JP2001342150A - Medicinal composition for suppressing unintentional behavior and use of running neuron-suppressing material for producing the same medicinal composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicinal composition capable of suppressing an unintentional behavior and not suppressing an intentional behavior, especially capable of treating wandering around, hyperkinesis, etc., and also a method for using a material capable of suppressing running neuron. SOLUTION: This medicinal treating composition for treating symptoms accompanying unintentional behaviors such as wandering around, hyperkinesis, etc., containing a material capable of performing a presynapse suppression or a postsynapse suppression of the running neuron, and the use of such material for producing the medicinal treating composition for the symptoms accompanying the unintentional behaviors such as wandering around, hyperkinesis, etc., are provided. Especially the medicinal treating composition for treating the above symptoms and the use of such composition for treating the above symptoms including a substance selected from a group consisting of GABAB receptor agonists, GABAA receptor agonists and GABAA receptor-reinforcing substances, or a combination of them, are provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a pharmaceutical composition for treating symptoms associated with unintentional movements, in particular wandering and hyperactivity, and to a pharmaceutical composition comprising a running neuron inhibitor and to the use of a running neuron inhibitor.

[0002]

2. Description of the Related Art In humans and some vertebrates such as dogs and cats, wandering, especially wandering at night, and hyperactivity, including attention deficit hyperactivity syndrome (ADHD), can be problematic. Wandering and hyperactivity are generally considered to require psychiatric treatment. In particular, wandering of the elderly was thought to be closely linked to Alzheimer's senile dementia.
Such conditions are often problematic for the patients themselves, especially as they suffer not only physically from patients suffering from other illnesses but also from the surrounding population. Here, wandering refers to causing "wandering away from home due to morbid urge" or "uncontrollable urge to wander or travel" (Stedman Medical Dictionary, 2nd revised edition, 1989, Medical View "Hyperactivity disorder" 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 described as "sometimes found in the medical dictionary." Hyperactivity has also been described as a major feature of hyperactivity and emotional instability (Dictionary of Medicine). 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, sleeping pills, or muscle relaxants that suppress systemic movements of patients have generally been used to treat such symptoms. However,
Such drugs cause various problems such as causing opacity of consciousness and systemic muscle relaxation. Furthermore, as antipodal treatments for wandering and hyperactivity, there may be a method of physically removing the freedom of the patient such as unavoidably fixing it to the bed or confining it, but these naturally cause a great deal of pain to the patient Things. In any case, therapies or drugs known so far deprive the patient of systemic freedom,
Alternatively, the main focus was on deliberate deprivation of behavior and significantly impaired the patient's quality of life.

On the other hand, independently of such clinical studies, various studies have been conducted in the study of nerves, focusing on the running movement of rats, particularly the nighttime running movement.
For example, the present inventors have reported that stimulation of the ventromedial nucleus of the rat hypothalamus (hereinafter abbreviated as VMH) with a water-absorbing polymer induces the running motion of the rat by the pressure stimulation (Yokawa et al.). , Physiology & B
ehavior (1989), 46, 713-717). The report shows that signals from VMH are required for rat locomotion, since excision around the VMH does not induce polymer locomotion. Furthermore, the present inventors have shown that the above-mentioned induction of rat running movement by the polymer is suppressed by administering GABA (γ-aminobutyric acid) to the polymer (Yokawa et al., Physio
l. & Behav (1990), 47, 1261-1264).

Also, the present inventors have reported that the running movement of rats is also induced by kainate-type glutamate receptor agonists (Narita).
Et al., Brain Res. (1993), 603, 243-247). According to this report, kainic acid induces rat locomotion, and this locomotion is not suppressed by GABA, and the kainic acid-type glutamate receptor antagonist DN
QX (6,7-dinitroquinoxaline-2,3-dione) (6,7-dinitr
oquinoxaline-2,3-dione). This indicates that the neurons that control running motility in rats are stimulated via kainate-type glutamate receptors, and that GABA _A receptors inhibit presynaptic inhibition of this kainate-type glutamate receptor. This suggests that the application more indirectly suppresses the neurons that control the rat's running movement. On the other hand, as for the GABA _B receptor, it has been reported that substances having antagonistic inhibitory activity against this receptor are useful for the treatment of convulsive diseases, Alzheimer's treatment, and memory-lowering diseases (Japanese Unexamined Patent Publication No.
243853).

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a pharmaceutical composition which suppresses unintentional behavior and does not suppress intentional behavior. In particular, an object of the present invention is to provide a pharmaceutical composition capable of treating wandering, hyperactivity and the like. Another object of the present invention is to provide a method for 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 the VMH which strongly suggests that it is involved in the running movement of rats, especially at night. We note that these behaviors in rats are neither reflexive nor intentional, and we conclude that VMH
We named these neurons as running neurons or running neurons and concluded that they are neurons that control unintended movements in rats. Here, the running neurons are present in the VMH in the rat as described above, but from the viewpoint of phylogeny, the hypothalamus containing the VMH is the lower center, and this region is considered to be well conserved in vertebrates. ing. From this, the present inventors believe that running neurons also exist in other vertebrates including humans and dogs. In addition, the present inventors have found clinically that patients with wandering usually provide irrational explanations for their actions or explain that they have forgotten or had no intention of wandering. And that hyperactivity is considered clinically unintentional, and behaviors such as wandering and hyperactivity in humans and some vertebrates are conventionally called "intentional behaviors." 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 and wandering, hyperactivity And so on. That is, by suppressing the output to the running neuron, the present inventors suppress wandering, behavior such as hyperactivity,
The inventors have invented a pharmaceutical composition and a method which do not suppress intentional movement. That is, the present invention is a pharmaceutical composition for treating a symptom associated with unintentional movement such as wandering or hyperactivity, comprising a substance that suppresses a presynaptic or a postsynaptic of a running neuron. The present invention is also the use of a substance that inhibits presynaptic or post-synaptic inhibition of a running neuron for producing a pharmaceutical composition for treating a symptom accompanied by unintentional movement such as wandering or hyperactivity. In particular, the present invention is a GABA _B receptor agonist, GABA _A receptor agonist,
_A substance for enhancing the action of GABA _A receptor, a substance selected from the group consisting of kainate-type glutamate receptor antagonists, or a combination thereof, for the treatment of symptoms accompanied by unintentional movements such as wandering and hyperactivity Compositions and their use for the manufacture of a pharmaceutical composition for the treatment of symptoms accompanied by unintentional movements such as wandering, hyperactivity and the like.

[0008]

DETAILED DESCRIPTION OF THE INVENTION Pharmaceutical compositions comprising one or more running neuron-inhibiting substances or the use of the running neuron-inhibiting substances for the preparation of such pharmaceutical compositions according to the invention are useful for the treatment of symptoms with unintentional behavior. It can be generally used, and particularly preferably used for symptoms accompanied by unintentional forward movement such as wandering and hyperactivity. Running neuron inhibitors 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), kainate-type glutamate receptor antagonists, and combinations thereof. More specifically, in addition to GABA, as a GABA _A receptor agonist,
Isogubacin (1,2,3,6-tetrahydro-4-pyridinecarboxylic acid)
cid), muscimol (5-aminomethyl-3-hydroxyisoxazole), T
HIP (4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol) (4,5,6,7-tetrahydroisoxazolo [5,4-c] pyr
idin-3-ol) and the like, as a GABA _B receptor agonist, baclofen (4-amino-3- (4-chlorophenyl) butanoic acid) (4-
amino-3- (4-chlorophenyl) butanoicacid), SKF97541 (3-
Aminopropyl (methyl) phosphinic acid) (3-aminopropy
l (methyl) phosphinic acid) and the like, benzodiazepine (benzodiazepine) and the like as GABA _A receptor enhancers, and kainate-type glutamate receptor antagonists CNQX
(6-cyano-7-nitroquinoxaline-2,3-dione) (6-cyano
-7-nitroquinoxaline-2,3-dione), CNQX disodium salt
(6-cyano-7-nitroquinoxaline-2,3-dione disodi)
um), DNQX, GAMS (γ-D-glutamylaminomethylsulphonic acid), NBQ
X (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo
[f] Quinoxaline-7-sulfonamide) (2,3-dioxo-6-nitr
o-1,2,3-4-tetrahydrobenzo [f] quinoxaline-7-sulphona
mide), 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-tet
rahydrobenzo [f] quinoxaline-7-sulphonamide disodiu
m) and the like, but are not limited thereto.

[0009] Bioassays can be used to determine whether a given substance has a running neuronal inhibitory effect. For example, a cannula guided by a 26 gauge stainless steel needle is implanted in the VMH of a rat and the rat is left for at least about 7 days for surgical recovery. After a recovery period, about 0.5 μl of saline
100 pmol of kainic acid can be injected through the internal cannula to check whether the inserted cannula has hit the running neuron. Rats that did not show running movement, ie, rats that did not respond to this treatment, can be excluded from further experiments. After three days, kainic acid (about 100 pmol) and the expected inhibitor (about 50 pmol to about 50 nmol) can be injected through the cannula. If a substance injected at the same time as kainic acid reduces or eliminates kainic acid-induced movement,
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 is preferably administered orally. Parenteral administration includes transdermal, ophthalmic,
This includes administration by inhalation, nasal administration, and intraperitoneal administration.
The dosage depends on the patient's age, symptoms, general health, weight,
It is determined according to the treatment plan, the desired effect, and the like. As a daily dose, the pharmaceutical composition of the present invention is preferably administered at about 0.1 mg / kg body weight to about 500 mg / kg body weight when the active ingredient, i.e., a running neuron inhibitor, is orally administered, preferably 1 mg / kg. kg to 100 mg / kg body weight, more preferably 10
mg / kg bw to 50 mg / kg bw, and for parenteral administration, from about 0.001 mg / kg bw
About 200 mg / kg body weight, preferably 0.005 mg / kg body weight to 20 mg / kg
It is prepared and administered to be administered at a dose of body weight, more preferably 0.05 mg / kg body weight to 2 mg / kg body weight.

The pharmaceutical composition of the present invention is generally administered about once to six times a day, preferably about once to three times a day. The pharmaceutical compositions of the present invention may be administered continuously over an extended period of time. However, when the time and period during which the symptoms appear strongly are limited, the administration may be performed only a limited number of times according to the symptoms during that time or period. In any case, when used in combination with other therapeutic agents or methods, the dosage of the pharmaceutical composition is adjusted according to the amount and nature of the treatment. For example, when used in combination with an antipsychotic, the dose 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, suspensions and the like can be used. For parenteral administration, sterile injectable or ophthalmic solutions, inhalable aerosols and the like can be employed.

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, in the case of parenteral administration, the osmotic pressure of the pharmaceutical composition of the present invention may be adjusted as necessary. As such excipients and additional substances, common pharmaceutically and physiologically acceptable substances can be used,
Examples include sugars such as lactose and galactose, starches such as corn starch, fatty acid salts such as magnesium stearate, alginic acid, talc, polyethylene glycol and the like.

[0013] The pharmaceutical composition of the present invention may contain the active ingredient, a running neuron inhibitor, in an amount of about 1 to 95% by mass or more, preferably about 10 to about 80% by mass based on the total mass. The proportion of the running neuron inhibitor can be selected according to the form of the pharmaceutical composition of the present invention, the desired effect, and the total amount of the pharmaceutical composition to be administered. In particular, in the case of oral administration, the pharmaceutical composition of the present invention contains 1 to 95% by mass, preferably 10 to 80% by mass, more preferably 20 to 70% by mass, particularly preferably about 20 to 70% by mass of a running neuron inhibitor as an active ingredient. 20 to about 60% by weight. When included in the diet, it is generally present in an amount of from about 0.001 to 10% by weight, preferably
It contains a running neuron inhibitor in a proportion of 1 to 1% by mass. For parenteral administration, the pharmaceutical compositions of the invention will generally contain from about 0.01 to 30% by weight of the total amount, preferably from 0.05 to 20% by weight.
Contains a running neuron inhibitor. In each case, when a plurality of running neuron inhibitors are included, the amount of each running neuron inhibitor can be adjusted according to its action and effect. Pharmaceutical compositions of the present invention, wandering, showing psychiatric with unintentional behavior such as hyperactivity, mammals including humans in general, for example, humans, dogs,
It can be used for the treatment of such symptoms in cats or livestock such as cattle and pigs. In addition, a running neuron inhibitor can be used for producing a pharmaceutical composition for suppressing unintentional behavior such as wandering and hyperactivity in mammals including humans.

[0014]

EXAMPLES Example 1: GABA _B receptor agonist SKF97541
7-week-old rats (Wistar Imamichi) were kept in cages with running wheels. The lighting conditions were illuminated at 7 o'clock and turned off at 19:00, and food and water were freely taken. They were kept untreated for 3 weeks and treated after they were fully caged. At this time, the running amount at night was almost constant. Treatment is with GABA _B receptor agonist SKF97541
Was administered by intraperitoneal administration of 1.0 mg / kg or 0.5 mg / kg around 18:00. As a control group, a physiological saline administration group was used. The running amount is read into the computer every 30 minutes from the sensor attached to the running wheel, and the total count at night is defined as the amount of nighttime activity.
For each individual, the post-treatment ratio, where the pre-treatment count was 1, was calculated. The result is shown in FIG. As is clear from FIG. 1, the SKF97541 0.5 mg / kg administration group also exhibited an inhibitory effect of about 40 to 60% as compared to the control group. SK
In the F97541 1.0 mg / kg administration group, an inhibitory effect of about 70% was observed. These results revealed that GABA _B receptor agonists had a significant effect on nighttime running of rats, and that the effect was dose-dependent.

Example 2: GABA_BReceptor agonist SKF9754
Effect of 1 on intentional behavior GABA was applied to rats bred as in Example 1._BReceptor
Agonist SKF97541 0.5mg / kg was intraperitoneally administered and administered
After 30 minutes to 3 hours, the rats are placed in water at 35 ° C to 37 ° C.
Was. The container is 55cm deep and the height from the water surface to the top of the container is 30
cm, cross section 1200cm ^TwoWas used. Lad in the pool
Forced swim and water with your forefoot every 5 minutes
The number was measured. As a control group, saline was administered.
Groups were used. As a result, the intentional exercise
GABA_BClearly not reduced by receptor agonists
It became clear (Fig. 2). This is GABA_BReceptor agoni
Shows that strike has little effect on intentional movement
ing.

Example 3 Analysis of Action of Running Neurons on Unintentional Behavior In rats bred in the same manner as in Example 1, the ventral medial nuclei of the hypothalamus on both sides were destroyed, and the amount of travel was measured. .
A tungsten wire coated with Deflon was passed through a glass tube (inner diameter 0.6 mm) and an outer diameter 1.0 mm, the upper end of the glass tube was fixed with an adhesive (Aron Alpha), and the wire and the glass tube were fixed. A 0.5 mm conducting wire was drawn out from the lower end of the glass tube, the coating on that portion was peeled off, and the lower end of the glass tube was fixed with a putty. The electrode fabricated as described above was used as a breaking electrode. Electrodes and rats raised as described above were anesthetized with pentobarbital, fixed in a stereotaxic apparatus,
Following the Paxinos and Watson brain map, the ventromedial nuclei of both hypothalamus were destroyed. The current flows through the isolator
A DC current of 5 mA was passed 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 forepaw of the rat. In addition, by inserting an electrode into the hypothalamic ventromedial nucleus, rats with electrodes removed after standing for 60 seconds without passing a current as a control group, using a rat in which the hypothalamic ventromedial nucleus was electrically destroyed, The daily travel was measured. The day when the destruction was performed was defined as day 0 (day 0). The count of the sensor attached to the running wheel is taken into the computer every 30 minutes, and the 24-hour integrated count is defined as the amount of nighttime activity, and the ratio after treatment when the count before treatment is set to 1 for each individual is calculated. did. As a result, it became clear that the daily running amount was significantly reduced in the hypothalamic ventromedial nucleus destruction group compared to the control group (FIG. 3).

Example 4: Analysis of the effect of running neurons on intentional behavior A forced swimming experiment was performed using rats in which the ventromedial nucleus of the hypothalamus was electrically destroyed in the same manner as in Example 3. 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. The results showed that in the hypothalamic ventromedial nucleus destruction group, the number of times the rats wore their forelimbs in water was not different from that of the control group (FIG. 4). This means that intentional movement is not inhibited in the hypothalamic ventromedial nucleus destruction group, that is, the running neuron destruction group.

Embodiment 5 FIG. Effect of GABA administration on wandering habit An 11-year-old male Pomeranian was used. It has been confirmed that this experimental dog has dementia and has a wandering habit.
Food was given about 200 g of canned dogs (maintenance beef cans, Japan Hills Colgate Co., Ltd.) twice a day in the morning and evening. Water was given ad libitum. Experiment at room temperature 2
The test was conducted in a room equipped with a 2 ° C. air conditioner. The 150cm la 90cm cage is illuminated with infrared light, and nighttime action is performed in black and white.
The trajectory of the behavior of the experimental dog was detected as data by a computer every 10 minutes. Behavior recording was performed for 800 minutes from around 18:00. After the experimental dog had been tamed in the experimental cage in advance, the behavior before the treatment was recorded for 2 days, and this record was taken before the treatment. 18 on treatment day
Occasionally canned dogs mixed with 150 mg of powdered GABA were given, and the nightly 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 start of wandering was defined as the point at which the robot started moving from a still state for 10 minutes or longer, and the stop of the movement was confirmed for at least 10 minutes thereafter, and the stop of the movement was defined as the end point of wandering. The action from the start of wandering to the end of wandering was defined as one event of wandering. One wandering event is defined as one episode, and the number of episodes and the average duration are shown in Table 1. As is clear from Table 1, the experimental dog showed a significant decrease in each of the parameters at the time of GABA administration of 150 mg as compared to before the treatment.

[0019]

[Table 1]

The same experiment was conducted to observe general symptoms, and no points to note were found. Therefore, it was considered that GABA was specifically acting on wandering behavior. These results indicate that running neuron inhibitors (GABA agonists, kainate-type glutamate receptor agonists) can be used to treat wandering and hyperactivity.

[0021]

EFFECT OF THE INVENTION By using the pharmaceutical composition of the present invention, unintentional movements such as wandering and hyperactivity can be suppressed without suppressing intentional movements. Further, by using the present invention, a therapeutic agent for suppressing unintentional movements such as wandering and hyperactivity can be manufactured.

[Brief description of the drawings]

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing a comparison between a control group and changes in the amount of running and eating during the night before and after administration of a GABA _B receptor agonist SKF97541 intraperitoneally. The vertical axis shows the ratio of the amount of travel before and after administration.

FIG. 2 is a graph showing the results of forced swimming experiments of GABA _B receptor agonist administration and control rats. The vertical axis represents the number of times the rats water their forelimbs per 5 minutes.

FIG. 3 is a graph showing the measurement results of the running amount of the hypothalamic ventromedial nucleus-disrupted group rat and the control group rat.

FIG. 4 is a graph showing the results of a forced swimming experiment of a rat with a hypothalamic ventromedial nucleus and a control group. The vertical axis is 10
The number of times the rat scratches the paw per minute is shown.

Continued on the front page (51) Int.Cl. ⁷ Identification code FI Theme coat II (Reference) A61K 31/5513 A61K 31/5513 31/662 31/662 A61P 25/28 A61P 25/28 43/00 111 43/00 111 F term (reference) 4C084 AA17 MA01 NA14 ZA152 ZA162 ZC412 4C086 AA01 AA02 BC16 BC55 BC67 CB22 DA34 MA01 MA04 NA14 ZA15 ZA16 ZC41 4C206 AA01 AA02 FA45 MA01 MA04 NA14 ZA15 ZA16 ZC41

Claims (16)

[Claims] 1. A pharmaceutical composition for treating a symptom with unintentional behavior, comprising one or more running neuronal inhibitors. 2. The pharmaceutical composition according to claim 1, wherein the unintentional behavior is wandering, hyperactivity. 3. The method according to claim 1, wherein the running neuron inhibitor is GABA.
_B receptor agonist, GABA _A receptor agonist, and
The pharmaceutical composition according to claim 1 or 2, which is a substance selected from the group consisting of GABA _A receptor enhancing substances, or a combination thereof. 4. The running neuron inhibitor is GABA _A.
4. The pharmaceutical composition according to claim 3, which is a receptor agonist. 5. The running neuron inhibitor is GABA _B.
4. The pharmaceutical composition according to claim 3, which is a receptor agonist. 6. The pharmaceutical composition according to claim 4, wherein the GABA _A receptor agonist is selected from the group consisting of GABA, isoguvacin, muscimol and THIP. 7. The pharmaceutical composition according to claim 5, wherein the GABA _B receptor agonist is selected from the group consisting of GABA, baclofen and SKF97541. 8. The pharmaceutical composition according to claim 3, wherein the GABA _A receptor potentiator is benzodiazepine. 9. Use of a running neuron inhibitor for the manufacture of a pharmaceutical composition for the treatment of a symptom with unintentional behavior. 10. The unintentional behavior is wandering, hyperactivity,
Use according to claim 9. 11. The method according to claim 11, wherein the running neuron inhibitor is GA.
BA _B receptor agonists, GABA _A receptor agonists, and, GABA _A, a receptor potentiator selected from the group consisting of substances or combinations thereof, The use according to claim 9 or 10. 12. The method according to claim 12, wherein the running neuron inhibitor is GABA.
The use according to claim 11, which is an _A receptor agonist. 13. The running neuron inhibitor is GABA.
The use according to claim 11, which is a _B receptor agonist. 14. The use according to claim 12, wherein the GABA _A receptor agonist is selected from the group consisting of GABA, isoguvacin, muscimol and THIP. 15. The use according to claim 13, wherein the GABA _B receptor agonist is selected from the group consisting of GABA, baclofen and SKF97541. 16. Use according to claim 11, wherein the GABA _A receptor potentiator is a benzodiazepine.