WO2014203696A1

WO2014203696A1 - Anti-epileptic drug

Info

Publication number: WO2014203696A1
Application number: PCT/JP2014/064120
Authority: WO
Inventors: 大内田　守; 伊織大守
Original assignee: 国立大学法人岡山大学
Priority date: 2013-06-20
Filing date: 2014-05-28
Publication date: 2014-12-24
Also published as: JPWO2014203696A1; JP6587299B2; JP2018203782A

Abstract

Provided is a novel anti-epileptic drug for the prevention and/or treatment of epileptic seizures that has a mode of action different from that of conventional anti-epileptic drugs. The anti-epileptic drug comprises as the active ingredient methylphenidate and/or a pharmaceutically acceptable salt thereof.

Description

Antiepileptic drugs

The present invention relates to treatment of seizures in epileptic patients, and more particularly to an antiepileptic drug that can be used for the prevention and / or treatment of epileptic seizures and the use thereof.

This application claims the priority of Japanese application No. 2013-129364, which is incorporated herein by reference.

Epilepsy has a prevalence rate of about 8 to 10 people per 1000 people, which is a common disease among neurological diseases. The main symptoms of epilepsy include convulsions (involuntary movements such as tonicity or clonicity) and absence seizures without convulsions (loss of consciousness). In recent years, the cause of epilepsy has been identified by the development of molecular genetics research. As a result, the relationship between epilepsy and various channel genes has been clarified, and some epilepsy syndromes have been considered as so-called channel diseases that develop due to channel gene mutations. In particular, mutations such as voltage-dependent Ca ²⁺ channels, voltage-dependent Na ⁺ channels, and K ⁺ channels have been detected in epileptic patients.

Febrile seizure is a disease with a high incidence that occurs in about 8% of children. Febrile seizures are generalized seizures that last for 1 to 5 minutes, mainly due to fever of 38 ° C or higher due to viral infections such as the common cold or bacterial infections. It develops from 6 months to about 5 years of age, and the majority of cases are cured by age 6. For this reason, active treatment is often unnecessary, and as a rule, it is a benign disease. However, among patients with febrile seizures that develop before the age of 1 year, in addition to patients with benign diseases that begin with febrile seizures, patients with persistent seizures after 6 years of age, Dravet syndrome (also known as infantile severe myoclonic epilepsy (Severe) Myoclonic Epilepsy in Infancy (SMEI)) is a mixture of patients with intractable epilepsy.

In today's clinical setting, how to control epileptic seizures is an important issue in treating epilepsy patients. Therefore, a therapeutic strategy is established, in which drug therapy using an antiepileptic drug is given priority. To date, antiepileptic drugs such as phenobarbital (PB), phenytoin (PHT), ethosuximide (ESM), acetazolamide (AZA), clonazepam (CZP), sodium valproate (VPA), and carbamazepine (CBZ) have been marketed. ing. However, in these drug therapies, there are so-called refractory epilepsy that makes it difficult to control seizures due to drug resistance with existing antiepileptic drugs, so it is necessary to use multiple antiepileptic drugs in combination over a long period of time. There is a problem that it must be done. Furthermore, many patients are forced to discontinue administration due to side effects caused by antiepileptic drugs. For example, CBZ, which is often used for partial seizures, has side effects such as liver dysfunction, sleepiness, and skin rash, and VPA, which is often used for general seizures, is liver dysfunction, thrombocytopenia, weight gain, tremor, Side effects such as hair loss can be mentioned, and these side effects have become a very serious problem particularly in pediatric epilepsy patients.

About 80% of patients with refractory Dravet syndrome and about 5-10% of patients with benign generalized epilepsy febrile seizure plus (GEFS +) have voltage-dependent sodium ion channel α1 subunit SCN1A gene mutations It has been found that SCN1A gene mutation is involved in the development of febrile seizures (Non-patent Documents 1-3).

In view of the above, it is desired to develop a new antiepileptic drug capable of enhancing antiepileptic action and improving side effects.

Methylphenidate is a central nervous system stimulant used for patients with attention deficit / hyperactivity disorder (ADHD) and narcolepsy (a brain disorder whose main symptom is a strong sleepiness attack). In general, about 10% of ADHD patients are known to have epilepsy. However, it has been reported that when methylphenidate is administered to an ADHD patient with epilepsy, the ADHD treatment is effective, but the seizure frequency of epilepsy deteriorates (Non-patent Document 4). There are no reports of mutations in the SCN1A gene in ADHD patients.

An object of the present invention is to provide a new antiepileptic drug having a mechanism of action different from that of conventional antiepileptic drugs for diseases accompanied by epileptic seizures.

The present inventors have focused on methylphenidate preparations in order to solve the above problems, and as a result of intensive studies, they have found that the onset of epileptic seizures can be suppressed and reduced, and the present invention has been completed.

That is, this invention consists of the following.
1. An antiepileptic drug for preventing and / or treating epileptic seizures, comprising methylphenidate and / or a pharmaceutically acceptable salt thereof as an active ingredient.
2. 2. The antiepileptic drug according to item 1, wherein the epilepsy is epilepsy caused by a mutant SCN1A gene.
3. 3. The antiepileptic drug according to item 1 or 2, wherein the epileptic seizure is a seizure seizure.

4). A method for preventing and / or treating epileptic seizures, comprising administering methylphenidate and / or a pharmaceutically acceptable salt thereof.
5. A method for preventing and / or treating epileptic seizures, comprising administering 0.05 to 5 mg / kg of methylphenidate and / or a pharmaceutically acceptable salt thereof per day.
6). A method for preventing and / or treating epileptic seizures, comprising administering 0.05 to 5 mg / kg of methylphenidate and / or a pharmaceutically acceptable salt thereof when in use.

The antiepileptic drug containing methylphenidate and / or a pharmaceutically acceptable salt thereof of the present invention as an active ingredient can confirm the effect of suppressing seizures and is useful for the prevention and / or treatment of epileptic seizures. It was considered.

It is a figure which shows the result of having confirmed the inhibitory effect of the febrile seizure by methylphenidate (MPH) about the model rat by the electroencephalogram. Example 1 It is a figure which shows the result of having confirmed the inhibitory effect of the febrile seizure attack by MPH by the seizure frequency about the model rat. Example 1 It is a figure which shows the result which confirmed the suppression effect of the febrile seizure attack by MPH by the duration of the attack about the model rat. Example 1 It is a figure which shows the result of having confirmed the inhibitory effect of the febrile seizure attack by MPH in the model rat by the time to seizure induction. Example 1 It is a figure which shows the result of having confirmed the inhibitory effect of the febrile seizure attack by MPH by the rectal temperature at the time of an attack about a model rat. Example 1

It relates to an antiepileptic drug for the prevention and / or treatment of epileptic seizures, comprising methylphenidate and / or a pharmaceutically acceptable salt thereof as an active ingredient.

Examples of pharmaceutically acceptable salts of methylphenidate include salts with inorganic bases (for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salt), Salts with organic bases (eg, organic amine salts such as triethylamine salt, diisopropylethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, etc. ), Inorganic acid addition salts (eg, hydrochloride, hydrobromide, sulfate, phosphate, etc.), organic carboxylic acids or sulfonic acid addition salts (eg, formate, acetate, trifluoroacetate, maleic acid) Salt, tartrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.), salt Sex or acidic amino acids (e.g., arginine, aspartic acid, glutamic acid, etc.), such as salts with, salts or acid addition salts with bases.

When the antiepileptic drug of the present invention is administered to a living body, it is preferably formulated into an appropriate dosage form and used, for example, tablets, powders, granules, fine granules, pills, capsules, solutions, emulsions, suspensions. It can be used in preparations such as suppositories, suppositories, syrups, lotions, ointments and poultices. Formulation into these dosage forms can be performed using appropriate pharmaceutically acceptable carriers, excipients, additives and the like.

For example, a preferred dosage form for intravenous administration is a liquid preparation. For example, purified water, physiological saline, alcohols such as ethanol, propylene glycol, glycerin, and polyethylene glycol, and a solvent such as triacetin are used. Can be done. Such preparations may further contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents and stabilizers. It can also be administered as a suspension.

In order to prepare solid preparations such as tablets, pills, powders, granules, and fine granules, for example, sodium bicarbonate, calcium carbonate, starch, sucrose, mannitol, carboxymethylcellulose and other carriers, calcium stearate, stearic acid It can be carried out by a conventional method by adding additives such as magnesium and glycerin. Also, enteric coatings are sprayed by spraying organic solvents or water solutions of enteric substances such as cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol phthalate, styrene-maleic anhydride copolymer, methacrylic acid-methyl methacrylate copolymer, etc. Can be formulated as an enteric preparation. The pharmaceutically acceptable carrier includes other auxiliary agents, fragrances, stabilizers, or preservatives that are usually used as necessary.

A pharmaceutical composition comprising methylphenidate and / or a pharmaceutically acceptable salt thereof as an active ingredient is suitable for attention deficit / hyperactivity disorder (ADHD) in childhood, as shown in the background section. There is a report. Regarding the dosage form and administration system when a pharmaceutical composition containing methylphenidate and / or a pharmaceutically acceptable salt thereof as an active ingredient is used as the antiepileptic drug of the present invention, a method known per se or a future development will be carried out. Any method can be applied.

Epilepsy in this specification is a chronic brain disease caused by various etiologies, and is characterized by recurrent seizures (epileptic seizures, seizures) derived from excessive discharge of cerebral neurons, and it is also rich in mutations. It refers to a disease or symptom accompanied by presentation of clinical and laboratory findings. The term epilepsy syndrome is a syndrome characterized by signs, symptoms combinations, etiology, triggering factors, age of onset, severity, and chronicity that accompany each time. It is also called electroencephalogram / clinical syndrome (Electroclinical syndrome), and includes young myoclonic epilepsy, West syndrome, Lennox-Gastaut syndrome, and so on.

Epilepsy seizures are broadly divided into general seizures and partial seizures. Examples of generalized seizures include tonic-clonic seizures, simple absence seizures, complex absence seizures (eg, other symptoms in addition to consciousness disorders, seizures with automatism or myoclonic seizures), point-to-point seizures, weakness seizures Etc. Examples of partial seizures include simple partial seizures and complex partial seizures, as well as secondary generalized seizures that start from partial seizures and cause generalized seizures. Examples of epileptic seizures in the present invention include tonic clonic seizures among the above-mentioned seizures. As a symptom of a tonic-clonic seizure, for example, convulsion can be mentioned. The convulsions are as described in the background section above. The seizures in the present invention are specific to seizures occurring in epileptic patients, and examples include seizures found in intractable epilepsy called Dravet syndrome (SMEI) and generalized epileptic febrile seizure plus (GEFS +).

Examples of epilepsy applied in the present invention include epilepsy accompanied by mutation of voltage-dependent sodium ion channel α1 subunit SCN1A gene among epilepsy, such as Dravet syndrome (SMEI) and generalized epileptic febrile seizure plus (GEFS +). . In addition, regarding epilepsy, the antiepileptic agent of the present invention can be used when it is recognized that the epilepsy is accompanied by the mutant SCN1A gene even if it is not diagnosed as Dravet syndrome or general epileptic febrile seizure plus. .

The method for determining the possibility of Dravet syndrome (SMEI) is not particularly limited, but for example, the method shown in Japanese Patent No. 4461263 can be applied. Specifically, for example, the determination can be made by calculating the following (a) to (i) as the risk score.
(A) Has experience of convulsions of the body (b) Has experience of convulsions (c) Has 5 or more seizures (d) Onset of thermal convulsions is less than 8 months old (e) Induction of convulsions by bathing (F) SCN1A gene truncation mutation exists (g) Partial seizure experience (h) SCN1A gene missense mutation exists (i) Myoclonic seizure experience

Among the above (a) to (i), the case where a mutation of the SCN1A gene is particularly preferred is mentioned, and the mutation may be either a truncation mutation or a missense mutation. As a method for analyzing mutations in the SCN1A gene, methods known per se, for example, the method shown in Japanese Patent No. 4461263 and all methods developed in the future can be applied in the field of genetic diagnosis.

The effective amount of methylphenidate and / or pharmaceutically acceptable salt thereof depends on the patient's age, weight, severity of symptoms, type of drug salt, etc. In this case, it is 0.05 to 5 mg / kg per day for both children and adults, preferably 0.1 to 3 mg / kg, more preferably 0.5 to 2 mg / kg.

The present invention can also be applied to a method for preventing epilepsy seizures and / or a method for treating epileptic seizures by using a pharmaceutical composition containing methylphenidate and / or a pharmaceutically acceptable salt thereof as an active ingredient. In the method for preventing epilepsy seizures and / or the method for treating epilepsy seizures, methylphenidate and / or a pharmaceutically acceptable salt thereof can be administered at 0.05 to 5 mg / kg per day. In addition, methylphenidate and / or a pharmaceutically acceptable salt thereof can be administered at a dose of 0.05 to 5 mg / kg. The administration method varies depending on symptoms and preparations, but when the action time of the active ingredient is short due to the dosage form of a pharmaceutical composition containing methylphenidate and / or a pharmaceutically acceptable salt thereof as an active ingredient, It can be taken 3 to 4 times a day, and can be selected as appropriate, such as twice a day or once a day if the active ingredient has a long action time. In addition, the antiepileptic agent of the present invention can be used in combination with an antiepileptic agent known per se or developed in the future when it is recognized that the antiepileptic agent is safe for living bodies.

When the antiepileptic drug of the present invention is administered for the prevention and / or treatment of epileptic seizures, it is orally or rectal, subcutaneous, intrathecal, intramuscular, intravenous, intraarterial, transdermal, etc. It can be administered parenterally.

In order to help understanding of the present invention, reference examples and examples will be shown and described in detail, but it goes without saying that the present invention is not limited thereto.

(Example 1) Inhibitory effect of convulsive seizure by methylphenidate In this example, a rat (Kyo811) having a mutation in the Scn1a gene is treated with methylphenidate (MPH) against hot spasm caused by a hot bath load. The effect was confirmed.

1. Preparation of Scn1a gene mutant rat (fever convulsion model rat) Non-patent document 3 (J Neurosci. 2010 Apr 21; 30 (16): 5744-53. Doi: 10.1523 / JNEUROSCI) .3360-09.2010.). In other words, a mutagen (N-nitro-N-ethylurea; ENU) was introduced into the abdominal cavity of male F344 rats, artificial mutations were introduced into the sperm DNA, sperm was extracted, and the resulting sperm A rat having a mutation in the voltage-dependent sodium ion channel Scn1a gene was prepared by a technique of artificial insemination (intracytoplasmic sperm injection) into an egg of a female rat.

As a result of genetic analysis, in the Kyo811 rat, the 4251st nucleotide “A” of the Scn1a gene was mutated to “C”, and as a result, asparagine (AAT), the 1417th amino acid, was changed to histidine (CAT). (N1417H). The 1417th asparagine is located in the pore-forming region involved in the ion permeation of the third domain of the sodium ion channel. As a result of functional analysis of the mutant voltage-dependent sodium channel, N1417H mutant sodium ion channel has abnormal channel function. It became clear that it was easy to cause convulsion. This mutant homozygous rat is a very useful rat as a model of thermal convulsions caused by warm bath load because it causes thermal convulsions after 3-4 minutes in a 45 ° C warm bath. Known as (GEFS +) model rat.

2. Confirmation of the effect of methylphenidate (MPH) 5 week-old Scn1a gene mutant rats (thermoconvulsive model rats) were treated with methylphenidate (MPH) at 0.5 mg / kg (14 animals) and 2 mg / kg (15 animals). It was administered internally. The control group received saline (Saline) (14 animals). One hour after drug administration, 45 ° C bathing was applied, and (1) EEG during seizure, (2) seizure frequency, (3) seizure duration, (4) time to induce seizure, and (5) Rectal temperature at the time of the seizure was measured. When the seizure occurred, the rat was removed from the warm bath. If no seizure occurred, the warm bath was stopped for 5 minutes (ie, the maximum time to induce a seizure (300 seconds)).

As a result, the results shown in FIGS. 1 to 5 were obtained.
(1) In the EEG during seizure, significant suppression of EEG during seizure was observed by administration of methylphenidate (MPH) (lower) compared to saline (Saline) administration (upper). (Figure 1)
(2) A decrease in seizure frequency was observed with MPH administration. (Figure 2)
(3) Significant shortening of seizure duration by MPH administration was observed. (Figure 3)
(4) Prolonged time required for the appearance of seizures due to MPH administration was observed. (Fig. 4)
(5) An increase in rectal temperature at the time of occurrence of a seizure, that is, a seizure induction threshold, was observed due to MPH administration. In other words, it became clear that seizures are unlikely to occur at the same temperature after MPH administration. (Fig. 5)

≥80% of intractable epilepsy Dravet syndrome and approximately 5-10% of patients with generalized epilepsy febrile seizures are thought to have SCN1A gene abnormalities. It was found that epileptic seizures in febrile convulsion model rats having a mutation in the Scn1a gene can be suppressed by taking the antiepileptic drug of the present invention, that is, a methylphenidate preparation (a drug for treating hyperactivity disorder and a drug for treating narcolepsy). Thus, the methylphenidate formulation was considered useful for the prevention and / or treatment of seizures associated with seizures. If the antiepileptic drug of the present invention can be used, options for a method for preventing and / or treating epileptic seizures can be increased. For example, side effects caused by existing antiepileptic drugs can be reduced.

Claims

An antiepileptic drug for preventing and / or treating epileptic seizures, comprising methylphenidate and / or a pharmaceutically acceptable salt thereof as an active ingredient.
The antiepileptic drug according to claim 1, wherein the epilepsy is epilepsy caused by a mutant SCN1A gene.
The antiepileptic drug according to claim 1 or 2, wherein the epileptic seizure is a seizure seizure.