherein the subject is administered the

pharmaceutical composition at a dose of from about 5 mg to about 10 mg of 4- aminopyridine, or a 4-aminopyridine derivative, or a combination thereof.

7. The method of any one of claims 1-6, wherein the subject is administered the

pharmaceutical composition twice daily.

8. The method of claim 7, wherein twice daily is about every 12 hours.

9. The method of any one of claims 1-8, wherein the pharmaceutical composition is administered repeatedly for at least two weeks.

10. The method of any one of claims 1-9, wherein the method comprises administering a same dose of the pharmaceutical composition repeatedly for at least two weeks.

11. A method of treating a subject with a radiculopathy, comprising: administering to the subject a continuous, sustained release pharmaceutical composition comprising from about 5 mg to about 15 mg of 4-aminopyridine, or a 4-aminopyridine derivative, or a combination thereof, wherein the pharmaceutical composition is administered twice daily for a period of at least two weeks.

12. A method of treating a subject with a radiculopathy, comprising: administering to the subject a continuous, sustained release pharmaceutical composition comprising about 15 mg or less of 4-aminopyridine, or a 4-aminopyridine derivative, or a combination thereof, wherein the method comprises administering a same dose of the pharmaceutical composition twice daily for a period of at least two weeks.

13. The method of any one of claims 1-12, wherein the pharmaceutical composition is administered repeatedly for about 2 to about 12 weeks.

14. The method of any one of claims 1-13, wherein the pharmaceutical composition is administered orally to the subject.

15. The method of any one of claims 1-14, wherein the pharmaceutical composition is administered in the form of a tablet.

16. The method of any one of claims 1-13, wherein the pharmaceutical composition is administered to the subject transdermally.

17. The method of any one of claims 1-16, wherein the pharmaceutical composition provides a release profile to obtain a C_avss of about 15 ng/ml to about 35 ng/ml.

18. The method of any one of claims 1-17, wherein the pharmaceutical composition provides a T_max of about 2 hours to about 6 hours after administration of the pharmaceutical composition.

19. The method of any one of claims 1-18, wherein the pharmaceutical composition provides a T_max of about 2 hours to about 5.2 hours after administration of the pharmaceutical composition.

20. The method of any one of claims 1-19, wherein the pharmaceutical composition, after administration to the subject, provides a release profile of the 4-aminopyridine, or a 4-aminopyridine derivative, or a combination thereof extending over at least 6 hours.

21. The method of any one of claims 1-20, wherein the radiculopathy is caused by

cervical spinal stenosis, thoracic spinal stenosis, lumbar spinal stenosis, disc herniation, or combinations thereof.

22. The method of any one of claims 1-21, wherein the therapeutically effective amount is in an amount that improves lower extremity function.

23. The method of claim 22, wherein the lower extremity function is walking.

24. The method of any one of claims 1-23, wherein the therapeutically effective amount is in an amount that increases speed of walking of the subject.

25. The method of any one of claims 1-21, wherein the therapeutically effective amount is in an amount that reduces pain in the neck and/or back of the subject.

26. The method of any one of claims 1-21, wherein the therapeutically effective amount is in an amount that reduces pain going down a leg of the subject.

27. The method of any one of claims 1-21, wherein the therapeutically effective amount is in an amount that decreases numbness, improves sensation, and/or decreases aberrant sensations in a foot of the subject.

28. The method of any one of claims 1-27, wherein the pharmaceutical composition is administered in combination with an additional therapeutic agent.

29. The method of claim 28, wherein the pharmaceutical composition is administered in combination with an anticonvulsant.

30. The method of any one of claims 1-29, wherein 4-aminopyridine and the derivative thereof are represented by a structu according to Formula I:

Formula I,

The method of any one of claims 1-30, wherein the pharmaceutical composition comprises 4-aminopyridine, 3,4-diaminopyridine, 3-hydroxy-4-aminopyridine, or combination thereof.