JP4581277B2 - Pharmaceutical composition for suppressing unintentional behavior, and use of a running neuron inhibitor for producing the pharmaceutical composition - Google Patents

Description

【００２０】
同様の実験を行い、一般症状を観察したところ注意すべき点は見いだされなかったため、GABAは徘徊行動に特異的に作用していると考えられた。これらの結果から、ランニングニューロン抑制物質（GABAアゴニスト，カイニン酸型グルタミン酸受容体アゴニスト）による徘徊・多動症治療の可能性が示された。
【００２１】
【発明の効果】
本発明の医薬組成物を使用することにより、意図的運動を抑制することなく、徘徊、多動等の非意図的運動を抑制することができる。また、本発明の使用により、徘徊、多動等の非意図的運動を抑制するための治療薬を製造することができる。
【図面の簡単な説明】
【図１】GABA_B受容体アゴニストSKF97541を腹腔内に投与し、投与前後の夜間の走行量・摂食量の変化を対照群と比較したものである。縦軸は投与前後の走行量の比を示す。
【図２】GABA_B受容体アゴニスト投与および対照ラットの強制水泳実験の結果を示すグラフである。縦軸は5分間あたりにラットが前足で水をかく回数を表す。
【図３】視床下部腹内側核破壊群ラット及び対照群ラットの走行量の測定結果を示すグラフである。
【図４】視床下部腹内側核破壊群ラット及び対照群ラットの強制水泳実験の結果を示すグラフである。縦軸は10分間あたりにラットが前足をかく回数を示す。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to pharmaceutical compositions for the treatment of symptoms associated with unintentional movements, in particular epilepsy, hyperactivity and pharmaceutical compositions comprising running neuron inhibitors and the use of running neuron inhibitors.
[0002]
[Prior art]
In some vertebrates, such as humans, dogs, and cats, epilepsy, particularly nocturnal epilepsy, and hyperactivity, including attention deficit hyperactivity syndrome (ADHD), can be problematic. Acupuncture and hyperactivity are generally considered to require psychiatric treatment, and in particular, elderly acupuncture was thought to be closely associated with Alzheimer-type senile dementia.
Such a condition is often problematic for the patient himself, especially for patients suffering from other illnesses, as well as being physically harmful to the surrounding people. Here, acupuncture refers to “waving away from home due to pathological urges” and “uncontrollable urge to wander and travel” (Stedman Medical Dictionary Revision 2nd Edition, 1989, Medical View) "Hyperactivity" or "hyperactivity syndrome" is a concept that includes "symptoms characterized by morbid excess energy", such as "small children with brain damage and intellectual deficits and epilepsy." It is a syndrome that has been said to be “sometimes seen” (The University of Medicine Dictionary). In addition, hyperactivity has been mainly characterized by excessive exercise and emotional instability (The Medical Dictionary). It is known that such symptoms are also seen in dogs. As suggested by the above description, abnormal behavior in these patients has been considered intentional.
[0003]
Therefore, antipsychotics, hypnotics, or muscle relaxants that suppress systemic movements of patients have been used to treat such symptoms. However, such drugs cause new problems such as consciousness turbidity and generalized muscle relaxation. Furthermore, as a confronting treatment for epilepsy and hyperactivity, there are cases where it is unavoidable to physically take away the patient's freedom, such as fixing to a bed or confinement, but these naturally cause great pain to the patient. Is. In any case, the therapies or drugs known so far are mainly those that deprive the patient of systemic freedom or deliberate freedom of action, and significantly improve the patient's quality of life. It was detrimental.
[0004]
On the other hand, independent of such clinical research, various studies have been conducted focusing on the running movement of rats, particularly the night running movement, in research on nerves. For example, it has been reported by the present inventors that when the rat hypothalamic ventral nucleus (hereinafter abbreviated as VMH) is stimulated by a water-absorbing polymer, the running motion of the rat is induced by the pressure stimulation (Yokawa et al. Physiology & Behavior (1989), 46, 713-717). In this report, it is shown that the signal from VMH is necessary for the running movement of the rat because the excision of running movement by the polymer does not occur when the VMH periphery is excised. Furthermore, the present inventors have shown that induction of rat running movement by the aforementioned polymer is suppressed by administering GABA (γ-aminobutyric acid) to the polymer (Yokawa et al., Physiol. & Behav ( 1990), 47, 1261-1264).
[0005]
It has also been reported by the present inventors that the running movement of rats is also induced by a kainate glutamate receptor agonist (Narita et al., Brain Res. (1993), 603, 243-247). According to this report, kainic acid induced the running movement of rats, and this running movement was not suppressed by GABA, and the kainic acid glutamate receptor antagonist DNQX (6,7-dinitroquinoxaline-2,3 -Dione) (6,7-dinitroquinoxaline-2,3-dione) is suppressed. This means that the neurons that control the running movement of the rat are stimulated via the kainate glutamate receptor, and that the GABA _A receptor exerts presynaptic inhibition on the kainate glutamate receptor. This suggests that the neurons that control the running movement of rats more indirectly can be suppressed by applying.
On the other hand, for GABA _B receptor, a substance having antagonistic inhibitory activity against this receptor is reported to be useful for treatment of convulsive diseases, Alzheimer's treatment, and memory-lowering diseases (Japanese Patent Laid-Open No. 4-243853). .
[0006]
[Problems to be solved by the invention]
An object of the present invention is to provide a pharmaceutical composition that suppresses unintentional behavior and does not suppress intentional behavior. In particular, an object of the present invention is to provide a pharmaceutical composition that can treat epilepsy, hyperactivity, and the like. Another object of the present invention is to provide a method of using a substance that suppresses running neurons.
[0007]
[Means for Solving the Problems]
As described above, the present inventors have suggested that there is a neuron in VMH that strongly suggests that it is involved in the running movement of rats, particularly the night running movement. Noting that these behaviors in rats are neither reflex nor intentional, we named this neuron present in VMH as a running neuron or a running neuron and governed unintentional movement in the rat. It is concluded that it is a neuron. Here, in rats, running neurons are present in VMH as described above. From the viewpoint of phylogeny, the hypothalamus containing VMH is the lower center, and this region is thought to be well conserved in vertebrates. ing. From this, the present inventors consider that running neurons are also present in other vertebrates including humans and dogs. In addition, we clinically know that patients who have hemorrhoids usually explain that their behavior is irrational or that they have forgotten or did not intend to have it. And that hyperactivity is considered to be clinically unintentional, and behaviors such as epilepsy and hyperactivity in humans and some vertebrates have traditionally been “intentional behavior”. Contrary to what was thought to be “unintentional behavior”, we were convinced of the existence of running neurons in vertebrates other than rats, such as humans and dogs, and input, trapping, and hyperactivity And so on. That is, the present inventors have invented a pharmaceutical composition and method that suppresses behavior such as wrinkles and hyperactivity and does not suppress intentional movement by suppressing output to running neurons.
That is, the present invention is a pharmaceutical composition for treating a symptom associated with unintentional movement such as epilepsy and hyperactivity, which contains a substance that suppresses running neurons before or after synapse.
The present invention also relates to the use of a substance that inhibits running neurons in a pre-synaptic or post-synaptic manner for producing a pharmaceutical composition for the treatment of symptoms associated with unintentional movements such as epilepsy and hyperactivity.
In particular, the present invention includes a GABA _B receptor agonist, a GABA _A receptor agonist, a substance that enhances the action of GABA _A receptor, a substance selected from the group consisting of kainate-type glutamate receptor antagonists, or a combination thereof. The present invention relates to a pharmaceutical composition for treating symptoms accompanied by unintentional movements such as epilepsy and hyperactivity, and to use these pharmaceutical compositions for the treatment of symptoms involving unintentional movements such as epilepsy and hyperactivity. .
[0008]
DETAILED DESCRIPTION OF THE INVENTION
The pharmaceutical compositions comprising one or more running neuron inhibitors of the present invention or the use of the running neuron inhibitors for the production of these pharmaceutical compositions can generally be used for symptoms involving unintentional behavior. In particular, it is preferably used for symptoms accompanied by unintentional forward movement such as epilepsy and hyperactivity. Running neuron inhibitory substances that can be used in the present invention include GABA _B receptor agonists, GABA _A receptor agonists, GABA _A receptor enhancers (substances that act on GABA _A receptors and enhance their effects), kainic acid type Glutamate receptor antagonists, and combinations thereof are included. More specifically, in addition to GABA, as GABA _A receptor agonists, isogubacin (1,2,3,6-tetrahydro-4-pyridinecarboxylic acid) (1,2,3,6-tetrahydro-4-pyridinecarboxylic acid) ), Muscimol (5-aminomethyl-3-hydroxyisoxazole), THIP (4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-3 -Ol) (4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol) etc. as a GABA _B receptor agonist, baclofen (4-amino-3- (4-chlorophenyl) butane Acid (4-amino-3- (4-chlorophenyl) butanoic acid), SKF97541 (3-aminopropyl (methyl) phosphinic acid), etc. as GABA _A receptor potentiators Benzodiazepine (benzodiazepine) and the like as a kainate glutamate receptor antagonist, CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), C NQX disodium salt (6-cyano-7-nitroquinoxaline-2,3-dione disodium), DNQX, GAMS (γ-D-glutamylaminomethyl) Sulfonic acid) (γ-D-glutamylaminomethylsulphonic acid), NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo [f] quinoxaline-7-sulfonamide) (2,3-dioxo -6-nitro-1,2,3-4-tetrahydrobenzo [f] quinoxaline-7-sulphonamide), NBQX disodium salt (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo [ f] quinoxaline-7-sulfonamide disodium) (2,3-dioxo-6-nitro-1,2,3-4-tetrahydrobenzo [f] quinoxaline-7-sulphonamide disodium) It is not limited to.
[0009]
Bioassays can be used to determine whether a given substance has a running neuron inhibitory effect. For example, a cannula guided by a 26 gauge stainless steel needle is implanted in the rat's VMH and the rat is left for at least about 7 days for surgical recovery. After the recovery period, about 100 pmol kainic acid in about 0.5 μl saline can be injected through the internal cannula to see if the inserted cannula is hitting the running neuron. Rats that did not show running motion, ie, rats that did not respond to this treatment, can be excluded from further experiments. After 3 days, kainic acid (about 100 pmol) and the expected inhibitor (about 50 pmol to about 50 nmol) can be infused through the cannula. When a substance injected simultaneously with kainic acid reduces or eliminates kainic acid-induced running motion, the substance can be recognized as a running neuron inhibitor.
[0010]
The pharmaceutical composition of the present invention may be administered orally or parenterally, but in general, oral administration is preferred. Parenteral administration includes transdermal, ophthalmic, administration by inhalation, nasal administration, and intraperitoneal administration. The dosage is determined according to the patient's age, symptoms, general health condition, weight, treatment plan, desired effect, and the like. As a daily dose, the pharmaceutical composition of the present invention is administered at a dose of about 0.1 mg / kg body weight to about 500 mg / kg body weight, preferably 1 mg / kg when the active ingredient, i.e., the running neuron inhibitor, is orally administered. It is prepared to be administered at a dose of kg body weight to 100 mg / kg body weight, more preferably 10 mg / kg body weight to 50 mg / kg body weight, or about 0.001 mg / kg body weight to about 200 mg / kg for parenteral administration. It is prepared and administered to be administered at a dose of kg body weight, preferably 0.005 mg / kg body weight to 20 mg / kg body weight, more preferably 0.05 mg / kg body weight to 2 mg / kg body weight.
[0011]
The pharmaceutical composition of the present invention is generally administered about 1 to 6 times per day, preferably about 1 to 3 times per day. The pharmaceutical composition of the present invention may be administered continuously over a long period of time. However, when the time and period in which the symptom appears strongly is limited, it may be administered only a limited number of times depending on the symptom in that time or period. In any case, when used in combination with other therapeutic agents or treatment methods, the dosage of the pharmaceutical composition is adjusted according to the amount and nature thereof. For example, when used in combination with an antipsychotic, the dosage of the pharmaceutical composition of the present invention is appropriately reduced accordingly.
When the pharmaceutical composition of the present invention is orally administered, general dosage forms such as tablets, capsules, powders, granules, syrups and suspensions can be used. When administered parenterally, sterilized forms for injection or eye drops, aerosols for inhalation and the like can be used.
[0012]
The pharmaceutical composition of the present invention contains a physiologically acceptable excipient. The pharmaceutical composition of the present invention may further contain a fragrance, a colorant, a disintegrant, a preservative for stabilization, a suspending agent, an emulsifier, a lubricant and the like, if necessary. In particular, when administered parenterally, the osmotic pressure of the pharmaceutical composition of the present invention may be adjusted as necessary. As such excipients and additional substances, pharmaceutically and physiologically acceptable common substances can be used, for example, sugars such as lactose, galactose, starches such as corn starch, stearins Fatty acid salts such as magnesium acid, alginic acid, talc, polyethylene glycol and the like are included.
[0013]
The pharmaceutical composition of the present invention may contain about 1 to 95% by weight or more, preferably about 10 to about 80% by weight of the total mass of the running neuron inhibitor as its active ingredient. The proportion of the running neuron inhibitor can be selected according to the form of the pharmaceutical composition of the present invention, the intended effect, and the total amount of the pharmaceutical composition to be administered. Particularly in the case of oral administration, the pharmaceutical composition of the present invention contains 1 to 95% by weight, preferably 10 to 80% by weight, more preferably 20 to 70% by weight, particularly preferably about 20 to about 60% by weight. When included in the diet, the running neuron inhibitor is generally contained in a proportion of about 0.001 to 10% by mass, preferably 0.01 to 1% by mass of the total amount. For parenteral administration, the pharmaceutical composition of the invention generally comprises a running neuron inhibitor in a proportion of about 0.01-30% by weight, preferably 0.05-20% by weight of the total amount. In any case, when a plurality of running neuron inhibitory substances are included, the amount of each running neuron inhibitory substance can be adjusted according to the action effect.
The pharmaceutical composition of the present invention is generally used in mammals including humans, such as man, dog, cat, or domestic animals such as cattle and pigs, exhibiting psychiatric disorders with unintentional behavior such as epilepsy and hyperactivity. Can be used for treatment of various symptoms. In addition, the running neuron inhibitor can be used to produce a pharmaceutical composition for suppressing unintentional behavior such as wrinkles and hyperactivity in mammals including humans.
[0014]
【Example】
Example 1: Effect of GABA _B receptor agonist SKF97541 on unintentional behavior Seven-week-old rats (Wistar Imamichi) were raised in cages with running wheels. The lighting conditions were 7 o'clock on and 19 o'clock off, and food and water were freely consumed. The animals were reared without treatment for 3 weeks, and were treated after they had become fully caged. At this time, the amount of travel at night was almost constant.
Treatment was performed by administering the GABA _B receptor agonist SKF97541 at 1.0 mg / kg or 0.5 mg / kg intraperitoneally around 18:00. As a control group, a physiological saline administration group was used. Percentage after treatment when the count of the sensor with the running wheel attached is taken into the computer every 30 minutes, the nighttime integrated count is defined as the amount of behavior at night, and the count before treatment for each individual is 1 Was calculated.
The result is shown in FIG. As is clear from FIG. 1, the SKF97541 0.5 mg / kg administration group showed an inhibitory effect of about 40 to 60% with respect to the control group. In the SKF97541 1.0 mg / kg administration group, an inhibitory effect of about 70% was observed. From these results, it was revealed that GABA _B receptor agonists had a significant effect on the night running amount of rats, and the effect was dose-dependent.
[0015]
Example 2: Effect of GABA _B receptor agonist SKF97541 on intentional behavior GABA _B receptor agonist SKF97541 0.5 mg / kg was intraperitoneally administered to rats reared in the same manner as in Example 1, and 30 to 3 minutes after administration. After a time, the rats were placed in 35 ° C-37 ° C water. A container having a depth of 55 cm, a height from the water surface to the top of the container of 30 cm, and a cross-sectional area of 1200 cm ² was used. Rats were forced to swim in the pool, and the number of times their water was drained with their front paws per 5 minutes was measured. As a control group, a group administered with physiological saline was used.
As a result, it has been clarified that the frequency of watering, which is an intentional exercise, is not reduced by the GABA _B receptor agonist (FIG. 2). This indicates that GABA _B receptor agonists have little effect on intentional movement.
[0016]
Example 3: Analysis of the action of running neurons on unintentional behavior For rats reared in the same manner as in Example 1, the hypothalamic ventral medial nuclei on both sides of the rats were destroyed and the amount of travel was measured.
The lead wire coated with Deflon was passed through a glass tube (inner diameter 0.6 mm) and outer diameter 1.0 mm, and the upper end of the glass tube was fixed with an adhesive (Aron Alpha) to fix the lead wire and the glass tube. A 0.5 mm wire was drawn from the lower end of the glass tube, the coating on that part was peeled off, and the lower end of the glass tube was fixed with a putty. What was produced by the above was made into the electrode for destruction. The electrodes and the rats reared as described above were anesthetized with pentobarbital, fixed to a stereotaxic apparatus, and the hypothalamic medial nuclei on both sides were destroyed according to the Paxinos and Watson brain map.
A current of 5 mA was passed through the isolator for 10 seconds. At this time, the negative pole of the isolator was connected to the electrode, and the positive pole was connected to the forelimb of the rat. In addition, by inserting an electrode into the hypothalamic ventral nucleus, leaving the electrode undisturbed for 60 seconds without passing an electric current as a control group, using a rat that electrically destroyed the hypothalamic ventral nucleus, Daily travel was measured. In addition, the day of destruction was defined as day 0.
The count of the sensor attached to the running wheel is taken into the computer every 30 minutes, the 24-hour cumulative count is defined as the amount of action at night, and the percentage after treatment when the count before treatment is 1 for each individual is calculated. did. As a result, it was found that the daily running amount in the hypothalamic ventral nucleus destruction group was significantly reduced compared to the control group (Fig. 3).
[0017]
Example 4: Analysis of the effect of running neurons on intentional behavior In the same manner as in Example 3, a rat in which the hypothalamic ventral medial nucleus was electrically destroyed was used to perform a forced swimming experiment. The forced swimming experiment was performed in the same manner as in Example 2. The control group was selected in the same manner as in Example 3. As a result, in the hypothalamic ventral medial nucleus destruction group, it was shown that the number of times the rats put their front paws in water was not different from the control group (FIG. 4). This means that intentional movement is not inhibited in the hypothalamic ventral medial nucleus destruction group, that is, the running neuron destruction group.
[0018]
Embodiment 5 FIG. Effect of GABA administration on sputum An 11 year old male Pomeranian was used. This experimental dog has dementia and is confirmed to have phlegm. On the 1st, we gave canned dogs (maintenance beef cans, Nihon Hills Colgate Co., Ltd.) about 200g in two mornings and evenings. Water was given freely.
The experiment was conducted in a room with air conditioning at room temperature of 22 ° C. The 150cm-la 90cm cage was illuminated with infrared light, the nighttime behavior was detected with a black and white CCD camera, and the behavioral trajectory of the experimental dog was captured as data into the computer every 10 minutes. The action recording was performed for 800 minutes from around 18:00. After experimental dogs were previously housed in an experimental cage, pre-treatment behavior was recorded for 2 days and this record was taken before treatment.
Canned dogs mixed with 150 mg of powdered GABA were given at 18:00 on the day of treatment, and the night's behavioral record for that day was taken after treatment. The travel time was expressed as the time traveled during the experiment, and the travel distance was expressed as the distance traveled during the experiment. The point at which the movement started from the stationary state for 10 minutes or more was set as the start of the kite, and the stop of the movement and the subsequent stop for 10 minutes or more were confirmed. The behavior from the beginning of the heel to the end of the heel was defined as one event of the heel. Table 1 shows the number of episodes and the average duration of each episode as one epilepsy event. As is clear from Table 1, experimental dogs showed a significant decrease in GABA at 150 mg and before treatment.
[0019]
[Table 1]

[0020]
A similar experiment was conducted and general symptoms were observed, but no points to be noted were found. Therefore, GABA was considered to act specifically on epilepsy behavior. These results indicated the possibility of treatment of epilepsy / hyperactivity disorder with running neuron inhibitor (GABA agonist, kainate glutamate receptor agonist).
[0021]
【The invention's effect】
By using the pharmaceutical composition of the present invention, unintentional movement such as wrinkles and hyperactivity can be suppressed without suppressing intentional movement. Moreover, the therapeutic agent for suppressing unintentional movements, such as acupuncture and hyperactivity, can be manufactured by use of this invention.
[Brief description of the drawings]
BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the change in night running and food intake before and after administration of the GABA _B receptor agonist SKF97541 intraperitoneally compared with a control group. A vertical axis | shaft shows the ratio of the running amount before and behind administration.
FIG. 2 is a graph showing the results of a forced swimming experiment in GABA _B receptor agonist administration and control rats. The vertical axis represents the number of times the rat waters the front paw every 5 minutes.
FIG. 3 is a graph showing measurement results of running amount of hypothalamic ventral medial nucleus destruction group rats and control group rats.
FIG. 4 is a graph showing the results of forced swimming experiments of rats with hypothalamic ventral medial nucleus destruction group and control group rats. The vertical axis shows the number of times the rat puts the front paws per 10 minutes.

Claims (2)

A pharmaceutical composition for oral administration for treating epilepsy or hyperactivity, comprising GABA. For the manufacture of a pharmaceutical composition for oral administration for the treatment of wandering or hyperactivity, use of GABA.

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