JP4936348B2 - Psychotropic drug - Google Patents

Description

  The present invention relates to a psychotropic drug for improving neurological symptoms such as improvement of manic symptoms, suppression of hyperactivity, anxiety, insomnia, irritability, etc., comprising pantetins, which are a kind of vitamin, as an active ingredient.

  As the word “stress” goes beyond the differences in age, gender, type of work, etc. and is widely used on a daily basis, stress is experienced in various scenes of modern human life. Load.

  In particular, when an animal accumulates mental stress that arises from mental stress or physical unpleasant stimuli, the animal becomes responsive to depression (such as depression, anxiety, weakness, and behavior atrophy). Symptoms) or behavioral divergent responses (symptoms) such as wheezing, hyperactivity, and aggressive behavior may occur, resulting in insomnia, irritability, and irritation.

  There are also many patients suffering from neurological disorders that exhibit depression or manic symptoms due to neurophysiological causes, particularly mental disorders commonly referred to as manic depression. Manic-depressive illness is a disease in which the mood is elevated and it becomes difficult to control self-behavior and thoughts, and depression that is depressed in mood and the amount of action decreases due to anxiety and lethargy.

  Furthermore, in recent years, children with a lack of concentration, impulsiveness, restlessness, and problems in school education, especially those with a high degree of hyperactivity syndrome or attention deficit hyperactivity disorder (ADHD = The number of children called attention deficit hyperactivity disorder is increasing.

  In response to stress-related or neurologic depressive mental illness, various countermeasures have been devised, such as temporarily or fundamentally removing the cause of stress, or receiving counseling. However, if the symptoms are relatively minor, the symptoms may be improved. However, there are many cases where it is not practical to remove the fundamental cause of stress, and there are problems such as requiring considerable time and effort. .

  In addition, treatments for psychiatric diseases by administration of drugs such as psychotropic drugs are widely performed. With regard to depressive symptoms, many patients suffer from such symptoms, and many depressive symptoms have been developed. However, most of them are not drugs that can be easily used because they may have the opposite effects depending on the dose and are highly dependent drugs.

  There is still a problem that there are fewer options for drugs available for manic symptoms compared to drugs for depression symptoms. In addition, lithium carbonate is recognized as a first-choice drug as anti-epileptic drugs, and examples include sodium valuroate, carbamazepine, and clonazepam, but these have little difference between the amount of effect and the amount of side effects. In addition to requiring strict control in taking, gastrointestinal disorders, movement disorders, dizziness, sweating, fever, headache, polyuria, as well as severe myocardial and renal side effects have been reported.

  In addition, methylphenidate hydrochloride is widely used as a therapeutic agent for ADHD, but it is a drug that is highly dependent and easy to acquire resistance. In particular, the target patient may be a child, and there are concerns about anxious psychotropic drug prescriptions such as methylphenidate hydrochloride.

  Surprisingly, the present inventors have conducted research on a substance exhibiting an improving action on experimental animals exhibiting manic symptoms. As a result, pantetin, which is widely known as a kind of vitamin B group, is irritated by stress and the like. The present invention has been completed by finding that it has the action of calming the state of excitement, excitement, and hyperactivity.

  That is, the present invention is a psychotropic drug containing panthetins as an active ingredient. For example, one or more panthetins selected from the group consisting of pantethine, pantethein, pantothenic acid, panthenol and salts thereof are preferred as active ingredients. It is a psychiatric drug. In particular, it relates to psychotropic drugs that are used as antiepileptic drugs, anti-ADHD drugs, or sedatives.

  Conventionally, pantethine is a component involved in the combustion of carbohydrates and fats in cells, and as a pharmaceutical, as a precursor of coenzyme A, there are debilitating diseases, hyperthyroidism, pantothenic acid deficiency or metabolic disorders. It has been used for the prevention and treatment of side effects caused by hyperlipidemia and laxative constipation, streptomycin and kanamycin, which are presumed to be involved, acute chronic eczema, blood disease platelet count, and improvement in bleeding tendency. However, there are no reports suggesting the improvement effect of pantethine on psychiatric disorders, particularly manic symptoms and ADHD.

  Pantethine is a compound produced by disulfide bonding of two molecules of pantethein (ND-pantothenoyl-β-aminoethanethiol). This pantethein is produced by enzymatic activation of pantothenic acid. In addition, pantothenic acid is produced from panthenol. All of these reactions proceed in vivo. Therefore, in the present invention, not only pantethine, but also pantethein, pantothenic acid, panthenol and salts thereof such as alkali metal salts such as sodium salt and potassium salt Alkaline earth metal salts such as calcium salts and magnesium salts can also be used.

  The effect of the pantethine of the present invention is demonstrated using a mouse subjected to a sleep deprivation stress.

  This sleep deprivation load was applied to the mouse by a method (platform method) in which the animal was placed in a free-feeding state on a cylinder surrounded by water of an appropriate depth for 20 hours and then returned to the cage and rested for 4 hours. The load given. Here, by reducing the area of the cylinder on which the mouse is placed, it is possible to cause epilepsy in the mouse.

  For example, when a sleep deprivation load is given to a mouse on a cylinder with a diameter of 2 cm placed in a water depth of 4 cm (narrow platform method, NP method), this mouse has a marked increase in spontaneous momentum and forced swimming test. , Reduced inactivity time, increased spontaneous momentum using Animex device, time to fall in rotating rod method (Dunhan et al., J. Am. Pharm. Ass., 46, 208-209, 1957) Are observed, and the number of spontaneous jumps within a certain time is observed. Such symptoms are behavioral patterns observed in patients who are mania. Hereinafter, a mouse that has developed this epilepsy symptom is referred to as an epilepsy model mouse.

  In addition, this mouse model mouse is highly alert, aggressive, sensitive to a slight stimulus, and clearly shows symptoms such as no rest. These symptoms are very similar to those of attention deficit passive syndrome (ADHD), and have the significance of ADHD as a model animal.

  In addition, this sputum model mouse is unable to fall asleep due to an arousal state despite being in a state of sleep deficiency due to a sleep deprivation load, and also exhibits stress-induced insomnia, so-called stressed model animals Can also be understood.

  Therefore, a substance capable of improving the above-mentioned symptoms by being administered to such a sputum model mouse or a mouse receiving a sleep deprivation load is an anti-epileptic drug, anti-ADHD drug or It can be evaluated as a drug that can be used as a sedative for various stresses.

  When pantethine is administered at a level of 27 to 133 mg / kg body weight / day to mice receiving a sleep deprivation load by the NP method, it significantly suppresses an increase in spontaneous exercise amount (jump frequency) caused by the load. can do. The effect of suppressing the increase in the amount of spontaneous exercise (the number of jumps) is almost the same as the effect when 2 to 4 mEq / kg body weight / day of lithium carbonate, which is the first choice drug as an antidepressant, is administered.

  In addition, when compared with methylphenidate that is widely used as an anti-ADHD drug, the administration effect of pantethine is as follows when methylphenidate is administered in an amount of 0.01 to 0.1 mg / kg body weight / day. Is almost equivalent.

  On the other hand, at the administration level of pantethine, it has not been reported that pantethine has any adverse side effects.

  Therefore, pantethine has a medicinal effect comparable to that of psychotropic drugs such as lithium carbonate and methylphenidate, and at the same time has no fear of side effects compared to such psychotropic drugs and is extremely safe for mania and ADHD. It can be said that the drug can be used as a psychiatric drug.

  The psychotropic drug of the present invention is a drug that can be used as a psychotropic drug that is extremely safe against mania and ADHD without fear of side effects.

  Panthetin, pantethein, pantothenic acid, panthenol, and salts thereof are easily available compounds that are widely manufactured and sold as pharmaceuticals or reagents.

  In addition, when one or more of pantethine, pantethein, pantothenic acid, panthenol and their salts are used as the psychotropic agent of the present invention, the compound itself may be administered directly, or tablets, granules, sustained release It may be processed into an arbitrary dosage form such as an agent or liquid and administered, or may be administered orally or intravenously. That is, in the present invention, there are no particular restrictions on the dosage form, administration method, etc. when administered to a patient, and appropriate excipients, diluents, other formulations, and other physiological activities as necessary. What is necessary is just to add an ingredient suitably, and to process and use for each desired dosage form.

  The dose may be adjusted within the range of about 1 to 2000 mg / day, preferably 5 to 1000 mg / day, depending on the sex, age, symptom level, etc. of the patient.

  Hereinafter, the effectiveness of the psychotropic drug of the present invention will be described with reference to examples.

(1) Experimental animals and sleep deprivation load ddY male mice weighing 19 to 21 g at the start of the experiment were used, and room temperature 22 ± 2 ° C., humidity 55 ± 10%, light / dark 12 hour cycle (8: Under constant conditions (00 to 20:00), solid feed and tap water were freely consumed.

  In the NP method, a cylinder (diameter: 2 cm, height: 4.8 cm) is fixed to a transparent plastic cage (length: 17.3 cm × width: 24.3 cm × height: 12.7 cm), and water is filled up to a height of 4 cm. The mice were placed on the cylinder for 20 hours and then put into a cage at the time of individual breeding and returned to the cage for 4 hours. The 20-hour sleep deprivation and 4-hour break made a daily load (one set). In addition, a mouse reared in a cage was prepared as a control. In both the NP method and the control, mice were allowed to eat and drink freely.

(2) Evaluation method 1) Forced swimming test (FST)
FST was performed according to the method of Porsolt et al. (Arch Int Pharmacolodyn Ther. Vol.229, 327-336, 1977).

  Mice were individually forced to swim in a glass 1000 ml beaker (diameter 11.5 cm, height 14.5 cm) containing 25 ° C. water to a height of 9 cm for 15 minutes. Thereafter, the mice were dried and given a predetermined sleep sleep load, and then forced swimming for 5 minutes was performed again under the same conditions as above, and each of immobility, struggle, and swimming was performed. The cumulative time (seconds) was measured over 5 minutes.

2) Rota-rod Test
This was performed according to the method of Dunhan et al. (J. Am. Pharm. Ass., 46, 208-209, 1957). Place the mouse on a 3cm diameter wooden horizontal bar that rotates at a speed of 15 revolutions per minute in the direction opposite to the direction of rotation. After 5 minutes of training, select one that stays on the bar for 3 minutes or more in advance. Provided.

  Distilled water was administered to the mice immediately after the sleep deprivation and allowed to stand for 30 minutes, then placed on a rotating rod under the above conditions, and the time (seconds) until the animal dropped from the rotating rod was measured. The maximum extension time was 300 seconds, 3 measurements were performed per mouse, and a 4-minute break was given between measurements. The average of three measurements was calculated.

3) Measurement of Spontaneous Momentum Spontaneous momentum was measured using the Animex device. After release of the sleeplessness load and 24 hours after the release, each mouse was placed in a transparent plastic cage (length 17.3 cm × width 24.3 cm × height 12.7 cm) and adapted to the environment for 15 minutes. Thereafter, distilled water or drug administration was performed, and the exercise amount for 120 minutes was measured.

4) Measurement of jumping behavior (jumping behavior) Distilled water or drug was administered to the mouse immediately after the release of sleep deprivation, allowed to stand for 15 minutes, and then placed in a 2000 mL plastic graduated cylinder (diameter 10 cm, height 46 cm). The number of jumps was measured every 5 minutes for 60 minutes. A jump of 4 cm or more was measured as one time.

5) Statistical processing The experimental results are shown as mean value (standard) and standard error (SEM). The significant difference test used Mann-Whitney U-test for comparison between the two groups, and followed the Fisher's PLSD test after analysis of variance post hoc test for multiple comparisons. A risk rate of 5% or less was determined to be significant. For this test, Stat view-J 5.0 for Macintosh was used.

(3) Results 1) Effects of sleep deprivation load Three sets of sleep deprivation load were applied to each of the NP method and the control. Immediately after the release of sleep deprivation, the mice were administered distilled water and left for 30 minutes, followed by forced swimming for 5 minutes. As a result of the test, mice with the NP method showed a significant reduction in immobility and an increase in swimming time, but no significant difference was observed in the postcard (FIG. 1).

  In addition, the mice prepared by the NP method showed a significant increase in the amount of spontaneous exercise in the mice by the NP method after the three sets of sleep deprivation compared to the control mice (FIG. 2). Furthermore, immediately after the release of 5 sets of sleep deprivation load, a significant increase in the amount of spontaneous exercise was observed in mice by the NP method (FIG. 3).

  Furthermore, when three sets of mice immediately after release of the sleep deprivation load were evaluated by the rotating rod method, the mice that had been subjected to the sleep deprivation load for 3 days by the NP method, stayed on the rotating rod as compared to the control mice. Decreased significantly (FIG. 4).

  From the above, it can be seen that in mice given a sleep deprivation load by the NP method, both spontaneous movement and the number of jumps remarkably increase and do not stay on the rotating rod for a long time, and thus exhibit a manic symptom.

2) Effect of pantensin The antiepileptic effect by administration of pantethine was examined by a change in spontaneous exercise amount (jump number). Immediately after the start of sleep deprivation and immediately after cancellation, 3 sets of sleep deprivation were given by the NP method while administering pantethine 133, 200 or 300 mg / kg body weight / day, and 15 minutes before the measurement of the number of jumps The final dose was performed and the change in the number of jumps was examined.

  As comparison objects, lithium carbonate 2 mol equivalent / kg, 2.83 mol equivalent / kg and 4 mol equivalent / kg, methylphenidate 0.01 mg / kg body weight, 0.1 mg / kg body weight, respectively, with pantethine Mice that were administered in the same manner and were given a sleep deprivation load by the NP method were prepared, and the number of jumps was examined.

  In the group of mice administered with lithium carbonate and methylphenidate, which are comparative subjects, the number of jumps decreased significantly and dose-dependently, and the anti-epileptic effect of these drugs was confirmed (FIGS. 5-a and c). .

  Compared to this comparative subject, the number of jumps was also dose-dependently and significantly decreased in the group of mice administered pantethine (FIG. 5-b). This result indicates that pantethine has an antidepressant effect, an anti-ADHD effect, and a sedative effect, like lithium carbonate and methylphenidate.

The result of the forced swimming test about the mouse | mouth which gave the sleep sleep load is shown. The change of the spontaneous exercise amount of the mouse | mouth which gave 3 sets of sleep deprivation load is shown. The change of the spontaneous exercise amount of the mouse | mouth which gave 5 sets of sleep deprivation load is shown. The result of the rotation bar method test about the mouse | mouth which gave the sleep sleep load is shown. The effect of suppressing the increase in the number of jumps of pantethine for mice given a sleep deprivation load by NP method is shown. Fig. 5-a shows the effect of methylphenidate administration, Fig. 5-b shows the effect of pantethine administration, and Fig. 5-c shows the effect of lithium carbonate administration.

Claims (5)

An anti-epileptic, anti-ADHD or sedative psychotropic drug containing pantethine as an active ingredient. The psychotropic drug according to claim 1, wherein a daily dose is 5 to 1000 mg.   The psychotropic drug according to claim 1 or 2, which is an antiepileptic drug.   The psychotropic drug according to claim 1 or 2, which is an anti-ADHD drug.   The psychotropic drug according to claim 1 or 2, which is a sedative.

Images