WO2012002522A1 - Therapeutic agent for indications for haloperidol, and beverage or food - Google Patents

Abstract

Disclosed are: a therapeutic agent for indications for haloperidol, which comprises α-lactoalbumin as an active ingredient; a beverage or food which contains the therapeutic agent for indications for haloperidol; α-lactoalbumin for use in the treatment of indications for haloperidol; and a method for treating indications for haloperidol, which comprises administering an effective amount of α-lactoalbumin to a patient who needs the treatment. The therapeutic agent for indications for haloperidol is safe and can be used in a simple manner.

Description

Haloperidol indication drug and food and drink

The present invention relates to a haloperidol indication therapeutic agent and a food or drink to which the haloperidol indication treatment agent is added.
This application claims priority based on Japanese Patent Application No. 2010-152386 filed in Japan on July 2, 2010, the contents of which are incorporated herein by reference.

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 are diseases caused by functional and organic disorders of the brain, and are treated with psychotherapy, electroconvulsive therapy, or pharmacotherapy using psychotropic drugs such as haloperidol. Yes.
Haloperidol [4- [4- (4-Chlorophenyl) -4-hydroxypiperidin-1-yl] -1- (4-fluorophenyl) butan-1-one] is derived from the analgesic meperidine by Janssen et al. And is a stimulant amphetamine It is a butyrophenone antipsychotic drug that was discovered as a drug that suppresses the momentum increase induced by. Haloperidol has a CNS inhibitory effect similar to that of chlorpromazine, and is more potent than chlorpromazine in nerve blockage in animal experiments and antagonism against apomorphine-induced vomiting. Haloperidol also shows acclimation and suppression of condition avoidance reactions. Clinically, haloperidol is said to be effective for positive symptoms (excited state, etc.) of schizophrenia and particularly good for ineffective cases of phenothiazines. In addition to schizophrenia, haloperidol is also used for bipolar disorder, delirium, dyskinesia, Huntington's disease, Turret disorder, amphetamine addiction, paranoia, severe confusion and excitement. Haloperidol is also effective for intractable rebellion, nausea and vomiting caused by causes other than mental illness, such as nausea and vomiting caused by side effects of anticancer drugs, nausea and vomiting, which are symptoms of motion sickness and Meniere's syndrome. ing.

On the other hand, α-lactalbumin (hereinafter sometimes abbreviated as α-LA) is a globular protein that occupies about 25% of whey protein, has 8 SH groups in the molecule, and has all S—S bonds. It is formed and the stability of the structure is high. α-LA is known to be a protein involved in lactose synthesis. Α-LA is also known as a calcium binding protein, and calcium is chelated by acidic amino acids in a loop formed by intramolecular SS bonds of α-LA. It is considered (Non-Patent Document 1).
In addition to the above, α-LA is known to have gelling properties and is used in foods as a masking effect and quality improver in addition to egg white substitutes and paste products (non-patented) Reference 2). In addition, it has been reported that α-LA has an anti-ulcer action, mucin production secretion promoting action, gastrointestinal motility regulating action, alcohol metabolism promoting action, aldehyde dehydrogenase expression promoting action, blood glucose level regulating action, etc. (Patent Documents 1 to 5 and Non-Patent Document 3). Analgesic and anti-inflammatory effects have also been reported (Non-patent Document 4).
In addition, α-LA has a high content of tryptophan, which is a precursor of serotonin (5-hydroxytryptamine), and the influence of α-LA intake on serotonin content in the brain has been studied. Serotonin is a neurotransmitter involved in memory, appetite, sleep and the like, and its regulation is made possible mainly by regulation of tryptophan, which is a precursor of serotonin. Serotonin in the brain is known to increase when the ratio of tryptophan to neutral amino acids in the blood (Trp / LNAA) increases. In Non-patent Document 5, regarding α-LA, when a rat is ingested an α-LA diet, the serotonin content in the brain is significantly increased 3 and 6 days after ingestion. Ingestion of LA diet (Trp / LNAA is 9) is a significant increase in Trp / LNAA in blood compared to ingestion of casein diet (Trp / LNAA is 4). In subjects under chronic stress, After ingestion of α-LA diet, prolactin, which is an indicator of changes in brain serotonin, is significantly increased, reducing mood when stress is applied, and improving the attention of subjects under chronic stress There is a report that there is a report. It has also been reported that a hydrolyzate of α-LA stimulates secretion of glucagon-like peptide-2 and growth of the small intestine in dairy animals (Non-patent Document 6). However, as a pharmacological action of α-LA, an action for preventing or treating a haloperidol indication such as schizophrenia has not been reported.

International Publication No. 01/007077 Pamphlet JP 2002-255848 A JP 2004-231643 A International Publication No. 04/056207 Pamphlet JP 2008-143861 A

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 of various known adverse effects including carcinogenesis.
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, the evaluation method is 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 easily evaluate the psychotropic effects of substances without being restricted by the classification of mental disorders (Japanese Patent Laid-Open No. 2011-033408).
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.
The experimental condition is selected from the group consisting of (1) to (6), for example.
(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 a test animal, a blood glucose increase response is induced by the continuous 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 blood glucose increase response is affected by the experimental conditions before the 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 above difference. Specifically, when there is no clear change in the glycemic response under one experimental condition and the glycemic response is enhanced or attenuated under another experimental condition, the administered drug has some psychotropic effect It can be judged that there is a possibility. 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, there is a possibility that the administered drug may have some psychotropic effect even if there is no clear change in the glycemic response under one experimental condition and the glycemic response is accelerated or delayed under another experimental condition. It can be judged that there is. 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 elevation 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 among 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 α-lactalbumin has a psychotropic effect similar to that of haloperidol, as shown in Test Example 1 described later. I found it. In addition, it was found to be effective in reducing nausea and vomiting.

This invention is made | formed based on the said knowledge, and has the following aspects.
[1] A therapeutic agent for haloperidol indication, comprising α-lactalbumin 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 and refractory rebellion The haloperidol indication therapeutic agent of description.
[4] The haloperidol indication therapeutic agent according to [1], wherein the haloperidol indication is selected from the group consisting of nausea and vomiting.
[5] A food and drink to which the haloperidol indication therapeutic agent according to any one of [1] to [4] is added.
[6] α-Lactalbumin for treatment of haloperidol indication.
[7] The α-lactalbumin according to [6], wherein the haloperidol indication is a positive symptom of schizophrenia.
[8] The haloperidol indication is selected from the group consisting of bipolar disorder, delirium, dyskinesia, Huntington's disease, Tourette disorder, amphetamine addiction, paranoia, confusion, excitement, and refractory rebellion [6] Α-Lactalbumin as described.
[9] The α-lactalbumin according to [6], wherein the haloperidol indication is selected from the group consisting of nausea and vomiting.
[10] A method for treating haloperidol indication, comprising administering an effective amount of α-lactalbumin to a patient in need of treatment.
[11] The method for treating haloperidol indication according to [10], wherein the haloperidol indication is a positive symptom of schizophrenia.
[12] The haloperidol indication is selected from the group consisting of bipolar disorder, delirium, dyskinesia, Huntington's disease, Tourette disorder, amphetamine addiction, paranoia, confusion, excitement and refractory rebellion [10] A method of treating the indicated haloperidol indication.
[13] The method for treating a haloperidol indication according to [10], wherein the haloperidol indication is selected from the group consisting of nausea and vomiting.

According to the present invention, a haloperidol indication therapeutic agent that can be used safely and easily can be provided.

10 is a graph showing the results of Test Example 6.

The therapeutic agent for haloperidol indication of the present invention contains α-lactalbumin (hereinafter abbreviated as α-LA) as an active ingredient.
α-LA has a haloperidol-like action, that is, a pharmacological action similar to haloperidol, and by taking an effective amount of α-LA, haloperidol indications 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's disorder, amphetamine addiction, paranoia, confusion, and excitement. Also included are refractory rebellion, nausea and vomiting. Nausea and vomiting are effective for nausea and vomiting as symptoms of mental illness, nausea and vomiting as side effects of anticancer drugs such as cisplatin, nausea and vomiting as symptoms of motion sickness and Meniere's syndrome.
“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 are not only positive symptoms such as delusions, hallucinations and hallucinations, but also various mental abnormalities ranging from cognitive impairment such as sensory abnormalities and negative symptoms such as withdrawal and depression. . From adolescence to middle age, the disease develops with symptoms that are characteristic of perception, thought, emotion, or behavior, 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 comprehensive comprehensive treatment system for early detection, treatment, rehabilitation activities, prevention of recurrence, etc. is desired. 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 as therapeutic agents for improving the positive symptoms of schizophrenia.
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 are often associated with side effects such as weight gain and exacerbation of diabetes.
On the other hand, α-LA, 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 α-LA sufficient to exert a therapeutic effect for haloperidol indication is administered by haloperidol. Can be taken on a daily basis, if necessary, on a long-term basis without causing the side effects (extrapyramidal disturbances, etc.) seen during

The α-LA used in the present invention is preferably derived from mammalian milk. In particular, when the haloperidol indication therapeutic agent of the present invention is used in a pharmaceutical composition for humans, foods and drinks, α-LA derived from human milk or its milk is traditionally used for foods and drinks. Α-LA derived from milk of mammals (such as cows, sheep, goats, etc.) is preferred, and those derived from milk are particularly preferred. This is because these have been used for human consumption during historical years, and thus have a very high level of safety for humans. Further, whey derived from milk is particularly suitable as a raw material for α-LA used in the present invention because it can be stably obtained in large quantities as a by-product of dairy production.
The amino acid sequence of α-LA derived from mammalian milk is EMBL-Accession No. registered in the database of European Molecular Biology Laboratory (EMBL). P00709 (human-derived α-LA), EMBL-Accession No. Amino acid sequences described in P00711 (bovine-derived α-LA) and the like can be exemplified.
Α-LA derived from milk of mammals can be produced by an ammonium sulfate precipitation method by a conventional method (for example, by Kinjiro Yukawa, “Latest Revised Dairy Technology Handbook”, Dairy Technology Promotion Association, pp. 120-122, 1975). it can. In addition, the iron chloride method [Journal of Food Science, Vol. 50, pp. 1531 to 1536, 1985], ultrafiltration method (Japanese Patent Laid-Open No. 5-268879) It can also be produced by an ion exchange method (Japanese Patent No. 2916047) or the like. More simply, commercially available α-LA (eg, Sigma, Davisco, etc.) can be used. Furthermore, recombinant α-LA produced by microorganisms, animal cells, transgenic animals or the like by genetic manipulation may be used.
As α-LA, it is also possible to use a pharmaceutically acceptable salt or pharmaceutically acceptable solvate of α-LA obtained by the above chemical or genetic engineering method. Examples of the salt include organic acid salts including inorganic acid salts such as hydrochloride and carboxylates such as acetate. Examples of the solvate include hydrates.
α-LA, α-LA pharmaceutically acceptable salts and α-LA pharmaceutically acceptable solvates may be used alone or in combination of two or more.

As an active ingredient of the therapeutic agent for haloperidol indication of the present invention, a hydrolyzate of α-LA may be used. In this case, the hydrolyzate may be used in combination with at least one selected from the above α-LA, α-LA pharmaceutically acceptable salts, and pharmaceutically acceptable solvates.
The hydrolyzate of α-LA can be obtained by hydrolyzing α-LA with a hydrolase. Hereinafter, a method for hydrolyzing α-LA with a hydrolase will be specifically described.

First, α-LA is dispersed in water or hot water and dissolved to prepare an α-LA solution.
The concentration of α-LA in the α-LA solution is not particularly limited, but a concentration range of about 5 to 15% (w / w) in terms of protein is desirable from the viewpoint of efficiency and operability. In addition, it is desirable to sterilize the α-LA solution at 70 to 90 ° C. for about 10 to 15 seconds from the viewpoint of preventing deterioration due to contamination with various bacteria.
Next, it is preferable to add an alkaline agent or an acid agent to the α-LA solution and adjust the pH of the solution to or near the optimum pH of the hydrolase used.
The alkali agent or acid agent used here may be any alkali agent or acid agent as long as it is acceptable for foods or pharmaceuticals. Specifically, examples of the alkali agent include sodium hydroxide, potassium hydroxide, potassium carbonate and the like, and examples of the acid agent include hydrochloric acid, citric acid, phosphoric acid, acetic acid and the like.

Next, a hydrolase solution is added to the α-LA solution.
The hydrolase is not particularly limited as long as it is an enzyme that hydrolyzes a protein, and is derived from an animal (for example, trypsin, chymotrypsin, pepsin, pancreatin), a plant (for example, papain), or a microorganism (for example, Examples thereof include proteases or peptidases of lactic acid bacteria, yeasts, molds, Bacillus subtilis, actinomycetes, etc., and endopeptidases are preferred, and among them, pig-derived pepsin is preferably used. One type of hydrolase may be used, or two or more types may be used in combination. When using 2 or more types of enzymes, each enzyme reaction may be performed simultaneously or separately.

Next, the hydrolysis of α-LA is started by maintaining the solution to which the hydrolytic enzyme has been added at an appropriate temperature, for example, 30 to 60 ° C., preferably 45 to 55 ° C., depending on the type of enzyme.
The hydrolysis reaction time is a time to reach a preferable decomposition rate while monitoring the decomposition rate of the enzyme reaction. In the present invention, the decomposition rate is preferably 6 to 80%, and particularly preferably 10 to 70%. In order for the hydrolyzate of α-LA to exhibit an action as an active ingredient of a therapeutic agent for haloperidol, it is preferable that the decomposition rate is at least the upper limit of the above range. When the above upper limit is exceeded, there is a risk of a decrease in flavor when the α-LA hydrolyzate is added to food and drink. In addition, when the value is lower than the lower limit of the above range, the decomposition is hardly progressed, but it is considered that it is substantially difficult to perform the decomposition in a certain condition, so the decomposition rate is 6%. The above is preferable.
The method for calculating the degradation rate of the protein (here α-LA) in this specification is based on the Kjeldahl method (edited by the Japan Food Industry Association, “Food Analysis Method”, page 102, Korin Co., Ltd., 1984). Measure the total nitrogen amount, and measure the formol-type nitrogen content of the sample by the formol titration method (Mitada et al., “Food Engineering Experiments”, Volume 1, page 547, Yokendo, 1970). Is a method for calculating the decomposition rate from the following equation.
Decomposition rate (%) = (formol nitrogen amount / total nitrogen amount) × 100

The enzyme reaction is stopped by deactivation of the enzyme in the hydrolyzed solution, and can be performed by heat deactivation treatment by a conventional method. The heating temperature and holding time of the heat deactivation treatment are appropriately set under conditions that allow for sufficient deactivation in consideration of the thermal stability of the enzyme used. The deactivation can be performed, for example, in a temperature range of 80 to 130 ° C. and a holding time of 30 minutes to 2 seconds.
After stopping the enzyme reaction, it is preferable to adjust the pH of the resulting reaction solution to near neutrality by adding an acid or alkali.

The solution containing the α-LA hydrolyzate obtained as described above can be used as it is for the therapeutic agent for haloperidol indication of the present invention. It can also be used as a concentrated solution concentrated by a method, and furthermore, this concentrated solution can also be used as a powder dried by a known method.

The therapeutic agent for haloperidol indication of the present invention may be composed only of α-LA, or may be a pharmaceutical composition containing α-LA and other components other than α-LA. The other ingredients are not particularly limited as long as they are pharmaceutically acceptable, and for example, active ingredients other than α-LA may be blended, and conventionally blended in pharmaceutical compositions. Further, a pharmaceutically acceptable additive (for example, a pharmaceutical carrier to be described later) can be blended.
As active ingredients other than α-LA, those known as active ingredients of haloperidol indication treatment drugs can be used, and the haloperidol indication treatment drug is selected from among known active ingredients depending on the haloperidol indication to be treated. It can be selected as appropriate. 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 present invention relates to a method for treating haloperidol indications, comprising administering an effective amount of α-LA to a patient in need of treatment, or an effective amount of α-LA and pharmaceutically effective for a patient in need of treatment. It includes a method of administering a pharmaceutical composition containing an acceptable additive.

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, inhalation, transdermal, intravenous and the like.
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 effective daily dose for treatment is usually 2 to 1000 mg / kg body weight, preferably 10 to 500 mg / kg body weight in terms of the solid content of α-LA per kg body weight. Is more preferable.
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, ointments, patches, injections and the like can be mentioned.
Formulation can be appropriately performed by a known method according to the dosage form.
In the formulation, only the active ingredient may be formulated, or a pharmaceutically acceptable formulation carrier may be blended as appropriate.
When the pharmaceutical carrier is blended, the blending amount of the active ingredient in the therapeutic agent for haloperidol indication 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.
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 a haloperidol indication treatment effect, the haloperidol indication agent is added to a pharmaceutical agent, food / drink product or nutritional agent, thereby adding the haloperidol indication agent to the haloperidol indication agent. It can be a medicinal product, food or drink or nutrient for treatment of indication.
One aspect of the invention is α-LA for the treatment of haloperidol indications.
Another aspect of the present invention is the use of α-LA to produce a haloperidol indication therapeutic agent.

<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 in the case of administering the therapeutic agent for haloperidol indication of the present invention can be 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 α-LA so that the above-mentioned daily dose can be easily taken. Usually, the amount of α-LA in the food or drink is preferably 0.1 to 99% (w / w), more preferably 1 to 95% (w / w).

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 an edible composition comprising α-LA and a carrier acceptable as a food or drink. For example, solid foods such as bread, chewing gum, gum drop (gummy), cookies, chocolate, confectionery, cereals, jam, ice cream, yogurt, jelly, etc., cream or gel food, green tea, black tea, oolong tea It is possible to make all food and drink forms such as teas such as juice, beverages such as juice, 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 treatment effect of haloperidol indication. Needless to say, the wording is included in the scope of the present invention. For example, it may be a word for improving haloperidol indication, 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, an act of describing the above-mentioned use in a product or product packaging relating to food or drink can be listed as an act of display, 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 imports, display advertisements related to products, price lists or transaction documents to display or distribute, or describe the above uses in information containing them, electromagnetic The act provided by the objective (Internet etc.) method etc. can be illustrated.
On the other hand, the displayed content (displayed 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, the display approved by the Ministry of Health, Labor and Welfare, for example, the display approved under the food system for specific health use and a similar system 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, the present invention will be described in more detail with reference to test examples and examples, but the present invention is not limited to the following examples.

<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 ad libitum.

[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.
α-LA: manufactured by Davisco.
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 collected 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. Effects 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 as described above 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. Effects of a single test substance administration on blood glucose elevation response on the day of acclimatization to the laboratory)
Measurement similar to the above (1-1. Effects of a single administration of haloperidol on the blood glucose elevation response on the day of acclimatization to the laboratory on the same day) except that the 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 dose 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 as described above 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 a single test substance administration on the blood glucose increase response 1 day after acclimatization to the laboratory)
Instead of haloperidol, the test substance shown in Table 4 was administered orally at the dose shown in Table 4. (2-1. Effect of single administration of haloperidol on glycemic response 1 day after acclimatization to the laboratory) Measurements were made.
Table 4 shows the measurement results.

(3-1. Effects of single oral administration of haloperidol on the blood glucose increase response measured after standing in a light box for 5 seconds one 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. 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 as described above 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. (3-1. Acclimatization to the laboratory. 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 elevation reaction was examined, as shown in Table 2, no significant effect was observed when any of ovalbumin, lactoperoxidase and α-LA 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 α-LA (1000 mg / kg, 2000 mg / kg) attenuated the blood glucose elevation response in a dose-dependent manner. Even at 1000 mg / kg, it showed a maximum value and was significant 1 hour after administration. The blood sugar rising response was attenuated.
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 when any of ovalbumin, lactoperoxidase, and α-LA 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 α-LA on the blood glucose elevation response was similar to that of haloperidol, a therapeutic drug for schizophrenia, suggesting that α-LA has a psychotropic effect similar to haloperidol. It was done.

<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 ad libitum.
[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, 4 to 6 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]
Similar to 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 ad libitum.
[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 α-LA on the standing behavior was confirmed.
[1. Test animal]
Similar to 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 ad libitum.
[2. Test sample]
Apomorphine: manufactured by Sigma. It was used by dissolving in physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.).
α-LA: manufactured by Davisco. 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.
Α-LA was prepared as a test sample 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 50 minutes after the administration of α-LA.

<Test Example 2-4>
In this study, the inhibitory effect on apomorphine-induced standing behavior when α-LA and haloperidol were used in combination was examined.
[1. Test animal]
Similar to 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 ad libitum.
[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.).
α-LA: manufactured by Davisco. 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. Thirty minutes later, α-LA 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.
The Mann-Whitney U test was used for the significance test.
[4. Test results and discussion]
Table 11 shows the results. Haloferidol had no significant effect on the standing behavior induced by apomorphine when administered alone at 0.2 mg / kg (see Test Example 2-2, Table 9), but when combined with α-LA, The total number of rising behaviors also decreased significantly.

<Test Example 3-1>
In this study, we examined the correlation between haloperidol and catalepsy (hardness symptoms), which is known as its side effects. In addition, it was confirmed that no catalepsy occurred even when α-LA was administered alone.
[1. Test animal]
Similar to 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 ad libitum.
[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.).
α-LA: manufactured by Davisco. 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, 4 to 7 per group, and haloperidol or α-LA was orally administered. Water for injection was orally administered to the control group.
As a measurement of catalepsy-inducing action, the mice were measured at a height of 6.5 cm at 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 wire stretched 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 α-LA administration group.

<Test Example 3-2>
In this study, it was confirmed that the catalepsy caused by haloperidol was not enhanced even when haloperidol (0.5 mg / kg) and α-LA were administered in combination.
[1. Test animal]
Similar to 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 ad libitum.
[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.).
α-LA: manufactured by Davisco. 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, α-LA was orally administered to the experimental group, and water for injection was orally administered to the control group.
As a measurement of catalepsy-inducing action, the mice were measured at a height of 6.5 cm at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 240 minutes, and 300 minutes after administration of haloperidol to mice. Catalepsy was determined to be positive when it was held by a wire stretched over and maintained for 60 seconds or longer.
[4. Test results and discussion]
The results are shown in Table 13.
A group in which water for injection was administered after administration of 0.5 mg / kg of haloperidol in which no occurrence of catalepsy was observed by single administration (see Test Example 3-1), a group in which α-LA was administered after administration of haloperidol 0.5 mg / kg, In all cases, the occurrence of catalepsy was slightly observed, but there was almost no difference in the incidence.

<Test Example 3-3>
In this study, it was confirmed that catalepsy caused by haloperidol was not enhanced even when haloperidol (1.0 mg / kg) and α-LA were administered in combination.
[1. Test animal]
Similar to 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 ad libitum.
[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.).
α-LA: manufactured by Davisco. 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, 7 mice per group, and haloperidol 1.0 mg / kg was orally administered.
After another 30 minutes, α-LA was orally administered to the experimental group, and water for injection was orally administered to the control group.
As a measurement of catalepsy-inducing action, the mice were measured at a height of 6.5 cm at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 240 minutes, and 300 minutes after administration of haloperidol to mice. Catalepsy was determined to be positive when it was held by a wire stretched over and maintained for 60 seconds or longer.
[4. Test results and discussion]
The results are shown in Table 14.
A group in which water for injection was administered after administration of 1.0 mg / kg of haloperidol in which the occurrence of catalepsy was clearly observed by single administration (see Test Example 3-1), a group in which α-LA was administered after administration of haloperidol at 1.0 mg / kg In both cases, catalepsy was observed, but almost no difference in the incidence was observed.

<Test Example 4>
In this study, it was confirmed that α-LA has an inhibitory effect on cisplatin-induced delayed emesis.
[1. Test animal]
A 12-16 week old ferret purchased from Marshall BioResource Japan was used. Prior to the test, a preliminary breeding period of 1 week or more was provided in a 12-hour light-dark cycle under an almost constant environment (temperature 18 to 28 ° C., humidity 30 to 80%). During pre-breeding and testing, water and food were ad libitum.
[2. Test sample]
Cisplatin: manufactured by Sigma. Used by dissolving in physiological saline (Otsuka Pharmaceutical).
α-LA: manufactured by Davisco. Used by dissolving in water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.).
[3. Test method]
Vomiting was induced by intraperitoneally administering cisplatin to a ferret at 5 mg / kg. Α-LA 200 mg / kg was orally administered at a 12-hour interval from 12 hours after cisplatin administration, that is, 12 hours, 24 hours, 36 hours, and 48 hours later (experimental group).
On the other hand, water for injection was orally administered at the same time and frequency as a control (control group). There were 5 ferrets in each group.
The number of vomitings, including vomiting, that occurred between 24 and 72 hours after cisplatin administration was measured.
[4. Test results and discussion]
The results are shown in FIG. There was a tendency to suppress the delayed emetic response induced by cisplatin by oral administration of α-LA.
From these results, it was shown that α-LA is also effective for nausea and vomiting due to side effects of anticancer drugs and motion sickness (motion sickness).

According to the present invention, a haloperidol indication therapeutic agent that can be used safely and easily can be provided.

Claims (13)

1. ¡A drug for treating haloperidol, containing α-lactalbumin as an active ingredient.
2. The haloperidol indication therapeutic agent according to claim 1, wherein the haloperidol indication is a positive symptom of schizophrenia.
3. The haloperidol according to claim 1, wherein 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 and refractory rebellion. Indication treatment drug.
4. The haloperidol indication therapeutic agent according to claim 1, wherein the haloperidol indication is selected from the group consisting of nausea and vomiting.
5. A food or drink to which the haloperidol indication therapeutic agent according to any one of claims 1 to 4 is added.
6. Α-Lactalbumin for the treatment of indications for haloperidol.
7. The α-lactalbumin according to claim 6, wherein the haloperidol indication is a positive symptom of schizophrenia.
8. 7. The α of claim 6, wherein the haloperidol indication is selected from the group consisting of bipolar disorder, delirium, dyskinetics, Huntington's disease, Tourette's disorder, amphetamine addiction, paranoia, confusion, excitement and refractory rebellion. -Lactalbumin.
9. The α-lactalbumin according to claim 6, wherein the indication of haloperidol is selected from the group consisting of nausea and vomiting.
10. A method for treating haloperidol indication, wherein an effective amount of α-lactalbumin is administered to a patient in need of treatment.
11. The method for treating haloperidol indication according to claim 10, wherein the haloperidol indication is a positive symptom of schizophrenia.
12. 11. The haloperidol according to claim 10, wherein the haloperidol indication is selected from the group consisting of bipolar disorder, delirium, dyskinesia, Huntington's disease, Tourette disorder, amphetamine addiction, paranoia, confusion, excitement and refractory rebellion. Indication treatment methods.
13. The method for treating haloperidol indication according to claim 10, wherein the haloperidol indication is selected from the group consisting of nausea and vomiting.

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