RU2772278C2 - Treatment of migraine - Google Patents

Abstract

FIELD: medicine; neurology; therapy.

SUBSTANCE: invention relates to the field of medicine, namely to neurology and therapy; it is intended for the treatment or prevention in a subject of migraine or one or several associated symptoms. A method for the treatment or prevention in a subject of migraine or one or several associated symptoms includes the administration to a subject of therapeutically or prophylactically effective amount of acetyl leucine or its pharmaceutically acceptable salt.

EFFECT: use of the invention provides for the possibility of treatment or prevention in a subject of migraine or one or several associated symptoms.

19 cl, 1 dwg, 10 ex

Description

The field of technology to which the invention belongs

The invention relates to leucine, acetyleucine or their pharmaceutically acceptable salts and especially to their use in the treatment and/or prevention of migraine and symptoms associated with it.

State of the art

Approximately 15% of the world's population is affected by migraines. Migraines are characterized by moderate to severe recurring headaches. Typically, headaches affect one side of the head, are throbbing, and last from 2 to 72 hours. Migraine symptoms include nausea, vomiting, and sensitivity to light, sound, or smell. The pain is often aggravated by physical activity.

Approximately 15-30% of people with migraine experience migraines with "aura" - a short-term visual disturbance that is a signal that a headache is coming soon. Occasionally, an aura may occur with little or no subsequent headache. This is known as acephalgic migraine or silent migraine. Subjects who suffer from migraines with aura often also suffer from migraines without aura. Pain intensity, headache duration, and frequency of attacks are variable.

Migraines are thought to be caused by a mixture of environmental and genetic factors. Although the underlying mechanisms are not fully understood, they are believed to involve the nerves and blood vessels of the brain. There are four possible phases of a migraine, although not all phases are always experienced:

• a prodrome that lasts hours or days before a headache;

• aura that immediately precedes the headache;

• the pain (or headache) phase and

• postdrome (effects experienced after a migraine).

Prodromal or early symptoms typically appear two hours to two days before the onset of pain or aura. Prodromal symptoms include altered mood, irritability, depression or euphoria, fatigue, cravings for certain food(s), muscle stiffness (especially in the neck), constipation or diarrhea, and sensitivity to light or noise. Prodromal symptoms may appear in migraines with and without aura (Rae-Grant 2004; Buzzi 2005; Rossi 2005; Samuels 2009).

The aura phase is a temporary focal neurological phenomenon that occurs before or during a headache (Aminoff 2009). The aura appears gradually over several minutes and usually lasts less than an hour. Symptoms may be visual, sensory, or motor in nature. The most common are visual effects (Olesen 2006).

Visual disturbances typically involve an area of partial visual field change that flickers (this is also known as atrial scotoma). The flicker typically starts at the center of the visual field and then spreads outward in zigzag lines. Some sufferers experience blurred vision, while others experience blurred vision or blindness in half of the visual field, usually on one side of the vertical midline (hemianopia).

The sensory aura may include pins and needles that start on one side of the arm and extend to the nose-mouth area on the same side. After the tingling wears off, numbness usually occurs. Other symptoms of the aura phase include speech or language disturbances, dizziness, and movement problems. Auditory hallucinations or delusions may also be experienced (Slap, 2008).

In the pain phase, headache is typically unilateral, throbbing, and moderate to severe in intensity (Tintinalli, 2010). In other cases, the pain may be bilateral, especially in patients who have migraines without aura. Less commonly, the pain may be in the neck or in the side or top of the head.

Pain is often accompanied by vomiting, sensitivity to light, sensitivity to sound, sensitivity to smells, fatigue and/or irritability (Aminoff, 2009). In basilar migraine, a migraine with neurological symptoms associated with the brain stem or with neurological symptoms on both sides of the body, common symptoms include a sense of the world spinning, dizziness, and confusion. Nausea occurs in almost 90% of people, and vomiting occurs in almost one third. Other symptoms include blurred vision, nasal congestion, diarrhea, frequent urination, pallor, sweating, swelling or tenderness of the scalp, and stiff neck.

Migraine postdrome refers to symptoms occurring immediately after the resolution of an acute headache (Bose, 2016). Many report soreness in the area where the migraine was, and there are a number of reports of deterioration in thinking within a few days after the headache has passed. The subject may feel tired or "hungry" and have headache, cognitive difficulties, gastrointestinal symptoms, mood changes, and weakness (Kelman, 2006).

The diagnosis of migraine is based on the signs and symptoms. The diagnosis of migraine without aura can be made according to the so-called "criteria 5, 4, 3, 2, 1" (International Headache Society, 2004):

• five or more attacks - for migraine with aura, two attacks are sufficient for a diagnosis;

• four hours - three days in duration;

• two or more of the following:

- unilateral (affecting half of the head);

- pulsating;

- pain of moderate or high intensity;

- deterioration in or causing avoidance of usual physical activity;

• one or more of the following:

- nausea and/or vomiting;

sensitivity to both light (photophobia) and sound (phonophobia).

If someone experiences two or more of the following: photophobia, nausea, or an inability to work or study during the day, the diagnosis is more likely.

Migraines can be divided into seven subclasses, some of which include additional items listed below.

• Migraine without aura or "common migraine" includes migraine headaches that are not accompanied by an aura.

• Migraine with aura or "classic migraine" usually includes migraine headaches accompanied by aura. Less commonly, an aura may occur without a headache or with a non-migraine headache. The other two variants are familial hemiplegic migraine and sporadic hemiplegic migraine, in which the individual has migraines with aura and accompanying motor weakness. Another variant is basilar-type migraine, where the headache and aura are accompanied by speech difficulties, world rotation, tinnitus, or a range of other brain stem-related symptoms, but without motor weakness.

• Childhood periodic syndromes that are commonly precursors to migraine include cyclic vomiting (repeated intense periods of vomiting), abdominal migraine (abdominal pain usually accompanied by nausea), and benign paroxysmal vertigo in children (periodic vertigo attacks).

• Retinal migraine includes migraine headaches accompanied by visual disturbances or even temporary blindness in one eye.

• Complications of migraine are described as migraine headaches and/or auras that are unusually prolonged or unusually frequent or associated with epileptic seizures or brain damage.

• Probable migraine describes conditions that have some of the characteristics of migraines, but where there is insufficient evidence to diagnose it as migraine with certainty (in the presence of concurrent drug abuse).

• Chronic migraine is a complication of migraines and is a headache that meets the diagnostic criteria for migraine headache and occurs over a longer period of time.

Common treatments for migraine include simple headache pain relievers such as ibuprofen or paracetamol (acetaminophen) and other anti-nausea drugs to avoid triggers.

The recommended initial treatment for those with mild to moderate symptoms is simple analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) or a combination of paracetamol, aspirin and caffeine (Gilmore, 2011). Several NSAIDs, including diclofenac, ibuprofen, and ketorolac, show evidence to support their use (Rabbie 2013; Derry 2013; Gilmore 2011). Aspirin can also relieve moderate to severe migraine pain with similar efficacy to sumatriptan (Kirthi, 2013).

Triptans or ergotamines may be prescribed for patients for whom simple drugs are ineffective. Triptans (eg, sumatriptan) can be effective for both pain and nausea and are initially recommended for those with moderate to severe pain or those with milder symptoms who do not respond to simple analgesics (Bartleson, 2010). Most side effects of triptans are mild, but in rare cases myocardial ischemia occurs, and therefore these drugs are not recommended for people with cardiovascular disease who have had a stroke or migraines that are accompanied by neurological problems. Triptans should also be used with caution in individuals with risk factors for vascular disease. Triptans are not habit-forming, but may cause headaches due to drug abuse if used for more than ten days per month (Tepper, 2010). Ergotamine and dihydroergotamine are older drugs still prescribed for migraines (Bartleson, 2010). They appear to be as effective as triptans and have harmful effects that are typically mild.

Medications used to prevent migraine attacks include metoprolol, valproate, topiramate, intravenous metoclopramide, and intranasal lidocaine (Armstrong 2013; Gilmore 2011). Metoclopramide is recommended for the treatment of individuals in the emergency department. Haloperidol can also be used in this group. A single intravenous dose of dexamethasone, when added to standard treatment for a migraine attack, is associated with a 26% reduction in headache recurrence over the next 72 hours (Colman, 2008).

Medications are more effective when used early in an attack. Frequent use of medications can lead to medication overuse headaches, where the headaches become more intense and more frequent. This can occur with triptans, ergotamines, and analgesics, especially opioid analgesics. Because of this, simple analgesics are recommended for use at most three days a week.

In light of the shortcomings associated with existing therapies and the reported prevalence of the condition in the general population, there remains a need to develop alternative treatments for migraine, in particular prophylactic treatment of the aura, which is not achieved using drugs known in the art today. The present disclosure addresses this need for an alternative treatment for migraines and describes leucine and acetyleucine, as well as pharmaceutically acceptable salts thereof, for use in the treatment or prevention of migraines.

The essence of the invention

Thus, the first aspect of the invention relates to leucine and acetyleucine or their pharmaceutically acceptable salts for use in the treatment or prevention of migraine or one or more symptoms associated with it.

A second aspect of the invention relates to a method for treating or preventing a migraine or one or more symptoms associated with a migraine in a subject, the method comprising administering to the subject a therapeutically or prophylactically effective amount of leucine, acetyleucine, or pharmaceutically acceptable salts thereof.

Description of drawings

Figure 1 shows similar activity of leucine and acetyleucine when exposed in vitro to Chinese hamster ovary (CHO) cells with Niemann-Pick (NPC) disease.

Detailed description

The invention encompasses substances, compositions and methods for the treatment and/or prevention of migraine in a subject.

Acetyl-DL-leucine has been used in France for the treatment of acute vertigo since 1957 and has an excellent safety profile. Despite numerous hypotheses, including membrane potential stabilization, its pharmacological and electrophysiological modes of action remain unclear (Vibert, 2001, Ferber-Viart, 2009). A study of FDG-µPET in a rat model of unilateral labyrinthectomy (Zwergal, 2016) 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 (Gunther, 2015). Improvements in the symptoms of cerebellar lesions in a number of cases in patients with cerebellar lesions of various etiologies (Strupp, 2013) confirm the therapeutic efficacy of acetyl-DL-leucine. In another series of cases, a beneficial effect was not found (Pelz, 2015). Quantitative gait analysis has shown that acetyl-DL-leucine also improves gait variability in patients with cerebellar ataxia (Schniepp, 2015). In a third recent study in 12 patients with Niemann-Pick type C disease (NPC), this remedy produced a significant improvement in ataxia (Bremova, 2015). In addition, a PET study of patients with ataxia of various etiologies treated with acetyl-DL-leucine showed increased metabolism in the midbrain and lower brain stem in immunocompetent cells (Becker-Bense, 2015), which may explain the observed beneficial effect.

However, to date there is no suggestion that acetyleucine could have therapeutic applications in the treatment of migraines or their symptoms, such as auras. The present application surprisingly shows that acetyleucine can be used to treat or prevent migraines. And, as stated in the present disclosure, it has also been found that leucine, or a pharmaceutically acceptable salt thereof, can also be used in the treatment of migraines or their symptoms.

References to "leucine" and "acetyleucine" throughout the application also include their pharmaceutically acceptable salts, even if not indicated.

"Subject", when used in the present description, may be a vertebrate, mammal or domestic animal. Therefore, the compositions of the invention can be used to treat any mammal, e.g. livestock (e.g. horse, cow, sheep or pig), companion animal (e.g. cat, dog, rabbit or guinea pig), laboratory animal (e.g. mouse or rats), or can be used for other veterinary applications. Preferably the subject is a human.

The term "treatment" as used herein refers to the reduction in frequency, alleviation or elimination of migraines or one or more of the symptoms associated with them.

The term "prophylaxis" as used herein refers to the prevention of migraines or one or more of the symptoms associated with them. In the case of all embodiments described in the present description, preferably leucine, acetyleucine or their pharmaceutically acceptable salts are used prophylactically.

Used in the present description, the term "relief" means making migraines or one or more of the symptoms associated with them, less severe or less intense than in the absence of treatment.

Used in the present description, the term "reduction in frequency" means a decrease in the occurrence of migraines or one or more symptoms associated with them, in a certain time frame relative to the occurrence in the absence of treatment.

In one preferred embodiment, leucine, acetyleucine, or pharmaceutically acceptable salts thereof reduce the frequency, alleviate or eliminate one or more migraine symptoms selected from headache, fatigue, aura, nausea, vomiting, light sensitivity, sound sensitivity, smell sensitivity, sweating , poor concentration, feeling hot or cold, abdominal pain and diarrhea.

As used herein, a symptom associated with migraine includes any clinical or laboratory manifestation associated with migraine and is not limited to what the subject may experience or observe.

One aspect of the invention relates to leucine, acetyleucine or their pharmaceutically acceptable salts for use in the treatment or, preferably, prevention of aura. Currently, there are no reports of drugs that are able to specifically prevent the aura. Preferably the aura is a visual aura.

Another aspect of the invention relates to leucine, acetyleucine or their pharmaceutically acceptable salts for use in the treatment or prevention of migraine associated with aura (eg, "classic migraine").

Another aspect of the invention relates to leucine, acetyleucine or their pharmaceutically acceptable salts for use in the treatment or prevention of migraine that is not associated with aura (eg, "common migraine").

Another aspect of the invention relates to leucine, acetyleucine or their pharmaceutically acceptable salts for use in the treatment or prevention of aura associated with migraine headache.

Another aspect of the invention relates to leucine, acetyleucine or their pharmaceutically acceptable salts for use in the treatment or prevention of aura that is not associated with migraine headache.

Another aspect of the invention relates to leucine, acetyleucine or their pharmaceutically acceptable salts for use in the treatment or prevention of hemiplegic migraine. In such an embodiment, migraine typically includes headache and aura, which are accompanied by motor weakness.

Another aspect of the invention relates to leucine, acetyllucine or their pharmaceutically acceptable salts for use in the treatment or prevention of sporadic hemiplegic migraine.

Another aspect of the invention relates to leucine, acetyleucine or their pharmaceutically acceptable salts for use in the treatment or prevention of vestibular migraine. Vestibular migraines can be defined according to the diagnostic criteria established by the Classification Committee of the Bàràny Society (Lempert 2012) and are typically characterized as follows.

A. At least 5 episodes of moderate to severe vestibular symptoms (defined by the Bàràny Society classification of vestibular symptoms) lasting 5 minutes to 72 hours.

B. Current or previous history of migraine with or without aura according to the International Classification of Disorders Accompanied by Headache (ICHD).

C. One or more signs of migraine with at least 50% vestibular episodes:

• headache with at least two of the following characteristics: unilateral location, throbbing, pain of moderate or severe intensity, aggravated by normal physical activity:

• photophobia or phonophobia;

• visual aura.

D. Not better explained by another vestibular or ICHD diagnosis.

Another aspect of the invention relates to leucine, acetyleucine or their pharmaceutically acceptable salts for use in the treatment or prevention of migraine that is not a vestibular migraine, or that is not a vestibular migraine associated with vertigo symptoms.

Another aspect of the invention relates to leucine, acetyleucine or their pharmaceutically acceptable salts for use in the treatment or prevention of migraine that is not associated with dizziness or symptoms of dizziness. In some embodiments, the migraine is not associated with acute dizziness or dizziness due to an acute peripheral vestibular disorder. In some embodiments, migraine is not associated with Meniere's vertigo or vertigo due to inflammation (vestibular neuritis) or toxic origin.

Another aspect of the invention relates to leucine, acetyleucine or their pharmaceutically acceptable salts for use in the treatment or prevention of migraine basilar type. In such an embodiment, migraine typically includes headache and aura accompanied by one or more of the following symptoms: difficulty speaking, the world spinning, ringing in the ears, and other brain stem related symptoms.

Another aspect of the invention relates to leucine, acetyleucine or their pharmaceutically acceptable salts for use in the treatment or prevention of retinal migraine. In such an embodiment, retinal migraine typically includes headaches accompanied by visual disturbances or temporary blindness.

Another aspect of the invention relates to leucine, acetyleucine or their pharmaceutically acceptable salts for use in the treatment or prevention of chronic migraine. As used herein, the term "chronic migraine" refers to a subject suffering from headaches more than fifteen days per month for three months, of which more than eight days are migraine headaches, in the absence of a prescription for a drug (as defined by the International Headache Society).

Another aspect of the invention relates to leucine, acetyleucine or their pharmaceutically acceptable salts for use in the treatment or prevention of episodic migraine. As used herein, the term "episodic migraine" refers to a subject suffering from a headache less than fifteen days per month for three months in the absence of a prescription for a drug (as defined by the International Headache Society).

Another aspect of the invention relates to leucine, acetyleucine or their pharmaceutically acceptable salts for use in the treatment or prevention of acute migraine.

Another aspect of the invention relates to leucine, acetyleucine or their pharmaceutically acceptable salts for use in the treatment or prevention of one or more prodromal symptoms associated with migraine. Preferably, the prodromal symptoms are selected from one or more of altered consciousness, irritability, depression or euphoria, fatigue, craving for certain food(s), stiff muscles (especially the neck), constipation, diarrhea, and sensitivity to smells and noise.

Another aspect of the invention relates to leucine, acetyleucine or their pharmaceutically acceptable salts for use in the treatment or prevention of pain associated with migraine.

Another aspect of the invention relates to leucine, acetyleucine or their pharmaceutically acceptable salts for use in the treatment or prevention of one or more postdromal symptoms associated with migraine. Preferably, the postdromal symptoms are selected from one or more of migraine pain, impaired thinking, fatigue, headache, cognitive difficulties, gastrointestinal symptoms, mood changes, and weakness.

In one preferred embodiment, leucine, acetyl-leucine, or a pharmaceutically acceptable salt thereof reduces, alleviates, or eliminates migraine migraines.

In one preferred embodiment, leucine, acetyleucine or their pharmaceutically acceptable salts weaken, lighten or eliminate the aura. More preferably, leucine, acetyleucine, or pharmaceutically acceptable salts thereof reduce, alleviate, or eliminate one or more symptoms selected from vision problems or visual disturbances, numbness or tingling, dizziness, balance problems, movement problems, speech difficulties, and loss of consciousness. Preferably, leucine, acetyleucine or their pharmaceutically acceptable salts prevent the onset of an aura, for example by preventing one or more of the above symptoms.

According to a second aspect, the invention relates to a method for treating or preventing a migraine or one or more symptoms associated with a migraine in a subject, comprising administering to the subject a therapeutically or prophylactically effective amount of leucine, acetyleucine, or pharmaceutically acceptable salts thereof.

The preferred features of the first aspect of the invention are also applicable to the second aspect.

Another aspect of the invention relates to a method of treating or preventing a migraine that is not a vestibular migraine or that is not a vestibular migraine associated with vertigo symptoms in a subject, comprising administering to the subject a therapeutically or prophylactically effective amount of leucine, acetyllucine, or their pharmaceutically acceptable salts.

Another aspect of the invention relates to a method of treating or preventing a migraine in a subject that is not associated with dizziness or symptoms of dizziness, comprising administering to the subject a therapeutically or prophylactically effective amount of leucine, acetyllucine, or their pharmaceutically acceptable salts.

A "therapeutically effective amount" or "prophylactically effective amount" of an agent is any amount that, when administered to a subject, is the amount of the agent that is required to produce the desired effect. The dose can be determined according to various parameters, especially according to the specific form of leucine or acetyleucine used; the age, weight, and condition of the patient being treated, the route of administration, and the desired treatment regimen. The physician will be able to determine the required route of administration and dosage for any particular patient. A typical daily dose may be from about 10 to 225 mg per kg, from about 10 to 150 mg per kg, preferably from about 10 to 100 mg per kg of body weight. For example, a prophylactically effective amount of acetyleucine used may be 0.5 g to 15 g per day, or 1 g to 10 g per day, preferably 1.5 g to 7 g per day. Further dosage details are provided below.

Leucine, acetyleucine and compositions thereof

Acetylleucine in racemic form and its salts are known for their effectiveness in the symptomatic treatment of vertigo of various origins, namely vertigo due to acute vestibular disorder. Acetylleucine is sold in racemic form by Pierre Fabre Medicament as an anti-vertigo drug called Tanganil®. Clinical results related to acetyleucine reported by various authors show an improvement in the symptomatology of vertigo in more than 95% of cases, including the disappearance of vertigo attacks.

In one preferred embodiment, the leucine, acetyleucine, or pharmaceutically acceptable salts thereof are in racemic form, which means that the compounds contain approximately equal numbers of enantiomers. On the other hand, leucine or acetyleucine may be present in an enantiomeric excess of either the L-enantiomer or the D-enantiomer. Racemic and enantiomeric forms can be obtained according to procedures known in the art.

In one particularly preferred embodiment, the leucine, acetyleucine or pharmaceutically acceptable salts thereof are in the form of the L-enantiomer.

In another embodiment, the leucine, acetyleucine, or pharmaceutically acceptable salts thereof are in the form of the D-enantiomer.

Preferably the leucine or acetyleucine is in free base form.

Leucine, acetyleucine or their pharmaceutically acceptable salts can be presented in the form of a composition and administered to the subject in accordance with methods known in the art.

Thus, leucine, acetyleucine or their pharmaceutically acceptable salts can be included in a pharmaceutical composition, optionally including one or more pharmaceutically acceptable carriers, diluents or excipients.

The active substance (composition) can be used to treat migraine in a subject as monotherapy (ie, use the active agent alone). On the other hand, for the treatment of migraine in a subject, the active substance (composition) can be used as adjuvant treatment with or in combination with known therapies.

The active substance (composition) may take any form from a number of different forms, depending in particular on the manner in which they are to be used. For example, the substance 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 should be borne in mind that the carrier in the pharmaceutical composition according to the invention should be a carrier that is well tolerated by the subject who receives it.

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

Suitable carriers or diluents for therapeutic use are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).

Examples of suitable carriers include lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol and talc. Examples of suitable diluents include ethanol, glycerin and water.

Examples of such suitable excipients for the various forms of pharmaceutical compositions described herein can be found in Handbook of Pharmaceutical ^Excipients , 2nd Edition, (1994), Edited by A Wade and PJ Weller. Examples of such excipients are gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silicon dioxide, and the like.

The choice of pharmaceutical carrier, excipient or diluent may be made in light of the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions may include, as or in addition to a carrier, excipient or diluent, any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizer(s). (s).

Examples of suitable binders include starch, gelatin, natural sugars such as glucose, lactose anhydrous, anti-caking lactose, beta-lactose, corn sweeteners, natural gums and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose. and polyethylene glycol.

Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.

Preservatives, stabilizers, coloring agents, and even flavoring agents may be included in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid, and p-hydroxybenzoic acid esters. Antioxidants and suspending agents may also be used.

In one preferred 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, compressants, inert binders, sweeteners , preservatives, colorants, coatings or substances to improve tablet disintegration. The carrier may also be an encapsulating material. In powders, the carrier is a finely divided solid which is admixed with the finely divided active ingredients of the invention. In tablets, the active substance may be mixed in suitable proportions with a carrier having the necessary compressibility properties and compressed into a shape and to the desired size. Powders and tablets preferably contain up to 99% of 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 preferred embodiment, the pharmaceutically acceptable carrier may be a liquid and 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. The active substance of the invention may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture thereof, or pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity regulators, stabilizers or osmoregulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing the additives mentioned above, such as cellulose derivatives, preferably 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 butter). For parenteral administration, the carrier may also be a fatty ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid formulations 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 used, for example, by intramuscular, intrathecal, epidural, intraperitoneal, intravenous, and especially subcutaneous injection. The active substance may be provided as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline or other suitable sterile injection medium.

The substances and compositions of the invention can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, saline or glucose is sufficient to make the solution isotonic), bile salts, gum arabic, gelatin, sorbitan monooleate , polysorbate 80 (esters of oleic acid and sorbitol and its anhydrides, copolymerized with ethylene oxide), etc. The substances used according to the invention can also be administered orally in the form of either a liquid or solid composition. 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.

On the other hand, leucine, acetyleucine and compositions including them can be administered by inhalation (ie, intranasally). Compositions can also be prepared for topical use. For example, creams or ointments can be applied to the skin.

The leucine and acetyleucine of the invention can be included in a slow or delayed release device. Such devices can, for example, be embedded on or under the skin and the drug can be released over weeks or even months. Such devices may be of particular advantage when long-term treatment with the leucine or acetyleucine used according to the invention is required, and when frequent administration (eg, at least daily administration) may typically be required.

In one particularly preferred embodiment, the pharmaceutical composition is in the form of a tablet. In tablets, the active substance may be mixed in suitable proportions with a medium having the necessary compressibility properties and compressed into the desired shape with the desired size. Tablets preferably contain up to 99% by weight of the active substance.

Thus, in one preferred embodiment, leucine, acetyleucine or a pharmaceutically acceptable salt thereof is provided in a solid dosage form suitable for oral administration, preferably in the form of a tablet.

Pharmaceutical preparations in solid oral dosage form, such as tablets, can be obtained by any method known in the field of pharmacy. Pharmaceutical preparations are usually obtained by mixing the active substance or its pharmaceutically acceptable salt with conventional pharmaceutically acceptable carriers, diluents or excipients.

The tablet may be prepared according to conventional methods known in the art and may or may not be coated. Tanganil®, for example, includes as excipients wheat starch, pregelatinized maize (corn) starch, calcium carbonate and magnesium stearate as excipients. The same or similar excipients can be used in the present invention. The exact composition of each 700 mg Tanganil® tablet is as follows: 500 mg acetyl-DL-leucine, 88 mg wheat starch, 88 mg pregelatinized maize (corn) starch, 13 mg calcium carbonate and 11 mg magnesium stearate. The same tablets can be used in the present invention. Alternatively, you can use a generic (reproduced) version of such tablets.

As discussed above, leucine, acetyleucine or their pharmaceutically acceptable salts can be prepared and administered as a pharmaceutical composition in any number of different forms. For example, leucine, acetyleucine or their pharmaceutically acceptable salts can be formulated into a pharmaceutical composition to facilitate delivery across the blood-brain barrier. As another example, leucine, acetyleucine or their pharmaceutically acceptable salts can be formulated into a pharmaceutical composition to bypass the blood-brain barrier. Drugs that facilitate delivery across the blood-brain barrier, or drugs suitable for administration by a route that bypasses the blood-brain barrier, can be used to obtain and administer leucine (non-acylated) as described herein. As shown in the present disclosure, exposure to leucine in cells exhibiting a lysosomal disease phenotype improves, similar to exposure to acetyllucine, cellular dysfunction (for example, by reducing lysosome storage volumes), thereby demonstrating similar activity of leucine and acetyllucine (see figure 1).

In one embodiment, the pharmaceutical composition (eg, comprising leucine or a salt thereof) is formulated for nano-delivery, eg, drug-carrier colloid systems. Suitable examples include, but are not limited to, liposomes, nanoparticles (e.g., polymeric, lipid, and inorganic nanoparticles), nanogels, dendrimers, micelles, nanoemulsions, polymersomes, exosomes, and quantum dots (see, e.g., Patel, 2017; Kabanov, 2004; Cheng, 2013; Lahde 2008).

In one embodiment, the pharmaceutical composition (eg, comprising leucine or a salt thereof) is formulated for direct delivery to the central nervous system (CNS), eg, by injection or infusion. Formulations 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 administration, and delivery via grafting to the nasal mucosa.

In one embodiment, the pharmaceutical composition is prepared for (and administered by) intranasal delivery (see, for example, Hanson, 2008). In one embodiment, the pharmaceutical composition is prepared for (and administered by) delivery via graft to the nasal mucosa. In one embodiment, the pharmaceutical composition is prepared for (and administered by) intracerebroventricular injection or infusion. In another embodiment, the pharmaceutical composition is prepared for (and administered by) intrathecal intracisternal injection or infusion. In one embodiment, the pharmaceutical composition is prepared for (and administered by) intrathecal injection or infusion in the lumbar region. For example, the active agent may be formulated into an intrathecal composition and/or administered intrathecally in the same or similar manner as described in Ory (2017).

Various methods may be used, including, without limitation, burr hole injection or cisternal or lumbar puncture, or the like known in the art. Various internal (eg, implanted) or external devices known in the art, such as pumps, catheters, reservoirs, etc., may be used for delivery.

In one embodiment, the administration interval is once every two weeks. In one embodiment, the administration interval is once every 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 every week. In one embodiment, the administration interval is two or more times a week. In one embodiment, the administration interval is daily. In one embodiment, the administration is continuous, such as a continuous infusion.

Leucine, or a pharmaceutically acceptable salt thereof, may be administered at a dose or amount equivalent to that disclosed herein for acetyleucine, adjusted to ensure that the dose is for direct CNS delivery or is delivered across the blood-brain barrier.

Similarly, acetyleucine, or a pharmaceutically acceptable salt thereof, may be administered at the dose or amount disclosed herein; the dose can be adjusted according to the route of administration (eg, direct delivery to the CNS).

Dosage

Leucine, acetyleucine or their pharmaceutically acceptable salts can be administered at a dose of from about 500 mg to about 15 g per day, or from about 500 mg to about 10 g per day, preferably from about 1.5 g to about 10 g per day. Preferably, leucine, acetyleucine or their pharmaceutically acceptable salts are administered orally in solid or liquid form.

At the beginning of treatment or in case of insufficiency, the dosage can be safely increased to 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, 10 g, 11 g, 12 g, 13 g, 14 g, 15 g per day.

If one enantiomer is administered, doses can be reduced accordingly. For example, if only leucine acetyl-L-leucine or only acetyl-D-leucine is administered, the dose may be 250 mg to 15 g per day, 250 mg to 10 g per day, 250 mg to 5 g per day, or preferably from 0.75 g to 5 g per day.

In accordance with the present invention, leucine, acetyleucine or their pharmaceutically acceptable salts can be administered at a dose that is higher than previously known and/or for longer treatment than previously known.

For example, in one preferred embodiment, the dosage administered is from about 1 g to about 15 g, or from about 1 g to about 10 g per day, more preferably from about 1.5 g to about 7 g per day. Preferably, the dose administered may be between 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 g and 15 g per day. More preferably, the dose administered may be between 2, 3, 4, 5, 6, 7, 8 or 9 g and 10 g per day. In one preferred embodiment, the dose administered may be greater 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 preferred embodiment, the dose is in the range of greater than 2 g but not greater than 6 g per day. In a preferred embodiment, these doses are administered in a solid oral dosage form, preferably tablets. In a preferred embodiment, these doses are doses of leucine or acetyleucine when in racemic form. Doses for leucine or acetyleucine, when there is an enantiomeric excess, can be less than the doses listed herein, for example, about 50% lower. Thus, the above dosage ranges, when divided in half, are also covered by the invention.

The total daily dose can be divided into several administrations, i.e. to achieve the desired dose may require the introduction of two or more times a day. As an example, the required number of tablets to provide a total daily dose of leucine or acetyleucine can be divided into two administrations (eg morning and evening) or three administrations (eg morning at noon and evening). Each dose is preferably administered with food. Thus, by way of example, a total dose of 3 g of acetyl-DL-leucine can be administered as two ^Tanganil® tablets (or equivalent) at breakfast, two other tablets at lunch, and two other tablets at lunch.

In one preferred embodiment, leucine, acetyleucine or their pharmaceutically acceptable salts are administered once a day.

In another preferred embodiment, leucine, acetyleucine or their pharmaceutically acceptable salts are administered twice a day.

In another preferred embodiment, leucine, acetyleucine or their pharmaceutically acceptable salts are administered three times a day, preferably in the morning, afternoon and evening.

In one preferred embodiment, leucine, acetyleucine or their pharmaceutically acceptable salts are administered at a dose of from about 500 mg to about 15 g per day.

In another preferred embodiment, leucine, acetyleucine or their pharmaceutically acceptable salts are administered at a dose of from about 1500 mg to about 6000 mg per day.

In another preferred embodiment, leucine, acetyleucine or their pharmaceutically acceptable salts are administered at a dose of from about 2500 mg to about 5500 mg per day.

In one preferred embodiment, leucine, acetyleucine or their pharmaceutically acceptable salts are administered in unit dosage form, the unit dosage form comprising 500 mg of the active substance.

In one preferred embodiment, leucine, acetyleucine or their pharmaceutically acceptable salts are administered in a total dose of about 3000 mg per day. More preferably, leucine, acetyleucine or their pharmaceutically acceptable salts are administered at a dose of 1000 mg three times a day, preferably two 500 mg tablets three times a day.

In another preferred embodiment, leucine, acetyleucine or their pharmaceutically acceptable salts are administered in a total dose of about 4500 mg per day. More preferably, leucine, acetyleucine or their pharmaceutically acceptable salts are administered at a dose of 1500 mg three times a day, preferably three 500 mg tablets three times a day.

In another preferred embodiment, leucine, acetyleucine or their pharmaceutically acceptable salts are administered in a total dose of about 5000 mg per day. More preferably, leucine, acetyleucine or their pharmaceutically acceptable salts are administered in one dose of four 500 mg tablets and two doses of three 500 mg tablets.

In another preferred embodiment, leucine, acetyleucine or their pharmaceutically acceptable salts are administered in a total dose of about 5500 mg per day. More preferably, leucine, acetyleucine or their pharmaceutically acceptable salts are administered in two doses of four 500 mg tablets and one dose of three 500 mg tablets.

The duration of treatment may vary according to clinical progression. For example, it may last seven days or more, 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. In one preferred embodiment, leucine, acetyleucine, or pharmaceutically acceptable salts thereof, is administered for a treatment duration of two weeks or more.

In another preferred embodiment, leucine, acetyleucine or their pharmaceutically acceptable salts are administered for three months or more, four months or more, five months or more, or six months or more. In one preferred embodiment, the duration of treatment is 1 year or more, 2 years or more, 3 years or more, 4 years or more, 5 years or more, or 10 years or more. In one preferred embodiment, the duration of treatment may be half the life of the patient.

Any and all combinations of dosage form, number of doses, dosage regimen and duration of treatment are contemplated and covered by the invention. The preferred combination is a total daily dose of 2 g to 6 g per day, taken in three doses per day, in the case of a treatment duration of two months or more. Another preferred combination is a total daily dose of more than 3 g, but not more than 5 g per day, taken in three doses per day, in the case of a treatment duration of six months or more. Preferably the dosage form is a solid oral dosage form, preferably tablets.

salt

The substances of the invention may be present in the form of salts, in particular pharmaceutically acceptable salts, or esters.

Pharmaceutically acceptable salts of the substances of the invention include suitable acid or base addition salts. A review of suitable pharmaceutical salts can be found in Berge et al., J. Pharm. Sci., 66, 1-19 (1977). Salts are formed, for example, with strong inorganic acids such as mineral acids, for example sulfuric acid, phosphoric acid or hydrohalic acids; with strong organic carboxylic acids, such as alkanecarboxylic acids with 1-4 carbon atoms, which are unsubstituted or substituted (eg with halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with amino acids, for example, aspartic or glutamic acid; with benzoic acid or organic sulfonic acids such as (C ₁ -C ₄ )-alkyl or arylsulfonic acids which are unsubstituted or substituted (eg with halogen), such as methane or p-toluenesulfonic acid.

Enantiomers/Tautomers

The invention also includes, where applicable, all enantiomers and tautomers of the substances of the invention. The corresponding enantiomers and/or tautomers can be isolated/obtained by methods known in the art.

Stereo and geometric isomers

Some of the substances of the invention may exist as stereoisomers and/or geometric isomers, for example they may have one or more asymmetric and/or geometric centers and may exist in two or more stereoisomeric and/or geometric forms. The present invention contemplates the use of all individual stereoisomers and geometric isomers of such substances and mixtures thereof. The terms used in the claims cover these forms, provided that said forms retain their respective functional activity (although not necessarily to the same extent).

The present invention also includes all suitable isotopic variants of the substance or pharmaceutically acceptable salts thereof. An isotopic variant of a substance of the invention, or a pharmaceutically acceptable salt thereof, is defined as one in which at least one atom is replaced by an atom with the same atomic number but an atomic mass different from that normally found in nature. Examples of isotopes that can be incorporated into the substance and its pharmaceutically acceptable salts include isotopes of hydrogen, carbon, oxygen, phosphorus, sulfur, fluorine and chlorine such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O , ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl, respectively. Certain isotopic variants of the substances and their pharmaceutically acceptable salts, for example those in which radioactive isotopes such as ³ H or ¹⁴ C are included, are useful in drug and/or tissue substrate distribution studies. Isotopes of tritium, i.e. ³ H, and carbon-14, i.e. ¹⁴ C are particularly preferred for their ease of preparation and detection. In addition, substitution by isotopes such as deuterium, i.e. ² H may provide some therapeutic benefits resulting from greater metabolic resistance, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopic variants of the substances of the invention and their pharmaceutically acceptable salts of the present invention, as a rule, can be obtained by conventional procedures using the appropriate isotopic variants of suitable reagents.

solvates

The present invention also includes solvate forms of the substance of the invention. The terms used in the claims cover these forms.

Polymorphs

The invention also relates to the substances of the invention in their various crystalline forms, polymorphic forms and (without) aqueous forms. It has been found in the pharmaceutical industry that chemical compounds can be isolated in any of these forms by slightly modifying the purification and/or isolation from the solvents used in the synthetic preparation of such compounds.

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

The invention will now be explained in more detail with the aid of the following non-limiting examples which demonstrate, inter alia, the usefulness of acetyleucine in the treatment of migraine in a subject.

Examples

Example 1

Case Study: Administration of Acetylleucine for Migraines

Tanganil® is obtained from Pierre Fabre Medicament (France) in the form of tablets.

Patient details

Female gender

Age 18

Height 1.75 m

Weight 65 kg

Treatment. Six tablets per day: two in the morning, two at noon and two in the evening. The exact composition of each Tanganil® tablet is as follows: 500 mg of acetyl-DL-leucine, 88 mg of wheat starch, 88 mg of pregelatinized maize (corn) starch, 13 mg of calcium carbonate and 11 mg of magnesium stearate.

Before Tanganil® treatment. Prior to treatment with Tanganil®, the subject experienced the following symptoms for approximately 6-9 months.

• Headache attacks lasting from a few minutes to half an hour, approximately 4-6 days a week, 1-4 times a day.

• Sudden attacks of dizziness. During these attacks, rapid head movements often lead to severe dizziness within a few seconds. Approximately 1-3 days per week; 1-2 times a day.

• Nausea without any provocative factor within a few minutes - an hour. Nausea disappears when the patient lies down or with the application of heat. Approximately 4-6 days a week, usually in the evening.

• Pain in and around the eyes/eyes when looking up or too far to the left or right, sometimes lasting all day. Approximately once every two weeks.

Prior to this 6-9 month period prior to Tanganil® treatment, the subject occasionally experienced dizziness and nausea, but almost never headaches. After treatment with Tanganil®, the subject notices a change in about two and a half weeks; most symptoms occur only half as often. After four weeks of treatment, the subject notes

• less frequent headache attacks; about twice a week, usually in the morning;

• almost no sudden attacks of dizziness; approximately once every two weeks;

• almost no nausea; approximately once every two weeks;

• Pain in and around the eyes/eye sockets has completely disappeared.

After five months on a dosage of six tablets per day (2-2-2 per day), the patient's symptoms return and she experiences

• increased frequency of headaches, about every two days several times a week;

• increased frequency of vertigo attacks, usually due to headache;

• symptoms of nausea about once a week;

• increased frequency and severity of ocular pain, including sometimes severity when the patient cannot keep one eye open and intense pain when looking or focusing on an object.

The dosage is increased to 9 tablets per day (3-3-3 per day), the total dosage is 4.5 g per day. During a follow-up period of six months, the patient

• does not have any additional headache attacks;

• does not have any bouts of dizziness;

• had only two brief episodes of nausea;

• had only one episode of pain behind the eyes.

The quality of life improved significantly, so that the subject was able to successfully pass the final exams in high school. The patient's symptoms improved, especially in the last few weeks of this treatment period:

• pain in the eyes/eye sockets has completely disappeared;

• almost completely disappeared nausea.

The patient shows that her symptoms recur very infrequently and she experiences only occasional bouts of dizziness and headache associated with fatigue or stress on very hot days, which the patient attributes to her circulation. The patient shows that drinking water helps relieve these attacks.

Example 2

Case Study: Administration of Acetylleucine for Vestibular Migraine

Patient details

Female gender

Age 18

Treatment. Six Tanganil® tablets per day: two in the morning, two at noon and two in the evening. Tanganil® tablets are as described in Example 1.

Prior to Tanganil® treatment, the patient experienced the following symptoms: a total of approximately 50 dizzy spells over a period of four months, each lasting approximately 20 minutes, 30% of which were accompanied by headache. This resulted in sick leave for at least three days a week. Three weeks after starting treatment with Tanganil® (2-2-2 per day), the patient did not suffer from other attacks. Also, there were no further attacks for a period of 14 weeks from the start of treatment.

Example 3

Case Study: Administration of Acetylleucine for Migraine with Aura

Patient details

Gender male

Age: adult

Treatment. Ten Tanganil® tablets per day: four in the morning, three at noon and three in the evening. Tanganil® tablets are as described in Example 1.

Prior to Tanganil® treatment, the patient experienced the following symptoms for at least one year:

• attacks of left-sided headache lasting several hours, 20% of which were accompanied by a visual aura lasting about 5 minutes;

- frequency about once a week; respond to 600 mg ibuprofen taken once a week;

• isolated visual aura in the left half of the field, lasting approximately 5 minutes;

frequency about four times a month.

After starting Tanganil® treatment for a period of two months, the patient reported only one isolated visual aura, one visual aura with migraine headache, and one left-sided migraine headache. Treatment ended after two months. After discontinuing this two-month treatment period, for a subsequent 4-week period, the patient reported a marked increase in the number of attacks, including six migraine headache attacks, one with visual aura, and one isolated visual aura. Treatment was then restarted for about a year, during which time the patient experienced one migraine headache without aura about every two months and one migraine headache with aura about every three months. Then the treatment was stopped, and in the next six weeks the patient experienced five attacks of migraine headache and three attacks with aura.

Example 4

Case Study: Administration of Acetylleucine for Migraine and Vestibular Migraine

Patient details

Gender male

Age 54

Treatment. Six Tanganil® tablets per day: two in the morning, two at noon and two in the evening for one week, followed by ten Tanganil® tablets per day: four in the morning, three at noon and three in the evening. Tanganil® tablets are as described in Example 1.

Prior to Tanganil® treatment, the patient experienced the following symptoms for at least one year:

• migraine headache attacks almost every other day, without improvement from ibuprofer or aspirin; improvement with Novalgin;

• bouts of dizziness accompanied by headache, frequency about three times a week;

• on extended sick leave and with significant weight loss (12 kg).

After starting Tanganil® treatment (2-2-2 for one week, then 4-3-3 per day) for a period of 4 weeks, the patient reported no more headache attacks and did not require pain medication. The headache returned when the drug treatment was stopped for one day, so the treatment continued.

Example 5

Case Study: Administration of Acetylleucine for Migraine

Patient details

Gender male

Age 54

Treatment. Tanganil® tablets were administered per day as described in Example 4. Tanganil® tablets were as described in Example 1.

Prior to Tanganil® treatment, the patient had experienced the following symptoms for several years:

• headache attacks lasting three to four hours, with a frequency of approximately 20-25 headaches per month;

• migraine attacks lasting three to four hours, with a frequency of approximately three or four per month, and migraine attacks with aura once or twice a year.

During six months of treatment with Tanganil®, the patient reported a reduction in the frequency of headache attacks to approximately three per month and a reduction in the frequency of migraine attacks to approximately two per month. The patient experienced an improvement in symptoms within a couple of days of starting treatment.

The patient continued to take Tanganil® for six months and then stopped treatment for three months. At five weeks after stopping treatment, the patient experienced an increase in the frequency of migraine attacks to four per month. The patient resumed treatment with Tanganil® and after three months experienced a reduction in the frequency of migraine attacks to two per month.

Example 6

Case Study: Administration of Acetylleucine for Migraines

Patient details

Age 38

Treatment. Tanganil® tablets were administered per day as described in Example 4. Tanganil® tablets were as described in Example 1.

Prior to Tanganil® treatment, the patient had experienced the following symptoms for several years:

• migraine attacks without aura lasting approximately three days, with a frequency of approximately twice a month (approximately six migraine days per month);

• with migraine attacks accompanying symptoms, including sensitivity to sound and light and sometimes diarrhea before migraine initiation.

Prior to starting Tanganil® treatment, the patient had most recently been treated with rizatriptan and naproxen. During almost eight weeks of treatment with Tanganil®, the patient reported a reduction in the frequency of migraine attacks to approximately four with reduced duration. Two attacks lasted two days and two attacks lasted only one day, compared to three migraine days per attack experienced prior to Tanganil® treatment.

The patient continued treatment with Tanganil® and experienced a reduction in migraine days from 6 per month to 1.33 per month within four months of treatment.

Example 7

Case Study: Administration of Acetylleucine for Vestibular Migraine

Patient details

Female gender

Age 70

Treatment. Ten Tanganil® tablets per day: four in the morning, three at noon and three in the evening. Tanganil® tablets are as described in Example 1.

Prior to Tanganil® treatment, the patient had experienced the following symptoms for several years:

• migraine attacks with a frequency of approximately 3.3 per month;

• symptoms of dizziness with seizures.

After starting Tanganil® treatment for a period of eight months, the patient reported ten seizures in total and a reduction in seizure frequency from 3.3 per month to 1.25 per month. The patient reported that the attacks were shorter and less intense, including symptoms of dizziness.

The subject continues to take this dosage. The quality of life has improved significantly.

Example 8

Case Study: Administration of Acetylleucine for Migraines

Patient details

Gender male

Age 65

Treatment. Ten Tanganil® tablets per day: four in the morning, three at noon and three in the evening. Tanganil® tablets are as described in Example 1.

Prior to Tanganil® treatment, the patient had experienced the following symptoms for several years:

• migraine attacks with and without aura, including chronic migraine, with a frequency of approximately 20 per month;

• daily headaches were treated with regular administration of pain medications.

Before starting Tanganil® treatment, the patient was on a variety of medications, including an almost daily administration of pain medication as well as triptan therapy. After starting treatment with Tanganil®, the patient reported migraine-free weeks within two months for the first time in years and without the need for additional medication. The patient reported a reduction in the frequency of attacks from approximately 20 per month to five per month, for a total of approximately eight headache days per month.

The subject continues to take this dosage. The quality of life has improved significantly.

Example 9

Case Study: Administration of Acetylleucine for Migraines

Patient details

Female gender

Age 27

Treatment. Ten Tanganil® tablets per day: four in the morning, three at noon and three in the evening. Tanganil® tablets are as described in Example 1.

Prior to Tanganil® treatment, the patient had experienced the following symptoms for several years:

• migraine attacks without aura with a frequency of approximately 12 per month;

• almost daily headaches.

After starting Tanganil® treatment, the patient reported a reduction in the frequency of migraine attacks from approximately 12 per month to four per month and a reduction in migraine days per month to four.

The subject continues to take this dosage. The quality of life has improved significantly.

Example 10

Chinese Hamster Ovary (CHO) NPC cells are treated in vitro for 72 hours with 1 mM acetyl-DL-leucine, acetyl-L-leucine, acetyl-D-leucine, DL-leucine, L-leucine, and D-leucine, respectively. The relative volume of lysosomes is determined with the LysoTracker.

NPC CHO cells are observed to have increased levels of LysoTracker fluorescence relative to the wild type control, indicative of increased lysosome volume of the disease phenotype.

Treatment of NPC CHO cells with each of acetyl-DL-leucine, acetyl-L-leucine, acetyl-D-leucine, DL-leucine, L-leucine and D-leucine significantly reduces the volume of lysosomes in the cells. The data presented in figure 1 shows the results for each treatment, where the volume of lysosomes is expressed as a fold change relative to untreated wild-type fibroblasts. Asterisks (**) indicate p values <0.01 vs. untreated NPC1-nil.

The data show that leucine and acetyleucine show similar activity in vitro and both are associated with the rectification of impaired lysosomal accumulation by reducing the volume of lysosomes.

Various modifications and variations of the invention without departing from the scope and spirit of the invention will be apparent to those skilled in the art. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed in the claims should not be unduly limited to such specific embodiments. Indeed, various modifications of the described embodiments for carrying out the invention, which are obvious to those skilled in the related fields, are contemplated to be covered by the present invention.

Each of the patent documents and each of the scientific articles referenced in the present specification are incorporated herein by reference in their entirety.

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Claims (19)

1. A method of treating or preventing a migraine or one or more symptoms associated with a migraine in a subject, comprising administering to the subject a therapeutically or prophylactically effective amount of acetyleucine or a pharmaceutically acceptable salt thereof. 2. The method of claim 1, wherein the subject is a human. 3. The method of claim 1, wherein the acetyleucine or a pharmaceutically acceptable salt thereof reduces, alleviates, or eliminates one or more of the symptoms associated with migraine, including headache, fatigue, aura, nausea, vomiting, sensitivity to light, sensitivity to sound , sensitivity to smell, sweating, poor concentration, feeling hot, feeling cold, stomach pain or diarrhea. 4. The method of claim 3, wherein acetyleucine, or a pharmaceutically acceptable salt thereof, reduces, alleviates, or eliminates headache. 5. The method of claim 3, wherein acetyleucine, or a pharmaceutically acceptable salt thereof, reduces, alleviates, or eliminates aura. 6. The method according to claim 5, in which the aura occurs with a headache. 7. The method of claim 5, wherein the aura occurs in the absence of a headache. 8. The method of claim 5, wherein the acetyleucine, or a pharmaceutically acceptable salt thereof, reduces, alleviates, or eliminates one or more aura symptoms, including vision problems or blurred vision, numbness or tingling, dizziness, balance problems, movement problems, problems with speech or loss of consciousness. 9. The method of claim 5 wherein acetyleucine or a pharmaceutically acceptable salt thereof treats or prevents pain associated with migraine. 10. The method of claim 1 wherein the migraine is hemiplegic migraine. 11. The method of claim 1 wherein the migraine is sporadic hemiplegic migraine. 12. The method of claim 1 wherein the migraine is vestibular migraine. 13. The method of claim 1, wherein the migraine is a basilar-type migraine. 14. The method of claim 1 wherein the migraine is retinal migraine. 15. The method of claim 1 wherein the migraine is chronic migraine. 16. The method of claim 1 wherein the migraine is an episodic migraine. 17. The method of claim 1 wherein the acetyleucine is in racemic form. 18. The method of claim 1 wherein the acetyleucine is in the form of the L-enantiomer in enantiomeric excess. 19. The method of claim 1 wherein acetyleucine is administered at a dose of about 500 mg to about 15 g per day.

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