RU2802288C2 - Therapeutic agents for the treatment of restless leg syndrome - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions concerns the treatment of restless legs syndrome (RLS). The use of leucine, acetyleucine, or a pharmaceutically acceptable salt thereof for the treatment of RLS or one or more symptoms associated with RLS in a subject in need thereof, wherein RLS is the primary RLS are proposed. Also a method of alleviating, suppressing, or eliminating one or more RLS symptoms in a subject in need thereof is provided, the said method comprises administering a therapeutically effective amount of leucine, acetyleucine, or a pharmaceutically acceptable salt thereof to the subject.

EFFECT: use of the group of inventions provides effective treatment of RLS, in particular, reduction, suppression or elimination of one or more symptoms associated with RLS.

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Description

This application claims priority to U.S. Provisional Application No. 62/631383, filed February 15, 2018, incorporated herein by reference in its entirety.

Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a neurological disorder that affects about 10% of adults, with a higher prevalence among women and the elderly. RLS is characterized by an overwhelming desire to move the body, usually accompanied by uncomfortable or strange sensations. The legs are most commonly affected, especially between the knee and ankle, but other areas such as the arms, torso, or even phantom limbs can also be affected. RLS sensations can range from aching or aching muscles to "itching that can't be scratched away," an unpleasant "incessant tickling," or even a "chilling" sensation. The sensations may occur or intensify during quiet wakefulness, such as when relaxing, reading, studying, or trying to sleep. For example, sitting or lying down (for example, when reading, flying in an airplane, watching TV) can evoke feelings and encourage movement.

Diagnostic criteria for RLS may include: (1) urge to move limbs with and without sensation; (2) worse at rest; (3) improvement with activity; and (4) worse in the evening or at night. Symptoms of RLS can make it difficult to sleep, and significant daytime problems such as excessive daytime sleepiness, as well as depression and anxiety, can also occur. The predominant symptom of RLS (but not only RLS) is known as periodic leg movements during sleep (PLMS), which most commonly occur in the lower extremities and are associated with disturbed sleep. The movements often occur about every 20-40 seconds and usually range from short muscle twitches, jerks, or upward flexions of the feet. Movements are often grouped into episodes lasting from a few minutes to several hours.

The uncomfortable or uncomfortable sensations associated with RLS are often temporarily relieved by movement, such as continuous rapid up and down movements of the leg and/or rapid closing and spreading of the legs. The sensations—and the need to move—may return immediately after movement stops, or later.

RLS can begin at any age, including childhood, and is a progressive condition for most people. Primary RLS is considered idiopathic or of unknown etiology. Primary RLS can progress and worsen with age. A family history of RLS is common, suggesting a genetic or hereditary link. RLS in children is often mistaken for neuralgic pain. Secondary RLS is usually associated with an underlying medical condition or the use of certain medications. Secondary RLS often begins later in life and may be associated with more rapid progression, but may resolve with treatment of the underlying condition. Research has suggested that the pathophysiology of RLS may be related to abnormalities in the dopaminergic system and iron metabolism.

The severity of RLS varies and can be measured using one or more scales. A well-known rating scale, known as the International Restless Leg Syndrome Research Group ("IRLS") Rating Scale, was developed by the International Restless Leg Syndrome Research Group ("IRLSSG") (http://www.irlssg.org/) (( Walters et al., Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep medicine. 2003 Apr 01;4(2):121–32. The IRLS is a 10-item scale with scores from 0 ( asymptomatic) to 40. Scores >30 are very severe, severe (21-30), moderate (11-20), and ≤10 mild.The scale is widely used for clinical assessment, research, and therapeutic trials of RLS.

Mild RLS may cause only minor irritation; however, severe RLS can have a detrimental effect on quality of life. It can interfere with work or social activities and impair function and emotional well-being. Sleep disturbance caused by RLS can lead to poor daytime functioning, anxiety, and depression. Additional long-term complications from sleep disturbance may include adverse cardiovascular events. Sleep deprivation and daytime fatigue are common reasons why RLS patients seek treatment. The main goal of treating RLS is to manage symptoms and improve the patient's function, daytime fatigue, and quality of life.

RLS is often treated with levodopa or dopamine agonists such as pramipexole or ropinirole. However, these drugs usually cause unwanted side effects. One serious treatment complication with long-term use of dopaminergic agents is a drug-induced worsening of symptoms, known as augmentation. Augmentation is characterized by more severe symptoms with earlier onset, shorter latency, and may extend to other parts of the body (usually the arms, but also the trunk and face). Impulse control disorders have also been reported in a significant percentage of RLS patients taking these drugs for a long time.

Thus, there is a need for more effective treatment of RLS and its symptoms without the unwanted side effects associated with current drug therapy.

The present invention addresses this need and describes leucine and acetyleucine for the treatment of RLS.

Acetylleucine in the racemate form (acetyl-DL-leucine) and its salts have been used to treat vertigo of various origins, especially Meniere's vertigo and vertigo of inflammatory (vestibular neuritis) or toxic origin. For example, acetyleucine is marketed by Pierre Fabre Medicament as a racemate as an anti-vertigo drug under the name Tanganil®. The clinical results of the use of the drug Tanganil®, reported by various authors, demonstrate an improvement in the symptoms of dizziness in more than 95% of cases, including the disappearance of dizziness attacks.

Acetyl-DL-leucine has been used in France for the treatment of acute vertigo since 1957. FDG-PET (positron emission tomography using the radiopharmaceutical fluorodeoxyglucose) study in a rat model of acute unilateral labyrinthectomy (Zwergal et al. (2016) Brain Struct Funct; 221 (1 ): 159-70) showed a significant effect of the L-enantiomer, N-acetyl-L-leucine, on postural compensation through activation of the vestibulo-cerebellum and deactivation of the posterolateral thalamus (Gunther et al. (2015) PLoS One; 10 (3): e0120891). Symptomatic improvement in cerebellar ataxia using acetyl-DL-leucine has been shown in a case series of patients with cerebellar pathology (Strupp et al. (2013) J Neurol; 260 (10): 2556-61). Another series of cases showed no positive results (Pelz et al. (2015) J Neurol; 262 (5): 1373-5). Quantitative gait analysis has shown that acetyl-DL-leucine improves temporal gait variability in patients with cerebellar ataxia (Schniepp et al. (2015) Cerebellum; 3:8). A one-month study in 12 patients with Niemann-Pick type C disease (NPC) showed symptomatic improvement in ataxia (Bremova et al. (2015) Neurology; 85 (16): 1368-75). In addition, a PET study of ataxic patients treated with acetyl-DL-leucine demonstrated increased metabolism in the midbrain and lower brainstem in responding patients (Becker-Bense et al. (2015) Abstract EAN).

However, acetyleucine is not known to treat RLS. As the examples described in this application confirm, in accordance with the present invention, it was found that leucine, acetyllucine, or a pharmaceutically acceptable salt thereof can be used in a method of treating RLS, for example, by significantly reducing the severity of the patient's RLS.

In one embodiment, the present invention provides leucine, acetyleucine, or a pharmaceutically acceptable salt thereof, for use in a method of treating RLS or one or more symptoms associated with RLS in a subject in need thereof.

In one embodiment, the present invention includes leucine, acetyleucine, or a pharmaceutically acceptable salt thereof, for use in a method of treating RLS or one or more symptoms associated with RLS in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of leucine, acetyleucine, or their pharmaceutically acceptable salt.

In one embodiment, leucine, acetyleucine, or a pharmaceutically acceptable salt thereof is disclosed for use in a method for reducing, inhibiting, or eliminating one or more symptoms associated with RLS in a subject in need thereof.

In one embodiment, the present invention includes leucine, acetyleucine, or a pharmaceutically acceptable salt thereof, for use in a method of reducing, inhibiting, or eliminating one or more symptoms associated with RLS in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of leucine , acetyleucine, or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for reducing, inhibiting, or eliminating one or more symptoms of restless leg syndrome (RLS) in a subject in need thereof, comprising administering a therapeutically effective amount of leucine, acetyleucine, or a pharmaceutically acceptable salt thereof to the subject.

"Subject" in the context of the present description may be a vertebrate, mammal or domestic animal. Therefore, the compositions of the present disclosure may be used to treat any mammal, e.g., livestock (e.g., horses, cows, sheep, or pigs), pets (e.g., cats, dogs, rabbits, or guinea pigs), laboratory animals (e.g., mice or rats), or may be used for other veterinary purposes. In one embodiment, the subject is a human. "Subject" and "patient" are interchangeable terms.

As used herein, the singular forms include the plural. The terms "approximately" and "approximately" mean almost the same as a reference number or value, including an acceptable degree of error for the quantity being measured, given the nature or accuracy of the measurements.

Used in this application, the terms "about" and "about" should be understood as including ± 20% of the specified amount, frequency or value. Numerical values given herein are approximate unless otherwise indicated, which means that the term "about" or "approximately" may be implied unless expressly stated otherwise.

The terms "use," use "or" applied "in the context of the present description refers to (1) providing, issuing, dosing and / or prescribing, either by a medical practitioner, or his authorized agent, or under his direction, compositions in accordance with the invention and (2 ) administration, ingestion or consumption by a patient or subject of a composition according to the invention.

References to "leucine" and "acetyl-leucine" throughout include their pharmaceutically acceptable salts, even if not explicitly stated.

The leucine or acetyleucine may be in racemic form, meaning that the compound contains approximately equal amounts of enantiomers. Alternatively, it may be present in an enantiomeric excess of either the L-enantiomer or the D-enantiomer. The leucine or acetyleucine may be in a single enantiomeric form of either the L-enantiomer or the D-enantiomer. In one embodiment, the single enantiomeric form is the L-enantiomer. Racemic and enantiomeric forms can be obtained in accordance with procedures known in the art.

A "pharmaceutically acceptable salt" as used herein is any salt preparation that is suitable for pharmaceutical use. Pharmaceutically acceptable salts include amine salts such as N,N'-dibenzylethylenediamine, chlorprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidine-1 '-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine, tris(hydroxymethyl)aminomethane, etc.; alkali metal salts such as lithium, potassium, sodium and the like; alkaline earth metal salts such as barium, calcium, magnesium and the like; transition metal salts such as zinc, aluminum and the like; other metal salts such as sodium hydrogen phosphate, disodium phosphate and the like; mineral acid salts such as hydrochlorides, sulfates and the like; and organic acid salts such as acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, fumarates and the like; but not limited to this.

Leucine, acetyleucine, or a pharmaceutically acceptable salt thereof, may be prepared and administered to a subject in accordance with teachings known in the art. For example, leucine, acetyleucine, or a pharmaceutically acceptable salt thereof may be formulated into a pharmaceutical composition. The pharmaceutical composition may contain leucine, acetyleucine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Reference to a pharmaceutical composition encompasses the active agent alone (eg leucine, acetyleucine or a pharmaceutically acceptable salt thereof) or in the form of a pharmaceutical composition.

The pharmaceutical composition may take any of a number of different forms, depending in particular on the manner in which it is used. Thus, for example, it may be in the form of a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micellar solution, transdermal patch, liposome suspension, or any other suitable form that can be administered to a human or animal. in need of treatment.

A "pharmaceutically acceptable carrier" as used herein is any known compound or combination of known compounds that are known to those skilled in the art to be useful in the manufacture of pharmaceutical compositions. It should be understood that the carrier of the pharmaceutical composition must be tolerated by the subject in which it is used.

In one embodiment, the pharmaceutically acceptable carrier may be a solid and the composition may be in the form of a powder or tablet. The solid pharmaceutically acceptable carrier may include one or more substances which may also act as flavoring agents, buffers, lubricants, stabilizers, solubilizers, suspending agents, wetting agents, emulsifiers, colorants, fillers, glidants, compression aids, inert binders, sweeteners. , preservatives, dyes, coatings or disintegrants, but is not limited to. The carrier may also be an encapsulating material. In powders, the carrier may be a finely divided solid which is in admixture with the finely divided active agents of the invention. In tablets, the active agent may be mixed with a carrier having the desired compression properties in suitable proportions and compressed into the desired shape and size. Powders and tablets may, for example, contain up to 99% active agents. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins. In another embodiment, the pharmaceutically acceptable carrier may be a gel and the composition may be in the form of a cream or the like.

The carrier may include, but is not limited to, one or more excipients or diluents. Examples of such excipients are gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silicon dioxide, etc.

In another embodiment, the pharmaceutically acceptable carrier may be a liquid. In one embodiment, the pharmaceutical composition is in the form of a solution. Liquid carriers are used in the preparation of solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. Leucine, acetyleucine or a pharmaceutically acceptable salt thereof may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavors, suspending agents, thickeners, colorants, viscosity regulators, stabilizers or osmoregulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as noted above, for example, cellulose derivatives such as sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, such as glycols) and their derivatives, and also oils (for example, fractionated coconut oil and peanut butter). For parenteral administration, the carrier may also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid compositions for parenteral administration. The pressurized liquid carrier may be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be administered, for example, by intramuscular, intrathecal, epidural, intraperitoneal, intravenous and subcutaneous injection. The active agent may be formulated as a sterile solid composition which may be dissolved or suspended during administration using sterile water, saline, or other suitable sterile injectable medium.

The compositions may be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (e.g., sufficient saline or glucose to make the solution isotonic), bile salts, gum arabic, gelatin, sorbitan monooleate, polysorbate 80 (oleate esters of sorbitol and their anhydrides copolymerized with ethylene oxide), etc. The compositions may also be administered orally in liquid or solid form. Compositions suitable for oral administration include solid forms such as pills, capsules, granules, tablets and powders and liquid forms such as solutions, syrups, elixirs and suspensions. Forms suitable for parenteral use include sterile solutions, emulsions and suspensions.

Alternatively, the compositions may be administered by inhalation (eg, intranasally). Compositions for topical application may also be prepared. For example, creams or ointments can be applied to the skin.

Leucine, acetyleucine, or a pharmaceutically acceptable salt thereof may be included in a slow or sustained release device. Such devices may, for example, be inserted on or under the skin and the drug may be released over weeks or even months. Such devices may be useful when long-term treatment with leucine or acetyleucine as used herein is required and may require frequent administration (eg, at least daily administration).

In one embodiment, the pharmaceutical composition is a solid oral dosage form such as a tablet. In tablets, the active agent may be mixed with a carrier, such as a pharmaceutically acceptable carrier having the necessary compression properties, in suitable proportions and compressed into the desired shape and size. Tablets may contain up to 99 wt.% active substances.

Pharmaceutical compositions in solid oral dosage form such as tablets may be prepared by any method known in the pharmaceutical art. Pharmaceutical compositions are usually prepared by mixing the active agent with conventional pharmaceutically acceptable carriers.

Tablets may be prepared as is known in the art. Tanganil®, for example, includes wheat starch, pregelatinized corn (maize) starch, calcium carbonate and magnesium stearate as excipients. The same or similar excipients, for example, can be used with the present invention.

Each 700 mg Tanganil® tablet contains the following composition: 500 mg acetyl-DL-leucine, 88 mg wheat starch, 88 mg pregelatinized corn starch, 13 mg calcium carbonate and 11 mg magnesium stearate. The same tablets, for example, can be used with the present invention.

As discussed above, leucine, acetyleucine or a pharmaceutically acceptable salt thereof may be formulated and administered as a pharmaceutical composition in any number of different forms. For example, leucine, acetyleucine or a pharmaceutically acceptable salt thereof may be formulated into a pharmaceutical composition to facilitate their delivery across the blood-brain barrier. As a further example, leucine, acetyleucine or a pharmaceutically acceptable salt thereof may be formulated into a pharmaceutical composition to bypass the blood-brain barrier. Formulations that facilitate delivery across the blood-brain barrier or that are suitable for administration in a manner that bypasses the blood-brain barrier can be used to produce and use leucine (not acetylated) as described herein.

In one embodiment, a pharmaceutical composition (eg, containing leucine or a salt thereof) is formulated for nano-delivery, eg, carrier drug colloid systems. Suitable examples include, but are not limited to, liposomes, nanoparticles (eg, polymeric, lipid, and inorganic nanoparticles), nanogels, dendrimers, micelles, nanoemulsions, polymersomes, exosomes, and quantum dots. See, for example, Patel et al., “Crossing the Blood-Brain Barrier: Recent Advances in Drug Delivery to the Brain,” CNS Drugs 31:109-133 (2017); Kabanov et al., “New Technologies for Drug Delivery across the Blood Brain Barrier,” Curr Pharm Des., 10(12):1355-1363 (2004); Cheng et al., “Highly Stabilized Curcumin Nanoparticles Tested in an In Vitro Blood–Brain Barrier Model and in Alzheimer’s Disease Tg2576 Mice,” The AAPS Journal, vol. 15, no. 2, pp. 324-336 (2013); Lahde et al. “Production of L-Leucine Nanoparticles under Various Conditions Using an Aerosol Flow Reactor Method,” Journal of Nanomaterials, vol. 2008, article ID 680897 (2008).

In one embodiment, the pharmaceutical composition (eg, containing leucine or a salt thereof) is formulated for direct delivery to the central nervous system (CNS), eg, by injection or infusion. Compositions and methods for direct delivery to the CNS are known in the art. See, for example, US Pat. No. 9,283,181. Examples of such administration include, but are not limited to, intranasal, intraventricular, intrathecal, intracranial, and delivery through a nasal mucosal graft.

In one embodiment, the pharmaceutical composition is formulated for (and administered via) intranasal delivery. See, for example, Hanson et al., “Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease,” BMC Neurosci. 9 (Suppl 3): S5 (2008). In one embodiment, the pharmaceutical composition is formulated to be delivered via (and administered by) a nasal mucosal graft. In one embodiment, the pharmaceutical composition is formulated for (and administered by) intracerebroventricular injection or infusion. In another embodiment, the pharmaceutical composition is formulated for (and administered by) intrathecal intracisternal injection or infusion. In one embodiment, the pharmaceutical composition is formulated for (and administered by) intrathecal lumbar injection or infusion.

Various techniques may be used, including, but not limited to, burr hole injection, cisternal or lumbar puncture, or the like, as is known in the art. Various devices can be used for delivery, both internal (eg, implanted) and external, such as pumps, catheters, reservoirs, etc. In one embodiment, the administration interval is once every two weeks.

In one embodiment, the administration interval is once a month. In one embodiment, the administration interval is once every two months. In one embodiment, the administration interval is twice a month. In one embodiment, the administration interval is once a week. In one embodiment, the administration interval is two or more times a week. In one embodiment, the administration interval is once a day. In one embodiment, the introduction is continuous, for example, continuous infusion.

In one embodiment, leucine, or a pharmaceutically acceptable salt thereof, may be administered at a dose or amount equivalent to those disclosed herein for acetyleucine, either direct delivery to the CNS or delivery across the blood-brain barrier.

Similarly, acetyleucine, or a pharmaceutically acceptable salt thereof, may be used in a dose or amount as described herein; the dose may be adjusted depending on the route of administration (eg, direct delivery to the CNS).

The present invention describes leucine, acetyleucine and their pharmaceutically acceptable salts, including their compositions and methods, for the treatment of RLS or one or more symptoms associated with RLS in a subject in need thereof.

A "subject in need" as used herein can be any subject who has RLS or one or more of the symptoms associated with RLS, and can also include any subject or patient who is at risk or suspected to be risk of developing RLS or one or more of the symptoms associated with RLS. The subject may or may not be diagnosed with RLS. For example, the subject may not yet have a diagnosis (clinical or otherwise) of RLS, but may have one or more symptoms of RLS. The subject may have a genetic, biochemical or other similar identifiable marker of RLS or an underlying condition with which RLS may be associated. A subject in need of this may be suspected of having or at risk of developing RLS. For example, the subject may have a genetic predisposition to RLS (eg, the subject may have one or more family members with RLS).

A "therapeutically effective amount" of an agent is any amount which, when administered to a subject, is the amount of the agent necessary to obtain the desired effect, which, according to the present invention, may be therapeutic and/or prophylactic. The dose may be determined according to various parameters such as the particular form of leucine or acetyleucine; age, body weight and condition of the patient to be treated; method of administration; and required mode. The doctor will be able to determine the appropriate route of administration and dosage for each individual patient. For example, the daily dose may be from about 10 to 225 mg/kg, from about 10 to 150 mg/kg, or from about 10 to 100 mg/kg of body weight.

In the context of the present invention, "treatment" refers to any indication of success in preventing or alleviating an injury, pathology, or condition of RLS and/or preventing or alleviating one or more symptoms associated with RLS, including any objective or subjective parameters such as relief, remission, reducing, suppressing, or eliminating symptoms, or increasing the tolerance of the injury, pathology, or condition for the subject; slowing down the rate of degeneration or degradation or worsening of the disorder; or improving the physical or mental well-being of the subject in need. Treatment of RLS or one or more symptoms associated with RLS may be based on objective and/or subjective parameters, including, for example, the results of a physical examination(s), neurological examination(s), and/or psychiatric assessment(s).

"Restless legs syndrome" (i.e., "RLS") as used herein includes any form of RLS, including primary RLS and secondary RLS. In one embodiment, the RLS is the primary RLS. In another embodiment, the RLS is a secondary RLS. In one embodiment, RLS is secondary to a disease or medical condition. Examples of such diseases or medical conditions include iron deficiency, kidney failure, uremia, peripheral neuropathy, varicose veins, neurodegenerative disease, stress, sleep deprivation, fibromyalgia, hyper- or hypothyroidism, pregnancy, smoking, vitamin deficiency (e.g. vitamin B12), mineral deficiencies (eg, magnesium deficiency), amyloidosis, Lyme disease, spinal nerve injury, rheumatoid arthritis, and Sjögren's syndrome. In one embodiment, RLS is secondary to a disease caused by a drug or substance. Examples of such drugs or substances include alcohol, caffeine, anticonvulsants (eg, phenytoin), antidepressants (eg, amitriptyline, paroxetine), antihypertensives (eg, beta-blockers), antipsychotics, and drug withdrawal (eg, vasodilators, sedatives, antidepressants). Examples of neurodegenerative diseases include Parkinson's disease, Huntington's disease, hereditary spastic paraparesis, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia, Lewy body dementia, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. In one embodiment, the neurodegenerative disease is a motor neuron disease (e.g., progressive bulbar palsy (PBP), pseudobulbar palsy, primary lateral sclerosis (PLS), amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), Huntington's disease, multiple sclerosis , Parkinson's disease, Canavan disease, frontotemporal lobar degeneration, narcolepsy, Peliceus-Merzbacher disease, and spinal muscular atrophy). In one embodiment, the neurodegenerative disease is parkinsonism, including primary or idiopathic, secondary or acquired, hereditary parkinsonism, and Parkinson-plus syndromes or multiple systemic degeneration. In one embodiment, the disease or medical condition is associated with dysfunction of the dopaminergic system, such as loss of dopaminergic cells.

A "symptom" associated with RLS includes any clinical or laboratory findings associated with RLS. The symptoms of RLS are often, but not necessarily, manifestations associated with an illness that the subject may feel or observe. Symptoms associated with RLS include, but are not limited to, calf sensations, periodic limb movements during sleep (PLMS), leg discomfort, urge to move, restlessness, sleep disturbances, excessive daytime sleepiness, and the like.

In one embodiment, leucine, acetyleucine, or a pharmaceutically acceptable salt thereof is used in a method for reducing, inhibiting, or eliminating one or more symptoms associated with RLS in a subject in need thereof. The method includes administering to a subject a therapeutically effective amount of leucine, acetyleucine, or a pharmaceutically acceptable salt thereof. In one embodiment, one or more of the symptoms is selected from any one or combination of calf sensations, occasional leg movements during sleep, leg discomfort, urge to move, restlessness, excessive daytime sleepiness, and sleep disturbances.

The severity of RLS or one or more symptoms of RLS may be assessed, for example, using a known scale, index, rating, or score. For example, a scale, index, rating, score, or other appropriate test may correspond to the severity of RLS in general, or the severity of one or more symptoms associated with RLS. In one embodiment, the treatment described herein improves such score from a value or degree characteristic of a symptomatic subject to a value or degree characteristic of an asymptomatic subject. In one embodiment, the treatment described herein improves such score from baseline. The baseline can be, for example, the state of the subject before starting any RLS treatment or before starting RLS treatment with leucine, acetyleucine, or a pharmaceutically acceptable salt thereof. Alternatively, the baseline may be, for example, the state of the subject after a certain period of time in the treatment of RLS.

In one embodiment, treatment with leucine, acetyleucine, or a pharmaceutically acceptable salt thereof, as described herein, reduces a subject's International Restless Leg Syndrome Study ("IRLS") score from baseline. In one embodiment, the IRLS score is reduced from baseline by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%. In one embodiment, the IRLS score is reduced by at least 60%, at least 70%, at least 80%, at least 90%, or 100%.

In one embodiment, acetyleucine or a pharmaceutically acceptable salt thereof may be used, for example, at a dose of from about 500 mg to 15 g per day, or in the range from about 500 mg to 10 g per day, for example, in the range from about 1.5 g to 10 g per day, as needed by oral solid or oral liquid route. Acetylleucine or a pharmaceutically acceptable salt thereof can be used, for example, at a dose corresponding to the dose of Tanganil®, which is prescribed to adults at a dose of 1.5 g to 2 g per day, 3-4 tablets in two divided doses, morning and evening.

If one enantiomer is used, doses may be reduced accordingly. For example, if acetyl-L-leucine alone or acetyl-D-leucine alone is used, the dose may vary from about 250 mg to 15 g per day, from about 250 mg to 10 g per day, or in the range from about 250 mg to 5 g per day, for example, from about 0.75 g to 5 g per day.

In one embodiment, the dosage used is in the range of about 1 g to 15 g per day, about 1 g to 10 g per day, or about 1.5 g to 7 g per day. This may be from about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 g to 15 g per day. This may be from about 2, 3, 4, 5, 6, 7, 8 or 9 g to 10 g per day. This may be more than 1.5 g per day, but less than 15, 14, 13, 12, 11, 10, 9, 8, 7, 6 or 5 g per day. In one embodiment, the dosage is from about 4 g to about 6 g per day. In one embodiment, the dosage is about 4 g to 5 g per day. In one embodiment, the dosage is about 4.5 grams per day. In one embodiment, the dose is about 5 g per day. In one embodiment, these doses are administered in a solid oral dosage form, especially tablets. In another embodiment, these doses are for acetyleucine in its racemic form. Doses of acetyleucine in the presence of an enantiomeric excess may be lower than those specified in this application, for example, approximately 50% lower. The above dosage ranges at halving are thus also expressly covered by the present invention.

In one embodiment, the total daily dose may be divided among several administrations, i.e. the introduction can be carried out two or more times a day to achieve a total daily dose. For example, the required number of tablets to provide a total daily dose of acetyleucine can be divided into two doses (eg morning and evening) or three doses (eg morning, noon and evening). Each dose may be suitably administered with or without food. For example, acetyleucine can be administered about 1 hour or about 2 hours before a meal, such as at least about 20 minutes, at least about 30 minutes, at least about 40 minutes, or at least about 1 hour before meal, or may be administered about 1 hour, about 2 hours, or about 3 hours after a meal, such as at least about 20 minutes, at least about 30 minutes, at least about 1 hour, at least about 1 .5 hours, at least about 2 hours or at least 2.5 hours after eating. For example, a total daily dose of 4.5 g of acetyl-DL-leucine may be given as three tablets of Tanganil® (or equivalent) before, during, or after breakfast, three additional tablets before, during, or after lunch, and three more tablets before, during or after dinner.

The use of leucine or acetyleucine as described herein may be initiated before or after a genetic, biochemical, or other similar identifiable marker of RLS or the medical condition or disease associated with RLS is found in the subject. Application may be initiated at or about the time a genetic, biochemical, or other similarly identifiable marker of RLS is found in the subject. Similarly, administration may begin at or about the time the subject is diagnosed with RLS.

The duration of treatment may be, for example, about seven days or more, about two weeks or more, about three weeks or more, about one month or more, about six weeks or more, about seven weeks or more, or about two months or more. In one embodiment, it is about three months or more, about four months or more, about five months or more, or about six months or more. The duration of treatment may be about 1 year or more, about 2 years or more, about 4 years or more, about 5 years or more, or about 10 years or more. The duration of treatment may correspond to the life expectancy of the patient.

Any and all combinations of dosage form, dose amount, dosing regimen, and duration of treatment are contemplated and covered by the description. In one embodiment, the dosage is about 4 g to about 10 g per day, taken in one, two, or three doses per day, for a duration of treatment of about two months or more. In another embodiment, the dose is greater than 4 g but not greater than 5 g per day, taken in one, two or three doses per day, for a duration of treatment of about six months or more. The dosage form may be a solid oral dosage form, especially tablets.

The pharmaceutical compositions described herein may be used as monotherapy (eg, the use of a single active agent) for the treatment of RLS in a subject. Alternatively, the pharmaceutical compositions may be used in addition to or in combination with other known treatments, for example, for the treatment of RLS and/or for the treatment of an underlying medical condition or disease.

Also provided is a method for treating RLS or one or more symptoms associated with RLS in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of leucine, acetyleucine, or a pharmaceutically acceptable salt thereof.

In one embodiment, administration of a therapeutically effective amount of leucine, acetyleucine, or a pharmaceutically acceptable salt thereof to a subject in need thereof reduces, suppresses, or eliminates one or more symptoms associated with RLS. In one embodiment, one or more of the symptoms is selected from any one or combination of calf sensations, occasional leg movements during sleep, leg discomfort, urge to move, restlessness, excessive daytime sleepiness, and sleep disturbances.

Also disclosed is a kit for the treatment of RLS in a subject, comprising an agent for diagnosing or predicting RLS and leucine, acetyleucine, or pharmaceutically acceptable salts thereof.

The kit may further include buffers or aqueous solutions. The kit may further contain instructions for the use of leucine, acetyleucine, or a pharmaceutically acceptable salt thereof, according to the method of the present invention.

All features described in this application (including any appended claims, abstract and drawings), and/or all steps of any method thus disclosed, may be combined with any of the above aspects in any combination, except for combinations where at least some of such features and/or steps are mutually exclusive.

Examples

Patient 1

The patient in this study was a 55-year-old woman with proximal lower limb weakness. She had neck flexor paresis slowly progressive from age 42 and was diagnosed (genetically confirmed) with type 2 myotonic dystrophy. After consultation at age 55, she reported no sensory symptoms, but complained of restless legs syndrome at night and during daytime rest periods for the past two years. Pre-treatment with a dopamine agonist did not result in symptom relief. Serum creatine kinase activity was only slightly elevated, up to 400 IU/L. The patient's condition was assessed using the RLS Diagnostic Index (RLS-DI) (see Walters et al., Sleep Med 2003; 4 (2): 121-132;). The patient's score on the International Restless Leg Syndrome Rating Scale (IRLS) was 36, and thus severe restless leg syndrome was diagnosed. The patient was started on acetyl-DL-leucine at a dose of 3 g per day for the first week, and then at a dose of 5 g per day for the second week. Within 14 days on acetyl-DL-leucine, IRLS decreased to 26, and after another 5 weeks, IRLS decreased to 9. Interruption of 4 weeks of treatment after 12 weeks of treatment increased IRLS to 28. Re-treatment again reduced the score to 8 after 2 weeks. Continued treatment for more than 22 weeks stabilized the IRLS score at 8.

Patient 2

The patient in this study was a 72-year-old woman with proximal lower limb weakness. She had neck flexor paresis slowly progressive since age 48 and was diagnosed (genetically confirmed) with type 2 myotonic dystrophy 15 years ago. After a consultation at the age of 72, she reported no sensory symptoms, but complained of restless legs syndrome at night and during rest periods during the day, occurring over the past eight years. Pretreatment with a dopamine agonist, L-dopa, pregabalin, and opioids did not result in sustained symptom relief. Serum creatine kinase activity was slightly increased to 300 IU/l. Iron measurements and all additional laboratory tests showed normal results. The patient was assessed by RLS-DI and the IRLS score was 32, and thus moderate to severe RLS was diagnosed. The patient was started on acetyl-DL-leucine at a dose of 3 g per day for the first week, and then at a dose of 5 g per day for the second week. Within 14 days of taking acetyl-DL-leucine, the IRLS score decreased to 22, and after another 5 weeks, the IRLS decreased to 7. Continued treatment for more than 28 weeks stabilized the IRLS score at 8.

Patient 3

The patient in this study was a 73-year-old male with mild proximal weakness of the upper and lower extremities, slowly progressive from the age of 50. The patient was diagnosed (genetically confirmed) with McArdle myopathy about 16 years ago. After a consultation at the age of 73, he reported no sensory symptoms, but complained of extreme fatigue and decreased stamina. The patient also reported restless legs syndrome at night and during rest periods during the day occurring within the last 12 years. Pre-treatment with the dopamine agonist, L-dopa, pregabalin did not provide sustained relief of symptoms. Serum creatine kinase activity was slightly elevated to 200 IU/l; however, the patient has had 5 episodes of rhabdomyolysis in the last 20 years. Repeated measurements of the iron content and all additional laboratory tests showed normal values. The patient was assessed by RLS-DI, the patient's IRLS score was 34, and thus severe RLS was diagnosed. The patient was started on acetyl-DL-leucine at a dose of 3 g per day for the first week, and then at a dose of 5 g per day for the second week. Within 21 days of treatment with acetyl-DL-leucine, IRLS decreased to 20, and after another 10 weeks, IRLS decreased to 10. Continued treatment for more than 30 weeks stabilized the IRLS score at 10. In addition, patient fatigue decreased. (Fatigue rating scale: 9 (minimum) to 63 (maximum)) 53 to 28.

Patient 4

The patient in this study was a 59-year-old woman with RLS symptoms and RLS of unknown etiology. After consultation at age 59, she reported no sensory symptoms, but complained of restless legs syndrome at night and during rest periods during the day for at least 15 years. Pre-treatment with the dopamine agonist, L-dopa, pregabalin did not provide sustained relief. Measurement of iron content and all additional laboratory tests showed normal values. The patient was assessed by RLS-DI and the IRLS score was 32, and thus moderate to severe RLS was diagnosed. The patient was started on acetyl-DL-leucine at a dose of 3 g per day for the first week, and then at a dose of 5 g per day for the second week. Within 14 days of treatment with acetyl-DL-leucine, IRLS decreased to 8, and after another 2 weeks, IRLS decreased to 6. Continued treatment for more than 4 weeks stabilized the IRLS at 6.

Claims (10)

1. The use of leucine, acetyleucine or a pharmaceutically acceptable salt thereof for the treatment of restless legs syndrome (RLS) or one or more symptoms associated with RLS in a subject in need thereof, wherein RLS is the primary RLS. 2. The use of claim 1, comprising administering to the subject a therapeutically effective amount of leucine, acetyleucine, or a pharmaceutically acceptable salt thereof. 3. Use according to claim 1 or 2, wherein the leucine is DL-leucine or the acetyleucine is acetyl-DL-leucine. 4. Use according to any one of claims 1 to 3, wherein the leucine or acetyleucine has an enantiomeric excess of the L-enantiomer or D-enantiomer. 5. Use according to any one of claims 1 to 4, comprising administering acetyleucine to a subject in need thereof in a therapeutically effective amount of from about 1 g to 15 g per day, from about 1 g to 10 g per day, from about 1.5 g up to about 7 g per day, from about 4 g to about 6 g per day, or from about 4 g to 5 g per day. 6. A method of alleviating, suppressing, or eliminating one or more symptoms of restless legs syndrome (RLS) in a subject in need thereof, comprising administering a therapeutically effective amount of leucine, acetyleucine, or a pharmaceutically acceptable salt thereof to the subject. 7. The method of claim 6, wherein the one or more symptoms are selected from calf sensations, occasional leg movements during sleep, leg discomfort, urge to move, restlessness, daytime sleepiness, and sleep disturbances. 8. The method according to claim 6 or 7, wherein the leucine is DL-leucine or the acetyl-leucine is acetyl-DL-leucine. 9. The method according to claim 6 or 7, wherein the leucine or acetyleucine has an enantiomeric excess of the L-enantiomer or D-enantiomer. 10. The method according to any one of claims 6 to 9, wherein the therapeutically effective amount is about 1 g to 15 g per day, about 1 g to 10 g per day, about 1.5 g to 7 g per day, about 4 g to 6 g per day, or about 4 g to 5 g per day.