KR20120116871A - Agent for treating patulous eustachian tube - Google Patents

Abstract

PURPOSE: A patulons eustachian tube treating agent including limaprost is provided to be used as enhancer of hearing impairment, earache, aliasing, neck and shoulder pain, headache, and depresson. CONSTITUTION: A patulons eustachian tube treating agent includes limaprost. The limaprost is limaprost alpha dex. The symptoms of the patulons eustachian tube are listening to own breathing, dizziness, hearing impairment, earache, neck and shoulder pain, headache, or depression. The patulons eustachian tube is for patients who oriental medicine, anti-anxiety agent, vitamin preparation or ATP formulation are ineffective. 5-10 micro grams of the formulation is administrated in patients having patulons eustachian tube three times a day for 1 day to 52 weeks. The formulation is formed by additionally mixing the oriental medicine, anti-anxiety agent, vitamin preparation or ATP formulation.

Description

GENT OPTREATING PATULOUS EUSTACHIAN TUBE}

The present invention relates to agents for the prevention, treatment and / or symptom improving of ear canal disease.

The ear is the organ responsible for hearing and balance, and is largely divided into the outer, middle and inner ear. The ear canal is a mucosa tube connecting the nasopharyngeal cavity and the middle ear cavity, and has a function of introducing outside air into the middle ear to equalize air pressure inside and outside the eardrum.

Open ear canal disease is a disease in which the closed ear canal is usually in an open state, and causes symptoms such as magnetic emphasis, feeling of obstruction, and self-breathing sound. As a cause of the canopia, stress, blood flow disorder, and rapid weight loss are considered, but the mechanism is unknown and has not yet been identified. Depending on the symptoms and severity, surgery such as drug therapy, injection of fat or silicone into the ear canal, spraying the chemical solution into the ear canal openings, inflamed and narrowed, and surgical procedures such as silicone ear canal pins and cartilage fragments. Surgery is performed, but no effective treatment is established.

In drug therapy, herbal medicines such as Gamiguibi-tang, anti-anxiety medicines, vitamin preparations, adenosine triphosphate preparations (hereinafter referred to as ATP preparations), and the like are used, but no drugs have established efficacy.

On the other hand, limaprost alphadex tablet is oral PGE ₁ with peripheral circulation improving action It is already used in the clinical field as a preparation and is known as a safe medicine. Limaprost alphadex tablet, a formulation containing limaprost, is useful as a prophylactic and / or therapeutic agent for peripheral circulatory disorders, and is very useful for ameliorating symptoms such as obstructive thrombosis and lumbar spinal stenosis. In addition, limaprost, which is an active ingredient of limaprost alphadex, has a vasodilating action, a platelet aggregation inhibiting action, and the like, and it is known that peripheral circulation is improved.

It has been reported that compounds having PGE receptor binding activity, such as limaprost, are effective for inner ear diseases and effective for endoscopic dizziness or endoscopic hearing loss (see Patent Document 1). However, the inner ear and the ear canal are completely different tissues, and so far there is no report that limaprost is effective for open ear canal disease.

Patent Document 1: Japanese Patent Publication No. 2007-023028

At present, no therapeutic drug has been established for the effect of open ear disease. It is an object of the present invention to provide an effective, safe, and orally administrable agent for the prevention, treatment and / or symptom amelioration of open ear disease.

MEANS TO SOLVE THE PROBLEM As a result of earnestly examining in order to solve the said subject, the present inventors discovered that limaprost could be a therapeutic agent of a canopy open disease. In addition, Limaprost has found that the herbal medicines and ATP preparations currently used in the clinical field are also effective for patients with invalid open mouth disease, and completed the present invention.

That is, the present invention is as follows.

1. a prophylactic, therapeutic and / or symptomatic improvement agent of open ear disease containing limaprosts,

2. The agent according to the above 1, wherein the limaprosts are limaprost alphadex,

3. The above symptom of open ear disease is at least one selected from magnetic emphasis, feeling of exhaustion, self-breathing, hearing, dizziness, dizziness, hearing loss, hearing loss, tinnitus, stiff neck, stiff shoulder, headache and depressive symptoms. Or the agent according to 2,

4. The agent according to any one of the above 1 to 3, wherein the open canopy is an open canopy in a patient in which the herbal medicine, anti-anxiety medicine, vitamin preparation and / or ATP preparation is invalid,

5. The amount of 5 µg-10 µg per time, in conversion of limaprost, to oral administration of the patients with oculopathy is administered orally three times a day for 1 to 52 weeks. Formulation,

6. The agent according to the above 5, wherein the patient with open canopy is a patient who is ineffective in herbal medicine, anti-anxiety medicine, vitamin preparation and / or ATP preparation,

7. The agent according to any one of the above 1 to 6, further comprising at least one agent selected from the group consisting of herbal medicines, anti-anxiety drugs, vitamin preparations and ATP preparations,

8. Use of limaprosts for the preparation of prophylaxis, treatment and / or symptom amelioration of open ear disease;

9. Limaprosts used to prevent, treat, and / or ameliorate symptoms of open ear canal disease, and

10. The present invention relates to a method for treating and / or symptomatic improvement of an open ear disease comprising administering an effective amount of limaprost to a patient of open ear disease.

Limaprosts are effective as a prophylactic and / or therapeutic agent for oculopathy. In addition, various symptoms such as self-emphasis, dyspnea, self-breathing hearing, whistling, dizziness, hearing loss, hearing loss, pain, tinnitus, stiff neck, shoulder stiffness, headache, and depression symptoms It is also valid as.

In addition, limaprosts are effective for patients who are ineffective for herbal medicines, ATP preparations, etc. used in the clinical field.

In addition, limaprosts are administered in combination with other drugs (eg, herbal medicine (Kamiguibitang, Banhabaekchulcheonmatang, Bojungikgi-tang, etc.), anti-anxiety drugs, vitamin preparations, ATP preparations, etc.) that are used for the treatment of ear canal disease. You may also

In the present invention, the term "treatment" not only completely cures the condition, but also suppresses the progression and worsening of symptoms even if not completely cured, stops the progression of the condition, or improves part or all of the condition. Inducing in the direction of healing means preventing, suppressing or delaying the onset of the condition, and alleviating the symptoms of improving symptoms.

Lima Frost

In this specification, "limaprost" means 1 or more types chosen from the group which consists of a clathrate compound containing limaprost, its salt, and limaprost.

The formulation of the present invention contains at least one selected from the group consisting of limaprost, its salt, and clathrate compound containing limaprost as an active ingredient, and the limaprosts, which are active ingredients, are lima to patients with oculopathy. It is not particularly limited as long as it is a formulation for oral administration in an amount of 5 μg to 50 μg, preferably 15 μg to 30 μg, more preferably 15 μg or 30 μg, for 1 to 52 weeks, in terms of frost, For example, limaprost as an active ingredient should just contain limaprost in the form as it is, or in the form of a clathrate compound, such as its salt or its cyclodextrin clathrate. What is necessary is just to contain 1 type (s) or 2 or more types of clathrate containing limaprost, its salt, and limaprost in the preparation of this invention.

In the present specification, limaprost is a general formula (I)

The chemical name is (E) -7-[(1R, 2R, 3R) -3-hydroxy-2-[(3S, 5S)-(E) -3-hydroxy-5-methyl- 1-nonenyl] -5-oxocyclopentyl] -2-heptanoic acid (Registry No. 74397-12-9).

As cyclodextrin clathrate compounds of limaprost, for example, α-cyclodextrin clathrate compounds of limaprost, β-cyclodextrin clathrate compounds, and γ-cyclodextrin clathrate compounds and the like can be cited.

The compound which contained limaprost represented by (alpha) -cyclodextrin is preferable. The chemical name of this compound is (E) -7-[(1R, 2R, 3R) -3-hydroxy-2-[(3S, 5S)-(E) -3-hydroxy-5-methyl-1-none Nil] -5-oxocyclopentyl] -2-heptanoic acid α-cyclodextrin inclusion compound (Registry No. 100459-01-6), generally known as limaprost alphadex. This is the same meaning as lima frost alphadex contained in the 15th revised Japanese pharmacy room.

In the present invention, unless otherwise indicated, symbols are obvious to those skilled in the art.

Indicates binding to the other side of the page (ie α-batch),

Indicates binding to the front of the ground (ie β-batch).

In addition, the salt of limaprost is a nontoxic salt, especially a pharmaceutically acceptable salt, and sodium salt or potassium salt is mentioned as such salt.

In the present invention, it is preferable to use limaprost in the form of α-cyclodextrin clathrate compound of limaprost represented by the above formula (II), that is, limaprost alphadex.

Open tuberculosis

Ear canal disease is a disease in which the closed ear canal is usually in an open state, and the symptom includes various symptoms of the ear canal, such as magnetic emphasis, dysfunction, self-breathing hearing, whistling, dizziness, and hearing. Degradation, hearing loss, earaches, tinnitus, stiff neck, stiff shoulders, headaches, and depressive symptoms.

The method for evaluating the open ear canal may be any method as long as it is a generally known method. For example, it can be diagnosed by listening to subjective symptoms or by using a handover function tester. Diagnosis using a pipe function tester includes a pipe transfer solid state dynamics method (TTAG), an acoustic transfer method, a pressure reduction method, a transfer pipe catheter flow method, and an impedance method.

Dosage and Method of Administration

The dosage of limaprosts used in the present invention may be any amount that is effective for improving ear canalism and its symptoms, and is not particularly limited. Preferably, the compound represented by the above formula (I) per adult It is preferable to administer 15 µg or 30 µg in terms of (limaprost). The dose of limaprost per dose is preferably 5 μg to 10 μg, particularly 5 μg or 10 μg in terms of limaprost. When limaprost is administered as a limaprost cyclodextrin clathrate (eg, limaprost alphadex), the limaprost contained in the limaprost cyclodextrin clathrate compound is 5 μg to 50 μg per day, preferably 15 What is necessary is just to administer by converting into the amount administered with respect to 30 micrograms, More preferably, 15 micrograms or 30 micrograms.

The administration method is preferably administered once to three times a day, and particularly preferably three times a day, morning, lunch and dinner, preferably after every meal. The period of administration may be any period as long as it is an effective period, and also depends on the kind and severity of symptoms. For example, one day to 52 weeks is preferable, and three days to 26 weeks are more preferable. More preferably, it is 1 to 12 weeks, Especially preferably, it is 2 to 8 weeks. During the administration period, the above amount of limaprost may be administered daily or intermittently, but preferably administered daily.

In the present invention, the route of administration of limaprosts is oral administration, and the formulation in the case of oral administration is preferably a solid preparation (eg, tablets, granules, capsules, etc.). In the solid preparation, limaprost may be contained as limaprost alphadex. More preferably, they are tablets (for example, predetermined tablets, nucleated tablets, coated tablets, three-layer tablets, and the like). Further, the tablet may be a sustained release preparation such as intraoral fast tablet. As a tablet containing lima frost, for example, opalmon tablet (brand name), proenal tablet (brand name), opaprosmon tablet (brand name), optiran tablet (brand name), zefloput tablet (brand name), rimalmon tablet (brand name) And limaprost alphadex tablets containing limaprost as limaprost alphadex, such as limaprost alphadex tablet 5 µg 'F' (trade name). In addition, as a tablet containing lima frost, as long as it is a tablet containing lima frost, it may be other than said tablet.

The amount of limaprosts in the tablet is preferably 5 μg to 10 μg, particularly 5 μg or 10 μg in terms of limaprost in one tablet. In the above purification, when limaprost is contained as a cyclodextrin clathrate of limaprost (for example, limaprost alphadex), 5 μg or 10 limaprost contained in the cyclodextrin clathrate of limaprost is contained. It is preferable to convert so that it may become microgram. As tablets containing limaprosts, limaprost alphadex tablets containing limaprost as limaprost alphadex are preferred.

In addition, limaprost may be administered in combination with other medicines used for the treatment of ear canal disease, such as herbal medicines (Kamiguibitang, Banhabaekchulcheon Matang, Bojungikgi-tang, etc.), anti-anxiety drugs, vitamin preparations, ATP preparations, and the like. good. Limaprost and the said other agent may be formulated in the single agent containing both, and may be administered simultaneously. Alternatively, both may be formulated and administered separately or simultaneously.

Process for the preparation of the compound used in the present invention

The limaprost or limaprost alphadex used for this invention can be manufactured by a well-known method, for example, the method of Unexamined-Japanese-Patent No. 55-100360. The salt and clathrate of limaprost can be obtained from limaprost by a known method. As described above, a drug containing limaprost α-cyclodextrin clathrate compound (limaprost alphadex) is commercially available.

toxicity

The toxicity of limaprosts, in particular limaprost and its cyclodextrin clathrate compounds (limaprost alphadex, etc.) used in the present invention is very low and is safe enough for use as a medicament.

Application to medicine

Limaprost used in the present invention is useful as a prophylactic, therapeutic and / or symptom improving agent for ear canal disease. Specifically, oral administration of limaprosts to limaprost for 15 µg or 30 µg per day for 1 to 52 weeks is effective in the opening of the ear canal. In addition, oral administration of limaprosts to limaprost for 15 ㎍ or 30 ㎍ per day for 1 day to 52 weeks, such as various symptoms of ear canal opening, such as magnetic stress, dyspnea, self-breathing noise, whistling Dizziness, hearing loss, hearing loss, headache, tinnitus, stiff neck, stiff shoulders, headaches, and depressive symptoms also improve.

Dosage target

In order to use limaprosts for this purpose, limaprosts are administered orally to patients with canopia. It is preferable to perform limaprost administration in combination with said preferable dose, administration method, administration period, administration route, formulation, etc.

In addition, limaprost is a patient that is ineffective for the use of drugs (eg, herbal medicine (Kamiguibitang, Banhabaekchulcheon Matang, Bojungikgi-tang, etc.), anti-anxiety drugs, vitamin preparations, ATP preparations, etc.) Also valid for.

Formulation

In the present invention, the solid preparation containing limaprosts can be produced by adding a pharmaceutically acceptable additive to limaprosts, if necessary, using a technique that is commonly used as a single preparation or a combination preparation. When formulated, limaprost may be used as limaprost alphadex.

When manufacturing the solid formulation containing lima frosts, you may contain the additive further besides lima frosts. The additives may be generally used in the preparation of the solid preparation, and include, for example, excipients, binders, lubricants, disintegrating agents, copulating agents, odorants, surfactants, flavoring agents, coloring agents, antioxidants, concealing agents, antistatic agents, and fluidizing agents. Agent, wetting agent, etc. can be used 1 type or in mixture of 2 or more types as appropriate.

Excipients include, for example, glucose, fructose, maltose, lactose, isomerized lactose, reduced lactose, sucrose, D-mannitol, erythritol, maltitol, xylitol, paratinose, trehalose, sorbitol, corn starch, potato starch, wheat starch, rice starch, Crystalline cellulose, talc, silicic anhydride, calcium phosphate anhydrous, precipitated calcium carbonate, calcium silicate, dextran (eg dextran, dextran 40, dextran 70, etc.), pullulan, dextrin, β-cyclodextrin, alpha starch Etc. can be mentioned. As the binder, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, polyvinylpyrrolidone, methyl cellulose, polyvinyl alcohol, carboxymethyl cellulose, partially alpha starch, alpha starch, sodium alginate, pullulan, arabian Rubber powder, gelatin, dextrin, etc. are mentioned, You may mix | blend suitably 1 type, or 2 or more types among these. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol, and the like. Examples of disintegrating agents include low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, hydroxypropyl starch, corn starch and the like. . Examples of the copulating agent include sucrose, D-sorbitol, xylitol, citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, taumartin, sodium saccharin, glycylizin dipotassium, sodium glutamate, and sodium 5'-inosinate. And sodium 5'-guanylate. Examples of the odorants include trehalose, malic acid, maltose, potassium gluconate, anise essential oil, vanilla essential oil, cardamom essential oil and the like. As surfactant, polysorbate (polysorbate 80 etc.), a polyoxyethylene polyoxypropylene copolymer, sodium lauryl sulfate, etc. are mentioned, for example. As a fragrance, lemon oil, orange oil, menthol, peppermint oil etc. are mentioned, for example. Examples of the colorant include titanium oxide, edible yellow No. 5, edible blue No. 2, iron trioxide and yellow trioxide. As antioxidant, sodium ascorbate, L-cysteine, sodium sulfite, vitamin E etc. are mentioned, for example. As a hiding agent, titanium oxide etc. are mentioned, for example. Examples of the antistatic agent include talc and titanium oxide. Examples of the fluidizing agent include light silicic anhydride, talc, hydrous silicon dioxide and the like. Examples of the humectant include polysorbate 80, sodium lauryl sulfate, sucrose fatty acid ester, macrogol, hydroxypropyl cellulose (HPC), and the like. These additives are generally mix | blended in the ratio normally used for oral dosage preparations. In addition to the above, an additive such as that described in a known document, for example, Yakuji Nibosha 2000 published in "Pharmaceutical Additives Dictionary" (edited by the Japan Pharmaceutical Additives Association), may be used.

The solid preparation containing limaprosts can be manufactured by a well-known method, and granules can be manufactured by granulating using a rotating granulator, a stirring granulator, a fluid granulator, a centrifugal rotating granulator, a dry granulator, etc., for example.

The said solid formulation can use granules obtained by the said method as a granule as it is, for example. Solid formulations also include capsules containing the granules. Capsules can be prepared by a known method, for example, the granules, and the addition of additives, if necessary, such as hard capsules [eg gelatin capsules, hydroxypropylmethyl cellulose (HPMC) capsules, pullulan capsules, polyvinyl alcohol (PVA) capsule, etc.] can be performed by using a capsule charger. Solid formulations also include tablets containing the granules. A tablet can be manufactured by a well-known method. For example, the granules and the additives may be mixed evenly if necessary, compression molded by a rotary tableting machine or the like to obtain a predetermined value, and the predetermined value may be used as a tablet as it is, or may be further coated with a coating base if necessary. In addition, it is also possible to prepare a mixed powder containing a drug or the like without granulation, and to refine it by a rotary tableting machine or the like. In addition, instead of the granules, limaprost and excipients are dissolved in a solvent (for example, water, an organic solvent (for example, ethanol, acetone, etc.), or a mixed solvent thereof, etc.), and a freeze-dried product is dried in a conventional manner. Tablets may be prepared. That is, after crushing the freeze-dried product containing limaprost, you may make a tablet by adding an additive, mixing, and tableting as needed.

(Example)

Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited thereto.

Example  One On open ear canal  About Lima Frost  Action

<Case 1>

(1) patient background

76 year old woman. The ear canal was diagnosed by subjective symptom such as magnetic stress and the ear canal tympanometry (TTAG) by the ear canal function tester.

(2) Effect of limaprost administration

To the patient, opalmon (limaprost alphadex tablet containing 5 μg of limaprost in one tablet) in combination with methicobal, an ATP preparation, which is a vitamin B12 preparation, is given once, three times a day (ie, Lima) 15 µg / 1 day in terms of frost) and 28 days. As a result, subjective symptoms disappeared and improvement of the ear canal opening finding by TTAG was confirmed.

<Case 2>

(1) patient background

62 year old male. It was diagnosed as open ear disease by subjective symptoms such as feeling of obstruction and TTAG.

(2) Effect of limaprost administration

Patients were treated with opalmon (limaprost alphadex tablet containing 5 μg of limaprost in one tablet) twice a day, three times a day (ie 30 μg / 1 day in terms of limaprost), 62 days. Administered. As a result, subjective symptoms improved in 20 days, subjective symptoms disappeared in 62 days, and open ear canal findings by TTAG improved.

<Case 3>

(1) patient background

46 year old male. It was diagnosed as canopia by TTAG and subjective symptoms such as feeling of obstruction and pain.

(2) Effect of limaprost administration

The patient was given herbal medicine (Kamiguibi-tang, Banhabaekchulcheon-tang) and anti-anxiety depas for 2 weeks, but the symptoms did not improve. For this reason, opalmon (limaprost alphadex tablet containing 5 μg of limaprost in 1 tablet) once a day, 3 times a day (that is, 15 μg / day in terms of limaprost) for 1 month Further administration. As a result, subjective symptoms disappeared and the transfer of open ear canal by TTAG was improved.

<Case 4>

(1) patient background

60 year old male. It was diagnosed as open ear disease by subjective symptoms such as feeling of obstruction and TTAG.

(2) Effect of limaprost administration

The patient was administered steroid preparations, predonin, vitamin B12 preparations, mechicobal, ATP preparations, and gamiguibi-tang for two weeks, but the symptoms did not improve. For this reason, predonin was converted to opalmon (15 µg / day in terms of limaprost) and used in combination with methcobale, ATP preparations, and Kamiguibi-tang. This improvement was confirmed, and loss of subjective symptoms and improvement of an ear canal opening finding by TTAG were confirmed for 45 days.

In addition, a steroid preparation is prescribed in anticipation of a major effect on an inner ear disease such as Meniere's disease, which is suspected of being involved.

<Case 5>

(1) patient background

71 year old male. It was diagnosed as open ear disease by subjective symptoms such as feeling of obstruction and TTAG.

(2) Effect of limaprost administration

The patient was treated with vitamin B12 preparations, such as mechicobal, ATP preparation, gamiguibi-tang, and opalmon (15 μg / day in terms of limaprost). Improvement of the canal opening was confirmed, and subjective symptoms disappeared at 1 month after administration.

As mentioned above, it was confirmed that limaprosts are effective for a canopia and its symptoms. In addition, it was confirmed that the herbal medicine, anti-anxiety medicine, vitamin preparation, and ATP preparation that are used in patients with oculopathy in the clinical field were effective for patients who were ineffective.

[Example]

Representative formulation examples used in the present invention are shown below.

Formulation example  One

350 g of dextran 40 was weighed and dissolved in 1875 g of purified water. 50 g of Limaprost alphadex was dissolved in it and then lyophilized according to a conventional method. To 4 g of the powder obtained, 26 g of dextrin, 252.9 g of lactose, 15 g of corn starch, 0.6 g of hard silicic anhydride and 1.5 g of stearic acid were mixed, and tableted at a tablet pressure of 800 kg / cm 2 using a rotary tableting machine. 2000 tablets containing 5 micrograms of the compound represented by the said general formula (I) per tablet (100 mg, 6.5 mm diameter) were obtained by drying on 60 degreeC and 0.1 kilopascal or less and conditions for 2 hours.

<Composition in 1 tablet of tablet (100 mg)>

Limaprost Alphadex 0.167 mg

(5 μg as the compound represented by Formula I)

Dextran 40 1.167 mg

Dextrin 8.67 mg

Lactose 84.3 mg

Corn starch 5.0 mg

Light silicic anhydride 0.20 mg

Stearic acid                               0.50 mg

100 mg

Limaprosts are effective as a prophylactic and / or therapeutic agent for ear canal disease. In addition, various symptoms such as self-emphasis, dyspnea, self-breathing hearing, whistling, dizziness, hearing loss, hearing loss, pain, tinnitus, stiff neck, shoulder stiffness, headache, and depression symptoms It is also valid as.

In addition, limaprosts are effective for patients who are ineffective for herbal medicines, anti-anxiety medicines, vitamin preparations and ATP preparations used in clinical settings.

Therefore, for prophylactic open disease in which no effective treatment method is established, new prophylactic, therapeutic and / or symptom improving agents can be provided.

Claims (7)

Agents for at least one of the prevention, treatment and symptomatic improvement of ear canal disease comprising limaprosts. The formulation according to claim 1, wherein the limaprosts are limaprost alphadex. The symptom of the open ear canal is selected from a self-emphasis, feeling of dysfunction, self-breathing hearing, wheezing, dizziness, hearing loss, deafness, ear pain, tinnitus, stiff neck, shoulder stiffness, headache and depressive symptoms. Formulations are one or more. The agent according to claim 1, wherein the at least one selected from herbal medicines, anti-anxiety medicines, vitamin preparations and ATP preparations is the opening of the ear canal in an invalid patient. The preparation according to claim 1 or 2, wherein the amount of 5 μg to 10 μg per dose, in terms of limaprost, is orally administered to the patient with the canal open disease, three times a day for 1 to 52 weeks. . The agent according to claim 5, wherein the at least one member selected from the Chinese medicine, anti-anxiety medicine, vitamin preparation, and ATP preparation is an invalid patient. The agent according to claim 1, further comprising at least one drug selected from the group consisting of herbal medicines, anti-anxiety drugs, vitamin preparations and ATP preparations.