JP2012012360A - Therapeutic agent for indications for haloperidol, and beverage or food - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a therapeutic agent for indications (symptom to which haloperidol is effective) for haloperidol which is safe and easily usable, instead of haloperidol which is a therapeutic agent for a positive symptom of schizophrenia, and to provide food and drink to which the therapeutic agent is added.SOLUTION: The therapeutic agent for indications for haloperidol contains lysozyme having a medicinal action similar to haloperidol as an effective component, and to food and drink to which the therapeutic agent is added. As the indications for haloperidol, a symptom is preferably selected from a group comprising bipolar disorder, delirium, dyskinesia, Huntington disease, Tourette disorder, amphetamine poisoning, paranoia, confusion, excitation, intractable hiccup, naucea, and vomiting.

Description

  The present invention relates to a haloperidol indication therapeutic agent and a food or drink to which the haloperidol indication treatment agent is added.

Human beings living in modern society, whether they like it or not, are inevitably exposed to various mental and physical stresses, and social structure changes and cultural Opportunities are also increasing due to transformation. In such a social environment subjected to considerable stress exposure, psychosomatic diseases are increased, and various mental diseases (mental disorders) and neurological diseases such as anxiety, depression, and insomnia are easily induced.
Psychiatric disorders refer to diseases caused by functional and organic disorders of the brain. Psychotherapy, electroconvulsive therapy, and pharmacotherapy using psychotropic drugs such as haloperidol are adopted for the treatment. .
Haloperidol is a butyrophenone antipsychotic drug that was discovered by Janssen et al. From the analgesic meperidine and was discovered as a drug that suppresses the momentum increase induced by the stimulant amphetamine. Haloperidol has a CNS inhibitory effect similar to that of chlorpromazine, and is more potent than chlorpromazine in the effects of blocking nerves in animals and antagonism against apomorphine-induced vomiting. It also shows habituation and suppression of condition avoidance reactions. Clinically, it is said to be effective for positive symptoms (excited state, etc.) of schizophrenia, and particularly good for invalid cases of phenothiazine drugs. In addition to schizophrenia, it is also used for bipolar disorder, delirium, dyskinesia, Huntington's disease, Turret disorder, amphetamine addiction, paranoia, severe confusion and excitement, refractory rebellion, nausea and vomiting .

  On the other hand, lysozyme is a protein discovered as an enzyme having a lytic action by Fleming in 1922, and is found in all living organisms (plants, animals, bacteria, algae, fungi, etc.). Lysozyme is a strongly basic protein that acts as a natural immune factor that protects against infections in higher animals. In addition, since microorganisms whose cell walls are partially lysed by lysozyme are more susceptible to the action of antibiotics, the action of many antibiotics is enhanced by lysozyme. Lysozyme is used as a therapeutic agent for rhinitis, fermentation prevention of cheese, etc. and as a food preservative (Non-patent Documents 1 to 4). Normalize and, as a result, suppress or improve nitrogen metabolism and have a beneficial effect on the digestive system etc. in mammals, so it is suggested to administer lysozyme to treat bacterial infections in livestock (Patent Document 1). In addition, as an action of lysozyme, an action to improve stress resistance and immunity of useful animals (Patent Document 2) and an inhibitory action on increase in blood glucose level (Patent Document 3) have been reported. However, as a pharmacological action of lysozyme, no action to prevent or treat haloperidol indications such as schizophrenia has been reported.

Supervised by Kazutomo Imagi and Tamio Yamakawa, Biochemistry Dictionary (4th edition), Tokyo Science Doujin; 2007: p.1434-1435 Encyclopedia of Medicine (15th edition), Nanzan-do; 1972, p.1594 Akahori Shiro, Mizushima Sanichiro, Protein Chemistry, Kyoritsu Shuppan; 1955, vol.3, p.321-330 Seed Planning, Current Status and Future Prospects of Protein & Peptide Foods, 1994, Seed Planning; 1994, p.39

JP-A 63-264424 Japanese National Patent Publication No. 11-514205 International Publication No. 06/088553 Pamphlet

As described above, haloperidol is used as a therapeutic agent for positive symptoms of schizophrenia. In addition, as other mental illnesses, it is also used as a therapeutic agent for bipolar disorder, delirium, dyskinesia, Huntington's disease, Turret disorder, amphetamine poisoning, paranoia, severe confusion and excitement. It is also effective for intractable rebellion, nausea and vomiting.
However, since haloperidol has side effects that cannot be ignored, it is necessary to pay sufficient attention to its use under the supervision of a doctor or the like.
In addition, because schizophrenic patients have a very high smoking rate, it can be considered that smoking may temporarily or even alleviate the symptoms of schizophrenia. However, smoking is not recommended under the supervision of a doctor or the like, unlike conventional therapeutic drugs, but smoking is not recommended because various adverse effects such as carcinogenesis are known.
Therefore, a substance that has the same pharmacological action (haloperidol-like action) as haloperidol, and is safe and easy to use is desired as a therapeutic drug for haloperidol.
This invention is made | formed in view of the said situation, Comprising: It aims at providing the haloperidol indication therapeutic agent which is safe and can be used simply.

In the development of psychotropic drugs, evaluation methods are important in selecting candidate substances and predicting therapeutic effects. Conventionally, as a method for evaluating psychotropic drugs, experimental pathological animals that have induced behavioral changes or behavioral abnormalities corresponding to the symptoms of the mental illness to be treated have been created, and their general behaviors are observed or spontaneous exercise is measured. A method for evaluating psychotropic effects is common. However, there are various problems with the evaluation method using experimental animals. First of all, it is difficult to create highly valid experimental animals. Mental illness is often less clear than other common illnesses, and even if it is classified as the same mental illness, it contains multiple mental illnesses and etiologies, or is classified as a different mental illness. May be based on the same etiology. For this reason, the experimental pathological animal described above may capture a part of a certain kind of mental illness, but it is difficult to say that it captures the whole picture. In such an evaluation method using experimental pathological animals with low validity, it is difficult to say that the obtained results accurately reflect the psychotropic effect. In addition, when observing and evaluating the behavior of animals, skill is required to obtain stable experimental results. In addition, there are also problems such as administration of stimulants and the like, special animals such as genetically modified animals, and expensive experimental devices such as conflict experimental devices.
Furthermore, in the conventional evaluation method, in order to evaluate the effects of a certain candidate substance on each disease state of a large number of mental disorders, completely different evaluation systems (for example, experimental disease animals corresponding to individual mental disorders) It is necessary to evaluate with. In other words, there are many candidate substances in the early stages of development, and it is unclear what kind of psychotropic action each candidate substance has, so the effect on each psychiatric disorder using each evaluation system Need to be evaluated. Therefore, there is a possibility that useful candidate substances may be leaked when narrowing down candidate substances in the initial stage of development.
As a result of intensive studies on various categories of psychotropic drugs, the present inventor has different effects on the glycemic response induced by continuous retention, depending on the administered drug, It has been found that even the same drug has different effects on the blood glucose elevation response due to differences in experimental conditions (such as different preloaded stimuli). Based on this knowledge, a patent application has been filed for an evaluation method that can easily and reproducibly evaluate the psychotropic effects of substances without being restricted by the classification of mental disorders (Japanese Patent Application No. 2009-178313).
Specifically, the evaluation method includes a step of continuously holding a test animal to which a substance has been administered and measuring a blood glucose level over time under the condition, and changing an experimental condition before the holding. And the psychotropic action is evaluated from the effect of the substance on the blood glucose elevation reaction induced by the retention. This experimental condition is preferably set in combination with a method for administering the substance and a treatment applied to the test animal before and / or after the substance is administered. For example, it is selected from the group consisting of (1) to (6).
(1) On the day of measurement, the test animal is moved from the breeding room to the laboratory to administer the substance.
(2) On the day of measurement, the test animal is moved from the breeding room to the laboratory, and before or after the substance is administered, a stimulus of exposure to a novel scene, electrical stimulation or retention is temporarily applied.
(3) On the day before measurement, the test animal is moved from the breeding room to the laboratory and acclimatized, then returned to the breeding room, and moved to the laboratory again on the day of measurement to administer the substance.
(4) On the day before the measurement, the test animal is moved from the breeding room to the laboratory, acclimated, returned to the breeding room, moved to the laboratory again on the day of the measurement, and before or after administering the substance, a novel scene Temporary load of exposure to, electrical stimulation and retention.
(5) Repeated administration of the substance until the day before the measurement.
(6) The substance is repeatedly administered until the day before the measurement, and on the day of the measurement, any of the exposure to a novel scene, electrical stimulation and retention is temporarily applied.

In the above evaluation method, when sustained retention is performed on the test animal, an elevated blood glucose response is induced by the persistent retention. Specifically, a blood glucose level begins to rise immediately after the start of continuous retention, and a reaction that decreases after reaching a maximum value is observed.
The hyperglycemic response is affected by the experimental conditions prior to continuous retention. For example, even if the same drug is used, if the administration method or prior stimulation is changed, a difference occurs in the blood glucose increase response. Therefore, the psychotropic effect can be evaluated from the difference. Specifically, if there is no clear change in the blood glucose elevation response under one experimental condition and the blood glucose elevation response is enhanced or attenuated under another experimental condition, the drug may have some psychotropic effect It can be judged that there is sex. The presence or absence of enhancement or attenuation of this blood glucose increase response, and the degree of enhancement or attenuation, for example, are compared with the control (blood glucose increase response observed when the above steps are performed under the same experimental conditions except that only the solvent is administered). It can be determined by comparison. Also, the drug may have some psychotropic effect when there is no clear change in the blood glucose elevation response under some experimental conditions and the blood glucose elevation response is accelerated or delayed under other experimental conditions It can be judged. Whether or not this blood glucose increase response is promoted or delayed, and the degree of the promotion or delay can be determined by comparison with a control, as described above. For example, when there is a difference in the time when the blood glucose level is continuously maintained It can be determined that the blood glucose elevation response is accelerated or delayed. Further, the degree of promotion or delay can be determined based on the magnitude of the deviation.
Moreover, even under the same experimental conditions, if the type of drug to be administered is changed, a difference occurs in the blood glucose increase reaction. For example, even if there is no clear change in the blood glucose elevation response when one drug is administered, the blood glucose elevation response is enhanced or attenuated, or the strength of the enhancement or attenuation is increased when another drug is administered. The difference is seen.
Therefore, the above process is performed twice or more by changing the experimental conditions, and by comparing the difference in the blood glucose elevation reaction in each step, the influence of the drug on the blood glucose elevation reaction under a plurality of experimental conditions (below) , Sometimes known as an action attitude.)
Since this action attitude varies depending on the psychotropic action of the drug, the evaluation method is also useful for comparing the psychotropic action between a plurality of drugs. Specifically, the present inventor, even if the influence on the blood glucose elevation response induced by the retention in the evaluation method is the same psychotropic drug, haloperidol, diazepam, clozapine, clomipramine, methylphenidate, lithium So we have confirmed that it is completely different.
As a result of observing the influence of various substances on the above-mentioned blood glucose elevation reaction using this difference, it was found that lysozyme has a psychotropic effect similar to haloperidol, as shown in Test Example 1 described later.

This invention is made | formed based on the said knowledge, and has the following aspects.
[1] A haloperidol indication therapeutic agent comprising lysozyme as an active ingredient.
[2] The therapeutic agent for haloperidol indication according to [1], wherein the haloperidol indication is a positive symptom of schizophrenia.
[3] The haloperidol indication is selected from the group consisting of bipolar disorder, delirium, dyskinesia, Huntington's disease, Tourette disorder, amphetamine addiction, paranoia, confusion, excitement, refractory rebellion, nausea and vomiting The therapeutic agent for haloperidol indication according to [1].
[4] A food or drink to which the haloperidol indication therapeutic agent according to any one of [1] to [3] is added.

  ADVANTAGE OF THE INVENTION According to this invention, the haloperidol indication therapeutic agent which can be used safely and easily can be provided.

The therapeutic agent for haloperidol indication of the present invention contains lysozyme as an active ingredient.
Lysozyme has a haloperidol-like action, that is, a pharmacological action similar to that of haloperidol. By taking an effective amount of lysozyme, haloperidol indication can be treated.
Here, “haloperidol indication” means a symptom in which haloperidol is effective for the treatment, and preferably includes a positive symptom of schizophrenia. Other examples include bipolar disorder, delirium, dyskinesia, Huntington's disease, Tourette disorder, amphetamine addiction, paranoia, confusion, and excitement. Also included are refractory rebellion, nausea and vomiting.
“Treatment” means ameliorating (including alleviating or alleviating) symptoms of haloperidol indication.
Schizophrenia affects 0.7-1.0% of the population, reaching hundreds of thousands in Japan. Approximately 75% of treated patients are extremely serious chronic illnesses that are not completely relieved and are creating long-term hospitalized patients. The main symptoms of this disease include various symptoms such as delusions, hallucinations, and hallucinations, as well as cognitive impairment such as sensory abnormalities and negative symptoms such as withdrawal and depression. It is. From adolescence to middle age, the disease develops with symptoms that are characteristic of perception, thoughts, emotions, and behaviors, and many are chronic and cause various difficulties in social adaptation. There are two types of psychiatric symptoms: positive symptoms (such as hallucinations, delusions, attenuating thoughts, tension symptoms, bizarre behavior) and negative symptoms (such as flattened emotions, motivation, social withdrawal). Due to the peculiarity of the disease state of this disease, establishment of a consistent comprehensive treatment system is desired, including early detection, treatment, rehabilitation activities, and recurrence prevention. Schizophrenia is a functional psychosis that is mainly caused by a predisposing factor, and is often associated with a genetic predisposition. However, at present, not only the cause of the onset but also the understanding of biological pathology is not clear.
Drugs that antagonize neurotransmitters, dopamine and serotonin have traditionally been considered useful as treatments to improve the positive symptoms of schizophrenia, and in many cases, long-term administration of these drugs for more than a year is essential . Specifically, butyrophenone compounds such as haloperidol, phenothiazine compounds, thioxanthine compounds, and benzamide compounds are frequently used. However, extrapyramidal disorders are known as side effects of these drugs.
As newer therapeutic agents for schizophrenia, serotonin-dopamine receptor antagonists such as clozapine which are also effective for negative symptoms are known. However, serotonin-dopamine receptor antagonists often have side effects such as weight gain and exacerbation of diabetes.
On the other hand, lysozyme, which is an active ingredient of the therapeutic agent for haloperidol indication of the present invention, is excellent in safety, and an effective amount of lysozyme sufficient to exert the therapeutic effect for haloperidol indication is found when haloperidol is administered. Can be taken on a daily basis, if necessary, on a long-term basis without causing side effects (extrapyramidal disorders, etc.).

  The lysozyme used in the present invention is not particularly limited, and a commercially available product may be used. For example, lysozyme is directly crystallized by adding seeds to a 5% salt solution of egg white. You may use what was extracted from raw materials, such as. In terms of easy availability, commercially available lysozyme (for example, manufactured by Sigma) is preferable. As described above, lysozyme is found in all living organisms (plants, animals, bacteria, algae, fungi, etc.), but is industrially produced exclusively by extraction from egg white.

The therapeutic agent for haloperidol indication of the present invention may be composed solely of lysozyme, or may be a composition containing lysozyme and other components other than lysozyme. The other component is not particularly limited as long as it is pharmaceutically acceptable. For example, an active ingredient other than lysozyme may be blended. In addition, additives that are conventionally blended in pharmaceutical compositions (for example, a pharmaceutical carrier to be described later) can be blended.
As active ingredients other than lysozyme, those known as active ingredients of haloperidol indication treatment drugs can be used, and the haloperidol indication treatment drug is appropriately selected from known active ingredients according to the haloperdol indication to be treated. it can. Specific examples include haloperidol, spiroperoperidol, chlorpromazine, fluphenazine, perphenazine, trifloperazine, chlorprothixene, flupentixol, tetrabenazine, lithium salt, aripiprazole, clozapine, quetiapine, risperidone, metoclopramide, scopolamine, diphenhydramine , Atropine, quinine and the like.

The administration route of the therapeutic agent for haloperidol indication of the present invention may be either oral or parenteral, preferably oral. Examples of parenteral administration routes include rectal and inhalation.
The dose of the therapeutic agent for haloperidol indication of the present invention may be appropriately set according to the administration route, the expected therapeutic effect and the like. For example, when administered orally, the daily dose is usually preferably 2 to 1000 mg / kg body weight, more preferably 10 to 500 mg / kg body weight in terms of the solid content of lysozyme per kg body weight.
The therapeutic agent for haloperidol indication of the present invention may be administered in a single dose or in several divided doses.

The therapeutic agent for haloperidol indication of the present invention can be appropriately formulated into a predetermined dosage form according to the administration method.
Examples of the dosage form of the haloperidol indication therapeutic agent of the present invention include, for oral administration, solid preparations such as powders, granules, tablets and capsules; solutions such as solutions, syrups, suspensions and emulsions; Can be mentioned. In the case of parenteral administration, suppositories, sprays and the like can be mentioned.
Formulation can be appropriately performed by a known method according to the dosage form.
At the time of formulation, only the active ingredient may be formulated, or a formulation carrier may be blended as appropriate.
When a pharmaceutical carrier is blended, the blending amount of the active ingredient in the haloperidol indication therapeutic agent of the present invention is not particularly limited, and may be appropriately determined according to the dosage form.

As the preparation carrier, various conventional organic or inorganic carriers can be used depending on the dosage form.
For example, as a carrier in the case of a solid preparation, excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents and the like can be mentioned.
Examples of excipients include sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbit; starch derivatives such as corn starch, potato starch, α-starch, dextrin and carboxymethyl starch; crystalline cellulose, hydroxypropylcellulose, hydroxypropyl Cellulose derivatives such as methylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium; gum arabic; dextran; pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium magnesium metasilicate; phosphate derivatives such as calcium phosphate; And carbonate derivatives thereof; and sulfate derivatives such as calcium sulfate.
Examples of the binder include gelatin, polyvinyl pyrrolidone, and Magrogol in addition to the above excipients.
Examples of the disintegrant include, in addition to the above excipients, chemically modified starch or cellulose derivatives such as croscarmellose sodium, sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidone.
Lubricants include: talc; stearic acid; stearic acid metal salts such as calcium stearate and magnesium stearate; colloidal silica; waxes such as bee gum and gallow; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; Carboxylic acid sodium salts such as sodium sulfate; sulfates such as sodium sulfate; leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid and silicic acid hydrate; starch derivatives and the like .
Examples of the stabilizer include paraoxybenzoic acid esters such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; acetic anhydride; sorbic acid and the like.
Examples of the flavoring agent include sweeteners, acidulants, and fragrances.
Examples of the carrier in the case of a solution for oral administration include a solvent such as water and a flavoring agent.

The therapeutic agent for haloperidol indication of the present invention can be used by adding to various pharmaceuticals, foods and drinks, nutrients and the like.
Since the haloperidol indication therapeutic agent of the present invention has an effect of treating haloperidol indication, the haloperidol indication agent is added to the pharmaceutical agent, food or drink, or nutritional agent, thereby adding the haloperidol indication therapeutic agent to the haloperidol indication. It can be a medicinal product, food or drink or nutrient for treatment of indication.

<Food &Drink>
The food / beverage products of the present invention are those to which the haloperidol indication therapeutic agent of the present invention described above is added. By ingesting the food / beverage product, the same effect as when administering the therapeutic agent for haloperidol indication of the present invention is obtained.
The addition amount of the haloperidol indication therapeutic agent can be appropriately adjusted according to the food or drink to be added, and is not particularly limited. In order to obtain an effective treatment effect for haloperidol, it is preferable to add the lysozyme so that the above-mentioned daily dose can be easily taken. Usually, the quantity from which the solid content concentration of lysozyme in food-drinks will be 0.1-99% (w / w) is preferable, and 1-95% (w / w) is more preferable.

The food / beverage products of this invention can be prepared by adding the haloperidol indication therapeutic agent of this invention to the existing food / beverage products containing another component.
Other ingredients contained in the food and drink can be used without particular limitation as long as they are approved for use in food and drink in accordance with food regulations such as the Food Sanitation Act, as long as the effect of treating haloperidol is not impaired. . For example, sugars such as dextrin and starch; proteins such as gelatin, soybean protein and corn protein; amino acids such as alanine, glutamine and isoleucine; polysaccharides such as cellulose and gum arabic; fats and oils such as soybean oil and medium chain fatty acid triglyceride Etc. can be contained.
The form of the food or drink of the present invention is not particularly limited, and includes any form of edible composition comprising lysozyme and a carrier acceptable as a food or drink. For example, solid food such as bread, chewing gum, cookies, chocolate, confectionery, cereals, jam, ice cream, yogurt, jelly, etc., cream or gel food, green tea, tea, oolong tea, etc., juice It is possible to make all food and drink forms such as beverages such as coffee and cocoa. Moreover, it can also mix | blend with a seasoning, a food additive, etc.

It is preferable to sell the food / beverage products of this invention as the food / beverage products by which the use with the haloperidol indication treatment was displayed.
Note that the wording used to display the above is not limited to the wording “for haloperidol indication treatment”, for example, and other words express the effect of treatment for haloperidol indication. Needless to say, the wording is included in the scope of the present invention. For example, the phrase “for improving haloperidol indication” may be used, and a specific haloperidol indication, for example, a positive symptom of schizophrenia may be displayed.

The “display” act (display act) includes all acts for informing consumers of the use, and if it is a display that can recall and analogize the use, the purpose of the display Regardless of the contents of the display, the object / medium to be displayed, etc., all fall under the “display” act of the present invention. However, it is preferable to display in such an expression that the consumer can directly recognize the application. Specifically, the act of describing the above-mentioned use in a product or product packaging relating to food or drink can be listed as a display act, and further, the product describing the above-mentioned use in the product or product packaging is transferred, delivered, and transferred. Or display for delivery, display and import activities, display advertisements on products, price lists or transaction documents to display or distribute the above, or describe the above uses in information containing them The act provided by the objective (Internet etc.) method etc. can be illustrated.
On the other hand, the displayed content (display content) is a display approved by the government or the like (for example, a display that is approved based on various systems determined by the government and is performed in a mode based on such approval). It is preferable to attach such display contents to advertising materials at sales sites such as packaging, containers, catalogs, pamphlets, POPs, and other documents.
Moreover, the display as health food, functional food, enteral nutrition food, special purpose food, health functional food, food for specified health, nutritional functional food, quasi drug, etc. can be illustrated. In particular, a display approved by the Ministry of Health, Labor and Welfare, for example, a display approved by a food system for specific health use or a system similar thereto can be exemplified. Examples of the latter can include a display as a food for specified health use, a display as a condition specific food for specified health use, a display that affects the structure and function of the body, a display of reduced disease risk, etc. Speaking of the health promotion law enforcement regulations (April 30, 2003 Ministry of Health, Labor and Welfare Ordinance No. 86) labeling as food for specified health use (especially labeling the use of health), and similar The display can be listed as a typical example.

  Next, although a test example and an Example are shown and this invention is demonstrated further in detail, this invention is not limited to a following example.

<Test Example 1>
[1. Test animal]
A 6-week-old male ddY mouse (Japan SLC) was purchased and kept in an almost constant environment (temperature 22 ± 2 ° C, 12 hours light-dark cycle (lighted from 8 am to 8 pm) in the breeding room) Humidity 55 ± 10%) was preliminarily raised for one week or more. During pre-breeding, water and food were freely consumed.

[2. Test sample]
Haloperidol: Wako Pure Chemical Industries, Ltd.
Ovalbumin: manufactured by Sigma.
Lactoperoxidase: A product extracted from bovine milk manufactured by Morinaga Milk Industry.
Lysozyme: Made by Sigma.
Haloperidol is suspended in water for injection (Otsuka Pharmaceutical Co., Ltd.) containing 1% (w / v) sodium carboxymethylcellulose (Wako Pure Chemical Industries, Ltd.), and other substances are water for injection (Otsuka Pharmaceutical Co., Ltd.). Used).

[3. Blood glucose measurement and statistical analysis]
Thirty minutes after administration of the substance, the mouse was started to be continuously maintained with an acrylic resin retainer (manufactured by Natsume Seisakusho). Blood was collected from the tail vein after 0 hours from the start of retention (immediately after the start of retention), 0.5 hours, 1 hour, 2 hours, and 4 hours. The glucose concentration in the blood was measured by an enzyme electrode method using a blood glucose meter (Glutest sensor, manufactured by Sanwa Chemical Laboratory Co., Ltd.).
The average value ± standard error was used to display the measurement result of the blood glucose level. The Mann-Whitney U test was used for the significant difference test.

[4. Test method]
(1-1. Effect of a single dose of haloperidol on the blood glucose elevation response on the day of acclimatization to the laboratory)
Mice preliminarily raised in the breeding room were transferred to the laboratory on the day of the measurement (no treatment on the previous day), divided into groups of 2 mice per cage, and body weight measurement was performed. To this mouse, haloperidol was orally administered at a dose shown in Table 1 (single administration), and after 30 minutes, the haloperidol was retained with an acrylic resin retainer (Natsume Seisakusho). Measurements were made.
As a control, the same measurement was performed except that water for injection was orally administered at a rate of 10 mL / kg instead of the drug.
The measurement results are shown in Table 1.

(1-2. Effect of single administration of test substance on blood glucose increase response on day of acclimatization to laboratory)
Measurement similar to the above (1-1. Effect of single administration of haloperidol on blood glucose elevation reaction on the day of acclimatization to the laboratory on the same day) except that test substance shown in Table 2 was orally administered at the dose shown in Table 2 instead of haloperidol Went.
The measurement results are shown in Table 2.

(2-1. Effects of a single administration of haloperidol on the blood glucose increase response 1 day after acclimatization to the laboratory)
Mice preliminarily raised in the breeding room were transferred to the laboratory and divided into groups of 2 mice per cage, and then body weight was measured. Then, after acclimatizing to the laboratory for 6 hours and measuring the body weight again, it was returned to the breeding room while being kept in the cage. One day after returning to the breeding room, the mouse was moved to the laboratory while being placed in a cage, and the body weight was measured. To this mouse, haloperidol was orally administered at a dose shown in Table 3 (single administration), and after 30 minutes, it was retained with an acrylic resin retainer (Natsume Seisakusho). Measurements were made.
As a control, the same measurement was performed except that water for injection was orally administered at a rate of 10 mL / kg instead of the drug.
Table 3 shows the measurement results.

(2-2. Effect of single administration of test substance on blood glucose increase response 1 day after acclimatization to laboratory)
Instead of haloperidol, the test substance shown in Table 4 was administered orally at the dose shown in Table 4. Similar to the above (2-1. Effect of single administration of haloperidol on blood glucose elevation after 1 day of acclimatization to the laboratory) Measurements were made.
Table 4 shows the measurement results.

(3-1. Effect of single oral administration of haloperidol on blood glucose increase response measured after standing in light box for 5 seconds after acclimatization to laboratory)
Mice preliminarily raised in the breeding room were transferred to the laboratory and divided into groups of 2 mice per cage, and then body weight was measured. Then, after acclimatizing to the laboratory for 6 hours and measuring the body weight again, it was returned to the breeding room while being kept in the cage. One day after returning to the breeding room, the mouse was moved to the laboratory while being placed in a cage, and the body weight was measured. This mouse was left in a light box of a light / dark experimental box (Ohara Seisakusho) for 5 seconds, and 30 minutes later, the drugs shown in Table 5 were orally administered at the doses shown in Table 5. After 30 minutes, the sample was retained with an acrylic resin retainer (Natsume Seisakusho), and the blood glucose level was measured while maintaining the state.
As a control, the same measurement was performed except that water for injection was orally administered at a rate of 10 mL / kg instead of the drug.
Table 5 shows the measurement results.

(3-2. Effect of single oral administration of test substance on blood glucose increase response measured after standing in light box for 5 seconds after acclimatization to laboratory)
Instead of haloperidol, the test substance shown in Table 6 was administered orally at the dose shown in Table 6 above (3-1. Acclimated to the blood glucose increase response measured after 5 days of habituation in the laboratory and left in a light box for 5 seconds. The same measurement as in the case of single oral administration of haloperidol was performed.
Table 6 shows the measurement results.

[5. Test results and discussion]
When the influence of haloperidol on the blood glucose elevation response on the day of acclimatization to the laboratory was examined, no clear effect was observed as shown in Table 1. Further, when the influence of the test substance on the blood glucose increase reaction was examined, as shown in Table 2, no significant effect was observed when any of ovalbumin, lactoperoxidase, or lysozyme was administered.
When the influence of haloperidol on the blood glucose increase response after 1 day of acclimatization to the laboratory was examined, as shown in Table 3, the blood glucose increase response was remarkably attenuated. Further, when the influence of the test substance on the blood glucose elevation reaction was examined, as shown in Table 4, even when ovalbumin (1000 mg / kg, 2000 mg / kg) or lactoperoxidase (2000 mg / kg) was administered, it was remarkable. Although no effect was observed, administration of lysozyme (1000 mg / kg, 2000 mg / kg) attenuated the blood glucose elevation response in a dose-dependent manner.
After studying the effect of haloperidol on the blood glucose elevation response measured after leaving in the light box for 5 seconds after acclimatization to the laboratory, as shown in Table 5, the blood glucose elevation response was significantly enhanced only immediately after administration. One hour after administration showing the maximum value, a tendency of attenuation was observed, and no clear effect was observed. Further, when the influence of the test substance on the blood glucose elevation reaction was examined, as shown in Table 6, no significant effect was observed even when lysozyme, ovalbumin, or lactoperoxidase was administered.

Table 7 shows the effect of each substance on the blood glucose increase response under the sustained retention under the above experimental conditions. Each code | symbol in Table 7 has the following meaning, respectively.
↑↑: Strongly enhances the blood sugar rising response.
↑: Increases the blood sugar rising response.
→: The effect on the blood sugar elevation reaction is small or unclear.
↓: Attenuates the blood sugar rising reaction.
↓↓: Strongly attenuates the blood sugar rise response.

  As shown in these results, the action attitude of lysozyme on the glycemic response was similar to that of haloperidol, a therapeutic drug for schizophrenia, suggesting that lysozyme has a psychotropic effect similar to haloperidol.

<Test Example 2-1>
In this study, we investigated the correlation between apomorphine administration and standing behavior.
[1. Test animal]
A 6-week-old ddY male mouse purchased from Japan SLC was used.
Prior to the test, a preliminary breeding period of one week or more was provided in a substantially constant environment (temperature 22 ± 2 ° C., humidity 55 ± 10%) with a 12-hour light / dark cycle. During pre-breeding, water and food were freely consumed.
[2. Test sample]
Apomorphine: manufactured by Sigma. It was used by dissolving in physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.).
[3. Test method]
The ddY male mice were divided into 5 groups of 4-6 mice per group, and apomorphine was administered subcutaneously at 4 doses from 0.2 mg / kg to 2 mg / kg. As a control, physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.) was administered subcutaneously.
The number of rising behaviors that occurred per minute was measured 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, and 60 minutes after administration of apomorphine.
[4. Test results and discussion]
Table 8 shows the results. When apomorphine was administered subcutaneously to mice, an increase in standing behavior was observed in a dose-dependent manner.

<Test Example 2-2>
In this test, the inhibitory effect of haloperidol on the standing behavior was confirmed.
[1. Test animal]
As in Test Example 2-1, 6-week-old ddY male mice purchased from Japan SLC were used.
Prior to the test, a preliminary breeding period of one week or more was provided in a substantially constant environment (temperature 22 ± 2 ° C., humidity 55 ± 10%) with a 12-hour light / dark cycle. During pre-breeding, water and food were freely consumed.
[2. Test sample]
Apomorphine: manufactured by Sigma. It was used by dissolving in physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.).
Haloperidol: Wako Pure Chemical Industries, Ltd. The suspension was used in water for injection (Otsuka Pharmaceutical Co., Ltd.) containing 1% (w / v) sodium carboxymethylcellulose (Wako Pure Chemical Industries, Ltd.).
[3. Test method]
The ddY male mice were divided into 4 groups of 6 mice, and were orally administered in three doses of haloperidol of 0.2 mg / kg, 0.5 mg / kg, and 1 mg / kg. As a control, water for injection (Otsuka Pharmaceutical Co., Ltd.) was orally administered.
One hour after administration of haloperidol, 2 mg / kg of apomorphine was subcutaneously administered.
From 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, and 60 minutes after the administration of apomorphine, the number of rising actions that occurred per minute was measured. The Mann-Whitney U test was used for the significance test.
[4. Test results and discussion]
Table 9 shows the results. Standing behavior induced by apomorphine was reduced in a dose-dependent manner by the administration of haloperidol.
In the haloperidol 1 mg / kg administration group, the total number of rising behaviors was also significantly reduced.

<Test Example 2-3>
In this test, the inhibitory effect of the lysozyme on the standing behavior was confirmed.
[1. Test animal]
As in Test Example 2-1, 6-week-old ddY male mice purchased from Japan SLC were used.
Prior to the test, a preliminary breeding period of one week or more was provided in a substantially constant environment (temperature 22 ± 2 ° C., humidity 55 ± 10%) with a 12-hour light / dark cycle. During pre-breeding, water and food were freely consumed.
[2. Test sample]
Apomorphine: manufactured by Sigma. It was used by dissolving in physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.).
Lysozyme: Made by Sigma. Used by dissolving in water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.).
[3. Test method]
The ddY male mice were divided into 4 groups with 6 or 8 mice per group.
As a test sample, lysozyme was prepared at 2000 mg / kg and orally administered to mice. As a control sample, water for injection (Otsuka Pharmaceutical Co., Ltd.) was orally administered.
One hour after administration of the test sample or control sample, 2 mg / kg of apomorphine was administered subcutaneously.
Starting from 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, and 60 minutes after the administration of apomorphine, the number of rising actions that occurred per minute was measured. The Mann-Whitney U test was used for the significance test.
[4. Test results and discussion]
Table 10 shows the results. The number of rising behaviors induced by apomorphine was significantly reduced 40 minutes after administration of lysozyme.

<Test Example 2-4>
In this study, we investigated the inhibitory effect on apomorphine-induced standing behavior when lysozyme and haloperidol were used in combination.
[1. Test animal]
As in Test Example 2-1, 6-week-old ddY male mice purchased from Japan SLC were used.
Prior to the test, a preliminary breeding period of one week or more was provided in a substantially constant environment (temperature 22 ± 2 ° C., humidity 55 ± 10%) with a 12-hour light / dark cycle. During pre-breeding, water and food were freely consumed.
[2. Test sample]
Apomorphine: manufactured by Sigma. It was used by dissolving in physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.).
Haloperidol: Wako Pure Chemical Industries, Ltd. The suspension was used in water for injection (Otsuka Pharmaceutical Co., Ltd.) containing 1% (w / v) sodium carboxymethylcellulose (Wako Pure Chemical Industries, Ltd.).
Lysozyme: Made by Sigma. Used by dissolving in water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.).
[3. Test method]
The ddY male mice were divided into 2 groups, each group consisting of 8 mice, and haloperidol 0.2 mg / kg was orally administered to each group of mice. After 30 minutes, lysozyme was orally administered to mice at 2000 mg / kg in the experimental group, and water for injection (Otsuka Pharmaceutical Co., Ltd.) was orally administered to the control group.
Furthermore, apomorphine 2 mg / kg was subcutaneously administered 1 hour after administration of the test sample or water for injection.
Then, the number of rising actions that occurred per minute was measured starting from 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, and 60 minutes after the administration of apomorphine.
[4. Test results and discussion]
Table 11 shows the results. In contrast to apomorphine-induced standing behavior, haloperidol had no significant effect when administered alone at 0.2 mg / kg (see Test Example 2-2, Table 9), but when combined with lysozyme, There was a decreasing trend in the number of times.

<Test Example 3-1>
In this study, we examined the correlation between haloperidol and catalepsy (hardness symptoms), which is known as its side effects. It was also confirmed that catalepsy did not occur even when lysozyme was administered alone.
[1. Test animal]
As in Test Example 2-1, 6-week-old ddY male mice purchased from Japan SLC were used.
Prior to the test, a preliminary breeding period of one week or more was provided in a substantially constant environment (temperature 22 ± 2 ° C., humidity 55 ± 10%) with a 12-hour light / dark cycle. During pre-breeding, water and food were freely consumed.
[2. Test sample]
Haloperidol: Wako Pure Chemical Industries, Ltd. The suspension was used in water for injection (Otsuka Pharmaceutical Co., Ltd.) containing 1% (w / v) sodium carboxymethylcellulose (Wako Pure Chemical Industries, Ltd.).
Lysozyme: Made by Sigma. Used by dissolving in water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.).
[3. Test method]
The ddY male mice were divided into 4 groups of 4 to 7 per group, and haloperidol or lysozyme was orally administered. Water for injection was orally administered to the control group.
As a measurement of catalepsy-inducing action, the mice were brought to a height of 6.5 cm 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 240 minutes and 300 minutes after administration of the test sample to the mice. Catalepsy was determined to be positive when held by a stretched wire and maintained in posture for 60 seconds or longer.
[4. Test results and discussion]
The results are shown in Table 12. No catalepsy was observed when haloperidol 0.5 mg / kg was orally administered. However, when haloperidol 1.0 mg / kg was orally administered, 2 to 4 of 5 cases were observed 60 to 300 minutes after administration. Catalepsy was observed.
On the other hand, no catalepsy was observed in the lysozyme administration group.

<Test Example 3-2>
In this study, it was confirmed that even when haloperidol (0.5 mg / kg) and lysozyme were administered in combination, catalepsy caused by haloperidol was not enhanced.
[1. Test animal]
As in Test Example 2-1, 6-week-old ddY male mice purchased from Japan SLC were used.
Prior to the test, a preliminary breeding period of one week or more was provided in a substantially constant environment (temperature 22 ± 2 ° C., humidity 55 ± 10%) with a 12-hour light / dark cycle. During pre-breeding, water and food were freely consumed.
[2. Test sample]
Haloperidol: Wako Pure Chemical Industries, Ltd. The suspension was used in water for injection (Otsuka Pharmaceutical Co., Ltd.) containing 1% (w / v) sodium carboxymethylcellulose (Wako Pure Chemical Industries, Ltd.).
Lysozyme: Made by Sigma. Used by dissolving in water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.).
[3. Test method]
The ddY male mice were divided into 2 groups of 7 mice, each of which was orally administered haloperidol 0.5 mg / kg.
After another 30 minutes, lysozyme was orally administered to the experimental group, and water for injection was orally administered to the control group.
To measure catalepsy-inducing action, 30, 60, 90, 120, 180, 240, and 300 minutes after administration of haloperidol to the mouse, the mouse was held on a 6.5 cm-high wire, and the posture was 60 seconds. When maintained above, it was determined that catalepsy was positive.
[4. Test results and discussion]
The results are shown in Table 13.
In the group in which water for injection was administered after administration of haloperidol 0.5 mg / kg in which no occurrence of catalepsy was observed by single administration (see Test Example 3-1), in the group in which lysozyme was administered after administration of haloperidol 0.5 mg / kg Although catalepsy was slightly observed, there was almost no difference in the incidence.

Claims (4)

  A haloperidol indication drug containing lysozyme as an active ingredient.   The haloperidol indication therapeutic agent according to claim 1, wherein the haloperidol indication is a positive symptom of schizophrenia.   The haloperidol indication is selected from the group consisting of bipolar disorder, delirium, dyskinesia, Huntington's disease, Tourette's disorder, amphetamine addiction, paranoia, confusion, excitement, refractory rebellion, nausea and vomiting. The haloperidol indication therapeutic agent as described in 2.   The food-drinks to which the haloperidol indication therapeutic agent as described in any one of Claims 1-3 was added.