WO2014093475A1 - Méthodes pour traiter la maladie de parkinson faisant intervenir des aminopyridines - Google Patents

Méthodes pour traiter la maladie de parkinson faisant intervenir des aminopyridines Download PDF

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WO2014093475A1
WO2014093475A1 PCT/US2013/074367 US2013074367W WO2014093475A1 WO 2014093475 A1 WO2014093475 A1 WO 2014093475A1 US 2013074367 W US2013074367 W US 2013074367W WO 2014093475 A1 WO2014093475 A1 WO 2014093475A1
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impairment
aminopyridine
patient
pharmaceutically acceptable
acceptable salt
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PCT/US2013/074367
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English (en)
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Corneliu C. LUCA
Carlos SINGER
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Acorda Therapeutics, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the invention relates to treatment of patients with Parkinson's disease and, in particular, motor impairments in patients with Parkinson's disease, using an aminopyridine.
  • Parkinson's disease is a central nervous system degenerative disorder. It is also known as idiopathic parkinsonism, or idiopathic Parkinson's disease. The cause of the disease remains unknown, but it is manifested by an impairment in neurons in the substantia nigra of the brain, resulting in lack of production of dopamine, a neurotransmitter. The reduction in dopamine levels can cause movement impairments via irregular nerve firing in the brain (National Institute of Neurological Disorders and Stroke, January 2006, NIH Publication No. 06- 139). Major motor impairments associated with PD include tremor, rigidity, bradykinesia, and postural instability.
  • An exemplary property of certain aminopyridines is that they are potassium channel blockers.
  • 4-aminopyridine (4-AP) is an example of an aminopyridine with such potassium channel blocking properties.
  • 4-AP plasma concentrations obtained in clinical studies, which are typically ⁇ 1 microM (94 ng/mL "1 ) the potassium channel blocking activity of 4-AP appears to be selective for certain types of these channels.
  • 4-AP is a broad-spectrum blocker of potassium channels.
  • the clinical neurologic effects of 4-AP are consistent with the molecular mechanism of potassium channel blockade. At the cellular level, this action may increase neuronal excitability, relieve conduction block in demyelinated axons, and potentiate synaptic and neuromuscular transmission.
  • Dalfampridine is the United States Adopted Name (US AN) for the chemical 4- aminopyridine (4-AP). It is FDA-approved as an extended release (ER), 10 mg tablet (see Ampyra ® package insert) indicated to improve walking in subjects with multiple sclerosis (MS), as demonstrated by an increase in walking speed. The approved therapeutic dose of
  • dalfampridine is a 10 mg extended release tablet to be taken twice daily, approximately 12 hours apart, with or without food.
  • dalfampridine-ER 10 mg twice daily were Responders, compared to patients taking placebo.
  • consistent improvements in walking speed were shown to be associated with improvements on a patient self-assessment of ambulatory disability, the 12-item Multiple Sclerosis Walking Scale (MSWS-12).
  • MSWS-12 12-item Multiple Sclerosis Walking Scale
  • aminopyridine is a mono- or di-aminopyridine.
  • the mono-aminopyridine is 3 -aminopyridine or 4-aminopyridine.
  • the di- aminopyridine is 3,4-diaminopyridine.
  • the mono-aminopyridine is 4- aminopyridine.
  • the patient is administered a pharmaceutically acceptable salt of an aminopyridine.
  • an aminopyridine itself, and not a pharmaceutically acceptable salt thereof, is used in any of the methods described herein.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered in a sustained release composition.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered in an immediate release composition.
  • the method in accordance with the invention comprises administering an aminopyridine or a pharmaceutically acceptable salt thereof once daily, twice daily or thrice daily.
  • the aminopyridine or the pharmaceutically acceptable salt thereof is administered to the patient once daily.
  • the aminopyridine or the pharmaceutically acceptable salt thereof is administered to the patient twice daily.
  • an aminopyridine (e.g., 4-AP) or a pharmaceutically acceptable salt thereof is in a sustained release composition, and is administered once or twice daily, preferably orally.
  • an aminopyridine (e.g., 4-AP) or a pharmaceutically acceptable salt thereof is in an immediate release composition, and is administered three times or more than three times daily, preferably orally.
  • an aminopyridine or a pharmaceutically acceptable salt thereof preferably a therapeutically effective amount of the aminopyridine or salt, is
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered to the patient orally.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered orally, it is formulated in a form of a tablet, a pill or a capsule.
  • an aminopyridine or a pharmaceutically acceptable salt preferably a therapeutically effective amount of the aminopyridine or salt
  • a sustained release composition b.i.d. (i.e., twice daily).
  • the patient is orally administered 10 mg of 4-aminopyridine twice daily.
  • twice daily administration comprises administration of an aminopyridine or a pharmaceutically acceptable salt thereof every 12 hours.
  • an aminopyridine or a pharmaceutically acceptable salt thereof in a sustained release composition provides a T max of about 2 hours to about 6 hours in a human.
  • an aminopyridine or a pharmaceutically acceptable salt thereof preferably a therapeutically effective amount of the aminopyridine or salt, is administered to the patient orally, in a sustained release composition once daily.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 4 mg to about 20 mg (e.g., about 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, 15, 16, 17, 17.5 or 20 mg) twice daily, preferably in a sustained release composition.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 4 mg to about 35 mg (e.g., about 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, 15, 16, 17, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, or 35 mg) once daily, preferably in a sustained release composition.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 5 mg to 20 mg, 5 mg to 15 mg, 5 mg to 10 mg, 5 mg to 7.5 mg, 7.5 mg to 12.5 mg, or 7.5 mg to 10 mg twice daily, or about 7.5 mg to 20 mg, 7.5 mg to 15 mg, 10 mg to 30 mg, 10 mg to 20 mg, 10 mg to 15 mg, 15 mg to 30 mg, 15 mg to 40 mg, or 20 mg to 40 mg once daily, preferably in a sustained release composition.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered at a dose of 5 mg twice daily, preferably in a sustained release composition.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered at a dose of 7.5 mg twice daily, preferably in a sustained release composition. In another embodiment, an aminopyridine or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg twice daily, preferably in a sustained release composition. In some of these embodiments, the aminopyridine is 4-aminopyridine. In specific embodiments, an aminopyridine or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 5 mg to 20 mg, 8 mg to 15 mg, 7.5 mg to 12.5 mg, or 10 mg to 15 mg once daily (e.g., in a sustained release
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered at a dose of 20 mg once daily, preferably in a sustained release composition. In one embodiment, an aminopyridine or a pharmaceutically acceptable salt thereof is administered at a dose of 15 mg once daily, preferably in a sustained release composition. In another embodiment, an aminopyridine or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg once daily, preferably in a sustained release composition. In a specific embodiment, an aminopyridine or a pharmaceutically acceptable salt thereof in a sustained release composition administered at a dose of 5 mg, 7.5 mg, or 10 mg twice daily provides a T max of about 2 hours to about 6 hours in a human. In a certain
  • an aminopyridine or a pharmaceutically acceptable salt thereof in a sustained release composition administered at a dose of 10 mg, 15 mg, or 20 mg once daily provides a T max of about 2 hours to about 6 hours in a human.
  • Motor impairments, or impairments of motor function, that can be treated in accordance with the methods described herein include, without limitation: general mobility impairments, walking impairments, gait impairments (e.g., gait freezing), unwanted acceleration of walking, postural instability, stooped posture, increase in falls, dystonia, dyskinesia, tremor, rigidity, bradykinesia, micrographia, dexterity impairment, motor coordination impairment, decreased arm swing, akathisia, speech impairment, problematic swallowing, sexual dysfunction, cramping and drooling.
  • the motor impairment treated in accordance with the methods described herein is either dyskinesia, dystonia, or motor fluctuation.
  • the motor impairment is either a tremor, bradykinesia, or rigidity.
  • the motor impairment treated in accordance with the methods described herein is an impairment in general mobility.
  • the motor impairment or the general mobility impairment treated in accordance with the methods described herein is an impairment in walking.
  • the walking impairment treated in accordance with the methods described herein is a decrease in walking speed.
  • the walking impairment treated in accordance with the methods described herein is unwanted acceleration in walking.
  • the general mobility impairment or walking impairment treated in accordance with the methods described herein is assessed (before or after
  • the motor impairment treated in accordance with the methods described herein is an impairment in stride time variability. In another embodiment, the motor impairment treated in accordance with the methods described herein is an impairment in double limb support variability.
  • the motor impairment or the general mobility impairment treated in accordance with the methods described herein is an impairment in gait in a patient with PD.
  • the impairment treated in accordance with the methods described herein is an abnormal gait in a patient with PD.
  • the impairment treated in accordance with the methods described herein is an abnormal manner and style of walking (i.e., walking gait) in a patient with PD.
  • impairments in gait that can be treated in accordance with the methods described herein include, without limitation, an impairment in stride length and freezing of gait.
  • the gait impairment treated in accordance with the methods described herein is an impairment in stride length.
  • the gait impairment treated in accordance with the methods described herein is freezing of gait. In another embodiment, the gait impairment treated in accordance with the methods described herein is an impairment in spatial gait kinematics. In another embodiment, the gait impairment treated in accordance with the methods described herein is an impairment in turning time.
  • the gait impairment treated in accordance with the methods described herein is assessed (before or after administration of an aminopyridine or a pharmaceutically acceptable salt thereof), or assayable, using 3D Gait analysis, Unified Parkinson's Disease Rating Scale (UPDRS), Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), axial MDS-UPDRS, Timed 25-foot Walk Test (T25FW) and/or Freezing of Gait Questionnaire (FOGQ).
  • UPDS Unified Parkinson's Disease Rating Scale
  • MDS-UPDRS Movement Disorder Society-Unified Parkinson's Disease Rating Scale
  • T25FW Timed 25-foot Walk Test
  • FOGQ Freezing of Gait Questionnaire
  • the motor impairment treated in accordance with the methods described herein is increase in falls.
  • the motor impairment treated in accordance with the methods described herein is a balance impairment, such as postural instability or postural imbalance.
  • gait freezing and/or postural instability in a patient with PD are treated in accordance with the methods described herein.
  • postural instability in a patient with PD is treated in accordance with the methods described herein.
  • the motor impairment is assayable by a 3D Gait Analysis, Unified Parkinson's Disease Rating Scale (UPDRS), Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), axial MDS-UPDRS, Freezing of Gait
  • UDRS Unified Parkinson's Disease Rating Scale
  • MDS-UPDRS Movement Disorder Society-Unified Parkinson's Disease Rating Scale
  • axial MDS-UPDRS Freezing of Gait
  • the motor impairment are assessed before and/or after the
  • Parkinson's Disease Rating Scale (UPDRS), Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), axial MDS-UPDRS, Freezing of Gait Questionnaire (FOGQ), Timed Up and Go test (TUG), or a Timed 25-Foot Walk test (T25FW).
  • the level of impairment is assessed after repeated administering of the aminopyridine or a pharmaceutically acceptable salt thereof.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered to a patient concomitantly with one or more additional drugs or therapy.
  • Concomitant administration can be concurrently, simultaneously, or sequentially (before or after).
  • concurrent administration can be over the same treatment period, e.g., on the same day, during the same week, or during the same two-week period, the same month, etc.
  • an aminopyridine or a pharmaceutically acceptable salt thereof can be administered concomitantly with another drug or drugs effective for the impairment associated with PD.
  • aminopyridine or a pharmaceutically acceptable salt thereof is a dopaminergic agent, an anticholinergic agent, amantadine, or an adenosine A 2 A receptor antagonist.
  • the patient is concomitantly treated with one or more dopaminergic agents.
  • the dopaminergic agent used concomitantly with an aminopyridine or a pharmaceutically acceptable salt thereof is a dopamine precursor (e.g., levodopa).
  • the dopaminergic agent used concomitantly with an aminopyridine or a pharmaceutically acceptable salt thereof is a dopamine agonist (e.g., apomorphine, bromocriptine, pramipexole, roprinirole or rotigotine).
  • the dopaminergic agent used concomitantly with an aminopyridine or a pharmaceutically acceptable salt thereof is a drug that inhibits dopamine metabolism (e.g., MAO-B inhibitor, or a COMT inhibitor).
  • Hoehn and Yahr (H & Y) Scale is a categorization of the severity of
  • stage 1 is the mildest form of PD
  • stage 5 is the most severe.
  • the patient treated in accordance with the methods provided herein is stage 1, stage 2, stage 3, stage 4, or stage 5 on the H & Y Scale (or stage 1 to stage 5 on the H & Y Scale).
  • the patient treated in accordance with the methods provided herein is stage 1, stage 2, or stage 3 on the H & Y Scale (or stage 1 to stage 3 on the H & Y Scale).
  • the patient treated in accordance with the methods provided herein is stage 1 or stage 2 on the H & Y Scale.
  • the patient treated in accordance with the methods provided herein is stage 1 on the H & Y Scale. In another embodiment, the patient treated in accordance with the methods provided herein is stage 2 on the H & Y Scale. In yet another embodiment, the patient treated in accordance with the methods provided herein is stage 3 on the H & Y Scale. In a further embodiment, the patient treated in accordance with the methods provided herein is stage 4 on the H & Y Scale.
  • a method for treating a motor impairment associated with Parkinson's disease in a human patient in need thereof comprising orally administering to the patient a sustained release composition of 4- aminopyridine.
  • 4-aminopyridine is administered to the patient in an amount of 10 mg twice daily.
  • the patient is concomitantly treated with a dopamine precursor and/or a dopamine agonist.
  • the motor impairment in the patient is an impairment in gait.
  • the motor impairment in the patient is an impairment in walking.
  • the motor impairment in the patient is a decrease in walking speed.
  • the motor impairment is levodopa- resistant and/or dopaminergic agonist-resistant.
  • the impairment is levodopa-resistant and/or
  • a gait impairment e.g., freezing of gait
  • a gait impairment e.g., freezing of gait
  • dopaminergic agonist-resistant is levodopa-resistant and/or dopaminergic agonist-resistant.
  • Cminss, C maxss , C avss values generally relate to blood plasma.
  • gait refers to the pattern of movement of the limbs during locomotion over a solid substrate. In one embodiment, gait is the manner and style of walking.
  • improvement designates an alteration in a parameter in a therapeutic direction.
  • improvement also comprises stabilization of a parameter that would otherwise be deteriorating or moving in a non-therapeutic direction.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not prohibited for human or veterinary administration (as the case may be) by a regulatory agency such as the Food and Drug Administration or European Medicines Agency.
  • aminopyridine refers to a salt prepared from a pharmaceutically acceptable nontoxic acid or base, including an inorganic acid or base, or an organic acid or base.
  • the pharmaceutically acceptable salt is prepared from a pharmaceutically acceptable non-toxic acid which can be an inorganic or organic acid.
  • nontoxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid.
  • the non-toxic acid is hydrochloric acid.
  • Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in S. M. Barge et al, "Pharmaceutical Salts," 1977, J. Pharm. Sci. 66: 1-19, which is incorporated herein by reference in its entirety.
  • Figure 1 shows information regarding 4-aminopyridine.
  • Figure 2 is a schematic showing the timetable of 4-AP and placebo dosing for the crossover trial described in Example 1 , Section 6.1.2.1.
  • FIG. 3A shows Timed Up and Go Test (TUG) changes after 4-AP
  • pretreatment (1-pre), 2 hours after administration of 4-AP (2 -post), after 48 hours (3-48h), 30 days post 4-AP (4-30d) and repeated at 90 days pre 4-AP (5-pre/90d) and post 4-AP (6-post).
  • FIG. 3B shows stride length changes after 4-AP administration. Stride is expressed as percentage from patient height. Measurements were performed at the following time points: pretreatment (1-pre), 2 hours after administration of 4-AP (2 -post), after 48 hours (3- 48h), 30 days post 4-AP (4-30d) and repeated at 90 days pre 4-AP (5-pre/90d) and post 4-AP (6- post).
  • the invention provides use of an aminopyridine or a pharmaceutically acceptable salt thereof for treating a patient with Parkinson's disease (PD) and, in particular, for treating impairments associated with PD in a patient with PD.
  • PD Parkinson's disease
  • disclosed herein are uses of an aminopyridine or a pharmaceutically acceptable salt thereof for treating a motor impairment, such as an impairment in gait, in a patient with PD.
  • Aminopyridines having the above structural formula wherein x is 1 are, e.g., 2- aminopyridine, 3- aminopyridine and 4- aminopyridine.
  • Aminopyridine compounds having the above structural formula wherein x is 2 are, e.g., 2,3-diaminopyridine; 2,5- diaminopyridine; 2,6- diaminopyridine; 3,4- diaminopyridine; 4,5- diaminopyridine and 4,6- diaminopyridine.
  • the aminopyridine is a mono- or di-aminopyridine. In one embodiment, the mono-aminopyridine is 3 -aminopyridine or 4-aminopyridine. In one
  • di-aminopyridine is 3,4-diaminopyridine.
  • a pharmaceutically acceptable salt of an aminopyridine may be used instead of or in addition to an aminopyridine in any or all of the methods of treating discussed herein.
  • a pharmaceutically acceptable salt of an aminopyridine i.e., any pharmaceutically acceptable salt of any of the aminopyridine
  • salts can be prepared, for example, 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.
  • a salt of a mono- or di-aminopyridine is used in the methods of the invention.
  • a salt of 3 -aminopyridine or 4-aminopyridine is used.
  • a salt of 3,4-diaminopyridine is used.
  • the pharmaceutically acceptable salt of an aminopyridine is prepared using acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, or p-toluenesulfonic acid.
  • one equivalent of an aminopyridine may form an acid salt with less than one or with one or more than one equivalent of an acid.
  • an aminopyridine, as used herein may form a dihydrochloride salt.
  • an aminopyridine, as used herein may form a phosphate salt.
  • an aminopyridine itself and not a pharmaceutically acceptable salt thereof, is used in any of the methods of treating PD, e.g., a motor impairment in a patient with PD, described herein.
  • the invention provides for treatment of patients who have Parkinson's disease (PD).
  • the invention provides for treatment of one or more impairments associated with PD in a patient with PD.
  • the impairment is levodopa-resistant and/or dopaminergic agonist-resistant.
  • provided herein are methods for treating one or more motor impairments in a patient with PD.
  • provided herein are methods for treating a walking impairment, for example a gait impairment, in a patient with PD. Such treating can be by administering any of the doses and dosage regimens described in this application.
  • Motor impairments, or impairments of motor function, that can be treated in accordance with the methods described herein include, without limitation: general mobility impairments, walking impairments, gait impairments (e.g., gait freezing), unwanted acceleration of walking, postural instability, stooped posture, increase in falls, dystonia, dyskinesia, tremor, rigidity, bradykinesia, micrographia, dexterity impairment, motor coordination impairment, decreased arm swing, akathisia, speech impairment, problematic swallowing, sexual dysfunction, cramping and drooling.
  • general mobility impairments e.g., walking impairments, gait impairments (e.g., gait freezing), unwanted acceleration of walking, postural instability, stooped posture, increase in falls, dystonia, dyskinesia, tremor, rigidity, bradykinesia, micrographia, dexterity impairment, motor coordination impairment, decreased arm swing, akathisia, speech impairment, problematic swallowing, sexual dysfunction, cramping
  • Additional motor impairments that can be treated in accordance with the methods described herein include, without limitation: global body control impairments, coordination or balance impairments, endurance impairment, impairment in hand function, fine hand coordination loss or impairment, impairment in grip strength, impairment in hand strength, impairment in manual dexterity, muscle weakness, muscle tone impairment, range of motion impairment, spasticity, strength impairment/weakness, impairment in limb function, upper extremity function impairment, lower extremity function impairment, impairment in lower extremity muscle strength, speech impairments (e.g., dysarthria), impairment in jaw function, impairment in chewing, and impairment in jaw articulation.
  • the motor impairment is levodopa-resistant and/or dopaminergic agonist-resistant.
  • the motor impairment treated in accordance with the methods described herein is an impairment in general mobility.
  • the motor impairment or the general mobility impairment treated in accordance with the methods described herein is an impairment in walking.
  • impairments in walking that can be treated in accordance with the methods described herein include, without limitation, an impairment in walking velocity (walking speed) and unwanted acceleration in walking.
  • the walking impairment treated in accordance with the methods described herein is an impairment in walking velocity (walking speed) and unwanted acceleration in walking.
  • the walking impairment treated in accordance with the methods described herein is unwanted acceleration in walking.
  • the general mobility impairment or walking impairment treated in accordance with the methods described herein is assessed (before or after
  • the motor impairment treated in accordance with the methods described herein is an impairment in stride time variability. In another embodiment, the motor impairment treated in accordance with the methods described herein is an impairment in double limb support variability.
  • the motor impairment or the general mobility impairment treated in accordance with the methods described herein is an impairment in gait.
  • the impairment treated in accordance with the methods described herein is an abnormal gait in a patient with PD.
  • the impairment treated in accordance with the methods described herein is an abnormal manner and style of walking (i.e., walking gait) in a patient with PD.
  • impairments in gait that can be treated in accordance with the methods described herein include, without limitation, an impairment in stride length and freezing of gait.
  • the gait impairment treated in accordance with the methods described herein is an impairment in stride length.
  • the gait impairment treated in accordance with the methods described herein is freezing of gait. In another embodiment, the gait impairment treated in accordance with the methods described herein is an impairment in spatial gait kinematics. In another embodiment, the gait impairment treated in accordance with the methods described herein is an impairment in turning time. In another embodiment, the impairment in gait is levodopa-resistant and/or dopaminergic agonist-resistant.
  • the gait impairment treated in accordance with the methods described herein is assessed (before or after administration of an aminopyridine or a pharmaceutically acceptable salt thereof), or assayable, using 3D Gait analysis, Unified Parkinson's Disease Rating Scale (UPDRS), Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), axial MDS-UPDRS, Timed 25-foot Walk Test (T25FW) and/or Freezing of Gait Questionnaire (FOGQ).
  • UPDS Unified Parkinson's Disease Rating Scale
  • MDS-UPDRS Movement Disorder Society-Unified Parkinson's Disease Rating Scale
  • T25FW Timed 25-foot Walk Test
  • FOGQ Freezing of Gait Questionnaire
  • the motor impairment or an impairment in general mobility treated in accordance with the methods described herein is an impairment in basic mobility skills such as walking, turning and/or changing the position from sitting to standing (or standing to sitting).
  • the general mobility impairment treated in accordance with the methods described herein is assessed (before or after administration of an aminopyridine or a pharmaceutically acceptable salt thereof), or assayable, using Timed Up and Go Test (TUG).
  • TMG Timed Up and Go Test
  • the motor impairment is levodopa-resistant and/or dopaminergic agonist-resistant.
  • the impairment in walking treated in accordance with the methods described herein is a decrease in walking speed.
  • the walking speed impairment treated in accordance with the methods described herein is assessed (before or after administration of an aminopyridine or a pharmaceutically acceptable salt thereof), or assayable, using Timed 25-foot Walk Test (T25FW).
  • the motor impairment treated in accordance with the methods described herein is increase in falls.
  • the motor impairment treated in accordance with the methods described herein is a balance impairment, such as postural instability or postural imbalance.
  • an impairment in postural balance treated in accordance with the methods described herein can be an impairment in postural balance while not in locomotion over a solid substrate.
  • an impairment in postural balance treated in accordance with the methods described herein can be an impairment in postural balance while in locomotion over a solid substrate.
  • the methods provided herein are for treating a postural balance impairment or postural instability in a patient with PD when the patient is sitting, standing, reaching,
  • the increase in falls treated in accordance with the methods described herein is assessed (before or after
  • gait freezing and/or postural instability in a patient with PD are treated in accordance with the methods described herein.
  • postural instability in a patient with PD is treated in accordance with the methods described herein.
  • the motor impairment treated in accordance with the methods described herein is dyskinesia, dystonia and/or a motor fluctuation (e.g., "ON'VOFF" fluctuation in responsiveness to a therapy with another drug, e.g., a dopaminergic agent).
  • the motor impairment treated in accordance with the methods described herein is dyskinesia and/or dystonia.
  • the motor impairment e.g., dyskinesia, dystonia or fluctuation
  • the motor impairment e.g., dyskinesia, dystonia or fluctuation
  • is assessed before or after administration of an aminopyridine or a pharmaceutically acceptable salt thereof), or assayable, using Unified Parkinson's Disease Rating Scale (UPDRS) or Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS).
  • UDRS Unified Parkinson's Disease Rating Scale
  • MDS-UPDRS Movement Disorder Society-Unified Parkinson's Disease Rating Scale
  • the motor impairment treated in accordance with the methods described herein is a tremor, bradykinesia, or rigidity.
  • parameters of gait include, without limitation, step width, step or stride length, step speed, step time, step length symmetry, step length/leg length ratio, velocity (e.g., endpoint sway velocity), base of support (e.g., dynamic base of support) and percentage of gait cycle spent in double or single support per walking trial.
  • parameters of gait include, without limitation, freezing of gait, posture, length of stride, width of base, speed and/or fluidity of motion, arm swing, bilateral symmetry of motor activity, and neurological deficits or signs.
  • the impairment in gait is levodopa-resistant and/or dopaminergic agonist- resistant.
  • the motor functions, including impairment of motor functions and improvement in motor functions, of the patient can be assessed using any method known in the art.
  • assessment tests can include, without limitation the Timed 25 Foot Walk Test (T25FW), 3D Gait Analysis, Unified Parkinson's Disease Rating Scale (UPDRS), Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), axial MDS-UPDRS,
  • T25FW can be used to assess walking and gait.
  • 3D Gait Analysis can be used to assess gait.
  • 3D Gait Analysis can be used to measure gait velocity and/or stride length (e.g., Peak Motus® Software, Peak Performance, Centennial, CO can be used in the methods described herein).
  • UPDRS can be used to measure motor and non-motor functions in a patient with PD.
  • UPDRS can be used to assess such motor impairments such as dyskinesias,
  • FOGQ is another test that can be used to assess gait.
  • FOGQ can be used to assess freezing of gait.
  • FOGQ can be used to assess susceptibility of a patient to falls.
  • TUG can be used to assess general mobility in a patient.
  • TUG can be used to assess basic mobility skills, e.g., in people who are elderly or have neurological conditions.
  • TUG may evaluate sit-to-stand, walking (e.g., 3 minute walking), turning, and/or returning to the chair functions in a patient.
  • Such assessments can be performed before and after administration of an aminopyridine or a pharmaceutically acceptable salt thereof to a patient in accordance with the methods disclosed herein.
  • a motor function in a patient with PD can be assessed before administering an aminopyridine and/or after
  • an aminopyridine or a pharmaceutically acceptable salt thereof, e.g., at or after 1,
  • the impairments treated in accordance with the methods described herein are impairments (e.g., motor impairments) assayable by one or more of the following tests: the timed 25 Foot Walk Test (T25FW), 3D Gait Analysis, Unified Parkinson's Disease Rating Scale (UPDRS), Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), axial MDS-UPDRS, Freezing of Gait Questionnaire (FOGQ), and the Timed Up and Go Test (TUG).
  • T25FW timed 25 Foot Walk Test
  • UDRS Unified Parkinson's Disease Rating Scale
  • MDS-UPDRS Movement Disorder Society-Unified Parkinson's Disease Rating Scale
  • FOGQ Freezing of Gait Questionnaire
  • TAG Timed Up and Go Test
  • the motor functions including impairments of motor functions and improvement in motor functions, can be assessed, without limitation, using: 2 minute walk test, 6 minute walk (6MW) test, Box & Block test, Six Spot Step Test, the Manual Muscle test for lower extremity function, Lower Extremity Manual Muscle Test (LEMMT), the Ashworth score, the Modified Ashworth Scale, grip strength test, 9-hole peg test, fine finger movement, rapid alternating fingers for upper extremity function, functional system scoring for sensory function, and finger-to-nose and heel-to-shin for ataxia.
  • 2 minute walk test or 6MW test can be used to measure walking
  • LEMMT can be used to measure lower extremity muscle strength
  • the Modified Ashworth Scale can be used to measure spasticity.
  • GAITRiteTM technology e.g., 26 foot GAITRiteTM
  • the NeuroCom SMART Balance Master® can be used to measure gait and balance parameters such as step length.
  • a Step Watch® accelerometer can be used to measure gait.
  • Art-accepted upper extremity function assessments include, without limitation,
  • Such assessments can be performed before and after administration of an aminopyridine or a pharmaceutically acceptable salt thereof to a patient in accordance with the methods disclosed herein.
  • a motor function in a patient with PD can be assessed before administering an aminopyridine and/or after administering an aminopyridine, e.g., at or after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days; 1, 2, 3, 4, 5, 6, 7, 8 weeks; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 months; or 1, 2, 3, 4, 5 years since the commencement of treatment in accordance with the methods described herein.
  • the treatment in accordance with the invention is to improve, ameliorate, or reduce the severity of an impairment (e.g., motor impairment such as a gait impairment) in a patient with PD.
  • the treatment in accordance with the invention is to improve an impairment (e.g., motor impairment such as a gait impairment) in a patient with PD.
  • the treatment in accordance with the invention is to improve general mobility in a patient with PD.
  • the treatment in accordance with the invention is to improve gait (e.g., to improve one, two or more parameters of gait) in a patient with PD.
  • the treatment in accordance with the invention is to improve freezing of gait, turning time, spatial gait kinematics, stride time variability, double limb support variability, stride velocity or stride length in a patient with PD.
  • the treatment in accordance with the invention is to improve postural imbalance or decrease incidence of falls in a patient with PD.
  • the treatment in accordance with the invention is to improve dystonia or dyskinesia in a patient with PD.
  • the treatment in accordance with the invention is to improve motor fluctuations in a patient with PD (e.g., "ON'VOFF" fluctuation in responsiveness to a therapy with another drug, e.g., a dopaminergic agent).
  • the impairment is levodopa-resistant and/or
  • the impairment in gait is levodopa- resistant and/or dopaminergic agonist-resistant.
  • the motor impairment is levodopa-resistant and/or dopaminergic agonist-resistant.
  • the level of an impairment can be assessed (e.g., by assessing one, two or more parameters of such impairment) after, or before and after, repeated administration of an aminopyridine or a pharmaceutically acceptable salt thereof.
  • Such method can be any method for evaluating the impairment described herein or known in the art.
  • treating a PD patient by administering an amount of an aminopyridine or a pharmaceutically acceptable salt thereof is effective to treat (e.g., improve, ameliorate, alleviate the symptoms of, or reduce the severity of) an impairment, such as a motor impairment, e.g., gait impairment, in a patient with PD.
  • treating a PD patient by administering an amount of an aminopyridine or a pharmaceutically acceptable salt thereof is effective to eliminate an impairment, such as a motor impairment, e.g., gait impairment, in a patient with PD.
  • the motor impairment that is effectively treated or eliminated as described above can be any motor impairment, e.g., any motor impairment described herein.
  • the motor impairment is levodopa-resistant and/or dopaminergic agonist-resistant.
  • an amount e.g., a therapeutically effective amount
  • a method for treating an impairment or maintaining an improvement in an impairment (such as a motor impairment, e.g., a gait impairment) in a patient with PD comprises administering an amount (e.g., a therapeutically effective amount) of an aminopyridine or a pharmaceutically acceptable salt thereof to said patient over an extended period of time.
  • a method for achieving sustained improvement in an impairment comprises continuing administration of an amount (e.g., a therapeutically effective amount) of an aminopyridine (such as 3,4-diaminopyridine, 4-aminopyridine and the like) or a pharmaceutically acceptable salt thereof to said patient over an extended period of time.
  • an aminopyridine such as 3,4-diaminopyridine, 4-aminopyridine and the like
  • the extended period of time is at least, or more than, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered to a patient for at least or more than: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 days; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22 weeks; 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 months; or 1, 2, 3, 4, 5, 10 or greater than 5 or 10 years.
  • the improvement(s) in an impairment (such as a motor impairment, e.g., a gait impairment) among patients with PD occur over periods of at least or more than: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21 days; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22 weeks; 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 months; or 1, 2, 3, 4, 5, 10, or greater than 5 or 10 years of treatment with an aminopyridine.
  • a therapeutic outcome of treatment in accordance with the methods described herein is assayed for and detected at any one, two, three, four, five or more, or each, of the following time points, and/or at a time point later than any one of the following time points: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, days; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks; 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 36, 42, 48, 54, 60, and 66 months; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6 and 6.5 years post-commencement of treatment with an aminopyridine or a pharmaceutically acceptable salt thereof.
  • treating a patient by administering an amount of an aminopyridine or a pharmaceutically acceptable salt thereof is effective to eliminate a motor impairment associated with PD, and/or effective to regain the motor function impaired by PD.
  • the administering of an aminopyridine or a pharmaceutically acceptable salt thereof is effective to restore a motor function impaired by PD.
  • aminopyridine administration restores one or more motor functions.
  • This is manifest or measured as an improvement, e.g., in motor function, general mobility, walking (e.g., walking velocity), gait (e.g., freezing of gait and/or stride length), postural instability, decrease in falls, dystonia, dyskinesia, answers to art-accepted measures of quality of life, or improvement in any other motor function described herein or known in the art.
  • treating a patient by administering an amount of an aminopyridine or a pharmaceutically acceptable salt thereof is effective to prevent a motor impairment, e.g., a gait impairment, associated with PD.
  • treating a patient by administering an amount of an aminopyridine or a pharmaceutically acceptable salt thereof is effective to prevent the onset of the symptoms of a motor impairment, e.g., a gait impairment.
  • treating a patient by administering an amount of an aminopyridine or a pharmaceutically acceptable salt thereof is effective to alleviate the symptoms of a motor impairment associated with PD.
  • treating a patient by administering an amount of an aminopyridine or a pharmaceutically acceptable salt thereof is effective to decrease the duration of a motor impairment associated with PD.
  • the motor impairment e.g., gait impairment
  • the motor impairment is levodopa-resistant and/or dopaminergic agonist-resistant.
  • Aminopyridines of the invention or pharmaceutically acceptable salts thereof are administered at a therapeutically effective dosage sufficient to treat an impairment associated with PD in a patient.
  • the treatment reduces the amount of symptoms of the impairment in the patient by at least about 10%, more preferably 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80%) relative to untreated subjects.
  • percent change quantification is preferably applied to assays of motor function that provide measurements of results in continuous linear scales, such as T25FW, etc. Other tests of motor function will not be expressed as percent change but would be predicted to result in a significant change with the appropriate statistical comparison. Such tests include semiquantative measures that assign values to the ability to perform certain skills.
  • treatment in accordance with the invention results in a statistically significant improvement in a motor impairment associated with PD (e.g., as measured by the patient's ability to perform certain task or skill) in comparison to a control.
  • control can be the patient's ability to perform the assessed task or skill prior to the commencement of treatment.
  • the impairment treated in accordance with methods provided herein is not tremor in a patient with PD. In other embodiments, the impairment treated in accordance with methods provided herein can be tremor in a patient with PD.
  • the invention further comprises a step of selecting, identifying, or diagnosing a patient with Parkinson's disease, in particular, idiopathic Parkinson's disease, prior to the administering step.
  • a patient is selected, identified or diagnosed with PD and with a motor impairment associated with PD (such as any of the motor impairments described in the section above, e.g., an impairment in general motor ability, walking impairment, gait impairment (e.g., gait freezing), balance impairment, postural instability, increased incidence of falls, dyskinesia or dystonia).
  • a patient is selected, identified or diagnosed with PD and with an impairment in gait.
  • a patient is selected, identified or diagnosed with PD and with gait freezing or postural instability.
  • the patient treated according to the methods provided herein has Parkinson's disease.
  • the invention provides for treatment of patients with some degree of motor impairment related to PD. This impairment can range from mild symptoms on one side of the body to wheelchair confinement in the most severe cases.
  • the patient treated in accordance with the methods described herein has one or more motor impairments (e.g., has been diagnosed with, or exhibits one or more symptoms of a motor impairment).
  • the patient treated in accordance with the methods described herein has an impairment due to neuronal damage in the area of the cortex or other region of the brain responsible for or involved with motor functions.
  • Preferred embodiments of the present invention relate to methods of using 4-aminopyridine for treating an impairment of motor function resulting from PD.
  • a patient treated in accordance with the methods described herein has an impairment which is levodopa-resistant and/or dopaminergic agonist- resistant.
  • a patient treated in accordance with the methods described herein has an impairment in gait (e.g., freezing of gait) which is levodopa-resistant and/or dopaminergic agonist-resistant.
  • a patient treated in accordance with the methods described herein has an motor impairment which is levodopa-resistant and/or dopaminergic agonist-resistant.
  • the patients or subjects that are treated by the methods of the invention include, but are not limited to, humans and non-human vertebrates such as wild, domestic and farm animals.
  • the patient treated in accordance with the invention is a mammal, e.g., a human, a cow, a dog, a cat, a goat, a horse, a sheep, or a pig.
  • the patient to whom an aminopyridine or a pharmaceutically acceptable salt thereof is administered is a human.
  • the human patient is 18 to 55 years old.
  • the human patient is 18 to 70 years old.
  • the human patient is 45 to 80 years old.
  • the human patient is 45 to 70 years old.
  • the human patient is 16 to 40 years old. In other embodiments, the human patient is greater than 45 years old. In a specific embodiment, the human patient is a female. In yet another specific embodiment, the human patient is a male. In one embodiment, the patient is a human adult.
  • the patient treated in accordance with the methods provided herein does not have a clinical history of seizures and/or epilepsy.
  • the patient has not experienced seizures and/or epilepsy in their lifetime, or has not experienced seizures and/or epilepsy 1, 2, 3, 4 or 5 years, or more than 5 years, prior to administration of an aminopyridine or a pharmaceutically acceptable salt thereof.
  • the patient treated in accordance with the methods provided herein has a clinical history of seizures and/or epilepsy.
  • the patient treated in accordance with the methods provided herein does not have renal impairment.
  • the patient does not have moderate to severe renal impairment (CrCl ⁇ 50 mL/min).
  • the patient treated in accordance with the methods provided herein does not have a clinical history of cardiac arrhythmia.
  • the patient treated in accordance with the methods provided herein has not had deep brain stimulation.
  • the patient treated in accordance with the methods provided herein does not have severe arthritis.
  • the patient treated in accordance with the methods provided herein has renal impairment, has a clinical history of cardiac arrhythmia, has had deep brain stimulation, or has severe arthritis.
  • Hoehn and Yahr (H & Y) Scale is a categorization of the severity of
  • stage 1 is the mildest form of PD
  • stage 5 is the most severe.
  • the patient treated in accordance with the methods provided herein is stage 1, stage 2, stage 3, stage 4, or stage 5 on the H & Y Scale (or stage 1 to stage 5 on the H & Y Scale).
  • the patient treated in accordance with the methods provided herein is stage 1, stage 2, stage 3, or stage 4 on the H & Y Scale (or stage 1 to stage 4 on the H & Y Scale).
  • the patient treated in accordance with the methods provided herein is stage 1 , stage 2, or stage 3 on the H & Y Scale (or stage 1 to stage 3 on the H & Y Scale).
  • the patient treated in accordance with the methods provided herein is stage 1 or stage 2 on the H & Y Scale.
  • the patient treated in accordance with the methods provided herein is stage 1 on the H & Y Scale.
  • the patient treated in accordance with the methods provided herein is stage 2 on the H & Y Scale.
  • the patient treated in accordance with the methods provided herein is stage 3 on the H & Y Scale.
  • the patient treated in accordance with the methods provided herein is stage 4 on the H & Y Scale. In yet another embodiment, the patient treated in accordance with the methods provided herein is stage 5 on the H & Y Scale. In one embodiment, the patient treated in accordance with the methods provided herein is stage 3 or lower on the H & Y Scale.
  • the patient treated in accordance with the methods described herein has idiopathic Parkinson's disease, a gait impairment (e.g., freezing of gait) or postural instability, and is stage 1 to stage 3 on the H & Y Scale.
  • the patient is administered another drug or therapy for PD concurrently with administration of an aminopyridine or a pharmaceutically acceptable salt thereof as described herein (see Section 5.6 below).
  • the patient is administered a dopaminergic agent (e.g., a dopamine agonist and/or levodopa) concurrently with administration of an aminopyridine or a pharmaceutically acceptable salt thereof as described herein.
  • the patient treated in accordance with the methods described herein has undergone surgery to treat PD.
  • a patient treated in accordance with the methods described herein does not have multiple sclerosis.
  • the aminopyridine used in such methods is 4-aminopyridine in a sustained release composition.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered in a sustained release composition.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered in a sustained release composition.
  • aminopyridine or a pharmaceutically acceptable salt thereof is administered in an immediate release composition.
  • the method in accordance with the invention comprises administering an aminopyridine or a pharmaceutically acceptable salt thereof once daily, twice daily or thrice daily.
  • an aminopyridine e.g., 4-AP
  • a sustained release composition is administered once or twice daily, for example, orally.
  • the daily dose of 4-AP is once a day, or is given as two, three, or four equally divided subdoses.
  • an aminopyridine e.g., 4-AP
  • a pharmaceutically acceptable salt thereof is in an immediate release composition, and is administered one, two, three times or more than three times daily, for example, orally.
  • a single dose of an aminopyridine or a pharmaceutically acceptable salt thereof is administered to a patient.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered to the patient orally, in a sustained release composition b.i.d. (i.e., twice daily).
  • twice daily administration comprises administration of a compound every 12 hours.
  • an aminopyridine in a sustained release composition provides a T max of about 2 hours to about 6 hours in a human.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered to the patient orally, in a sustained release composition once daily.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 4 mg to about 20 mg (e.g., about 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, 15, 16, 17, 17.5 or 20 mg) twice daily, preferably in a sustained release composition.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 4 mg to about 35 mg (e.g., about 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, 15, 16, 17, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, or 35 mg) once daily, preferably in a sustained release composition.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 5 mg to 20 mg, 5 mg to 15 mg, 5 mg to 10 mg, 5 mg to 7.5 mg, 7.5 mg to 12.5 mg, or 7.5 mg to 10 mg twice daily, or about 7.5 mg to 20 mg, 7.5 mg to 15 mg, 10 mg to 30 mg, 10 mg to 20 mg, 10 mg to 15 mg, 15 mg to 30 mg, 15 mg to 40 mg, or 20 mg to 40 mg once daily, preferably in a sustained release composition.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered at a dose of 5 mg once daily or twice daily, preferably in a sustained release composition.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered at a dose of 7.5 mg once daily or twice daily, preferably in a sustained release composition. In another embodiment, an aminopyridine or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg once daily or twice daily, preferably in a sustained release composition. In some of these embodiments, the aminopyridine is 4-aminopyridine. In specific embodiments, an aminopyridine or a pharmaceutically acceptable salt thereof is administered at a dose of 7.5 mg once daily or twice daily, preferably in a sustained release composition. In another embodiment, an aminopyridine or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg once daily or twice daily, preferably in a sustained release composition. In some of these embodiments, the aminopyridine is 4-aminopyridine. In specific embodiments, an aminopyridine or a pharmaceutically acceptable salt thereof is administered at a dose of 7.5 mg once daily or twice daily, preferably in a sustained release composition. In another embodiment, an aminopyridine or a pharmaceutically acceptable salt
  • aminopyridine or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 5 mg to 20 mg, 8 mg to 15 mg, 7.5 mg to 12.5 mg, or 10 mg to 15 mg once daily (e.g., in a sustained release composition).
  • a patient is treated in accordance with the methods described herein for a period of time that is, e.g., for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 10 years, or more than 5 or 10 years.
  • the treatment regimen (a particular dose and frequency of administration, which can be selected from any described herein) is stable over a period of time, e.g., for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 6 months, or at least 1 year.
  • a patient with PD is treated with 5 mg 4-aminopyridine in an immediate release composition thrice daily.
  • the impairment being treated is freezing of gait, unwanted acceleration of walking, or an impairment in gait (e.g., stride length, turning time, stride time variability, double limb support variability, velocity, spatial gait kinematics, etc.) as assessed by any method known in the art (e.g., UPDRS, Movement Disorder Society-UPDRS (MDS-UPDRS), axial MDS-UPDRS, TUG test, T25FW, FOGQ, and/or 3D Gait Analysis).
  • UPDRS Movement Disorder Society-UPDRS
  • MDS-UPDRS Movement Disorder Society-UPDRS
  • axial MDS-UPDRS axial MDS-UPDRS
  • a patient with PD is treated with 4-aminopyridine-SR.
  • the patient is instructed to take the drug twice daily.
  • the patient is instructed to take 4-aminopyridine-SR in a dose of 4-aminopyridine selected from 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, or 25 mg bid.
  • one of the daily doses of 4-aminopyridine-SR is different from the other dose, and in a particular embodiment a morning dose is higher than the evening dose. In one embodiment, at least one of the twice daily doses of 4-aminopyridine-SR is 10 mg 4-AP.
  • the patient is instructed to take 4-aminopyridine-SR once daily.
  • the patient is instructed to take 4-aminopyridine-SR in a dose of 4- aminopyridine selected from 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 31.5, 32, 32.5, 33, 33.5, 34, 34.5, 35, 35.5, 36, 36.5, 37, 37.5, 38, 38.5, 39, 39.5, or 40 mg once daily.
  • the once daily dose of 4-aminopyridine-SR is 10 mg 4-AP.
  • the sustained release composition of an aminopyridine or a pharmaceutically acceptable salt thereof results in the release of the aminopyridine or a pharmaceutically acceptable salt thereof from the dosage formulation at a sustained rate such that a therapeutically beneficial blood level is maintained over a period of at least about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, hours, or more than 18 hours, or more than 24 hours, or more than 30 hours.
  • the amount of the aminopyridine or a pharmaceutically acceptable salt thereof results in the release of the aminopyridine or a pharmaceutically acceptable salt thereof from the dosage formulation at a sustained rate such that a therapeutically beneficial blood level is maintained over a period of at least about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, hours, or more than 18 hours, or more than 24 hours, or more than 30 hours.
  • the amount of the aminopyridine or a pharmaceutically acceptable salt thereof results in the release of the aminopyridine or a pharmaceutically acceptable salt thereof from the dosage formulation at
  • aminopyridine or a pharmaceutically acceptable salt thereof in the oral dosage formulations according to embodiments of the present invention establishes a therapeutically useful plasma or CNS concentration through t.i.d., b.i.d., or q.d. administration of the pharmaceutical composition.
  • a therapeutically effective amount of an aminopyridine or a pharmaceutically acceptable salt thereof is between 4 mg and 17.5 mg (e.g., 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, 15, 16, 17 or 17.5 mg), or in the range from 4 to 40 mg, and in a specific embodiment, it is administered once daily or twice daily, preferably in a sustained release composition.
  • aminopyridine or a pharmaceutically acceptable salt thereof is administered in a sustained release composition.
  • aminopyridine or a pharmaceutically acceptable salt thereof is administered in an immediate release composition.
  • a therapeutically effective amount of 4- aminopyridine, or a pharmaceutically acceptable salt thereof is between 4 mg and 17.5 mg (e.g., 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, 15, 16, 17 or 17.5 mg), or in the range from 4 to 40 mg, and, in a specific embodiment, it is administered once daily or twice daily, preferably in a sustained release composition.
  • twice daily administration is administration of an aminopyridine or a pharmaceutically acceptable salt thereof every 12 hours.
  • an aminopyridine e.g., 4-aminopyridine
  • an aminopyridine is administered in an amount in the range of 4 to 17.5 mg (e.g., 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, 15, 16, 17 or 17.5 mg) twice daily in a sustained release composition, or is administered in an amount in the range of 8 to 40 mg (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 ,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 mg) once daily in a sustained release composition.
  • 4 to 17.5 mg e.g., 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, 15, 16, 17 or 17.5 mg
  • 8 to 40 mg e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 ,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 mg
  • a method in accordance with the invention wherein said therapeutically effective amount of an aminopyridine (such as 3,4-diaminopyridine, 4-aminopyridine and the like) or a pharmaceutically acceptable salt thereof is 10 milligrams in a sustained release composition twice daily.
  • said therapeutically effective amount of an aminopyridine (e.g., 4-aminopyridine) or a pharmaceutically acceptable salt thereof is 5 milligrams in a sustained release composition twice daily.
  • a method is provided wherein said therapeutically effective amount of an aminopyridine (e.g., 4-aminopyridine) or a pharmaceutically acceptable salt thereof is 7.5 milligrams in a sustained release composition twice daily. In another embodiment, a method is provided wherein said therapeutically effective amount of an aminopyridine (e.g., 4- aminopyridine) or a pharmaceutically acceptable salt thereof is 10 milligrams in a sustained release composition twice daily. In another embodiment, a method is provided wherein said therapeutically effective amount of an aminopyridine (e.g., 4-aminopyridine) or a
  • a pharmaceutically acceptable salt thereof is 12.5 milligrams in a sustained release composition twice daily.
  • a method is provided wherein said therapeutically effective amount of an aminopyridine (e.g., 4-aminopyridine) or a pharmaceutically acceptable salt thereof is 15 milligrams in a sustained release composition twice daily.
  • a method is provided wherein said therapeutically effective amount of an aminopyridine (e.g., 4- aminopyridine) or a pharmaceutically acceptable salt thereof is 17.5 milligrams in a sustained release composition twice daily.
  • a method wherein the therapeutically effective amount of an aminopyridine (e.g., 4-aminopyridine) or a pharmaceutically acceptable salt thereof is 20 milligrams in a sustained release composition once daily.
  • said therapeutically effective amount of an aminopyridine (e.g., 4-aminopyridine) or a pharmaceutically acceptable salt thereof is 8, 10, 11, 12, 12.5, 13, 14, 15, 16, 17, 17.5, 18, 19, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27.5, 30 or 35 milligrams in a sustained release composition once daily.
  • a method in accordance with the invention comprises administration of a therapeutically effective amount of 4-aminopyridine, or a pharmaceutically acceptable salt thereof, in a total daily amount of 8, 10, 11, 12, 12.5, 13, 14, 15, 16, 17, 17.5, 18, 19, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27.5, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 milligrams in a sustained release composition.
  • An exemplary embodiment comprises twice daily administration where 15 milligrams in a sustained release composition is administered in the morning; and 10 milligrams in a sustained release composition is administered in the evening.
  • An exemplary embodiment comprises twice daily administration where 12.5 milligrams in a sustained release composition is administered in the morning; and 7.5 milligrams in a sustained release composition is administered in the evening.
  • Another exemplary embodiment comprises administration of a total daily amount in a once daily composition.
  • a method in accordance with the invention comprises administration of a therapeutically effective amount of 4-aminopyridine, or a pharmaceutically acceptable salt thereof, in a total daily amount of 8, 10, 11, 12, 12.5, 13, 14, 15, 16, 17, 17.5, 18, 19, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27.5, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 milligrams in an immediate release composition.
  • an immediate release composition comprising an aminopyridine or a pharmaceutically acceptable salt thereof is administered three times daily or more than three times daily (e.g., 4, 5, or 6 times daily).
  • an aminopyridine e.g., 4-aminopyridine
  • SR sustained-release
  • ER extended release
  • an aminopyridine-SR 10 mg which is preferred for b.i.d. dosing, other dosing regimens are within the scope of the invention; accordingly other amounts of active ingredient in sustained-release formulations are also encompassed within the scope of the invention.
  • a sufficient amount of an aminopyridine such as 4-aminopyridine, is provided such that it elicits the steady state levels that are within the range obtained by use of 4-aminopyridine-SR; in one embodiment these steady state values are a maximum concentration at steady state (C maxss ) and minimum concentration at steady state
  • the steady state values can be plasma levels, levels on the brain side of the blood:brain barrier, or levels in the CSF. Preferably, these are plasma levels.
  • a sufficient amount of aminopyridine such as 4- aminopyridine, is provided that it elicits the steady state levels that differ not more than about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% from the average steady state level (C avss ) obtained by use of 4-aminopyridine-SR.
  • the steady state values can be plasma levels, levels on the brain side of the blood:brain barrier, or levels in the CSF. Preferably, these are plasma levels.
  • a method in accordance with the invention is described wherein said therapeutically effective amount of an aminopyridine, e.g., 4- aminopyridine, or a pharmaceutically acceptable salt thereof, achieves a C m i nss of at least or more than: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ng/ml.
  • a method is described wherein said therapeutically effective amount of an aminopyridine (e.g., 4- aminopyridine) or a pharmaceutically acceptable salt thereof achieves an average of at least or more than: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ng/ml.
  • a method is described wherein said therapeutically effective amount of an aminopyridine (e.g., 4-aminopyridine) or a pharmaceutically acceptable salt thereof achieves an average of about 20 ng/ml, which comprises an average lower limit value of from 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ng/ml, and an average upper limit value of 20, 21, 22, 23, 24, 25, 26, or 27 ng/ml.
  • an amount of drug is given to an individual patient (e.g., a dose amount) wherein that dose amount corresponds to an amount that when administered to a normative or reference population obtains an average C m i nss of at least or more than: 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ng/ml.
  • Fluid or tissue levels e.g., C maX ss, C avS s
  • a method is described wherein said therapeutically effective amount of an aminopyridine or a
  • a pharmaceutically acceptable salt thereof achieves a C m i nss in a range of about 5 to 25 ng/ml, 10 to 18 ng/ml, 13 to 15 ng/ml, or 15 to 30 ng/ml.
  • a method is described wherein said therapeutically effective amount of an aminopyridine or a pharmaceutically acceptable salt thereof achieves a C m i nss of about 20 ng/ml.
  • a method is described wherein said therapeutically effective amount of an aminopyridine or a
  • a Cmi nss of about 20 ng/ml comprises a lower limit value of from 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ng/ml, and an upper limit value of 20, 21, 22, 23, 24, 25, 26, or 27 ng/ml.
  • a method of treating a PD-related motor impairment in a patient comprising: administering a therapeutically effective amount of an aminopyridine (e.g., 4-aminopyridine) or a pharmaceutically acceptable salt thereof to said patient such that a Cmi nss in a range of 5 to 25 ng/ml, 10 to 20 ng/ml, 15 to 30 ng/ml, or 12 to 20 ng/ml is obtained.
  • an aminopyridine e.g., 4-aminopyridine
  • a pharmaceutically acceptable salt thereof e.g., a pharmaceutically acceptable salt thereof
  • a method for treating a PD-related motor impairment in a patient comprises administering a therapeutically effective amount of an aminopyridine (e.g., 4-aminopyridine) or a pharmaceutically acceptable salt thereof to said patient such that a C m i nss in a range of at least 12 ng/ml to 15 ng/ml is obtained.
  • a method for treating a PD-related motor impairment in a patient comprises: administering a therapeutically effective amount of an aminopyridine (e.g., 4-aminopyridine) or a pharmaceutically acceptable salt thereof to said patient such that a C m i nss in a range of at least 13 ng/ml to 15 ng/ml is obtained.
  • an amount of drug is given to an individual patient (e.g., a dose amount) wherein that dose amount corresponds to a dose that when administered to a normative or reference population obtains an average Cmi nss of at least or more than: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ng/ml; the plasma levels (e.g., C m i nss , C maxss , C avss ) in reference population can be referred to as a normative values.
  • a method in accordance with the invention comprises administering a therapeutically effective amount of an individual patient (e.g., a dose amount) wherein that dose amount corresponds to a dose that when administered to a normative or reference population obtains an average Cmi nss of at least or more than: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ng/ml; the plasma levels (e.g., C m i nss , C maxs
  • aminopyridine e.g., 4-aminopyridine
  • a pharmaceutically acceptable salt thereof to a patient such that a C m i nss of at least 11 or 12 ng/ml is obtained.
  • a method in accordance with the invention wherein said therapeutically effective amount of an aminopyridine or a
  • the aminopyridine or a pharmaceutically acceptable salt thereof achieves a T max of about 2 hours to about 6 hours in a patient.
  • the aminopyridine or a pharmaceutically acceptable salt thereof is administered in a sustained-release composition (e.g., once daily, twice daily or thrice daily).
  • the aminopyridine is 4-aminopyridine.
  • the therapeutically effective amount of 4-aminopyridine can be any amount disclosed herein.
  • the patient is a human.
  • a therapeutically effective amount of 4- aminopyridine administered once daily, twice daily or three times daily in a sustained-release composition achieves a T max of about 2 hours to about 6 hours in a human.
  • a method in accordance with the invention wherein said therapeutically effective amount of an aminopyridine, e.g., 4- aminopyridine, or a pharmaceutically acceptable salt thereof achieves a C maxss of the following, or less than the following values: 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 ng/ml.
  • an aminopyridine e.g., 4- aminopyridine
  • a pharmaceutically acceptable salt thereof achieves a C maxss of the following, or less than the following values: 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23,
  • a method wherein said therapeutically effective amount of an aminopyridine (e.g., 4-aminopyridine) or a pharmaceutically acceptable salt thereof achieves an average C maxss of the following, or less than the following values: 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 ng/ml.
  • an aminopyridine e.g., 4-aminopyridine
  • a pharmaceutically acceptable salt thereof achieves an average C maxss of the following, or less than the following values: 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 ng/ml.
  • an amount of drug is given to an individual patient (e.g., a dose amount) wherein that dose amount corresponds to an amount that when administered to a normative or reference population obtains an average C maxss of the following, or less than the following values: 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 ng/ml.
  • Fluid or tissue levels e.g., C m i nss , C maxss , C avss
  • normative values e.g., C m i nss , C maxss , C avss
  • a method wherein said therapeutically effective amount of an aminopyridine (e.g., 4- aminopyridine) or a pharmaceutically acceptable salt thereof achieves a C maxss in a range of about 15 to 30 ng/ml, 25 to 35 ng/ml, 25 to 40 ng/ml, or 35 to 55 ng/ml.
  • a method is provided wherein said therapeutically effective amount of an aminopyridine or a pharmaceutically acceptable salt thereof achieves a C maxss of about 30 ng/ml.
  • a method wherein said therapeutically effective amount of an aminopyridine (e.g., 4-aminopyridine) or a pharmaceutically acceptable salt thereof achieves a C maxss in a range that comprises a lower limit value of from 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 ng/ml, and an upper limit value of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 ng/ml.
  • an aminopyridine e.g., 4-aminopyridine
  • a pharmaceutically acceptable salt thereof achieves a C maxss in a range that comprises a lower limit value of from 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 ng/ml, and an upper limit value of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,
  • an aminopyridine e.g., 4-aminopyridine
  • a aminopyridine e.g., 4-aminopyridine
  • pharmaceutically acceptable salt thereof achieves an average C maxss of, or less than: 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 ng/ml.
  • an amount of drug is given to an individual patient (e.g., a dose amount) wherein that dose amount corresponds to a dose that when administered to a normative or reference population obtains an average C maxss of, or less than: 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 ng/ml; the plasma levels (e.g., C m i nss , C maxss , C avss ) in reference population can be referred to as a normative values.
  • the actual dosage amount of an aminopyridine, a pharmaceutically acceptable salt thereof, or a composition comprising an aminopyridine administered to a subject may be determined by physical and physiological factors such as age, sex, body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the subject and on the route of administration. These factors are readily determined by a skilled artisan.
  • the practitioner responsible for administration will typically determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject. The dosage may be adjusted by the individual practitioner in the event of any complication or alteration in patient status.
  • a sustained release composition of 4-aminopyridine is administered to a patient in the methods of the invention, most preferably at 10 mg 4- aminopyridine twice daily.
  • the invention also provides pharmaceutical compositions comprising an aminopyridine or a pharmaceutically acceptable salt thereof as described herein.
  • Such pharmaceutical compositions can comprise an amount (e.g., a therapeutically effective amount) of an aminopyridine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is suitable for oral administration and can be, for example, a pill, tablet or capsule.
  • Pharmaceutical compositions can be as described, for example, in U.S. Patent Application Publication No. 2005/0276851, published December 15, 2005 and U.S. Patent Application Publication No. 2005/0228030, published October 13, 2005, the contents of each of which are incorporated by reference herein in their entireties.
  • a pharmaceutical composition can be, for example, an immediate release composition, a controlled release composition, or a sustained release composition.
  • the pharmaceutical composition comprises a sustained release composition of 4- aminopyridine.
  • the pharmaceutical compositions of the invention are administered to a patient for any of the uses described herein.
  • An aminopyridine or a pharmaceutically acceptable salt thereof is preferably administered to a patient orally or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions, or syrups.
  • Suitable formulations can be prepared by methods commonly employed using conventional, organic or inorganic additives, such as one or more of: an excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose or starch), a disintegrator (e.g., starch, carboxymethylcellulose, hydroxypropylstarch, low substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), a flavoring agent (e.g., citric acid, menthol, g
  • propylparaben e.g., citric acid, sodium citrate or acetic acid
  • a suspending agent e.g., methylcellulose, polyvinyl pyrroliclone or aluminum stearate
  • a dispersing agent e.g., hydroxypropylmethylcellulose
  • a diluent e.g., water
  • base wax e.g., cocoa butter, white petrolatum or polyethylene glycol
  • aminopyridine or a pharmaceutically acceptable salt thereof can be prepared using one, two, three or more, or all, of the following additives: colloidal silicon dioxide, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide.
  • a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof.
  • suitable formulations e.g., suitable formulations such as tablets for oral administration
  • pharmaceutically acceptable salt thereof are prepared using one or more of the following excipients: hydroxypropyl methylcellulose, USP; microcrystalline cellulose, USP; colloidal silicon dioxide, NF; magnesium stearate, USP; and Opadry White.
  • the amount of an aminopyridine or a pharmaceutically acceptable salt thereof that is present in the pharmaceutical composition is preferably an amount that will exercise the desired effect.
  • aminopyridine or a pharmaceutically acceptable salt thereof can be administered orally.
  • an aminopyridine or a pharmaceutically acceptable salt thereof can be administered orally.
  • composition is formulated in a form of a tablet, a pill or a capsule.
  • An aminopyridine or a pharmaceutically acceptable salt thereof can also be administered intradermally, intramuscularly, intraperitoneally,
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered to the patient intravenously.
  • the mode of administration is left to the discretion of the health-care practitioner.
  • compositions can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories and suspensions and the like.
  • compositions can be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit, which may be, e.g., a single tablet or capsule or convenient volume of a liquid.
  • Capsules can be prepared by any known method, such as mixing an aminopyridine or a pharmaceutically acceptable salt thereof with a suitable carrier or diluent and filling the proper amount of the mixture in capsules.
  • Carriers and diluents include, but are not limited to, inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
  • Tablets can be prepared by known methods such as direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
  • the pharmaceutical composition is a sustained release tablet or capsule of 4-AP.
  • Concomitant administration can be concurrently, simultaneously, or sequentially (before or after).
  • concurrent administration can be over the same treatment period, e.g., on the same day, during the same week, or during the same two-week period, the same month, etc.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered to a patient concomitantly with one or more additional drugs or therapy.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered concomitantly with another drug or drugs effective for the impairment associated with PD.
  • the drug(s) administered concomitantly with an aminopyridine or a pharmaceutically acceptable salt thereof is a dopaminergic agent, an anticholinergic agent, amantadine, or an adenosine A 2 A receptor antagonist.
  • the dopaminergic agent used concomitantly with an aminopyridine or a pharmaceutically acceptable salt thereof is a dopamine precursor (e.g., levodopa).
  • the dopaminergic agent used concomitantly with an aminopyridine or a pharmaceutically acceptable salt thereof is a dopamine agonist (e.g., apomorphine, bromocriptine, pramipexole, roprinirole or rotigotine).
  • the dopaminergic agent used concomitantly with an aminopyridine or a pharmaceutically acceptable salt thereof is a drug that inhibits dopamine metabolism (e.g., MAO-B inhibitor, or a COMT inhibitor).
  • the MAO-B inhibitor can be selegiline, rasagiline or zydis selegiline HC1.
  • the COMT inhibitor can be entacapone or tolcapone.
  • the anticholinergic agent used concomitantly with an aminopyridine or a pharmaceutically acceptable salt thereof is trihexyphenidyl, benztropine or ethopropazine.
  • the combination of an aminopyridine or a pharmaceutically acceptable salt thereof and one, two or more additional drug(s) is a fixed dose combination.
  • an aminopyridine or a pharmaceutically acceptable salt thereof and one or more additional drug(s) can be formulated in one composition, such as a pill, a tablet or a capsule.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered to a patient concomitantly (e.g., at the same time, before or after) with physical therapy, occupational therapy, or speech therapy.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered to a patient with PD who uses an assistive device (e.g., cane crutches, or a wheeled walker).
  • the aminopyridine (or salt thereof) and other drug or therapy is administered at the same doctor's visit, or within 1, 2, 3, 4, 5, 6, or 12 hours, or within 1, 2, 3, 4, 5, 6, or 7 days, of each other.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered to a patient without an additional drug or therapy for PD, or without one or more of additional treatments for PD (such as those described above).
  • treatment in accordance with the invention is more effective than treatment with another drug or therapy known to be used for the treatment of PD.
  • treatment of patients on levodopa therapy with an aminopyridine (or salt thereof) using the methods described herein decreases the necessary levodopa dosage in comparison with levodopa therapy alone.
  • dalfampridine-ER produces at least a 20% increase in walking speed and/or stride length in patients with Parkinson's disease while on dopaminergic medication.
  • Surgical procedures such as pallidotomy, thalamotomy and deep brain stimulation (DBS) are also used to treat motor impairments in Parkinson's disease patients.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered to a patient with PD before, during and/or after pallidotomy, thalamotomy or DBS.
  • an aminopyridine or a pharmaceutically acceptable salt thereof is administered to a patient concomitantly with Occupational or Physical Therapy.
  • a patient treated in accordance with the methods described herein does not concomitantly receive Occupational or Physical Therapy.
  • treatment in accordance with the invention is more effective than such other drug, surgery or therapy alone.
  • the primary objective of this study is to evaluate the efficacy of dalfampridine-ER 10 mg (i.e., a sustained release formulation of 10 mg 4-aminopyridine) for walking impairment in Parkinson's disease.
  • the primary outcome measure will be the change in walking velocity and stride length as measured with a 3 dimensional gait analysis system.
  • the secondary objective of this study is to evaluate the efficacy of dalfampridine-ER 10 mg (i.e., a sustained release formulation of 10 mg 4-aminopyridine) on other outcome measures.
  • the exploratory outcome measures that will be studied are: UPDRS score, TUG score, FOGQ and Timed 25 -foot Walk.
  • Parkinson's disease that are administered dalfampridine-ER.
  • Assessment of the change in walking function is accomplished via 3D motion capture, with walking speed and stride length as the primary outcome measures. This method will assure high sensitivity and will help reduce the number of patients needed to treat.
  • the crossover design minimizes the number of patients to treat. Each patient will serve as its own control so no healthy subjects are required for the study.
  • the half life of the drug is around 6 hours, so that 2 weeks washout is considered sufficient. For symptomatic benefit, 4 weeks of treatment was deemed to be sufficient to detect changes.
  • the 3D gait analysis system will allow objective quantification of walking and will be sensitive enough to detect small changes in the walking parameters.
  • the 3 -dimensional gait analysis is carried out using the Peak Motus system, which uses 8 cameras to capture the coordinates of moving points. The points are detected using optical sensors attached to a person's joints at specified locations. With these coordinates, accurate biomechanical data are produced, including velocities, center of mass, distances, and angles. These measures enable the calculation of other measures, such as step length, symmetry of posture, and ground clearance, among others.
  • the secondary objective will be to examine the effect on clinical measures of walking such as Timed Up and Go Test, Timed 25 -Foot Walk, Freezing of Gait Questionnaire and on Unified Parkinson Disease Rating Scale.
  • the incidence of adverse effects and tolerability of dalfampridine-ER will also be part of secondary objectives.
  • the walking velocity and stride length are the primary efficacy measures and are able to detect subtle changes and with a reasonable patient number (20). A larger number of patients would be required for the study if the primary efficacy outcome were TUG (30).
  • a total of 20 patients will be recruited to complete the study. Patients will be randomized to 2 arms: placebo versus dalfampridine-ER. The population from which these subjects will be selected are PD patients of both genders age 45-80. Women of childbearing potential will be excluded. See 6.1.9 for justification of the selected sample sizes.
  • Gait dysfunction will be assessed using FOG questionnaire.
  • Age more than 45 at onset of disease is to avoid young onset PD cases.
  • PD patients with age more than 80 are excluded due to possibility of dizziness and associated comorbidities.
  • Subjects that may have gait impairment due to other causes will be excluded (i.e. arthritis, congestive heart failure).
  • Patients that are required to use an assistive device will be allowed to participate but will be required to use the device in all visits. Patients will take their medication as usual and clinical tests will be done while on medication.
  • 3D Gait analysis will be performed using an 8-camera 30 motion capture system (Peak Motus® Software, Peak Performance, Centennial, CO). A physical therapist experienced in computerized gait analysis systems will run the study. An array of 21 reflective markers will be placed bilaterally at the lateral malleoli, 5th ray metatarsal-phalangeal joints, heels, lateral knee joints, greater trochanters, anterior superior iliac spines, shoulders, elbows, and wrists as well as at C7, T10, and the sacrum. For each walking test session, subjects will walk five times across a 6-m walkway at their preferred walking speed; subjects will be allowed to rest between walking tests. Subjects will use assistive devices as required during testing.
  • Unified Parkinson's disease rating Scale (UPDRS) will be performed by a
  • UPDRS contains 4 sections. Part 1 assesses the non-motor aspects of daily living, part 2 motor aspects of daily living, part 3 is a motor examination of PD patient and part 4 quantifies the presence of motor complications like dyskinesias, fluctuations or dystonia.
  • Timed Up and go test is a mobility test that is used to measure the basic mobility skills of people who are elderly or have neurological conditions. It includes a sit- to-stand component as well as walking 3 m, turning, and returning to the chair. People perform these tasks using regular footwear and customary walking aids. The measured outcome is the time in seconds to complete the entire sequence. Five measurements will be performed and mean time of the best 3 will be recorded.
  • Timed 25-foot walk test (T25FW) is a functional walking assessment that measures the time required for the patient to walk 25 feet. Five measurements will be performed and the 3 best measurements will be recorded.
  • Freezing of gait Questionnaire is a clinician administered patient-reported rating scale that has been validated in patients with PD and consists of 16 items regarding gait and falls.
  • the Montreal Cognitive Assessment is a brief screening instrument for MCI (mild cognitive impairment) and dementia in Patients with Alzheimer and Parkinson's disease.
  • the MoCA is divided into 7 subscores: visuospatial/executive (5 points); naming (3 points); memory (5 points for delayed recall); attention (6 points); language (3 points); abstraction (2 points); and orientation (6 points).
  • Viscospatial/executive 5 points
  • naming 3 points
  • memory 5 points for delayed recall
  • attention points
  • language 3 points
  • orientation (6 points).
  • One point is added if the subject has ⁇ 12 years of education.
  • Screening visit is the initial visit where eligibility is determined based on the inclusion and exclusion criteria. Walking analysis and clinical questionnaires are performed during four scheduled visits. See Table 1. Table 1
  • Dispense medication First dose of medication will be administered while under direct supervision of physician. Dalfampridine-ER 10 mg or placebo will be dispensed after the walking clinical assessments are done. Due to safety reasons patients will be monitored in the office for three hours. Side effects such as dizziness or worsening of tremors will be monitored. Vital signs will be monitored pre and post medication administration.
  • Dispense medication First dose of medication will be administered while under direct supervision of physician. Dalfampridine-ER 10 mg or placebo will be dispensed after the walking clinical assessments are done. Due to safety reasons patients will be monitored in the office for three hours. Side effects such as dizziness or worsening of tremors will be monitored. Vital signs will be monitored pre and post medication administration.
  • An unscheduled visit may be performed at any time during the study at the subject's request or as deemed necessary by the Principal Investigator. An unscheduled visit can occur if patient experiences side effects. The date and reason for the unscheduled visit will be recorded in the source documentation.
  • Walking velocity and stride length will be measured 5 times via 30 motion capture with Peak Motus system in the gait laboratory.
  • PD patients mean walking velocity is 101.3 cm/s ⁇ 20.84 while in normal subjects the velocity is 127.05 cm/s ⁇ 16.48.
  • stride length PD patients mean value is 102.18 cm ⁇ 18.57, while controls have an average of 131.32 cm ⁇ 13.18. The best 3 recordings will be used for quantification of effect of medication.
  • TUG will be measured using a stop watch.
  • mean value of TUG is 9.52 sec with SD (standard deviation) of 1.38 while for Parkinson's disease patients, the mean value of TUG is 13.83 sec with SD of 4.41.
  • the best 3 recordings out of 5 measurements will be used for quantification.
  • Timed 25-foot walk test (T25FW) is a functional walking assessment that measures the time required for the patient to walk 25 feet. Five measurements will be performed and the 3 best measurements will be recorded.
  • Freezing of gait Questionnaire will be administered by the clinical coordinator. It consists of 16 items regarding gait and falls and is reported as a score from 0-16.
  • Unified Parkinson's disease rating Scale (UPDRS) will be performed by a
  • UPDRS contains 4 sections. Part 1 assesses the non-motor aspects of daily living, part 2 motor aspects of daily living, part 3 is a motor examination of PD patient and part 4 quantifies the presence of motor complications like dyskinesias, fluctuations or dystonia.
  • MoCA The Montreal Cognitive Assessment (MoCA) is a brief screening instrument for mild cognitive impairment and will be performed by a Movement Disorder Specialist.
  • the MoCA is divided into 7 sub-scores: visuospatial/executive (5 points); naming (3 points); memory (5 points for delayed recall); attention (6 points); language (3 points);
  • the Clinical Coordinator will assess the subject's compliance with the study requirements. This will include checks of protocol compliance, concomitant medication use, diary card data, and use of study drug in order to assess the reliability of subject-generated data. Subjects who fail to comply with the study requirements may be withdrawn from the study.
  • Dalfampridine-ER is a potassium channel blocker, available in a 10 mg tablet strength. Each tablet contains 10 mg dalfampridine, formulated as an extended release tablet for twice-daily oral administration. Placebo pills will also be also provided.
  • Subjects will be assigned to treatment or placebo arm by computer randomization. Pre-assigned drug kits will be supplied.
  • An adverse experience is any symptom, sign, illness, or experience which develops or worsens during the course of the study, whether or not the event is considered related to study drug.
  • Possible adverse events to be considered are nausea, asthenia, headache, fatigue, insomnia, dizziness or worsening of tremors.
  • a serious adverse drug experience is defined as any adverse experience that occurs at any dose that results in any of the following outcomes: death; a life-threatening adverse experience; inpatient hospitalization, a persistent or significant disability/incapacity.
  • the statistical power estimate is based on a range of sample sizes, effect sizes (defined as mean difference between dalfampridine-ER and placebo groups divided by the square root of the within mean square error), at a 0.05 significance level with a two-sided t test.
  • a total sample size of 20 PD patients will achieve at least 80% power to uncover an effect size of 0.94 at a significance level of 0.05 for a two-sided test.
  • This effect size is corresponding to a mean difference of 14 cm in stride length (14% change) given that the square root of the within mean square error is 15.
  • T25FW ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • Hu CL Liu Z, Zeng XM, Liu ZQ, Chen XH, Zhang ZH and Mei YA, 4-aminopyridine, a Kv channel antagonist, prevents apoptosis of rat cerebellar granule neurons.
  • His gait freezing episodes were present on a daily basis and interfered significantly with his daily activities. His freezing of gait questionnaire score was 16 while OFF levodopa and did not change in the ON state. For his freezing of gait, dopamine receptor agonists or dopamine augmentation have not been useful. Due to his severe freezing of gait, the patient was started on 4-AP 5 mg p.o. three times daily to evaluate the effects on walking and freezing of gait. At the time 4-AP was administered, the patient was only on levodopa and not on selegiline or amantidine.
  • T25FW Foot Walk
  • FOGQ Freezing of Gait Questionnaire
  • MDS-UPDRS MDS-UPDRS were assessed pretreatment, and 2 hours, 48 hours, and 30 days after the initiation of treatment. After 2 days of treatment, the patient reported significant improvement of FOG that persisted at 90 days into the treatment. The measures were repeated pre and post 4-AP 90 days into the treatment. For the 90 days pre and post 4-AP measurements, the patient was instructed to stop the 4-AP 3 days in advance and come for measurements and the patient was ON levodopa at the time of
  • Velocity 60.2 +/- 59.3 +/- 59.48 +/- 59.4 +/- 59.9 +/- 64.7 +/- P 0.0001 (% stature/s) 0.49 0.2 0.4 0.1 0.8
  • TUG test showed significant improvement from 16.7 s at baseline to 14.0 s +/-0.5 48 hours after 4-AP administration.
  • the effects on TUG lasted through the course of treatment at day 30 (12.7 s +/- 0.9) and upon discontinuation of 4-AP at day 90 returned to 16.2 s +/- 1.1 (see Figure 3 A).
  • TUG improved significantly (11.8 s +/-1.6).
  • Velocity normalized by height
  • stride length increased from 43.8 +/-0.7 to 58.3 +/- 0.9
  • turning time decreased from 3.73 s +/-0.5 to 2.93 s +/-0.36.
  • 4-AP may have a short term effect, seen in the patient as improvement in FOG and TUG, but also a long term effect that is manifested as an increase in stride length and a reduction in gait variability.

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Abstract

L'invention concerne des méthodes et des compositions pour traiter des patients atteints de la maladie de Parkinson et, en particulier, de troubles moteurs chez des patients atteints de la maladie de Parkinson, au moyen d'une aminopyridine.
PCT/US2013/074367 2012-12-11 2013-12-11 Méthodes pour traiter la maladie de parkinson faisant intervenir des aminopyridines WO2014093475A1 (fr)

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WO2017058869A1 (fr) 2015-09-29 2017-04-06 Acorda Therapeutics, Inc. Compositions à libération prolongée de 4-aminopyridine
CN107205950A (zh) * 2014-11-04 2017-09-26 阿达玛斯医药公司 金刚烷胺组合物的施用方法
WO2018186866A1 (fr) 2017-04-06 2018-10-11 Cobb Joseph E Jr Compositions à libération prolongée de 4-aminopyridine
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CN107205950A (zh) * 2014-11-04 2017-09-26 阿达玛斯医药公司 金刚烷胺组合物的施用方法
JP2017533211A (ja) * 2014-11-04 2017-11-09 アダマス ファーマシューティカルズ， インコーポレイテッド アマンタジン組成物を投与する方法
EP3215132A4 (fr) * 2014-11-04 2018-07-11 Adamas Pharmaceuticals, Inc. Méthodes d'administration de compositions d'amantadine
EP3909569A1 (fr) * 2014-11-04 2021-11-17 Adamas Pharmaceuticals, Inc. Procédés d'administration de compositions d'amantadine
WO2017058869A1 (fr) 2015-09-29 2017-04-06 Acorda Therapeutics, Inc. Compositions à libération prolongée de 4-aminopyridine
WO2018186866A1 (fr) 2017-04-06 2018-10-11 Cobb Joseph E Jr Compositions à libération prolongée de 4-aminopyridine
US12029820B2 (en) 2021-07-13 2024-07-09 Acorda Therapeutics, Inc. Sustained release compositions of 4-aminopyridine

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