Clozapine-induced salivation ameliorating agent

Abstract

The purpose of the present invention is to provide an ameliorating agent for clozapine-induced salivation. The clozapine-induced salivation ameliorating agent according to the present invention contains dextromethorphan, a compound having an antagonistic effect on NMDA-type glutamate receptors, or a compound having an agonistic effect on sigma-1 receptors as an active ingredient.

Description

Technical Field

[0001] The present invention relates to an agent for improving clozapine-induced salivation. Background Art

[0002] Clozapine, which is known as the only approved antipsychotic drug for the treatment of treatment-resistant schizophrenia, exhibits "clozapine-induced sialorrhea (CIS)" as a side effect, and the reduction of the quality of life (QOL) of patients has become a problem. At present, as a treatment for the aforementioned salivation, an anticholinergic drug having an antagonistic action on muscarinic receptors is used.

[0003] The object of Patent Document 1 is to provide a method of using a muscarinic agonist and an agent using such a muscarinic agonist, which can obtain a therapeutic effect related to the activation of muscarinic receptors with fewer side effects. In Patent Document 1, a method for treating a central nervous system disease is disclosed, which includes the step of co-administering a muscarinic activator and a muscarinic inhibitor to a patient, and the aforementioned central nervous system disease is selected from schizophrenia, diseases related to schizophrenia, muscarinic diseases, movement disorders, mood disorders, cognitive disorders, attention disorders, and addiction disorders.

[0004] In addition, at present, for CIS, treatments with anticholinergic drugs (pirenzepine, trihexyphenidyl, biperiden) and α2 stimulants (clonidine) have been reported (see Non-Patent Document 1).

[0005] Prior Art Documents

[0006] Patent Documents

[0007] Patent Document 1: Japanese Patent Laid-Open No. 2015-83612

[0008] Non-Patent Documents

[0009] Non-Patent Document 1: David Taylor et al. (eds.), Masashi Mimura, Hiroyuki Uchida, Takefumi Suzuki (transl.), "The Maudsley Prescribing Guidelines 14th Japanese Edition", published on October 5, 2022, Wiley Publishing Japan, Ltd. Summary of the Invention

[0010] Problems to be Solved by the Invention

[0011] The currently used anticholinergic drugs have limited effects on improving clozapine-induced sialorrhea. Moreover, there are concerns about side effects such as weakened antipsychotic effects, memory impairment, and constipation that may occur with clozapine and its active metabolite N-desmethylclozapine (refer to Non-Patent Document 1).

[0012] An object of the present invention is to provide an agent for improving clozapine-induced sialorrhea.

[0013] Means for solving the problem

[0014] The present inventors conducted in-depth studies and found that dextromethorphan is effective in improving clozapine-induced sialorrhea. The present inventors further conducted studies and found that compounds having an antagonistic action on NMDA-type glutamate receptors and compounds having an agonistic action on σ-1 receptors are effective in improving clozapine-induced sialorrhea, thereby completing the present invention.

[0015] The present invention includes the following aspects.

[0016] <1> An agent for improving clozapine-induced sialorrhea, which contains a compound having an antagonistic action on NMDA-type glutamate receptors as an active ingredient.

[0017] <2> The clozapine-induced sialorrhea improver according to <1>, wherein the compound having an antagonistic effect on the NMDA-type glutamate receptor is at least one selected from the following, its pharmaceutically acceptable salt, or their hydrates: minocycline, WIN 55,212-2, CP 55,940, CPP, aripiprazole, dizocilpine (MK-801), 3-methoxyphencyclidine (3-MeO-PCP), phencyclidine, MXE (methoxetamine), ketamine, S-ketamine, R-ketamine, norketamine, S-norketamine, R-norketamine, memantine, amantadine, acamprosate, methadone, levomethadone, S-methadone, latrepirdine, tiletamine, selfotel, aptiganel, besonprodil, delsemine, dizocilpine maleate, gavestinel, licostinel, neramexane mesylate, perzinfotel, remacemide hydrochloride, traxoprodil mesylate, D-(-)-2-amino-5-phosphonovaleric acid (D-AP5), haloperidol, atomoxetine, oseltamivir, kynurenic acid, procaine, felbamate, mephenesin, huperzine A, linalool, orphenadrine, ifenprodil, pentamidine, dextromethorphan, and dextromethorphan.

[0018] <3> A clozapine-induced sialorrhea improver, which contains a compound having an agonistic effect on the σ-1 receptor as an active ingredient.

[0019] <4> The clozapine-induced sialorrhea improving agent according to <3>, wherein the compound having an agonistic effect on the σ-1 receptor is at least one selected from the following, its pharmaceutically acceptable salt, or their hydrate: fluvoxamine, sertraline, S(+)-fluoxetine, (±)-fluoxetine, citalopram, imipramine, paroxetine, desipramine, R(-)-fluoxetine, (±)-norfluoxetine, donepezil, dextromethorphan, ifenprodil, SA4503, dehydroepiandrosterone 3-sulfate (alias: DHEA-S), (+)-SKF10,047, (-)-SKF10,047, (+)-pentazocine, (-)-pentazocine, PPBP, igmesine (alias: JO-1784), PRE-084, ilirodipine (alias: SL82.0715), DTG203, pridopidine, and AF710B (alias: aka ANAVEX3-71).

[0020] <5> A clozapine-induced sialorrhea improving agent, which contains dextromethorphan, its pharmaceutically acceptable salt, or their hydrate as an active ingredient.

[0021] <6> The clozapine-induced sialorrhea improving agent according to <5>, wherein the dosage of dextromethorphan, its pharmaceutically acceptable salt, or their hydrate is 0.2 mg / kg / day or more and 3.0 mg / kg / day or less.

[0022] <7> A method for improving clozapine-induced sialorrhea, which is characterized by administering an effective amount of a compound having an antagonistic effect on the NMDA type glutamate receptor, its pharmaceutically acceptable salt, or their hydrate.

[0023] <8> A method for improving clozapine-induced sialorrhea, which is characterized by administering an effective amount of a compound having an agonistic effect on the σ-1 receptor, its pharmaceutically acceptable salt, or their hydrate.

[0024] <9> A method for improving clozapine-induced sialorrhea, which is characterized by administering dextromethorphan, its pharmaceutically acceptable salt, or their hydrate.

[0025] <10> Use of a compound having an antagonistic effect on the NMDA type glutamate receptor, its pharmaceutically acceptable salt, or their hydrate in the preparation of a clozapine-induced sialorrhea improving agent.

[0026] <11> Use of a compound having an agonistic effect on the σ-1 receptor, a pharmaceutically acceptable salt thereof, or a hydrate thereof in the preparation of an agent for improving clozapine-induced sialorrhea.

[0027] <12> Use of dextromethorphan, a pharmaceutically acceptable salt thereof, or a hydrate thereof in the preparation of an agent for improving clozapine-induced sialorrhea.

[0028] Advantages of the Invention

[0029] According to the present invention, there is provided an agent for improving clozapine-induced sialorrhea. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] [ Figure 1-1 Figure 1-1 is a graph showing the results of Experiment 1.

[0031] [ Figure 1-2 Figure 1-2 is a graph showing the results of Experiment 1.

[0032] [ Figure 2 Figure 2 is a graph showing the results of Experiment 2.

[0033] [ Figure 3-1 Figure 3-1 is a graph showing the results of Experiment 3.

[0034] [ Figure 3-2 Figure 3-2 is a graph showing the results of Experiment 3.

[0035] [ Figure 4 Figure 4 is a graph showing the results of Experiment 4.

[0036] [ Figure 5 Figure 5 is a graph showing the results of Experiment 5. DETAILED DESCRIPTION OF THE INVENTION

[0037] Hereinafter, the present invention will be described in detail by way of exemplary embodiments, but the present invention is not limited to the embodiments described below.

[0038] In addition, unless otherwise specified in the text, all technical terms and scientific terms used in this specification have the same meanings as those commonly understood by those skilled in the technical field to which the present invention pertains. Furthermore, any materials and methods equivalent or similar to those described in this specification can be used in the same manner in the practice of the present invention. Moreover, all publications and patents cited in this specification in connection with the invention described herein, for example, those representing methods, materials, etc. that can be used in the present invention, constitute a part of this specification.

[0039] In this specification, the description of "A to B" representing a numerical range means a numerical range including A and B as endpoints. The same applies to "A through B".

[0040] [Improver for clozapine-induced sialorrhea]

[0041] The first embodiment of the improver for clozapine-induced sialorrhea of the present invention contains dextromethorphan, its pharmaceutically acceptable salt, or a hydrate thereof as an active ingredient.

[0042] The second embodiment of the improver for clozapine-induced sialorrhea of the present invention contains a compound having an antagonistic effect on NMDA-type glutamate receptors as an active ingredient.

[0043] The reason why a compound having an antagonistic effect on NMDA-type glutamate receptors is effective in improving clozapine-induced sialorrhea is not limited by the following theory, but it is considered that by activating NMDA-type glutamate receptors via clozapine, sialorrhea may be induced, and by administering a compound having an antagonistic effect on NMDA-type glutamate receptors, sialorrhea is improved.

[0044] The third embodiment of the improver for clozapine-induced sialorrhea of the present invention contains a compound having an agonistic effect on σ-1 receptors as an active ingredient.

[0045] The reason why a compound having an agonistic effect on σ-1 receptors is effective in improving clozapine-induced sialorrhea is not limited by the following theory, but it is considered that by inactivating σ-1 receptors via clozapine, sialorrhea may be induced, and by administering a compound having an agonistic effect on σ-1 receptors, sialorrhea is improved.

[0046] In the present invention, the subject to which the improver for clozapine-induced sialorrhea is administered only needs to exhibit clozapine-induced sialorrhea, and any mammal is preferred, including: humans; non-human primates other than humans, including chimpanzees, other anthropoid apes, and monkey species; livestock such as cattle, sheep, pigs, goats, and horses; domestic mammal pets such as dogs and cats; and small animals or experimental animals including rodents such as mice, rats, and guinea pigs. Among them, humans are preferred.

[0047] <Clozapine-induced sialorrhea>

[0048] Clozapine-induced sialorrhea is excessive salivation visible as a side effect due to the administration of clozapine.

[0049] That is, the subject to which the improver for clozapine-induced sialorrhea of the present invention is administered is a patient with treatment-resistant schizophrenia, and moreover, is a patient who has received treatment with clozapine, further administered clozapine, and exhibits clozapine-induced sialorrhea.

[0050] Clozapine has the following structure.

[0051] [Chemical formula 1]

[0052]

[0053] Clozapine is a therapeutic drug for drug-resistant schizophrenia, and is administered to patients with schizophrenia who have shown drug resistance to treatment with other antipsychotic drugs (patients who meet the criteria of poor response or poor tolerance).

[0054] In the treatment of drug-resistant schizophrenia, clozapine is usually orally administered to adults at 12.5 mg on the first day and 25 mg on the second day, once a day. After the third day, the dosage is increased by 25 mg every day according to symptoms. In principle, the dosage is increased to 200 mg per day over a period of 3 weeks. However, if the daily dosage exceeds 50 mg, it is orally administered in 2 to 3 times. The maintenance dose of clozapine is 200 to 400 mg per day, divided into 2 to 3 times, and appropriately increased or decreased according to symptoms. However, the increase is separated by more than 4 days, and the increase is not more than 100 mg per day, and the maximum dosage is up to 600 mg per day.

[0055] Clozapine-induced sialorrhea is a side effect observed in 46.8% of users according to the appendix of Clozaril (an oral medicine containing clozapine as an active ingredient, manufactured by Novartis Pharma), and is a high-frequency side effect.

[0056] <Compounds having antagonistic activity on NMDA-type glutamate receptors>

[0057] NMDA-type glutamate receptors (hereinafter also referred to as "NMDA receptors") are a type of glutamate receptors, and unlike AMPA receptors and kainate receptors, which are other subtypes of glutamate receptors, NMDA (N-methyl-D-aspartate) acts selectively as an agonist.

[0058] The compound having an antagonistic effect on NMDA receptors (hereinafter also referred to as "NMDA receptor antagonist") may be a competitive inhibitor (selective antagonist), a functional antagonist such as an open channel inhibitor, or an agonist, without particular limitation.

[0059] In addition, the binding site of the selective antagonist is not particularly limited, and examples thereof include a PCP binding site and the like.

[0060] As an NMDA receptor antagonist, for example, referring to Reference 1 (Shunya Inada, Hiroshi Endo, "Compounds Acting on the Excitatory Amino Acid Nervous System", Clinical Psychopharmacology 23: 827-839, 2020 Seika Shoten), it is preferably selected from at least one of the following, its pharmaceutically acceptable salts, or their hydrates: minocycline, WIN 55,212-2, CP 55,940, CPP (3-[(3R)-3-carboxypiperazin-1-yl]propylphosphonic acid), aripiprazole, dizocilpine (MK-801), 3-methoxyphencyclidine (3-MeO-PCP), phencyclidine, MXE (methoxetamine), ketamine, S-ketamine, R-ketamine, norketamine, S-norketamine, R-norketamine, memantine, amantadine, acamprosate, methadone, levomethadone, S-methadone, ladostigil, tiletamine, seftazime, atigabine, besirledi, delucemine, dizocilpine maleate, gavestinel, licostinel, neramexane mesylate, perzinfotel, remacemide hydrochloride, tresopide mesylate, D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5), haloperidol, atomoxetine, oseltamivir, kynurenic acid, procaine, felbamate, mephenesin, huperzine A, linalool, orphenadrine, ifenprodil, pentamidine, dextrophan, and dextromethorphan.

[0061] <Compound having an agonist action on the σ-1 receptor>

[0062] The σ-1 receptor is a chaperone protein located in the endoplasmic reticulum (ER) that controls calcium signal transduction via the IP3 receptor. It has been reported that the σ-1 receptor is a transmembrane protein expressed in many different tissue types, and in particular, it is expressed more abundantly in specific regions of the central nervous system. The σ-1 receptor is thought to be associated with diseases such as schizophrenia, depression, and dementia, but its endogenous ligand has not been fully identified.

[0063] As a compound having an agonist effect on the σ-1 receptor (hereinafter, also referred to as "σ-1 receptor agonist"), for example, refer to Reference 2 (Narita N, Hashimoto K, Tomitaka S, Minabe Y. Interactions of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brain. Eur J Pharmacol. 1996 Jun 20;307(1):117-9. PMID: 8831113 DOI: 10.1016 / 0014-2999(96)00254-3), Reference 3 (Hashimoto K, Ishiwata K. Sigma receptor ligands: possible application as therapeutic drugs and as radiopharmaceuticals. Curr Pharm Des. 2006;12(30):3857-76. PMID: 17073684 DOI: 10.2174 / 138161206778559614), Reference 4 (Nishimura T, Ishima T, Iyo M, Hashimoto K. Potentiation of nerve growth factor-induced neurite outgrowth by fluvoxamine: role of sigma-1 receptors, IP3 receptors and cellular signaling pathways. PLoS One. 2008 Jul 2;3(7):e2558. PMID: 18596927 DOI: 10.1371 / journal.pone.0002558), Reference 5 (Bogar F, Fulop L, Penke B. Novel Therapeutic Target for Prevention of Neurodegenerative Diseases: Modulation of Neuroinflammation with Sig-1R Ligands. Biomolecules. 2022 Feb 25;12(3):363. PMID: 35327555 DOI: 10.3390 / biom12030363), preferably at least one selected from the following, its pharmaceutically acceptable salts, or their hydrates: fluvoxamine, sertraline, S(+)-fluoxetine, (±)-fluoxetine, citalopram, imipramine, paroxetine, desipramine, R(-)-fluoxetine, (±)-norfluoxetine as antidepressants; donepezil as an anti-dementia drug; dextromethorphan as an antitussive; SA4503 as an experimental reagent of a selective σ-1 receptor agonist; dehydroepiandrosterone 3-sulfate (alias: DHEA-S) as an endogenous substance; ifenprodil, (+)-SKF10,047, (-)-SKF10,047, (+)-pentazocine, (-)-pentazocine, PPBP, igmesine (alias: JO-1784), PRE-084, ilirodine (alias: SL 82.0715), DTG203, pridopidine and AF710B (alias: aka ANAVEX3-71).

[0064] Since dextromethorphan has high safety for humans, low possibility of causing side effects when combined with clozapine, low possibility of weakening the antipsychotic effect of clozapine, and high improvement effect on clozapine-induced sialorrhea, as an active ingredient of the clozapine-induced sialorrhea improver of the present invention, it is more preferably at least one selected from dextromethorphan and its active metabolite dextrorphan, its pharmaceutically acceptable salts, or their hydrates, and further preferably dextromethorphan, its pharmaceutically acceptable salts, or their hydrates.

[0065] Dextromethorphan has the following structure.

[0066] [Chemical formula 2]

[0067]

[0068] In the formula, R 1 is -CH3, -CH2D, -CHD2, or -CD3, and R 2 is -CH3, -CH2D, -CHD2, or -CD3. In addition, D means deuterium.

[0069] Dextromethorphan is commercially available under names such as MEDICON and is used as an antitussive, etc. In addition, dextromethorphan and its pharmaceutically acceptable salts are also included in general drugs as components of analgesics and antitussives, and are also used as analgesics or opioid enhancers. It is often used as dextromethorphan hydrobromide hydrate, but is not limited thereto.

[0070] In addition, a part of dextromethorphan can be deuterated.

[0071] As pharmaceutically acceptable salts, for example, mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, nitrate; sulfonate salts such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethanesulfonate; organic acid salts such as oxalate, tartrate, citrate, maleate, succinate, acetate, trifluoroacetate, benzoate, mandelate, ascorbate, lactate, gluconate, malate, etc.; amino acid salts such as glycinate, lysinate, arginate, ornithinate, glutamate, aspartate; or base addition salts such as inorganic salts like lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt or salts with organic bases such as ammonium salt, triethylamine salt, diisopropylamine salt, cyclohexylamine salt, N-methyl-D-glucamine salt. In addition, the salts include hydrates.

[0072] In the present invention, the exemplified NMDA receptor antagonists and σ-1 receptor agonists have asymmetric centers, and in such cases, there are various optical isomers. As long as the NMDA receptor antagonists and σ-1 receptor agonists respectively have an antagonistic effect on the NMDA receptor and an agonistic effect on the σ-1 receptor, they can exist as individual optically active forms of (R) and (S), and as racemates or (RS) mixtures. In addition, in the case of compounds having two or more asymmetric centers, there are further diastereoisomers due to their respective optical isomerisms, but the NMDA receptor antagonists and σ-1 receptor agonists can be mixtures containing all these types in any proportion. For example, diastereoisomers can be separated by methods well-known to those skilled in the art, such as fractional crystallization, etc. In addition, optically active forms can be obtained by organic chemical methods well-known for this purpose.

[0073] In addition, there are cases where the exemplified NMDA receptor antagonists and σ-1 receptor agonists have geometric isomers such as cis-forms and trans-forms, and further, there are cases where they have tautomerism and various tautomers exist. The compounds of the present invention can be their isomers and mixtures containing their isomers in any proportion.

[0074] Furthermore, in the case where the exemplified NMDA receptor antagonists and σ-1 receptor agonists or their salts form hydrates or solvates, they are also included within the scope of the present invention.

[0075] In the case where the active ingredient of the clozapine-induced sialorrhea improver of the present invention is dextromethorphan, its pharmaceutically acceptable salt, or their hydrates (hereinafter, also referred to as dextromethorphan, etc.), the dosage of dextromethorphan, etc. administered to humans is preferably 0.2 mg / kg / day or more and 3.0 mg / kg / day or less, more preferably 0.5 mg / kg / day or more, and still more preferably 1.0 mg / kg / day or more.

[0076] In addition, there is no particular limitation on the number of administrations of dextromethorphan and the like to humans per day. It is preferably 1 or more and 5 or less times, more preferably 2 or more times, further preferably 3 or more times, and preferably 4 or less times.

[0077] The daily dosage of dextromethorphan and the like to humans is preferably 10 mg / day or more and 120 mg / day or less, more preferably 15 mg / day or more, more preferably 30 mg / day or more, and further preferably 45 mg / day or more.

[0078] Regarding the clozapine-induced sialorrhea improver of the present invention, the dextromethorphan, NMDA receptor antagonist or σ-1 receptor agonist contained can be administered alone or in combination with a pharmaceutically or pharmacologically acceptable additive.

[0079] As additives, commonly used excipients or diluents can be used, and adhesives, disintegrants, lubricants, coating agents, sugar coating agents, pH adjusters, solubilizers or aqueous or non-aqueous solvents can be used as needed. Specifically, water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, potato starch, corn starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, liquid sugar, methyl cellulose, polyvinylpyrrolidone, alkyl p-hydroxybenzoate, talc, stearic acid, magnesium stearate, agar, pectin, gum arabic, glycerin, sesame oil, olive oil, soybean oil, cocoa butter, ethylene glycol, low-viscosity hydroxypropyl cellulose (HPC-L), microcrystalline cellulose, carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (CMC-Na), etc., and other commonly used ones can be cited. In addition, hydrates of the above compounds can also be used.

[0080] As the clozapine-induced sialorrhea improver of the present invention, commercially available preparations containing dextromethorphan, NMDA receptor antagonist or σ-1 receptor agonist, and preparations and mixtures that will be commercially available in the future can be used. For example, MEDICON, etc. as an antitussive, and a mixture of deuterated dextromethorphan and quinidine, that is, AVP-786, etc. being developed by Otsuka Pharmaceutical Co., Ltd.

[0081] The clozapine-induced sialorrhea improver of the present invention can be in any form of solid composition, liquid composition and other compositions, and the best one can be selected as needed.

[0082] The clozapine-induced sialorrhea improver of the present invention can add the aforementioned additives to dextromethorphan, NMDA receptor antagonist or σ-1 receptor agonist, and can be prepared into tablets, pills, capsules, granules, powders, powders, liquids, emulsions, suspensions, injections, patches, etc. by common pharmaceutical techniques.

[0083] In addition, the clozapine-induced sialorrhea improver of the present invention can be formulated by forming an inclusion complex with dextromethorphan, an NMDA receptor antagonist or a σ-1 receptor agonist, and α, β or γ-cyclodextrin or methylated cyclodextrin, etc.

[0084] Regarding the clozapine-induced sialorrhea improver of the present invention, the compound that can be used in combination with dextromethorphan, an NMDA receptor antagonist or a σ-1 receptor agonist can be a single preparation (formulation agent), or two or more preparations (combination agents) obtained by formulating separately. Examples of the compound that can be used in combination include improvers for other side effects of clozapine and clozapine, stabilizers of NMDA receptor antagonists, etc.

[0085] When formulating these compounds separately into two or more preparations, the individual preparations can be administered simultaneously or with a certain time interval. In this case, either one can be administered first. These two or more preparations can also be administered at different frequencies per day. In addition, these two or more preparations can be administered by different routes.

[0086] When formulating these compounds separately into two preparations, there are also cases of administering simultaneously or at a very short interval. For example, it is preferably described in documents such as the appendices and sales brochures of commercially available drugs the intention of using them in combination.

[0087] In addition, it is also preferable to formulate these active ingredients separately into the form of a kit consisting of two preparations.

[0088] Dextromethorphan, an NMDA receptor antagonist or a σ-1 receptor agonist can be administered orally as it is. In addition, it can also be administered orally as a preparation containing dextromethorphan, an NMDA receptor antagonist or a σ-1 receptor agonist as an active ingredient.

[0089] The dosage and administration schedule of dextromethorphan, an NMDA receptor antagonist or a σ-1 receptor agonist vary depending on the administration subject, administration route, symptoms, etc. For example, in the case of oral administration to adult patients, the usual single dose is 0.1 mg to 1000 mg, preferably 1 mg to 200 mg, and it is preferably administered once to five times a day, or once every two to three days.

[0090] Examples

[0091] The present invention will be more specifically described by the following examples. However, the examples only represent simple examples of the present invention and do not limit the scope of the present invention.

[0092] [Preparation of CIS model animals]

[0093] Referring to existing research (Ishikawa S, J. Pharmacol. Exp. Ther., 2020, Nov; 375(2):376-384), CIS model animals were prepared.

[0094] As experimental animals, male Wistar rats (manufactured by Clea Japan) at 6 - 8 weeks of age were used. Additionally, except for the period from 1 hour before to the measurement of saliva volume described below, water and regular feed were freely available for drinking and eating. Furthermore, for clozapine as the administered drug, Clozaril 100mg tablets (manufactured by Novartis Pharma) were dissolved in distilled water for use.

[0095] Rats were orally administered clozapine at 25mg / kg / day, 50mg / kg / day, and 100mg / kg / day (1mL / kg) once, and the saliva volume was measured 4 times a day, every 6 hours starting from 1 hour after administration, but no increase in saliva secretion volume was observed.

[0096] In addition, rats were orally administered clozapine at 25mg / kg / day, 50mg / kg / day, and 100mg / kg / day (1mL / kg) once a day. After 7 days of administration, the saliva volume was measured 24 hours after the final administration. As a result, in the 25mg / kg / day administration group, the saliva volume did not increase, but in the 50mg / kg / day and 100mg / kg / day administration groups, the saliva volume significantly increased from the 3rd day of administration.

[0097] Based on the above, rats that were orally administered clozapine at 100mg / kg / day (1mL / kg) once a day for 7 consecutive days were used as CIS model animals.

[0098] In addition, the method for measuring saliva volume is as follows.

[0099] <Measurement of Saliva Volume>

[0100] Water and food were restricted 1 hour before the measurement of saliva volume.

[0101] As the method for measuring saliva volume, a small piece of cotton ball was placed in the mouth of the fixed rat and wiped for 10 seconds (to suck saliva into the cotton ball). This was repeated 3 times, and the mass change of the cotton ball was measured. The saliva volume collected during a total of 30 seconds was measured.

[0102] [Experiment 1]

[0103] Using the above - mentioned CIS model animals (CIS model rats), the dosage and timing of dextromethorphan (DXM), an NMDA receptor antagonist, were studied. In Experiment 1, the following was done for groups A - C of CIS model rats.

[0104] <1st day to 7th day>

[0105] Group A (control): Administered orally with distilled water (DW) (1 mL / kg) once a day

[0106] Groups B and C: Administered orally with clozapine 100 mg / kg / day (1 mL / kg) once a day

[0107] <8th day to 14th day>

[0108] Group A: Administered intraperitoneally with normal saline (1 mL / kg) once a day + Administered orally with distilled water (DW) (1 mL / kg)

[0109] Group B: Administered intraperitoneally with normal saline (1 mL / kg) once a day + Administered orally with clozapine 100 mg / kg / day (1 mL / kg)

[0110] Group C: Administered intraperitoneally with DXM (30 mg / kg / day) once a day + Administered orally with clozapine 100 mg / kg / day (1 mL / kg)

[0111] <14th day>

[0112] Measure the saliva volume before drug administration on the 14th day (measurement 24 hours after drug administration until the 13th day).

[0113] <Results>

[0114] Compared with Group A (control group), the saliva volume on the 14th day increased significantly in Group B administered with clozapine (p < 0.01). In addition, from the 8th day to the 13th day, a decrease in the saliva volume on the 14th day was observed in Group C administered with both clozapine and dextromethorphan. The results are shown in Figure 1-1 .

[0115] When comparing the change in the saliva volume on the 14th day with that on the 7th day as a reference, in Group C (DXM 30 mg / kg / day), it decreased significantly (p < 0.01). The results are shown in Figure 1-2 .

[0116] [Experiment 2]

[0117] Measure the saliva volume 24 hours after DXM administration in Experiment 1 above. Since the half-life of DXM in humans is short (3.2 ± 0.3 - 3.6 ± 0.3 hr), measure it 1 hour after administration to study the acute effect.

[0118] Using the above CIS model animals (CIS model rats), the following study was conducted on the acute effect of dextromethorphan (DXM).

[0119] <Day 1 to Day 7>

[0120] Groups A and B: Clozapine was orally administered once a day at a dose of 100 mg / kg / day (1 mL / kg). To acclimatize the model animals to saliva measurement, wiping was performed daily.

[0121] <Day 8 to Day 9>

[0122] Group A: Saline (1 mL / kg) was intraperitoneally administered once a day.

[0123] Group B: DXM (30 mg / kg / day) was intraperitoneally administered once a day.

[0124] On Day 9, 1 hour after DXM administration, salivary volume was measured.

[0125] <Results>

[0126] Compared with Day 1 (d1), on Day 7 (d7), salivary volume significantly increased by clozapine administration (p > 0.01). In addition, on Days 8 and 9, in Group B where DXM (30 mg / kg / day) was also administered in addition to clozapine, salivary volume 1 hour after administration on Day 9 (d9) significantly decreased (p < 0.01). The results are shown in Figure 2 .

[0127] [Experiment 3]

[0128] The dose-dependence of the inhibitory effect of clozapine-induced sialorrhea was studied by changing the dose of dextromethorphan (DXM).

[0129] Using the above CIS model animals (CIS model rats), the following study was conducted on the dose-dependence of the acute effect of DXM.

[0130] <Day 1 to Day 7>

[0131] Group A (control): Distilled water (DW) (1 mL / kg) was orally administered once a day.

[0132] Groups B, C, D, and E: Clozapine was orally administered once a day at a dose of 100 mg / kg / day (1 mL / kg).

[0133] In addition, to acclimatize the model animals to saliva measurement, wiping was performed on Days 5 and 6.

[0134] <Day 8 to Day 9>

[0135] Group A: Saline (1 mL / kg) was intraperitoneally administered a total of 3 times.

[0136] Group B: Saline (1 mL / kg) was administered intraperitoneally three times in total.

[0137] Group C: DXM (3 mg / kg) was administered intraperitoneally three times in total.

[0138] Group D: DXM (30 mg / kg) was administered intraperitoneally three times in total.

[0139] Group E: DXM (60 mg / kg) was administered intraperitoneally three times in total.

[0140] The above-mentioned dosage of the drug was administered once in the morning and once in the afternoon on the 8th day, and once in the morning on the 9th day, for a total of three administrations. The salivary volume was measured 1 hour after the final administration.

[0141] <Results>

[0142] Compared with Group A (control), the salivary volume increased significantly on the 7th day by clozapine (p < 0.01). The results are shown in Figure 3-1 .

[0143] Compared with Group A, the significant difference in Group B was P < 0.05, in Group D was P < 0.01, and in Group C was P < 0.001.

[0144] When comparing the change in salivary volume from the 7th day to the 9th day (1 hour after administration), the salivary volume decreased significantly in Group D (DXM 30 mg / kg) and Group E (DXM 60 mg / kg) (p < 0.05 and p < 0.001). In addition, compared with Group C (DXM 3 mg / kg), the salivary volume decreased significantly in Group E (DXM 60 mg / kg) (p < 0.01). The results are shown in Figure 3-2 .

[0145] According to the results of Experiment 1 and Experiment 2, in the model rats with clozapine-induced sialorrhea, the salivary volume decreased significantly by the administration of dextromethorphan. Further, according to the results of Experiment 3, the effect of dextromethorphan showed a dose-dependence.

[0146] [Experiment 4]

[0147] The improvement effect (acute-phase effect) of MK-801, a selective NMDA receptor antagonist, and SA4503, a selective σ-1 receptor agonist, on clozapine-induced sialorrhea was studied. In Experiment 4, Groups A to C of the CIS model rats were conducted as follows.

[0148] <Day 1 to Day 7>

[0149] Group A (control), Group B, Group C: Clozapine 100 mg / kg / day (1 mL / kg) was administered orally once a day.

[0150] <Day 8 - Day 9>

[0151] Group A (control): Administer saline (1 mL / kg) intraperitoneally, a total of 3 times

[0152] Group B: Administer MK - 801 (0.1 mg / kg) intraperitoneally, a total of 3 times

[0153] Group C: Administer SA4503 (1 mg / kg) intraperitoneally, a total of 3 times

[0154] In addition, the intraperitoneal administration was carried out once in the morning and once in the afternoon on the 8th day, and once in the morning on the 9th day, for a total of 3 administrations. The saliva volume was measured 1 hour after the final administration.

[0155] <Results>

[0156] The results of Experiment 4 are shown in Figure 4 .

[0157] Compared with Group A (control), on the 9th day, in the group administered MK - 801 (Group B), which is a selective NMDA receptor antagonist, the saliva volume was significantly reduced (p < 0.01).

[0158] In addition, similarly, compared with Group A (control group), on the 9th day, in the group administered SA4503 (Group C), which is a selective σ - 1 receptor agonist, the saliva volume was significantly reduced (p < 0.05).

[0159] According to the results of Experiment 4, in the model rats with clozapine - induced sialorrhea, the administration of an NMDA receptor antagonist and a σ - 1 receptor agonist showed a significant reduction in saliva volume.

[0160] [Experiment 5]

[0161] Regarding the improvement effect of MK - 801, a selective NMDA receptor antagonist, on clozapine - induced sialorrhea, and regarding the improvement effect (acute - phase effect) on clozapine - induced sialorrhea in the case of co - administration of MK - 801, a selective NMDA receptor antagonist, and D - serine or glycine, an NMDA receptor agonist, the following was carried out for Groups A - D of CIS model rats in Experiment 5.

[0162] <Day 1 - Day 7>

[0163] Group A (control), Group B, Group C, Group D: Administer clozapine orally at 100 mg / kg / day (1 mL / kg) once a day

[0164] <Day 8 - Day 9>

[0165] Group A (control): One hour after oral administration of the solvent (5 mL / kg), saline (1 mL / kg) was intraperitoneally administered. The above administrations were carried out three times in total.

[0166] Group B: One hour after oral administration of the solvent (5 mL / kg), MK-801 (0.1 mg / kg) was intraperitoneally administered. The above administrations were carried out three times in total.

[0167] Group C: One hour after oral administration of D-serine (900 mg / kg), MK-801 (0.1 mg / kg) was intraperitoneally administered. The above administrations were carried out three times in total.

[0168] Group D: One hour after oral administration of glycine (900 mg / kg), MK-801 (0.1 mg / kg) was intraperitoneally administered. The above administrations were carried out three times in total.

[0169] In addition, the above administrations were carried out once in the morning and once in the afternoon on the 8th day, and once in the morning on the 9th day, for a total of three administrations. The saliva volume was measured one hour after the final administration.

[0170] <Results>

[0171] The results of Experiment 5 are shown in Figure 5 .

[0172] Compared with Group A (control), on the 9th day, in the group administered MK-801 (Group B), which is a selective NMDA receptor antagonist, the saliva volume was significantly reduced (p < 0.05).

[0173] Compared with Group B, in Group C, in which D-serine, an NMDA receptor agonist, was also administered in addition to MK-801, the reduction in saliva volume was significantly antagonized (p < 0.05), and the saliva volume was at the same level as that of Group A.

[0174] Similarly, compared with Group B, in Group D, in which glycine, an NMDA receptor agonist, was also administered in addition to MK-801, the reduction in saliva volume was significantly antagonized (p < 0.01), and the saliva volume was at the same level as that of Group A.

[0175] Based on the results of Experiment 5, it was shown that clozapine-induced sialorrhea was improved by an NMDA receptor antagonist, and its improvement effect was antagonized by an NMDA receptor agonist.

[0176] Industrial Applicability

[0177] It has been shown that clozapine-induced sialorrhea, a side effect of clozapine as a therapeutic drug for treatment-resistant schizophrenia, is improved by dextromethorphan, a compound having an inhibitory effect on NMDA-type glutamate receptors, or a compound having an agonistic effect on σ-1 receptors.

[0178] Dextromethorphan has been used as an antitussive agent, etc., and its safety for the human body has been fully evaluated, and it can provide an agent for improving clozapine-induced sialorrhea with high safety.

Claims

1. An agent for improving clozapine-induced sialorrhea, which contains a compound having an antagonistic effect on NMDA-type glutamate receptors as an active ingredient.

2. The clozapine-induced sialorrhea improver according to claim 1, wherein, The compound having an antagonistic effect on NMDA-type glutamate receptors is at least one selected from the following, its pharmaceutically acceptable salt, or their hydrates: minocycline, WIN55,212-2, CP 55,940, CPP, aripiprazole, dizocilpine (MK-801), 3-methoxyphencyclidine (3-MeO-PCP), phencyclidine, MXE (methoxetamine), ketamine, S-ketamine, R-ketamine, norketamine, S-norketamine, R-norketamine, memantine, amantadine, acamprosate, methadone, levomethadone, S-methadone, latrepirdine, tiletamine, seftazime, atigabine, besirotide, delucemine, dizocilpine maleate, gavestinel, licostinel, neramexane mesylate, perampanel, remacemide hydrochloride, troxopide mesylate, D-(-)-2-amino-5-phosphonovaleric acid (D-AP5), haloperidol, atomoxetine, oseltamivir, kynurenic acid, procaine, felbamate, mephenesin, huperzine A, linalool, orphenadrine, ifenprodil, pentamidine, dextrophan, and dextromethorphan.

3. An agent for improving clozapine-induced sialorrhea, which contains a compound having an agonistic effect on σ-1 receptors as an active ingredient.

4. The clozapine-induced sialorrhea improver according to claim 3, wherein, The compound having an agonistic effect on σ-1 receptors is at least one selected from the following, its pharmaceutically acceptable salt, or their hydrates: fluvoxamine, sertraline, S(+)-fluoxetine, (±)-fluoxetine, citalopram, imipramine, paroxetine, desipramine, R(-)-fluoxetine, (±)-norfluoxetine, donepezil, dextromethorphan, ifenprodil, SA4503, dehydroepiandrosterone 3-sulfate (alias: DHEA-S), (+)-SKF10,047, (-)-SKF10,047, (+)-pentazocine, (-)-pentazocine, PPBP, igmesine (alias: JO-1784), PRE-084, ilirotide (alias: SL 82.0715), DTG203, pridopidine, and AF710B (alias: akaANAVEX3-71).

5. An agent for improving clozapine-induced sialorrhea, which contains dextromethorphan, its pharmaceutically acceptable salt, or their hydrates as an active ingredient.

6. The clozapine-induced sialorrhea improver according to claim 5, wherein, The dosage of dextromethorphan, its pharmaceutically acceptable salt, or their hydrates is 0.2 mg / kg / day or more and 3.0 mg / kg / day or less.

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