JP2005035999A - Monoamine reuptake inhibitor given by mixing lycium chinense thereinto - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an oral composition safe even when administered for a long period, by finding out a substance having high safety, derived from a natural product, and having monoamine reuptake inhibitory action, for the purpose of improving or preventing light depression including a gloomy mood, a depressive state, or a sense of fatigue. <P>SOLUTION: This composition for improving or preventing the light depression including the gloomy mood, the depressive state, or the sense of fatigue is given by mixing Lycium chinense thereinto. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention is a composition capable of improving mild depression or depression and preventing transition to severe depression by improving depression, irritability, reduced motivation, difficulty in concentrating attention, etc. About. Alternatively, the present invention relates to a composition capable of preventing overwork (overwork) by improving a feeling of fatigue without fatigue and restoring an appropriate feeling of fatigue commensurate with fatigue.

  Due to stress due to changes in the living environment and working environment or continuous physical and mental work, such as manual labor, sports, office work, information processing work, etc., modern people are depressed and fatigue not necessarily commensurate with the degree of fatigue I am troubled by the feeling.

  Depression and depression include long-term depression and depression, psychomotor suppression such as reduced motivation and reduced interest and interest, irritability, anxiety, agitation, reduced attention, and reduced concentration Psychiatric symptoms such as thought cessation, mainly due to sleep disorders such as insomnia and sleepiness during work, digestive disorders such as diarrhea, constipation, and loss of appetite, physical symptoms such as weight loss, sexual dysfunction and decreased libido It is a disease that causes a major hindrance to daily life. In recent years, the number of patients presenting with these symptoms has increased and is not only one of the most frequently affected mental illnesses, but is becoming a very common disease.

  In today's stressed society, the number of severely depressed patients is increasing, and the number of people presenting with depression is increasing rapidly, creating a serious social problem. If depression continues, mild depression will develop, and there is a possibility that it will eventually shift to severe depression. The person himself / herself is difficult to recognize that he / she has developed depression or depression, and has a tendency to be difficult to understand from the surroundings, making early detection and treatment difficult. However, it is known that even in the initial depression, the patient is aware of characteristic symptoms such as depression, irritability, reduced motivation, and difficulty in concentrating attention. Improving these subjective symptoms in daily life is thought to lead to the prevention and treatment of mild depression or depression, which in turn leads to the prevention of severe depression.

  Many hypotheses have been put forward as the pathogenesis of depression and depression, but many studies have revealed that brain monoaminergic nervous system functioning is largely involved in the onset. . The basis of treatment for depression and depression is to take rest while adjusting the onset factors, but in fact, drug therapy is central to the treatment, and brain monoaminergic activity that has decreased as such drugs Natural products such as synthetic drugs and crude drugs that activate the function of the nervous system are known.

  Synthetic drugs include monoamine oxidase (MAO) inhibitors, tricyclic antidepressants, tetracyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-noradrenaline reuptake inhibitors and reversible MAO-A inhibition There are medicines. Among them, most frequently used drugs have a monoamine reuptake inhibitory action as a main action. However, while these drugs have excellent effects, they also have side effects such as blurred vision, dry mouth, constipation, urinary retention, orthostatic hypotension, tachycardia, arrhythmia, sedation, epilepsy-inducing action, and malignant syndrome. Care should be taken when prescribing mild to moderate depression and depression (see Non-Patent Documents 1 and 2). As a natural product, Hypericum perforatum L. is well known. There are many cases in which Hypericum perforatum has been traditionally used as a medical plant in the western cultural sphere in the past, and in recent years mild to moderate depression has been used as an indication. However, the interaction with drugs due to induction of drug metabolizing enzymes is a problem.

  On the other hand, fatigue due to continuous physical work and mental work, that is, a decrease in work performance and physiological reaction during manual labor, sports, office work, and information processing work occur. Moderate fatigue accompanied by fatigue due to intense work or continuous work is normal, and fatigue is reduced by sufficient sleep and rest, that is, reduced work performance and fluctuating physiological responses are recovered, and fatigue is also lost .

Fatigue can be annoying to talk, annoyed, not enthusiastic about things, worried about things, loss of perseverance, etc., sleepiness and dullness, difficulty in concentrating attention, localized discomfort Etc., subjective symptoms similar to depression are intertwined in a complex manner.
A moderate feeling of fatigue prevents the accumulation of fatigue by making the body and body aware of fatigue, and maintains healthy work performance. However, there may be a case where only a feeling of fatigue remains after recovery from fatigue, or a feeling of loose fatigue after waking up. In addition, it may be easy to feel tired without lowering work performance. Thus, since actual fatigue does not necessarily correlate with fatigue, there is a difference between the two, and there may be an excessive sense of fatigue that does not match the degree of fatigue. The feeling of fatigue remaining after recovery from fatigue reduces work efficiency, and the decay of the feeling of fatigue during continuous fatigue can cause overwork.

  It has been elucidated that the functional change of the monoaminergic nervous system in the brain is also greatly involved in this feeling of fatigue (see Non-Patent Document 3), and it is excessive or attenuated by normalizing the monoaminergic nervous system. It is thought that improving the abnormal feeling of fatigue leads to the maintenance of healthy work performance and, in turn, the prevention of overwork.

  Dicoppi (earth bone crust) is a herbal medicine obtained by drying eggplant-like wolfberry (Lucium chinense Mill) or Neykakuko (Lucium barbarum L.). Zicopi has blood pressure lowering action, heart rate reducing action, blood glucose lowering action and antipyretic action, etc., treatment of hypertension, treatment of juvenile flat warts and generalized eczema, treatment of pain due to pulpitis, malaria Although clinical examples used for the treatment of this disease have been reported (see Non-Patent Document 4), no effect on depression or depression and fatigue has been reported.

Miura Tadanori, "The Appearance of SNRI and its Historical Background", Clinical Psychopharmacology, 3 (4), Hoshiwa Shoten, 311-318, 2000 Tajima Osamu, “SNRI Interactions and Side Effects”, Clinical Psychopharmacology, 3 (4), Hoshiwa Shoten, 353-361, 2000 Masaaki Tanaka “Overworked Death and Fatigue-Brain Mechanisms leading to Overworked Death”, History of Medicine, Vol.204.No.5, pp362-364,2003.2.1 Chuyaku Dictionary, Volume 2, pp1043-1045, Shogakukan Co., Ltd., 1985

  The object of the present invention is to improve mild depression or depression by improving symptoms such as depression, depression, motivation, decreased interest, irritation, anxiety, and difficulty in concentrating attention. An object of the present invention is to provide a composition for preventing overwork by preventing depression or improving a feeling of fatigue without fatigue and recovering a moderate feeling of fatigue commensurate with fatigue.

  As a result of intensive studies to solve the above problems, the present inventors have found that an extract derived from dicoppi has a monoamine reuptake inhibitory action, particularly a strong noradrenaline reuptake inhibitory action, and completes the present invention. It came. In other words, unlike synthetic drugs, there are few side effects and Zicopi, which can be administered in various forms such as pharmaceuticals, quasi drugs, foods, etc., is a mild depression or depression that many modern people are potentially affected. It came to be thought that it was very effective in the improvement or prevention of a state or a feeling of fatigue.

One embodiment of the present invention is a monoamine reuptake inhibitor characterized by containing dicoppi.
Another aspect of the present invention is a noradrenaline reuptake inhibitor characterized by containing dicoppi.
Another aspect of the present invention is a composition for improving or preventing mild depression or depression, characterized by containing dicoppi.
Another aspect of the present invention is a composition for ameliorating or preventing a mental symptom of depression or depression, characterized by containing dicoppi.
Another aspect of the present invention is a composition for improving or preventing at least one subjective symptom selected from feeling of depression, feeling of depression and feeling of depression, characterized by containing dicoppi.
Another aspect of the present invention is a composition for improving or preventing at least one subjective symptom selected from annoyance, agitation, tension and anxiety, characterized by containing dicoppi.
Another aspect of the present invention is a composition for improving or preventing at least one subjective symptom selected from reduced concentration, attention, reduced patience, and sleepiness, characterized by containing dicoppi. .
Another aspect of the present invention is the improvement of at least one subjective symptom selected from reduced motivation, decreased motivation, decreased interest, decreased interest, decreased joy and boredom, characterized by containing dicoppi Or it is a composition for prevention.
Another aspect of the present invention is a composition for improving the feeling of fatigue, characterized by blending dicoppi.

  According to the present invention, it is possible to provide a composition for improving or preventing mild depression or depression such as depressive mood, or fatigue feeling with little side effects and safety even when taken for a long period of time.

  The present invention has an inhibitory effect on the reuptake of monoamines such as serotonin, noradrenaline, dopamine, etc., such as depression and depression, anxiety and irritation, decreased motivation and decreased interest, difficulty in concentrating attention, etc. Has an effect of improving or preventing depression or fatigue.

  Dicoppi is a herbal medicine obtained by drying the root bark of the solanaceous wolfberry (Lucium chinense Mill) or Neika wolfberry (Lucium barbarum L.). In addition to the herbal powder, an extract can also be used. The extract can be easily produced by extraction treatment usually performed by those skilled in the art using water, lower aliphatic alcohol (eg, methanol, ethanol, isopropyl alcohol, etc.), lower aliphatic ketone (eg, acetone, etc.), or a solvent containing these. it can. The produced extract can be made into a concentrated extract or a dried extract by a treatment such as heat treatment, freeze-drying or reduced-pressure drying. The extract thus obtained may be further purified by chromatography or the like.

  Even when dicoppi is administered as a tincture once a day for 7 days in mice, the lethal dose is very high and there is no clear accumulation in the body. In addition, even when 80 g / kg of decoction is injected into the stomach of a rabbit, it is known that the amount of exercise only decreases, and that it recovers to normal after 3 to 4 hours and is highly safe (non-patent document) 4). Therefore, the inhibitors and compositions of the present invention are considered applicable to the improvement or prevention of mild to moderate depression or symptoms and fatigue, which are not prescribed by existing synthetic pharmaceuticals.

  Zicopi herbal powder and extracts can be used as they are as monoamine reuptake inhibitors and compositions for improving or preventing depression or depression or fatigue, but if necessary, the effects of the invention can be improved. It can be mixed with any carrier (water-soluble vitamins and fat-soluble vitamins, these vitamin derivatives, minerals, herbal medicines, these extracts, organic acids, coenzymes) and the like within an unimpaired qualitative and quantitative range. For example, when Zicoppi is used for the prevention and cure of diseases such as hypertension treatment, it is a refreshing lotus drink (Bakumondou, Bukuryu, Ogon, Shazenshi, carrot, ogi, licorice and rennic) , Peony, chimo, chimpi, toki, touki, bakumondo, sandalwood, bukuryu, licorice, mint, and baimo), there is a fact that the action of dicoppi is remarkable due to the interaction with other herbal medicines, etc. There is little possibility of attenuation or serious side effects, and it can be mixed.

  The inhibitor and composition of the present invention can be administered orally in dosage forms such as tablets, granules, powders, capsules, liquids and the like containing any commonly used optional ingredient.

  Examples of such optional components include pharmaceuticals, excipients, binders, coating agents, lubricants, sugar coatings, disintegrating agents, bulking agents, flavoring agents, emulsifying / solubilizing / dispersing agents, and stabilizers. , PH adjusting agents, isotonic agents and the like can be preferably exemplified. By treating these according to a conventional method, the inhibitor and the composition of the present invention can be produced.

  Mild depression or depression such as depressed mood, and the use of dicoppi when used as a composition for improving or preventing fatigue, depends on age, sex, and route of administration, but is usually adult About 50 mg to 15000 mg per day, preferably 100 mg to 10000 mg.

  The present invention will be specifically described below with reference to examples and test examples.

Example 1 Manufacture of extract After extraction by adding 1000 parts by weight of 50% ethanol solution to 100 parts by weight of dried dicoppi consisting of the root bark of Lucium chinense Mill, which is produced in Jiangsu Province, China The ethanol was distilled off. Furthermore, the extract was obtained by concentration under reduced pressure.
The extract obtained by the above extraction treatment had an extract yield of 7.07%, loss on drying of 35.0%, and a comparison with the drug substance of 9.2.

Test example 1
The dicoppi extract obtained in Example 1 was subjected to a test for evaluating monoamine reuptake inhibitory activity by the following test method.

Preparation of crude synaptosomes:
After removing the brains of 10-week-old male Crj: CD (SD) IGS rats (Nippon Charles River), the frontal cortex, hypothalamus and striatum were rapidly divided under ice-cooled conditions. After removing blood vessels from each brain region under ice-cooling conditions, each was homogenized with 0.32 mol / L sucrose, and the crude nuclear fraction was separated by centrifugation under conditions of 1000 × G and 4 ° C. From the resulting supernatant, crude synaptosomes were prepared by centrifugation under conditions of 20000 × G and 4 ° C. (prepared at the time of use).

Buffer adjustment:
The buffers used for the monoamine reuptake inhibition reaction test were 118 mmol / L NaCl, 4.7 mmol / L KCl, 1.2 mmol / L MgSO ₄ , 1.2 mmol / L KH ₂ PO ₄ , 25.0 mmol / L NaHCO _3. 1.27 mmol / L CaCl ₂ , 11.0 mmol / L glucose, 0.1 mmol / L purerrin, 1.14 mmol / L ascorbic acid, 0.067 mmol / L EDTA2Na at the final reaction concentration during the monoamine reuptake inhibition reaction test It was prepared as follows. The buffer solution was aerated with 95% oxygen and 5% carbon dioxide mixed gas under ice-cooling conditions (prepared at the time of use).

Preparation of crude synaptosome preparation:
Crude synaptosome specimens were prepared by diluting crude synaptosomes prepared from the frontal cortex, hypothalamus, and striatum with a buffer solution so that the wet tissue weight was reduced to 400 to 800 times during the monoamine reuptake inhibition reaction. (Prepared on use).

Preparation of [3H] labeled monoamine solution for uptake measurement:
[3H] noradrenaline, [3H] dopamine, and [3H] serotonin solutions were prepared by diluting with a buffer solution so that the concentration would be 5 nmol / L during the monoamine reuptake inhibition reaction (prepared at the time of use).

Preparation of extract solution:
As the extract, the dicoppi extract produced in Example 1 was used and dissolved in a 25% DMSO solution so as to have a concentration of 50 g / L as an initial dry extract. Then, it diluted so that it might become final concentration of 10 mg / L, 30 mg / L, and 100 mg / L of DMSO of 0.25 v / v% and dry extract at the time of monoamine reuptake inhibition reaction, respectively.

  Hypericum perforatum extract was used as a positive herbal medicine. Hypericum perforatum extract powder containing 7.1% loss on drying, 0.3% hypericin and 3.4% hyperifolin was used. A Hypericum perforatum extract was prepared in the same manner as the dicoppi extract.

Monoamine reuptake inhibition reaction test:
After adding 50 μL of the extract solution and 350 μL of the crude synaptosome specimen to the microtube and mixing, a pre-reaction treatment at 25 ° C. for 15 minutes was performed. Thereafter, 100 μL of [3H] -labeled monoamine solution was added, and a reaction treatment was performed at 25 ° C. for 2 hours. In order to calculate the total uptake amount, a microtube to which a buffer solution was added without adding an extract solution was prepared. In order to calculate the amount of non-specific uptake, without addition of extract or buffer, desipramine hydrochloride was added so that the final concentration was 1 μmol / L during the noradrenaline reuptake inhibition reaction, and the final concentration was 10 μmol / day during the serotonin reuptake inhibition reaction. A microtube was prepared in which clomipramine hydrochloride was added to L, and dopamine hydrochloride was added to a final concentration of 10 μmol / L during dopamine reuptake inhibition reaction. Furthermore, in the noradrenaline reuptake inhibition reaction test, a microtube to which both the extract and desipramine solutions were added was prepared. Three microtubes with the same contents were prepared in order to conduct a reaction test by measuring each concentration at three points.

[3H] Measurement of labeled monoamine uptake:
After the above reaction, the solution was immediately suction filtered using Whatman GF / C glass filter paper moistened with 0.3 v / v% polyethyleneimine. The filter paper was washed twice with 1 mL of physiological saline composed of 0.9 w / v% NaCl, and dried at 45-50 ° C. for 60 minutes or more. The radioactivity of [3H] -labeled monoamine on the filter paper was measured using a conventional liquid scintillation and scintillation counter.

Calculation of inhibition rate of monoamine reuptake:
The non-specific uptake amount was subtracted from the total uptake amount to obtain a specific uptake amount. The monoamine reuptake inhibition rate of the extract was defined as the rate of decrease in the amount of uptake due to the addition of the extract.
The test results are shown in Tables 1, 2 and 3.

Test example 2
About the dicoppi extract obtained in Example 1, the test which evaluates a reserpine induction hypothermia inhibitory effect by the following test method was implemented.

Animals used:
Male Crj: CD-1 (ICR) mice (Charles River Japan) having a body weight of 32 to 38 g were used during the test. The animals were bred under conditions of free intake of food and water for at least 5 days including the date of acquisition. The breeding conditions were room temperature 23 ± 3 ° C., humidity 50 ± 20%, lighting time 12 hours, ventilation frequency 10 times / hour, 8-12 animals / cage.

Preparation of reserpine solution:
Reserpine solution is diluted with Japanese Pharmacopoeia Water for Injection (Hikari Pharmaceutical Co., Ltd.) using Japanese Pharmacopoeia Reserpine Injection (Apopron Injection 1mg, Daiichi Pharmaceutical Co., Ltd.) to a concentration of 2.0mg / 10mL. (Prepared at the time of use).

Preparation of extract solution:
The extract solution is the dicoppi extract produced in Example 1, and 4w / v% polyoxy-POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil- 60) Suspended in aqueous solution. Then, it diluted and prepared so that it might become a density | concentration of 256 mg / 10mL and 512 mg / 10mL.
A Hypericum perforatum extract was prepared in the same manner as the dicoppi extract.

Reserpine-induced hypothermia suppression test:
It is well known that reserpine induces hypothermia by reducing the function of the noradrenergic nervous system, and this hypothermia is suppressed by an antidepressant having an inhibitory effect on noradrenaline reuptake (J. Pharmacol. Exp. Ther., 298 (2), 581-591 (2001), Pharmacol. Ther., 45 (3), 425-455 (1990)).

Two mice / cage were placed in a small cage (175 mm × 275 mm × H 130 mm). The reserpine solution was intraperitoneally administered at a volume of 10 mL / kg mouse body weight from 10 to 11 am. The extract solution was orally administered at 1 and 3 hours after administration of the reserpine solution so that the volume of the extract was 10 mL per kg of the mouse body weight. Body temperature was measured 5 hours after administration of the reserpine solution. The body temperature was measured by measuring the rectal temperature (measurement site: 1.5 cm from the anus) using an electronic thermometer (measurement accuracy ± 0.05 ° C.). Only the respective solvents were administered to the normal group. Reserpine solution and solvent were administered to the 0 mg / kg administration group. The number of animals per group (number of animals) was 8 to 16, and the test results were expressed as average values (standard error). The significant difference test was Student's t-test, and was considered significant at a risk rate of less than 5% (P <0.05).
The test results are shown in Table 4.

Test example 3
In order to examine the monoamine reuptake inhibitory action obtained in Test Example 1 in more detail, a monoamine reuptake inhibitory reaction test was performed in terms of the drug substance.

Preparation of extract solution:
As the extract, the dicoppi extract produced in Example 1 was used and dissolved in a 25% DMSO solution so that the initial concentration was 25 g / L in terms of dry bulk drug weight. Then, it diluted to the final concentration of 0.25 v / v% DMSO, 10 mg / L, 30 mg / L, 100 mg / L at the monoamine reuptake inhibition reaction test.

Monoamine reuptake inhibition reaction test The same buffer as in Test Example 1 was used as a buffer solution for the dopamine and serotonin reuptake inhibition reaction test. Buffers used for the noradrenaline reuptake inhibition reaction test include 119 mmol / L NaCl, 4.8 mmol / L KCl, 1.2 mmol / L MgSO ₄ , 2.0 mmol / L CaCl ₂ , 10.0 mmol / L glucose, 0.1 mmol / L purerin, 5.68 mmol / L ascorbic acid, and 25 mmol / L Tris were prepared at final reaction concentrations during the monoamine reuptake inhibition reaction test. Other test methods were performed in the same manner as in Test Example 1.

Test example 4
About the dicoppi extract obtained in Example 1, the effect | action with respect to a mouse | mouth spontaneous movement was evaluated by the following test method.

Animals used:
Male Crj: CD-1 (ICR) mice (Charles River Japan) 6-9 weeks old were used during the test. The animals were raised under conditions of free intake of food and water for at least 5 days including the date of acquisition. Breeding conditions were room temperature 23 ± 3 ° C, humidity 50 ± 20%, lighting time 12 hours, ventilation frequency 10 times / hour, 8-12 animals / cage.

Preparation of extract solution:
As the extract solution, the dicoppi extract produced in Example 1 was used, and 1 w / v% POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil) was adjusted to a concentration of 6.4 g / 10 mL in terms of dry bulk drug weight. −60) Suspended in aqueous solution.

Mouse locomotor test:
Mice were orally administered with 6.4 g / kg dicoppi extract, and the spontaneous movement for 30 minutes was measured 60 minutes after the administration with a momentum measuring device (Supermex: Muromachi Kikai Co., Ltd.). Spontaneous exercise was shown as a count.

  As shown in Test Example 1, dicoppi exhibited a stronger monoamine reuptake inhibitory effect than Hypericum perforatum at an extract concentration of 10 mg / L.

  As shown in Test Example 2, dicoppi was significantly suppressed at a dose of 256 mg / kg extract against reserpine-induced hypothermia. Compared to Hypericum perforatum, which showed significant suppression at the 512 mg / kg extract dose, dicoppi suppressed reserpine-induced hypothermia at low doses.

  As shown in Test Example 3, dicoppi showed a strong noradrenaline reuptake inhibitory action.

  As shown in Test Example 4, no effect on mouse spontaneous movement was observed.

  From the above results, it was revealed that dicoppi is effective in improving or preventing mild depression such as depressed mood and depression, and fatigue.

Ziccoppi has excellent monoamine reuptake inhibitory activity and few side effects, so it can be applied to pharmaceuticals, quasi drugs, foods, etc. for mild depression or depression such as depressed mood and improvement or prevention of fatigue. Expected to be used.

Claims (9)

  A monoamine reuptake inhibitor comprising dicoppi.   A noradrenaline reuptake inhibitor comprising dicoppi.   A composition for improving or preventing mild depression or depression, characterized in that it contains dicoppi.   A composition for ameliorating or preventing a psychiatric symptom of mild depression or depression, characterized by containing dicoppi.   A composition for improving or preventing at least one subjective symptom selected from depression, depression, and depression, characterized in that it contains dicoppi.   A composition for improving or preventing at least one subjective symptom selected from irritability, irritability, agitation, tension and anxiety, characterized by blending dicoppi.   A composition for improving or preventing at least one subjective symptom selected from a decrease in concentration, a decrease in attention, a decrease in perseverance, and sleepiness, characterized in that it contains dicoppi.   A composition for improving or preventing at least one subjective symptom selected from decreased motivation, decreased motivation, decreased interest, decreased interest, decreased joy and boredom, characterized by containing dicoppi. A composition for improving the feeling of fatigue, characterized by containing dicoppi.