RU2837641C2 - Acetyleucine or pharmaceutically acceptable salt thereof for improving motor function and cognitive function - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine and involves using acetylleucine or a pharmaceutically acceptable salt thereof for improving cognitive function in a subject suffering age-related cognitive decline. Age-related cognitive decline is selected from perception, memory, imaging, awareness, logical reasoning, reasoning and judgment. Subject may also exhibit gait disturbance, postural imbalance and/or spatial orientation disturbance.

EFFECT: group of inventions provides treating cognitive decline in a subject in need of improved reaction rate, vigilance or both reaction rate and vigilance, or suffers from gait disturbance, postural imbalance and/or spatial orientation disturbance.

13 cl, 6 dwg, 2 tbl, 12 ex

Description

Field of technology to which the invention relates

The present invention relates to acetylleucine and its pharmaceutically acceptable salts, and in particular to their use for improving motor function and cognitive function, for example in the elderly.

State of the art

The changes that occur with aging can impair a person's ability to move. Mobility problems may include unsteadiness when walking, difficulty sitting up or standing up, or falls. Muscle weakness, joint problems, pain, pathological conditions, and neurological (brain and nervous system) disorders—common in older adults—can all contribute to mobility problems. Sometimes several moderate disorders occur simultaneously and together seriously affect mobility.

In addition to potential mobility issues, all aging people experience some degree of cognitive decline, often with symptoms including forgetfulness, decreased ability to concentrate, decreased problem-solving ability, and/or poor spatial awareness. If left untreated, symptoms can progress to more serious conditions such as dementia and depression, or even Alzheimer's disease.

Many factors are thought to contribute to age-related cognitive decline, including oxidative stress and free radical damage, chronic low-grade inflammation, decreased hormone levels (such as estrogen, testosterone, dehydroepiandrosterone, and pregnenolone), dysfunction of the intimal arterial lining (endothelium), insulin resistance, excess body weight, suboptimal nutrition, loneliness, lack of social connections, and high stress, among others.

Unfortunately, there are few therapeutic options currently available for patients with signs and symptoms of aging, such as impaired motor and cognitive function. Therefore, there remains a need for new treatments that can benefit older adults by preventing or reducing such symptoms.

Furthermore, although impairment of motor and/or cognitive function is often associated with aging, such features can also be observed in any subject who has lower baseline levels of motor and/or cognitive function. There remains a need for new treatments to prevent or reduce such symptoms in patients who suffer from them.

Disclosure of invention

The present invention provides acetylleucine or a pharmaceutically acceptable salt thereof for use in a method of improving cognitive function, motor function, or cognitive function and motor function in a subject.

In one embodiment, acetylleucine or a pharmaceutically acceptable salt thereof is provided for use in a method of improving cognitive function in a subject. In another embodiment, acetylleucine or a pharmaceutically acceptable salt thereof is provided for use in a method of improving motor activity in a subject.

In a further embodiment, the subject is an elderly subject.

Additionally provided is acetylleucine or a pharmaceutically acceptable salt thereof for use in a method of improving motor function and/or cognitive function in an elderly subject.

In another embodiment, a method is provided for improving motor function and/or cognitive function in an elderly subject, comprising administering to the subject a therapeutically effective amount of acetylleucine or a pharmaceutically acceptable salt thereof.

In one embodiment, the cognitive function is one or more elements selected from the group consisting of perception, memory, imagery, consciousness, reasoning, thinking, and judgment.

According to the present description, acetylleucine or a pharmaceutically acceptable salt thereof can be used to treat age-related decline in cognitive function and/or motor function.

In one embodiment, acetylleucine is used in a dose of 1.5 to 10 g, such as 4 to 10 g per day. In another embodiment, acetylleucine is used in a dose of greater than 4 g to no more than 6 g per day.

The dose of acetylleucine can be administered, for example, in two or more doses. In one embodiment, the dose of acetylleucine is administered in three doses.

In one embodiment, the method comprises administering acetylleucine with a treatment duration of two weeks or more. In another embodiment, the method comprises administering acetylleucine with a treatment duration of seven weeks or more.

In one embodiment, the method comprises administering acetylleucine at a dose of 1.5 g to 10 g, such as 4.5 g to 10 g, per day, three times a day for a treatment duration of two months or more.

In one embodiment, the subject is a very elderly subject. The subject may be otherwise healthy except for the impairment of motor function and/or cognitive function, wherein the motor function and/or cognitive function has decreased as the subject ages, i.e., has decreased due to the aging process.

In one embodiment, the subject does not have dizziness and/or a neurological and/or neurodegenerative disease, disorder, or condition. In one embodiment, the subject does not have dizziness.

In another aspect, the present invention provides the use of acetylleucine or a pharmaceutically acceptable salt thereof for improving cognitive function, motor function, or cognitive function and motor function in a subject.

In another aspect, the present invention provides a method for improving cognitive function, motor function, or cognitive function and motor function in a subject, the method comprising administering to the subject a therapeutically effective amount of acetylleucine or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides the use of acetylleucine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for improving cognitive function, motor function, or cognitive function and motor function in a subject.

Description of drawings

Figure 1 illustrates performance on the psychomotor vigilance task at baseline and during the treatment period. (A) Data are presented as mean ± standard deviation (SD) for daily measurements, n = 13 (baseline), 28 (treatment), or 11 (washout), ****, p < 0.0001. Statistical significance was determined using one-way ANOVA with Tukey's correction. (B) Each individual data point is the mean of the 10 trials that make up a daily test (mean ± SD, n = 10). The dotted line indicates the division between baseline/treatment/washout periods.

Figure 2 illustrates performance on the psychomotor vigilance task at baseline and during the treatment period. (A) Data are presented as mean ± SD for daily measurements, n = 11 (baseline), 25 (treatment), or 8 (washout), * p < 0.05. Statistical significance was determined using one-way ANOVA with Tukey's correction. (B) Each individual data point is the mean of the 10 trials that make up a daily test (mean ± SD, n = 10). The dotted line indicates the division between baseline/treatment/washout periods.

Figure 3 illustrates performance on the psychomotor vigilance task at baseline and during the treatment period. (A) Data are presented as mean ± SD for daily measurements, n = 11 (baseline), 18 (treatment), or 5 (washout). Statistical significance was determined using one-way ANOVA with Tukey's correction. (B) Each individual data point is the mean of the 10 trials that make up a daily test (mean ± SD, n = 10). The dotted line indicates the division between baseline/treatment/washout periods.

Figure 4 illustrates performance on the psychomotor vigilance task at baseline and during the treatment period. (A) Data are presented as mean ± SD for daily measurements, n = 6 (baseline), 10 (treatment), or 9 (washout). Statistical significance was determined using one-way ANOVA with Tukey's correction. (B) Each individual data point is the mean of the 10 trials that make up a daily test (mean ± SD, n = 10). The dotted line indicates the division between baseline/treatment/washout periods.

Figure 5 illustrates performance on the psychomotor vigilance task at baseline and during the treatment period. (A) Data are presented as mean ± SD for daily measurements, n = 9 (baseline), 20 (treatment), or 3 (washout). Statistical significance was determined using one-way ANOVA with Tukey's correction. (B) Each individual data point is the mean of the 10 trials that make up a daily test (mean ± SD, n = 10). The dotted line indicates the division between baseline/treatment/washout periods.

Figure 6 illustrates performance on the psychomotor vigilance task at baseline and during the treatment period. (A) Data are presented as mean ± SD for daily measurements, n = 12 (baseline), 23 (treatment), or 9 (washout). Statistical significance was determined using one-way ANOVA with Tukey's correction. (B) Each individual data point is the mean of the 10 trials that make up a daily test (mean ± SD, n = 10). The dotted line indicates the division between baseline/treatment/washout periods.

Implementation of the invention

According to the present invention, it has been found that acetylleucine (N-acetylleucine) or a pharmaceutically acceptable salt thereof improves motor function and cognitive function. In particular, according to the present invention, it has been found that acetylleucine or a pharmaceutically acceptable salt thereof improves motor function and cognitive function in elderly people.

Acetylleucine in the form of racemate and its salts is known for its effectiveness in the treatment of dizziness of various origins, in particular, Meniere's syndrome and dizziness of inflammatory (vestibular neuritis) or toxic origin.

Acetylleucine is supplied by Pierre Fabre Medicament in the form of a racemate as an anti-vertigo drug under the trade name Tanganyil®. Clinical results related to this drug, presented by various authors, demonstrate an improvement in the symptoms of vertigo in more than 95% of cases, including the disappearance of attacks of vertigo.

Acetyl-DL-leucine has been used in France for the treatment of acute vertigo since 1957. Despite numerous hypotheses, including stabilization of the membrane potential, its pharmacological and electrophysiological mechanisms of action remain unclear (1, 2). An FDG-μPET study in a rat model of acute unilateral labyrinthectomy (3) showed a significant effect of the L-enantiomer of N-acetyl-L-leucine on postural compensation by activating the vestibulocerebellum and deactivating the posterolateral thalamus (4). Improvement of cerebellar symptoms was observed in a case series of patients with cerebellar disorders of various etiologies (5). However, another case series did not show a benefit (6). In a third recent case series of 12 patients with Niemann-Pick disease type C, this agent produced improvement in ataxic symptoms (7). Furthermore, a PET study in patients with cerebellar ataxia of various etiologies treated with acetyl-DL-leucine demonstrated increased metabolism in the midbrain and lower brainstem in responding patients (8), which could explain the observed benefits.

Surprisingly, the present inventors have shown that acetylleucine can also be used for elderly people who, in addition to showing normal signs of aging, may be in good health. In particular, it was found that acetylleucine can improve motor function and cognitive function in elderly people. This was completely unexpected, since such beneficial effects were not observed and could not be expected from the prior art.

The present inventors demonstrate that acetylleucine can be used to treat subjects who have disorders other than ataxia (e.g., other than disorders such as cerebellar ataxia and Niemann-Pick disease) and other than vertigo. For example, subjects treated in accordance with the present invention may be otherwise healthy except that they have impaired motor performance, where motor performance has been impaired due to the aging process. The discovery that acetylleucine can be used to treat disorders unrelated to vertigo was unexpected.

Accordingly, the present invention provides acetylleucine or a pharmaceutically acceptable salt thereof for use in a method of improving motor function and/or cognitive function in an elderly subject.

Acetylleucine 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. In one embodiment, acetylleucine is present in an enantiomeric excess of the L-enantiomer. Racemic and enantiomeric forms may be prepared according to known methods in the art.

"Pharmaceutically acceptable salt" as referred to herein is any salt preparation that is suitable for pharmaceutical use. Pharmaceutically acceptable salts include amine salts such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonium, diethanolamine and other hydroxyalkylamine, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole, diethylamine and other alkylamine, piperazine, tris(hydroxymethyl)aminomethane and the like; 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 are not limited to them.

"Motor function" refers to the subject's ability to move. Motor function can be assessed in older adults using one or more simple tests. As shown in the examples, the "get up and go" test is a simple test capable of measuring motor activity. In this test, the speed of getting up from a sitting position and moving to a target point is analyzed as described in the examples. For example, the test can begin with the subject sitting in a chair. When the stopwatch is started, the subject must get up without assistance and move to the target point. The target point can be 2-10 m away, 4-6 m if necessary. The stopwatch is stopped when the subject reaches the target point. Any changes in motor function, for example over time or during treatment, can be monitored using the "get up and go" test at two or more points in time and comparing the results, as shown in the examples. Other suitable tests for measuring motor function include those used in the Elderly Mobility Scale (EMS), a 20-item validated instrument for assessing frail elderly subjects (9) that takes into account changes in locomotion, balance, and key positions.

The phrase "improvement in motor function" as used herein means a positive change in the subject's ability to move. A positive change can be measured using any of the above tests on two or more occasions, such as a first occasion to measure baseline motor function and a second occasion to measure motor function over a period of time (in which treatment may be administered). The more confident the subject feels due to improved stability (e.g., due to treatment), the faster he or she completes the test. Motor function can be said to improve when there is at least about a 5% increase in activity in the relevant test between the two time points. For example, an increase in activity of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100% is observed in the corresponding test between two time points. As a further example, an increase in activity of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100% may be observed in the corresponding test between two time points. The two time points may be separated from each other by one week, two weeks, three weeks, four weeks, two months, three months, four months, five months or even six months. The treatment may be applied during the interim period. Thus, as an example, "improvement in motor function" may mean that the subject demonstrates at least about a 5% increase in speed from a baseline as measured using the "get up and go" test as defined herein. For example, the subject may demonstrate an increase in speed in this test of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100%. Further, for example, the subject may demonstrate an increase in speed on this test of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%.

In one embodiment, the subject has a motor impairment associated with aging.

As used herein, the term "aging-related movement disorder" refers to a decline in movement that is a direct consequence of the aging process; this is distinct from a decline in movement that is not a direct consequence of the aging process. Clinical manifestations may differ between subjects with an aging-related movement disorder and subjects with a movement disorder that is not a direct consequence of the aging process, such as subjects with ataxia. A subject with ataxia may manifest as a zig-zag gait, while a subject with an aging-related movement disorder may manifest as an increased tendency to fall. For example, cerebellar ataxia is not an aging-related movement disorder.

In addition to the motor function assessments described above, the motor function of a subject with aging-related motor impairment may be tested, for example, using a balance assessment and/or by monitoring the number of falls experienced by the subject.

According to the present invention, acetylleucine or a pharmaceutically acceptable salt thereof can be used to improve balance in a subject, wherein the subject has an imbalance associated with aging. According to the present description, the imbalance associated with aging is not dizziness.

According to the present description, a subject may, for example, not have benign paroxysmal positional vertigo (BPPV); vestibular neuritis; vertigo associated with Meniere's disease, Wallenberg syndrome, cerebellar ischemia, perilymphatic fistula, or acoustic neuroma; or recurrent vertigo of traumatic or toxic origin.

According to the present description, acetylleucine or a pharmaceutically acceptable salt thereof can be used to treat an imbalance associated with aging.

According to the present invention, acetylleucine or a pharmaceutically acceptable salt thereof can be used to increase the resistance of a subject, for example, when standing and/or walking, where the subject has a decrease in resistance associated with aging.

According to the present invention, acetylleucine or a pharmaceutically acceptable salt thereof can be used to reduce unsteadiness in a subject while walking, wherein the subject exhibits increased unsteadiness associated with aging.

According to the present disclosure, acetylleucine or a pharmaceutically acceptable salt thereof can be used to treat a gait disorder in a subject, wherein the gait disorder is associated with aging. The subject may have a senile gait disorder.

According to the present invention, acetylleucine or a pharmaceutically acceptable salt thereof can be used to increase gait speed and/or step frequency in a subject, wherein the subject has deteriorated gait speed and/or step frequency associated with aging.

According to the present description, acetylleucine or a pharmaceutically acceptable salt thereof can be used to treat a subject who has a predisposition to falls, where the predisposition to falls is associated with aging.

"Cognitive function" can mean any mental process that involves symbolic operation, such as perception, memory, imagery, consciousness, reasoning, thinking, and judgment. Measurement of cognitive functioning includes assessment instruments designed to assess, for example: (a) general intelligence, (b) nonverbal intelligence, (c) achievement, (d) attention/executive functioning, (e) memory and learning, (f) visual-motor and motor functioning, and (g) language. Such assessment instruments are well known in the art and include, for example, the Wechsler Adult Intelligence Scale and the Woodcock-Johnson III Tests of Cognitive Ability (both tests for assessing general intelligence), the Raven's Progressive Matrices Test (for assessing nonverbal intelligence), the Wide Span Achievement Test and the Woodcock-Johnson III Tests of Achievement (for assessing academic achievement), the Conners Continuous Maintenance of Function II Test (for assessing attention/executive functioning), the Broad Assessment of Memory and Learning (for assessing memory and learning), the Bender Visual-Motor "Gestalt" Test, the Halstead-Reitan Grip Strength Test, the Halstead-Reitan Finger Tapping Test, and the Lafayette Hole Plate Test (all for assessing visual-motor and motor function), and the Peabody Picture Vocabulary Test (for assessing language).

Cognitive function may also be assessed using reaction time and/or vigilance tests, such as the psychomotor vigilance task (e.g., as described in the examples). This test assesses components including fine motor skills; psychomotor speed; attention deficits; vigilance instability; and fatigue-induced impulsivity.

For example, the psychomotor vigilance task (PVT) is a sustained attention reaction time task that measures the speed with which subjects respond to a visual stimulus. The subject monitors a screen and taps the screen as quickly as possible when visual stimuli appear. The visual stimuli then disappear and reappear (at irregular time intervals) for example 10 times during the test, with the subject tapping the screen as quickly as possible on each reappearance. The test results are quantified from the average of, for example, 10 reaction times.

Any change in cognitive function, for example over time or with treatment, can be monitored by using one or more of these well-established tests at two or more time points and comparing the results.

The phrase "improvement in cognitive function" as used herein means a positive change in the subject's ability to perform a symbolic operation, such as perceiving, remembering, creating a mental image, having clarity of thought, knowing, reasoning, thinking, or judging. The positive change may be measured using any of the above tests on two or more occasions, such as a first occasion measuring baseline cognitive function and a second occasion measuring cognitive function after a period of time (during which treatment may be administered). Cognitive function may be said to be improved when there is at least approximately a 5% increase in activity in the relevant test between the two time points. For example, an increase in activity of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100% is observed in the corresponding test between two time points. In another example, an increase in activity of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% is observed in the corresponding test between two time points. The two time points may be separated from each other by one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, or even six months. The treatment may be administered during the interim period. Thus, as an example, "improvement in cognitive function" may mean that the subject demonstrates at least a 5% increase in performance over a baseline level, as measured by a well-developed Wechsler Adult Intelligence Scale. For example, the subject may demonstrate an increase in performance on this test of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100%. Further, for example, the subject may demonstrate an increase in activity in this test of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%.

According to the present invention, acetylleucine or a pharmaceutically acceptable salt thereof can be used to increase the speed of a reaction, such as the speed at which a subject responds to a visual stimulus.

In one embodiment, the subject has a decline in cognitive function associated with aging.

The term "decline in cognitive function associated with aging" as used in this application refers to a decline in cognitive function that is a direct consequence of the aging process; as opposed to a decline in cognitive function that is not a direct consequence of the aging process. Clinical manifestations may differ between subjects with a decline in cognitive function associated with aging and subjects with a decline in cognitive function that is not a direct consequence of the aging process.

The term "improvement" may include treatment and/or alleviation of any motor impairment and/or cognitive decline in a subject. Thus, age-related motor impairment and/or cognitive decline may be partially or completely treated using acetylleucine as described herein.

Also contemplated and encompassed by the present invention is the prevention of motor impairment and/or cognitive decline in the elderly using acetylleucine as described herein. Thus, age-related motor impairment and/or cognitive decline may not develop at all when using acetylleucine as described herein.

Acetylleucine or a pharmaceutically acceptable salt thereof may be formulated and administered to a subject, such as an elderly subject, in accordance with known teachings in the art.

Thus, acetylleucine or a pharmaceutically acceptable salt thereof can be prepared as a pharmaceutical composition, optionally containing a pharmaceutically acceptable carrier.

The active agent (composition) can be used as a monotherapy (i.e., using only the active agent) to improve motor and/or cognitive function in a subject, such as an elderly subject. Alternatively, the active agent (composition) can be used as an adjunct to or in combination with known treatment methods to improve motor and/or cognitive function in a subject, such as an elderly subject.

The active agent (composition) may take any of several different forms, depending, for example, on the manner in which it is to be used. Thus, for example, the agent or composition may be in the form of a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micellar solution, transdermal patch, liposomal suspension or any other suitable form that can be administered to a human or animal in need of treatment. It is understood that the carrier of the pharmaceutical composition according to the invention should be a carrier that is well tolerated by the subject to which it is administered.

A "pharmaceutically acceptable carrier" as referred to herein is any known compound or combination of known compounds known to those skilled in the art that can be used to prepare pharmaceutical compositions.

In a further embodiment, the pharmaceutically acceptable carrier may be a solid, and the composition may be in the form of a powder or a tablet. A solid pharmaceutically acceptable carrier may include one or more substances that may also act as flavoring agents, buffers, lubricants, stabilizers, solubilizers, suspending agents, wetting agents, emulsifiers, coloring agents, fillers, glidants, compression aids, inert binders, sweeteners, preservatives, dyes, coatings or disintegrants for tablets, but is not limited to them. The carrier may also be an encapsulating material. In powders, the carrier is a finely divided solid that is in admixture with finely divided active agents according to the present invention. In tablets, the active substance may be mixed with a carrier having the necessary properties for compression in suitable proportions and compressed into the desired shape and size. Powders and tablets, for example, contain up to 99% of the active substances. 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.

In another embodiment, the carrier may include one or more auxiliary substances or diluents, but is not limited to them. Examples of such auxiliary substances are gelatin, acacia, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silicon dioxide, and the like.

However, in another embodiment, the pharmaceutically acceptable carrier may be a liquid, and the pharmaceutical composition is in the form of a solution. Liquid carriers are used to prepare solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active agent according to the present invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier, such as water, an organic solvent, a mixture of water and an organic solvent, 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 indicated above, for example, cellulose derivatives such as sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols such as glycols) and their derivatives, and oils (for example, fractionated coconut oil and peanut oil). For parenteral administration, the carrier may also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in compositions in sterile liquid form for parenteral administration. The liquid carrier for pressurized compositions may be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions that are sterile solutions or suspensions can be administered, for example, intramuscularly, intrathecally, epidurally, intraperitoneally, intravenously and subcutaneously. The active agent can be prepared as a sterile solid composition that can be dissolved or suspended during administration using sterile water, physiological solution or other suitable sterile injection medium.

The agents and compositions of the present invention can 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, acacia, gelatin, sorbitan monooleate, polysorbate 80 (esters of sorbitan oleates and their anhydrides copolymerized with ethylene oxide), and the like. The agents used in accordance with the invention can also be administered orally in either 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 administration include sterile solutions, emulsions, and suspensions.

Acetylleucine and compositions containing it may alternatively be administered by inhalation (e.g. intranasally). Compositions may also be formulated for topical use. For example, creams or ointments may be applied to the skin.

Acetylleucine according to the present invention can be included in a device for slow or prolonged release. Such devices can, for example, be introduced into the skin or under the skin, and the drug can be released for weeks or even months. Such devices can be used when long-term treatment with acetylleucine used according to the present invention is required, and which usually requires frequent administration (for example, at least daily administration).

In one embodiment, the pharmaceutical composition is in the form of a tablet. In tablets, the active agent can be mixed with a carrier having the necessary compression properties in suitable proportions and compressed into the desired shape and size. Tablets can contain up to 99% by weight of active agents.

Thus, in one embodiment, acetylleucine or a pharmaceutically acceptable salt thereof is contained in a solid dosage form suitable for oral administration, especially in the form of a tablet.

Pharmaceutical compositions in solid oral dosage form, such as tablets, can be prepared by any method known in the pharmaceutical art. Pharmaceutical compositions are usually prepared by mixing the active substance or a pharmaceutically acceptable salt thereof with conventional pharmaceutically acceptable carriers, diluents or excipients.

The tablet may be formulated as known in the art. For example, Tanganyil® includes wheat starch, pregelatinized corn starch, calcium carbonate and magnesium stearate as fillers. The same or similar fillers may be used in the present description.

The exact composition of each Tanganyil® 700 mg tablet is as follows: 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 may be used in this description.

Alternatively, a generic version of these tablets may be used.

Acetylleucine or a pharmaceutically acceptable salt thereof may be administered in a dose of 500 mg to 10 g per day, preferably 1.5 g to 10 g per day (e.g. 1 g to 10 g, 2 g to 10 g, 3 g to 10 g, 4 g to 10 g, 1 g to 5 g, 2 g to 5 g, 3 g to 5 g, or 4 g to 5 g per day), if necessary in solid oral or liquid oral form. For example, Tanganil® is prescribed to adults in a dose of 1.5 g to 2 g per day for the symptomatic treatment of dizziness episodes, i.e. 3-4 tablets in two doses morning and evening. According to this prescription, the duration of treatment varies depending on the clinical progression (from 10 days to 5 or 6 weeks). At the beginning of treatment or in case of failure, the dosage can be safely increased to 3 g or even 4 g per day.

According to the present invention, acetylleucine or a pharmaceutically acceptable salt thereof can be administered at a dose that is higher than previously known and/or for a duration of treatment that is longer than previously known.

For example, the dose used may be from 4 to 10 g per day, such as from 4.5 to 10 g per day. It may be from 5; 5.5; 6; 6.5; 7; 7.5; 8; 8.5; 9 or 9.5 g to 10 g per day. It may be more than 4 g per day, but less than 10; 9.5; 9; 8.5; 8; 7.5; 7; 6.5; 6; 5.5 or 5 g per day. For example, the dose may be in the range of more than 4 g and not more than 6 g per day, such as in the range of more than 4 g and not more than 5 g per day, such as from 4.25 g to 4.75 g per day. In a further embodiment, these doses are used in a solid oral dosage form, in particular in a tablet. In another embodiment, these doses are for acetylleucine in its racemic form. Doses for acetylleucine in enantiomeric excess may be lower than those given here, for example, about 50% lower. Thus, the above-described dose ranges, when halved, are also clearly encompassed by the invention.

The total daily dose may be divided into several applications, for example, two or more applications per day may be required to achieve the required dose. As an example, the required number of tablets to provide the total daily dose of acetylleucine may be divided into two administrations (e.g. morning and evening) or three administrations (e.g. morning, midday and evening). Each dose is suitably administered with food. Thus, as an example, a total daily dose of 4.5 g of acetyl-DL-leucine may be administered as three tablets of ^Tanganyil® (or equivalent) with breakfast, three other tablets with lunch and three other tablets with dinner.

The duration of treatment may vary depending on the clinical progression. It may take seven or more days, two weeks or more, three weeks or more, one month or more, six weeks or more, seven weeks or more, or two months or more. For example, it may take three months or more, four months or more, five months or more, or even six months or more.

Any and all combinations of dosage form, dose, administration regimen and duration of treatment are contemplated and encompassed by the invention. An exemplary combination is a total daily dose of 4.5 to 10 g per day, taken in three doses per day, for a treatment duration of two months or more. Another exemplary combination is a total daily dose of more than 4 g to no more than 5 g per day, taken in three doses per day, for a treatment duration of six months or more. The dosage form may be, for example, a solid oral dosage form, in particular tablets.

Treatment may be initiated, for example, when motor function impairment and/or cognitive impairment are observed in the subject.

Treatment may be initiated, for example, when motor function impairment and/or cognitive impairment is observed in an elderly subject.

"Subject" as used in this application may be a vertebrate, a mammal or a domestic animal. Therefore, the compositions according to the description can be used to treat any mammal, such as livestock (e.g., horses), domestic animals, or can be used in other veterinary applications. Further, for example, the subject is a human.

"Elderly" as used in this application may refer to subjects of advanced age. For example, it may mean men and women aged 70 or more, 75 or more, 80 or more, 85 or more, or 90 or more. The term also includes non-human subjects in the relevant later years of life.

The elderly subject may be a very elderly subject, i.e., the subject is otherwise healthy in addition to exhibiting normal signs of aging. In one embodiment, the subject does not have dizziness or any (clinically apparent) neurological or neurodegenerative disease, disorder, or condition. In an alternative embodiment, the elderly subject may have dizziness and/or a (clinically apparent) neurological or neurodegenerative disease, disorder, or condition in addition to normal signs of aging.

According to another embodiment, a method is provided for improving motor function and/or cognitive function in a subject, such as an elderly subject, wherein the method comprises administering a therapeutically effective amount of acetylleucine or a pharmaceutically acceptable salt thereof to the subject.

A "therapeutically effective amount" of an agent is any amount that, when administered to a subject, provides the amount of the agent necessary to produce the desired effect. For example, a therapeutically effective amount of acetylleucine used may be from 4 to 10 g per day, such as from 4.5 to 10 g per day. Further, for example, the amount of the agent may be from greater than 4 g to no more than 5 g per day, and, for example, from about 4.25 g to 4.75 g per day.

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

Examples

The present invention will be described in more detail in the following examples, which demonstrate the usefulness of acetylleucine or a pharmaceutically acceptable salt thereof for improving motor function and cognitive function, for example, in the elderly.

Example 1

Subject

The subject is a 90-year-old male, a retired physician, with no evidence of dementia. He has had progressive postural imbalance for five years without extrapyramidal or cerebellar manifestations. For the past two years, he has had incomplete arousal disorder but has a normal sleep pattern. He had polio in his twenties and has manifestations of post-polio syndrome, including partial vocal cord paralysis, muscle weakness, and spinal malalignment. He leads an independent, active life, reads widely, and uses a laptop computer to communicate with his family. His only medication was eye drops for glaucoma at the time of this study.

Initial treatment

Treatment protocol

Treatment with acetyl-DL-leucine (Tanganil®) was initiated because the patient suffered from balance and gait disturbances. He began a one-month course of nine 500 mg tablets taken three times daily (TID) with meals, for a total daily dose of 4.5 g.

Measurement of motor function

The subject's ability to move was measured in the home environment using the "get up and go" test. This test involved standing up from a chair without assistance and walking the length of his living room to his kitchen. The test was performed seven consecutive days before treatment and for the next seven consecutive days after starting treatment with Tanganyil®.

Results

By 7-10 days of treatment, the subject was more confident in walking due to improved balance. In the home environment, when performing the "get up and go" test, the average time it took the subject to rise unassisted from a chair and walk the length of his living space to his kitchen before treatment with Tanganil® was 40±3 seconds. The average time it took to do this when treatment began was 30±2 seconds. Accordingly, the subject walked 25% faster than before treatment. He had difficulty getting into and out of bed, and this difficulty disappeared at the same time.

After 2-3 weeks of treatment, the subject suddenly described being fully awake upon waking and that his mind was clearer. His family noted a significant improvement in his cognitive function, spatial orientation, and general behavior. He was able to navigate his surroundings without any of the confusion that was evident before treatment. For example, his home contains numerous doors, and before treatment he often had to stop and think about which door to open to get to a certain room. After treatment, this decreased, indicating, in part, improved memory.

After one month, the subject stopped taking acetyl-DL-leucine. He maintained good balance for two weeks, and then this parameter worsened, while his consciousness gradually decreased to his pre-treatment level over one month. The results of the "get up and go" test were also similar to his pre-treatment performance level.

Second treatment

Treatment protocol

The same subject then began another month of treatment, that is, another month-long course of nine 500 mg capsules taken three times daily with meals (total daily dose 4.5 g).

Results

The improvements the subject noticed in the first month of treatment quickly returned.

Further treatment

Treatment protocol

The subject now continues treatment with acetyl-DL-leucine (Tanganil®) at a dose of 4.5 g per day.

Results

The improvements noted by the subject during the first and second months of treatment continued. The confusion that was evident before treatment was now completely absent.

He has not experienced any side effects for over eighteen months.

Conclusions

The subject and his family acknowledge that treatment with acetyl-DL-leucine resulted in significant benefits across multiple neurological systems, particularly motor function and cognitive function, which significantly improved the patient's quality of life.

Example 2

The subject is a 75-year-old male patient with balance disorder/age-related gait disorder and impaired spatial orientation (non-vertigo vertigo) resulting in backward falls. In addition, the subject exhibits a very discrete symmetric hypokinetic-rigid syndrome. The subject was diagnosed with balance disorder in 2016. DaTscan examination showed a borderline pathological condition (i.e. decreased dopamine receptors indicating possible Parkinson's disease), however, no improvement was observed with L-Dopa treatment. On MRI, the subject showed non-specific white matter lesions and mild atrophy of the right motor cortex.

Day 0: The patient was started on a treatment regimen of acetyl-DL-leucine, 3 g/day for the first week, then 5 g/day.

Day 14: The subject was followed up. An improvement in dizziness symptoms was found, as well as a significant reduction in the frequency of falls. No change in hypokinetic-rigid syndrome was noted.

Day 56: Treatment was stopped.

Day 62: Subject was followed up. The patient noted an increase in dizziness symptoms two days after stopping treatment (noting a feeling of intoxication).

The study is ongoing and the subject has returned to continuous treatment.

Example 3

An 86-year-old male patient was diagnosed with a mild, slowly progressive postural imbalance and gait disorder five years ago. He described it as feeling like a sailor on a ship when walking. The subject had to use a cane from time to time. The patient had no symptoms when sitting or lying down. The subject also suffers from atrial fibrillation and has bilateral hip replacements.

Clinical examination of the subject revealed slow gait with increased body sway. There was evidence of moderate polyneuropathy. There was no evidence of vestibular, oculomotor, or cerebellar dysfunction.

Laboratory tests of the vestibular system were normal. Posturography showed increased body sway. Gait analysis showed small steps and decreased gait speed. MRI of the brain was normal.

The patient was treated with Tanganyil® 500 mg in 3 separate doses during the day - 1 g after waking up, 1 g before lunch and 1 g before dinner for one week, then 2 g after waking up, 1.5 g before lunch and 1.5 g before dinner.

According to the subject's wife, 22 days after starting treatment with acetylleucine, there was a significant reduction in dizziness and imbalance, and a significant improvement in gait. Improvement was reported to begin in the second week of treatment. The medication was well tolerated.

Further trials were not yet possible due to the subject suffering from an unrelated illness (flu), but treatment is ongoing.

Conclusion

The patient and his wife reported improved gait, decreased dizziness and balance problems.

Example 4

An 89-year-old male patient presented with gait disturbance and postural imbalance for three years. There were no symptoms in the sitting or lying position. The symptoms progressed slowly. The patient had bilateral hearing loss but was otherwise mildly affected.

Clinical examination of the patient revealed slow gait with increased body sway when standing with eyes closed. No vestibular, oculomotor, or cerebellar dysfunction was noted.

Laboratory test results of the vestibular system (using the head impulse test, video stream impulse test, caloric irrigation, vestibular evoked myogenic potentials) were normal.

A video recording of the patient's gait was made and the gait was quantitatively analyzed (results are shown in Table 1).

An MRI of the patient's brain revealed mild subcortical vascular encephalopathy.

The patient was then treated with Tanganyil® (500 mg) in 3 separate doses during the day - 1 g after waking up, 1 g before lunch and 1 g before dinner for one week, then 2 g after waking up, 1.5 g before lunch and 1.5 g before dinner.

Three weeks after starting treatment with acetylleucine, the patient and his daughter reported that his gait and balance had improved significantly. He could stand up much more easily and quickly. He also reported that climbing stairs had become much easier. Video analysis showed that the patient was now even able to run. The drug was very well tolerated.

Conclusion

Improved gait, decreased dizziness and balance disorders during treatment with Tanganyil® were noted by the patient and his daughter, and confirmed by gait analysis and video. The drug was also well tolerated.

Results of quantitative gait analysis before and after treatment:

Table 1

Before treatment After 3 weeks of treatment Mean value (± SD) Normal walking speed (cm/sec) 88 96 88.03 (25.96) Maximum walking speed (cm/sec) 141 157 120.79 (31.17) Step frequency (steps/min) 92 100 102.89 (4.12) Spread width (distance between the center of the heel of one foot to the line of motion of the other foot) (cm) 9.3 8.1 11.79 (3.53) Stride cycle length (distance between two consecutive points of contact of the foot with the ground) (cm) 116 116 102.80 (28.51) % of time during two periods of the gait cycle in which both feet are in contact with the ground simultaneously 27.2 25.5 24.33 (2.77) Coefficient of variation (CV) of leg swing time: CV = (standard deviation/mean) x 100 1.6 1.8 3.25 (1.13)

As a result, during treatment with acetylleucine it was also noted:

- increase in the gait speed chosen at one’s own discretion from 88 to 96 cm/sec;

- increase in maximum gait speed from 141 to 157 cm/sec; and

- increase in step frequency (steps per minute) from 92 to 100.

Overall, there was significant improvement documented through these quantitative measures.

Example 5

A 77-year-old patient presented with progressive gait disorder with short steps and problems with gait initiation for over five years. MRI showed subcortical vascular encephalopathy (due to hypertension for many years). DaTscan examination showed a slight decrease in dopamine receptors. No improvement was observed during L-Dopa treatment.

Day 0: The patient reported four falls in the previous three months, and the patient's spouse reported mild cognitive impairment in the patient. The diagnosis was confirmed by a marked decrease in gait speed and impaired gait initiation.

Quantitative gait analysis with the GAITRite® system showed a significant reduction in peak gait speed (84 cm/sec) and self-selected gait speed (55 cm/sec).

The patient was treated with 3 g/day of acetyl-DL-leucine for two weeks with significant improvement in gait as reported by the patient and his wife.

Treatment was then discontinued due to worsening symptoms.

Day 28: Re-evaluation revealed gait disturbance which was recorded via video. Treatment with acetyl-DL-leucine 3 g/day was restarted.

Day 42: Upon further evaluation, the subject's spouse reported a dramatic improvement in function and quality of life. The spouse reported that the subject's gait was even better than two years ago. No further falls were noted.

Clinical examination showed a significant improvement in gait and balance, and the patient could now even run (documented via video).

Quantitative gait analysis showed an increase in maximum gait speed from 84 cm/sec to 130 cm/sec (running was not quantified) and self-selected gait speed from 55 cm/sec to 62 cm/sec.

The subject is currently undergoing ongoing treatment with follow-up scheduled examinations.

Example 6

A 59-year-old male patient was diagnosed with postural imbalance with occasional falls and trips (with a frequency of 2-3 times per month). His main complaints are problems moving up and down and problems walking on uneven surfaces. The subject did not show a tendency to fall in a specific direction. The patient also complained of a slowly progressive decline in cognitive ability, especially in terms of short-term memory and cognitive flexibility. His family members noticed persistence and episodic absent-mindedness when interacting with him. In terms of comorbidities, he was previously diagnosed with insulin-dependent diabetes mellitus and hypothyroidism with thyroxine therapy.

The patient was examined clinically using the following clinical assessments: maximal walking distance; timed get up and go test; SARA ataxia rating scale.

The patient was also examined using posturography after 1 month of therapy with Tanganyil® 500 mg (2 g upon awakening, 1.5 g before lunch and 1.5 g before dinner). The patient took the medication 30 minutes before meals or at least 2 hours after meals.

Baseline (before treatment): The maximum walking distance until the patient could no longer walk due to fatigue was 1 km. The get-up-and-go test was 25.4 sec. The SARA score was 6.5/40. Clinical examination revealed increased postural imbalance with bilateral intention tremor and dysmetria. Standing with the feet together was possible due to increased omnidirectional sway, which was especially noticeable in the spinal and anteroposterior axes. Consistent support and gait were impossible due to an increased risk of falling. The average time in the 8-meter walk test was 6.5 sec. Tuning fork examination showed bilaterally decreased proprioception at the medial malleolus.

During treatment with Tanganyil® (2 g upon awakening, 1.5 g before lunch and 1.5 g before dinner) for 1 month, the following assessments were made:

Objective measurements: The maximum walking distance increased to 1.5 km. The results of the "get up and go" test while taking the drug were 21.2 sec. The results on the SARA scale were 2/40. The previously noted swaying became noticeably calmer. Standing with the legs together, as well as consistent support and gait, were possible with an increase in omnidirectional sway. The average time for the 8-meter walk test was 4.4 seconds.

Subjective analysis: The patient was more energetic, more flexible and interactive, especially after the morning dose. Since the patient was interested in doing independent work in his home and garden, he described that he had more strength to do these activities, he did them much faster and more efficiently in his daily life. His family members noted that he was more consistent in communication and his executive functions had improved. He was subjectively more stable, both when walking and when moving up and down stairs. He did not need to hold on to the side rails to maintain balance. Moreover, he did not record any falls during the 1-month treatment period.

Side effects: Drowsiness was observed with the 2 g/1.5 g/1.5 g daily regimen. The dose was reduced to 1 g upon awakening, 1 g before lunch and 1 g before dinner, daily after 1 month of treatment. This resulted in the cessation of these side effects.

Current status: The improvements described above have not changed with lower doses (1g/1g/1g) for over 4 months. Side effects have not returned. The incidence of falls is currently 0 to 1/month.

Example 7

Subject

The subject is a 66-year-old male with no apparent dysfunction in cognitive ability or motor function/balance.

Study design

The subjects' reaction speed and mental clarity were assessed using the Mind Metrics application (psychomotor vigilance task, 10 trials per test). The psychomotor vigilance task (PVT) is a sustained attention reaction time task that measures the speed with which subjects respond to a visual stimulus. The subject monitors a screen and taps the screen as quickly as possible when visual stimuli appear. The visual stimuli then disappear and reappear (at irregular time intervals) for example 10 times during the test, with the subject tapping the screen as quickly as possible on each reappearance. Test performance is quantified as an average of 10 reaction times. Tests were conducted daily under comparable conditions. Subjects were assessed for 2 weeks prior to acetylleucine administration, which constitutes the baseline period.

From day 15, the subject took 5 g of acetyl-DL-leucine (Tanganil® 500 mg, Pierre Fabre) daily. The medication was taken at least 2 hours after and 30 minutes before meals. The daily dose of 5 g was taken in 3 separate doses during the day - 2 g upon awakening, 1.5 g before lunch and 1.5 g before dinner.

Daily treatment and analysis continued for 4 weeks. The subject then began a 2-week washout period.

Because of the noted improvement in balance with treatment, we measured balance ability at the end of the treatment period and at the end of the washout period. This assessment required the subject to close their eyes and lift their non-dominant leg approximately 6 inches off the ground. It was then determined how long the subject could remain upright and without significant sway. This was repeated three times and the averages were determined.

Subjective measurements

The subject reported an improvement in overall clarity of consciousness and a reduction in the time it took to transition from a sleep state to full wakefulness. He also noticed an improvement in his balance.

Objective measurements

Treatment with 5 g/day acetyl-DL-leucine was associated with significant improvements in psychomotor vigilance task performance compared to baseline (0.444 ms vs. 0.307 ms, p < 0.0001) (Figure 1A). After treatment initiation on day 15, test performance began to improve, reaching a new, lower baseline level that was maintained from day 19 to the end of the treatment period (Figure 1B). After the initiation of washout, a significant decrease in test performance was observed (Figure 1B), although there was no significant difference across treatment periods (0.307 ms (treatment) vs. 0.3224 ms (washout), p-0.4747). Test results during the washout period were also significantly better than those during the baseline period (0.322 ms (washout) vs. 0.444 ms (baseline), p < 0.0001).

Balance was assessed on the last day of the treatment period. The subject was able to maintain balance for 7.27 seconds (mean of 3 trials). This test was repeated at the end of the washout period. The length of time the subject could maintain balance decreased to 4.01 seconds (mean of 3 trials).

Adverse events

The subject reported feeling slightly dizzy/faint on one occasion during the first week of treatment. The subject reduced the daily dose from 5 g to 3 g for one day only and reported that the dizziness/faintness had decreased. The following day the daily dose was increased to 5 g. Dosage was maintained at this level for the remainder of the 4-week treatment period, with no recurrence of dizziness or faintness.

Example 8

Subject

The subject is a 29-year-old male with no evidence of cognitive or motor/balance dysfunction.

Study design

The subject's reaction speed and mental clarity were assessed using the Mind Metrics application (psychomotor vigilance task, 10 trials per test). Tests were performed daily under comparable conditions. The subject was tested for 2 weeks before acetylleucine administration, which constitutes the baseline period. From day 15, the subject took 5 g of acetyl-DL-leucine (Tanganil® 500 mg, Pierre Fabre) daily. The medication was taken at least 2 hours after and 30 minutes before meals. The patient took a daily dose of 5 g in 3 separate doses during the day - 2 g upon awakening, 1.5 g before lunch and 1.5 g before dinner. Daily procedures and assessments continued for 4 weeks. The subject then began a 2-week washout period.

Subjective measurements

The subject reported an improvement in overall mental clarity. He also reported a decrease in anxiety, possibly related to the increase in mental clarity. He reported no difference in maintaining balance.

Objective measurements

Treatment with 5 g/day acetyl-DL-leucine was associated with a small but statistically significant improvement in psychomotor vigilance task performance compared with baseline (0.3145 ms vs. 0.3032 ms, p < 0.05) (Figure 2A). Test performance did not differ significantly during the washout period from either baseline or treatment values (0.3032 ms vs. 0.3145/0.3104 ms, respectively).

Adverse events

No adverse events were observed.

Example 9

Subject

The subject is a 55-year-old woman with no apparent cognitive or motor/balance dysfunction.

Study design

The subject's reaction speed and mental clarity were assessed using the Mind Metrics application (psychomotor vigilance task, 10 trials per test). The tests were performed daily under comparable conditions. The subject was tested for 2 weeks before taking acetylleucine, which constitutes the baseline period. From day 15, the subject took 5 g of acetyl-DL-leucine (Tanganil® 500 mg, Pierre Fabre) daily. The subject took the medication at least 2 hours after and 30 minutes before meals. The daily dose of 5 g was taken in 3 separate doses during the day - 2 g upon awakening, 1.5 g before lunch and 1.5 g before dinner. Daily procedures and assessments continued for 4 weeks. The subject then began a 2-week washout period.

Balance ability was measured at the end of the treatment period and at the end of the washout period. This assessment required the subject to close her eyes and lift her non-dominant leg approximately 6 inches off the ground. It was then determined how long the subject could remain upright and without significant sway. This was repeated three times and the averages were taken.

Subjective measurements

The subject reported a reduction in the time it took to go from a "sleeping" to a "fully awake" state. The treatment period coincided with the commute to work and the time difference was 8 hours.

Objective measurements

Treatment with 5 g/day acetyl-DL-leucine was not associated with significant changes in psychomotor vigilance task performance compared to baseline (0.2983 ms (baseline) vs. 0.3025 ms (treatment), p-5105) (Figure 3A). Test performance was not significantly different during the washout period from either baseline or treatment values (0.3053 ms vs. 0.2983/0.3025 ms, respectively). Observation of individual day results from baseline and the treatment period showed that values over the treatment period may show relatively little change (Figure 3B).

The lack of significant change in the results of the psychomotor vigilance task may be due to the fact that the subject has a relatively fast baseline reaction speed.

Balance was assessed on the last day of the treatment period. The subject was able to maintain balance for 12 seconds (mean of 3 trials). This test was repeated at the end of the washout period. The duration of time the subject was able to maintain balance decreased to 8 seconds (mean of 3 trials).

Adverse events

No adverse events were noted.

Example 10

Subject

The subject is a 50-year-old male with no apparent cognitive or motor/balance dysfunction.

Study design

The subject's reaction speed and mental clarity were assessed using the Mind Metrics application (psychomotor vigilance task, 10 trials per test). Tests were performed daily under comparable conditions. The subject was tested for 1 week before taking acetylleucine, which constitutes the baseline period.

Beginning on day 8, the subject took 5 g of acetyl-DL-leucine (Tanganil® 500 mg, Pierre Fabre) daily. The patient took the medication at least 2 hours after and 30 minutes before meals. The daily dose of 5 g was administered in 3 separate doses throughout the day - 2 g upon awakening, 1.5 g before lunch, and 1.5 g before dinner. Daily procedures and assessments continued for 2 weeks. The subject then began a 1-week washout period.

Subjective measurements

The subject did not notice any difference before and after taking the medication.

Objective measurements

Treatment with 5 g/day acetyl-DL-leucine was associated with a small, non-significant decrease in psychomotor vigilance task performance compared to baseline (0.3112 ms (baseline) vs. 0.3365 ms (treatment), p-0.1545) (Figure 4A). Test performance did not differ significantly during the washout period from either baseline or treatment values (0.3129 ms vs. 0.3112/0.3365 ms, respectively).

The lack of significant change in performance on the psychomotor vigilance task may be due to the subject having a relatively fast baseline reaction speed.

Adverse events

No adverse events were noted.

Example 11

Subject

The subject is a 53-year-old male with no apparent cognitive or motor/balance dysfunction.

Study design

The subject's reaction speed and mental clarity were assessed using the Mind Metrics application (psychomotor vigilance task, 10 trials per test). Tests were performed daily under comparable conditions. The subject was tested for 2 weeks before taking acetylleucine, which constitutes the baseline period.

Beginning on day 15, the subject took 5 g of acetyl-DL-leucine (Tanganil® 500 mg, Pierre Fabre) daily. The subject took the medication at least 2 hours after and 30 minutes before meals. The daily dose of 5 g was administered in 3 separate doses throughout the day - 2 g upon awakening, 1.5 g before lunch, and 1.5 g before dinner. Daily procedures and assessments continued for 4 weeks. The subject then began a 2-week washout period.

We measured balance ability at the end of the treatment period and at the end of the washout period. This assessment required the subject to close their eyes and raise their non-dominant leg approximately 6 inches off the ground. It was then determined how long the subject could remain upright and without significant sway. This was repeated three times and the averages were determined.

Subjective measurements

The subject noted an improvement in overall clarity of consciousness and a reduction in the time required to transition from a sleep state to full wakefulness.

Objective measurements

Treatment with 5 g/day acetyl-DL-leucine was associated with statistically significant improvements in psychomotor vigilance task performance compared to baseline (0.3771 ms (baseline) vs. 0.3385 ms (treatment), p < 0.01) (Figure 5A). Test results showed a statistically significant decrease during the washout period (0.423 ms) compared to baseline values (0.3885 ms, p < 0.01), but there was no significant difference compared to baseline (0.3777 ms, not significant).

Balance was assessed on the last day of the treatment period. The subject was able to maintain balance for 7.9 seconds (average of 3 trials). This test was repeated at the end of the washout period. The subject's balance time decreased to 3.1 seconds (average of 3 trials).

Adverse events

No adverse events were noted.

Example 12

Subject

The subject is a 48-year-old woman with no apparent cognitive or motor/balance dysfunction.

Study design

The subject's reaction speed and mental clarity were assessed using the Mind Metrics application (psychomotor vigilance task, 10 trials per test). Tests were performed daily under comparable conditions. The subject was tested for 2 weeks before taking acetylleucine, which constitutes the baseline period.

From day 15 onwards, the subject took 5 g of acetyl-DL-leucine (Tanganil® 500 mg, Pierre Fabre) daily. The subject took the medication at least 2 hours after and 30 minutes before meals. The daily dose of 5 g was taken in 3 separate doses during the day - 2 g upon awakening, 1.5 g before lunch and 1.5 g before dinner. Daily procedures and assessments continued for 4 weeks. The subject then began a 2-week washout period.

Subjective measurements

The subject reported feeling less tired than usual and taking less time than usual to transition from sleep to full wakefulness.

Objective measurements

Treatment with 5 g/day acetyl-DL-leucine was associated with statistically significant improvements in psychomotor vigilance task performance compared to baseline (0.3238 ms (baseline) vs. 0.2996 ms (treatment), p < 0.001) (Figure 6A). Test results showed a statistically significant decrease during the washout period (0.3374 ms) relative to treatment values (0.2996 ms, p < 0.001), but no significant difference relative to baseline (0.3238 ms, ns).

Adverse events

No adverse events were noted.

Taken together, these examples demonstrate the usefulness of acetylleucine in a range of subjects, including the elderly, in terms of motor function and cognitive function. This is advantageous as there are now several therapeutic options available to patients with these very common signs and symptoms of aging. Table 2 summarizes the data from Examples 7-12. As can be seen, acetylleucine was shown to enhance cognitive function and/or motor function. Furthermore, patients with high baseline reaction times showed the best clinical effects.

The present invention is further described by means of the following numbered paragraphs:

1. Acetylleucine or a pharmaceutically acceptable salt thereof for use in a method of improving cognitive function, motor function, or cognitive function and motor function in a subject.

2. Acetylleucine or a pharmaceutically acceptable salt thereof for use in accordance with paragraph 1, wherein the use is carried out in the treatment of age-related decline in cognitive function and/or motor function.

3. Acetylleucine or a pharmaceutically acceptable salt thereof for use according to paragraph 1 or 2, wherein the subject has a decline in cognitive function associated with aging and/or a decline in motor function associated with aging.

4. Acetylleucine or a pharmaceutically acceptable salt thereof for use according to any of paragraphs 1-3, wherein the subject is a human aged 40 years or more, 50 years or more, 60 years or more, 70 years or more, 75 years or more, 80 years or more, 90 years or more, or 95 years or more.

5. Acetylleucine or a pharmaceutically acceptable salt thereof for use according to any of paragraphs 1-4, wherein the subject is an elderly subject.

6. Acetylleucine or a pharmaceutically acceptable salt thereof for use according to any of paragraphs 1-5, wherein the use is carried out in a method for improving cognitive function in said subject.

7. Acetylleucine or a pharmaceutically acceptable salt thereof for use according to any of paragraphs 1-5, wherein the use is carried out in a method for improving motor function in said subject.

8. Acetylleucine or a pharmaceutically acceptable salt thereof for use according to any of paragraphs 1-6, wherein the cognitive function is one or more selected from the group consisting of perception, memory, imagery, consciousness, reasoning, thinking, and judgment.

9. Acetylleucine or a pharmaceutically acceptable salt thereof for use in the method according to any of paragraphs 1-8, wherein said acetylleucine is in racemic form, in an enantiomeric excess of the L-enantiomer, or in an enantiomeric excess of the D-enantiomer.

10. Acetylleucine or a pharmaceutically acceptable salt thereof for use in a method according to any of paragraphs 1-9, wherein said method comprises administering acetylleucine at a dose of from 1.5 g to 10 g, such as from 4 g to 10 g, per day.

11. Acetylleucine or a pharmaceutically acceptable salt thereof for use in a method according to any of paragraphs 1-9, wherein said method comprises administering acetylleucine at a dose of from 500 mg to 10 g per day, such as in the range of from 1 g to 10 g, from 1.5 g to 10 g, from 2 g to 10 g, from 3 g to 10 g, from 4 g to 10 g, from 4.5 g to 10 g, from 1 g to 5 g, from 2 g to 5 g, from 3 g to 5 g, or from 4 g to 5 g per day, optionally in solid oral form or in liquid oral form.

12. Acetylleucine or a pharmaceutically acceptable salt thereof for use in the method according to paragraph 10, wherein said method comprises the use of acetylleucine in a dose of more than 4 g to no more than 6 g per day.

13. Acetylleucine or a pharmaceutically acceptable salt thereof for use in a method according to any of paragraphs 10-12, wherein said method comprises administering said dose in two or more doses.

14. Acetylleucine or a pharmaceutically acceptable salt thereof for use in the method of paragraph 13, wherein said method comprises administering the said dose in three divided doses.

15. Acetylleucine or a pharmaceutically acceptable salt thereof for use in a method according to any of paragraphs 1-14, wherein said method comprises administering acetylleucine for a treatment duration of two weeks or more.

16. Acetylleucine or a pharmaceutically acceptable salt thereof for use in the method of paragraph 15, wherein said method comprises administering acetylleucine for a treatment duration of seven weeks or more.

17. Acetylleucine or a pharmaceutically acceptable salt thereof for use in a method according to any of paragraphs 1-16, wherein said method comprises administering acetylleucine at a dose of 4.5 to 10 g per day, in three doses per day, for a treatment duration of two months or more.

18. Acetylleucine or a pharmaceutically acceptable salt thereof for use in a method according to any of paragraphs 1-16, wherein said method comprises administering acetylleucine at a dose of 4.5 to 10 g per day, in three divided doses per day, for a treatment duration of two months or more, for example administering acetylleucine at a dose in the range of more than 4 g to no more than 5 g per day, in three divided doses per day, for a treatment duration of six months or more.

19. Acetylleucine or a pharmaceutically acceptable salt thereof for use in the method of any of paragraphs 1-18, wherein the subject is a very elderly subject.

20. Acetylleucine or a pharmaceutically acceptable salt thereof for use in the method of paragraph 19, wherein the subject does not have dizziness or a neurological or neurodegenerative disease, disorder or condition.

21. Acetylleucine or a pharmaceutically acceptable salt thereof for use in reducing the time from awakening to full wakefulness.

22. Acetylleucine or a pharmaceutically acceptable salt thereof for use in improving balance in a subject wherein the subject has a balance disorder associated with aging.

23. Acetylleucine or a pharmaceutically acceptable salt thereof for use in the treatment of imbalances associated with aging.

24. Acetylleucine or a pharmaceutically acceptable salt thereof for use in increasing the resistance of a subject, for example, when standing and/or walking, where the subject has decreased resistance associated with aging.

25. Acetylleucine or a pharmaceutically acceptable salt thereof for use in reducing the unsteadiness of a subject when walking, wherein the subject has increased unsteadiness associated with aging.

26. Acetylleucine or a pharmaceutically acceptable salt thereof for use in improving the gait of a subject, wherein the subject has an age-related gait disorder.

27. Acetylleucine or a pharmaceutically acceptable salt thereof for use according to paragraph 26, wherein the use increases gait speed and/or step frequency in said subject.

28. Acetylleucine or a pharmaceutically acceptable salt thereof for use in preventing or reducing falls in a subject wherein the subject has an age-related predisposition to falls.

29. Acetylleucine or a pharmaceutically acceptable salt thereof for use in enhancing reaction speed, such as for use in enhancing reaction speed in a subject in response to a visual stimulus, such as where the subject experiences a decrease in reaction speed associated with aging.

Literature

(1) Vibert N, Vidal PP. In vitro effects of acetyl-DL-leucine (tanganil) on central vestibular neurons and vestibulo-ocular networks of the guinea pig. Eur J Neurosci 2001 February;13(4):735-48.

(2) Ferber-Viart C, Dubreuil C, Vidal PP. Effects of acetyl-DL-leucine in vestibular patients: a clinical study following neurotomy and labyrinthectomy. Audiol Neurootol 2009;14(1):17-25.

(3) Zwergal A, Schlichtiger J, Xiong G, Beck R, Gunther L, Schniepp R et al. Sequential [F]FDG microPET whole-brain imaging of central vestibular compensation: a model of deafferentation-induced brain plasticity. Brain Struct Funct 2014 October 1.

(4) Gunther L, Beck R, Xiong G, Potschka H, Jahn K, Bartenstein P et al. N-acetyl-L-leucine accelerates vestibular compensation after unilateral labyrinthectomy by action in the cerebellum and thalamus. PLoS One 2015;10(3):e0120891.

(5) Strupp M, Teufel J, Habs M, Feuerecker R, Muth C, van de Warrenburg BP et al. Effects of acetyl-DL-leucine in patients with cerebellar ataxia: a case series. J Neurol 2013 Oct;260(10):2556-61.

(6) Pelz JO, Fricke C, Saur D, Classen J. Failure to confirm the benefit of acetyl-DL-leucine in degenerative cerebellar ataxia: a case series. J Neurol 2015 May;262(5):1373-5.

(7) Bremova T, Malinova V, Amraoui Y, Mengel E, Reinke J, Kolnikova M et al. Acetyl-dl-leucine in Niemann-Pick type C: A case series. Neurology 2015 October 20;85(16):1368-75.

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Claims (13)

1. Use of acetylleucine or a pharmaceutically acceptable salt thereof to improve cognitive function in a subject experiencing age-related cognitive decline, wherein the age-related cognitive decline is selected from perception, memory, imagery, awareness, logical reasoning, thinking, and judgment. 2. The use according to claim 1, wherein the cognitive function of the subject improves after treatment by at least 10% compared to the baseline measurement. 3. The use according to claim 1, wherein acetylleucine is administered at least twice a day to achieve a total daily dose of from about 1.5 to about 10 g. 4. The use according to claim 1, wherein acetylleucine is administered at least twice a day to achieve a total daily dose of from about 4.5 to about 10 g. 5. Use according to claim 1, wherein the duration of treatment is at least 2 weeks, at least 7 weeks, or is continuous treatment. 6. The use according to paragraph 1, wherein the subject is an elderly subject or a very elderly subject. 7. Use of acetylleucine or a pharmaceutically acceptable salt thereof to improve cognitive function in a subject who exhibits age-related cognitive decline and who requires improvement in reaction speed, alertness, or both reaction speed and alertness. 8. Use of acetylleucine or a pharmaceutically acceptable salt thereof to improve cognitive function in a subject who exhibits age-related cognitive decline and suffers from gait disturbance, postural imbalance and/or spatial orientation disturbance. 9. The use according to any one of claims 1, 7 or 8, wherein acetylleucine is in the form of a racemate. 10. The use according to any one of claims 1, 7 or 8, wherein acetylleucine is the L-enantiomer. 11. Use according to any one of claims 1, 7 or 8, wherein acetylleucine is administered at a dose of 500 mg to 10 g per day. 12. Use according to item 11, wherein acetylleucine is administered in a dose of more than 500 mg to no more than 3 g per day. 13. Use according to claim 11, wherein acetylleucine is administered in a dose of more than 500 mg to no more than 2 g per day.