WO2018151285A1 - Prophylactic or therapeutic drug for itching skin diseases - Google Patents

Prophylactic or therapeutic drug for itching skin diseases Download PDF

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WO2018151285A1
WO2018151285A1 PCT/JP2018/005629 JP2018005629W WO2018151285A1 WO 2018151285 A1 WO2018151285 A1 WO 2018151285A1 JP 2018005629 W JP2018005629 W JP 2018005629W WO 2018151285 A1 WO2018151285 A1 WO 2018151285A1
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cholecystokinin
receptor antagonist
pruritic skin
skin disease
receptor
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PCT/JP2018/005629
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French (fr)
Japanese (ja)
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史也 楠部
光俊 冨永
建二 ▲高▼森
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学校法人順天堂
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Priority to JP2018568647A priority Critical patent/JP7144052B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to a preventive or therapeutic agent for pruritic skin diseases such as atopic dermatitis.
  • systemic pruritus such as atopic dermatitis, contact dermatitis, psoriasis, psoriasis, etc., as well as systemic pruritus such as cirrhosis, renal failure, malignant lymphoma, etc.
  • sexual pruritus is present.
  • atopic dermatitis and the like it causes a strong itch, so that it is a problem that the symptoms are worsened by scratching. The mechanism of itching has not been clarified.
  • Non-Patent Documents 1 and 2 BNP receptor and GRP receptor
  • an object of the present invention is to find a new itching neurotransmitter and provide a new means of treating itching.
  • the present inventor conducted a search for a new iterative neurotransmitter using NC / Nga mice (AD / NC / Nga mice) with atopic dermatitis.
  • AD-NC / Nga mice The expression of cholecystokinin gene was strongly expressed in dorsal root ganglia (DRG), compared with NC / Nga mice without dermatitis, and it was found that cholecystokinin is an itching neurotransmitter.
  • DDG dorsal root ganglia
  • the present invention provides the following [1] to [5].
  • a prophylactic or therapeutic agent for pruritic skin diseases comprising a cholecystokinin-2 receptor antagonist as an active ingredient.
  • the cholecystokinin-2 receptor antagonist is L-365260, YM022, CI-988, Z-360, proglumide, CI-1015, PD135158, LY225910, YF476, LY-288513 or RP-69758 [ The prophylactic or therapeutic agent according to [1] or [2].
  • [4] Use for the production of a cholecystokinin-2 receptor antagonist for the manufacture of a prophylactic or therapeutic drug for pruritic skin diseases.
  • [5] The use according to [4], wherein the pruritic skin disease is pruritic skin disease accompanied by aronesis.
  • the cholecystokinin-2 receptor antagonist is L-365260, YM022, CI-988, Z-360, proglumide, CI-1015, PD135158, LY225910, YF476, LY-288513 or RP-69758 [ Use of 4] or [5].
  • [7] A cholecystokinin-2 receptor antagonist for preventing or treating pruritic skin diseases.
  • the cholecystokinin-2 receptor antagonist is L-365260, YM022, CI-988, Z-360, proglumide, CI-1015, PD135158, LY225910, YF476, LY-288513 or RP-69758 [ 7] or [8] a cholecystokinin-2 receptor antagonist.
  • a method for preventing or treating pruritic skin diseases comprising administering an effective amount of a cholecystokinin-2 receptor antagonist.
  • the method according to [10], wherein the pruritic skin disease is pruritic skin disease accompanied by aronesis.
  • the cholecystokinin-2 receptor antagonist is L-365260, YM022, CI-988, Z-360, proglumide, CI-1015, PD135158, LY225910, YF476, LY-288513 or RP-69758 [ [10] or [11].
  • a screening method for a prophylactic or therapeutic drug for pruritic skin disease which comprises measuring an antagonistic action of a subject against cholecystokinin-2 receptor.
  • a prophylactic or therapeutic drug for pruritic skin disease by a completely new mechanism is provided.
  • the number of seizures of scratching behavior 3 hours after administration of cholecystokinin 8S is shown.
  • the time course of scratching behavior up to 3 hours after administration of cholecystokinin 8S is shown.
  • the time course of the aronesis score after administration of cholecystokinin 8S is shown.
  • action of the CCK1R antagonist and the CCK2R antagonist with respect to the aronosis score after cholecystokinin 8S (0.5 nmol) administration is shown.
  • action of the CCK1R antagonist and the CCK2R antagonist with respect to the aronesis score after cholecystokinin 8S (1.0 nmol) administration is shown.
  • FIG. 2 shows the effect of a CCK2 receptor antagonist on the amount of spontaneous movement.
  • action of the CCK2 receptor antagonist oral administration with respect to a cholecystokinin induction aronesis is shown.
  • variation of transepidermal water transpiration (TEWL) and SC hydration in the skin of a dry skin model mouse is shown.
  • Fig. 4 shows spontaneous scratching behavior in a dry skin model mouse.
  • mouth is shown.
  • cholecystokinin 8S (CCK8S) is an itching neurotransmitter and a neuropeptide that induces aronesis
  • a CCK-2 receptor (CCK-2R) antagonist is an itching skin disease Has been found to be useful as a prophylactic or therapeutic drug.
  • the active ingredient of the preventive or therapeutic agent for pruritic skin diseases of the present invention is a cholecystokinin-2 receptor antagonist (CCK-2R antagonist).
  • Cholecystokinin is a peptide belonging to the gastrin family, and CCK-2 receptor antagonists are conventionally known to have a gastric motility enhancing action and an analgesic action or an analgesic enhancing action. No effect on itching is known.
  • Examples of the CCK-2R antagonist include the following known compounds.
  • the CCK-2 receptor antagonist suppresses allonosis caused by cholecystokinin 8S, which is a partial peptide of cholecystokinin, and prevents or treats pruritic skin disease in mammals including humans.
  • Aronesis means that itching is caused by a stimulus that does not inherently cause itching.
  • pruritic skin diseases include atopic dermatitis with pruritus, allergic dermatitis such as contact dermatitis, psoriasis, psoriasis, and dry skin.
  • these CCK-2 receptor antagonists are highly safe because they suppress allonesis caused by cholecystokinin 8S at doses that do not exhibit central effects.
  • the medicament of the present invention can be made into pharmaceutical compositions of various dosage forms containing a CCK-2 receptor antagonist as an active ingredient.
  • the dosage forms include tablets, granules, fine granules, powders, capsules, liquid preparations for oral administration, intravenous injection preparations, transdermal preparations, rectal administration preparations, etc. However, oral preparations are particularly preferred.
  • compositions can be formulated with a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers include lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, ethanol, carboxymethylcellulose, carboxymethylcellulose calcium.
  • Salt magnesium stearate, talc, acetylcellulose, saccharose, titanium oxide, benzoic acid, p-hydroxybenzoate, sodium dehydroacetate, gum arabic, tragacanth, methylcellulose, egg yolk, surfactant, sucrose, simple syrup, citric acid, distillation Water, ethanol, glycerin, propylene glycol, macrogol, sodium phosphate-sodium hydrogen, sodium dihydrogen phosphate, sodium phosphate, grape , Sodium chloride, phenol, thimerosal, p-hydroxybenzoic acid ester, there are sodium hydrogen sulfite, depending on the form of the preparation, are used in admixture with glycyl -L- alanyl -L- histidine or a salt thereof.
  • the content of the active ingredient of the present invention in the pharmaceutical composition of the present invention varies greatly depending on the form of the preparation and is not particularly limited, but is usually 0.01 to the total amount of the composition. 100% by mass, preferably 1 to 100% by mass.
  • the dose of the medicament of the present invention varies depending on the symptom, age and administration method of the patient to be administered, but it is preferably 10 to 2000 mg per day as an CCK-2 receptor antagonist for adults.
  • the dose can be divided into 1 to 4 times per day.
  • the screening method for a prophylactic or therapeutic drug for pruritic skin disease of the present invention can be carried out by measuring the antagonistic action of a subject against CCK-2 receptor.
  • CCK-2 receptor antagonism can be examined by measuring antagonism between CCK or a partial peptide thereof and a subject using cells or tissues having CCK-2 receptor.
  • the pruritic action can be directly evaluated by measuring the scratching behavior of a non-human animal to which cholecystokinin or a partial peptide thereof and a subject have been administered. It can also be performed by measuring the scratching behavior of a dry skin model animal.
  • cholecystokinin More specifically, it is only necessary to examine whether or not aronesis induced by administering cholecystokinin or a partial peptide thereof to a non-human animal such as a mouse or a rat is suppressed when the subject is administered.
  • partial peptides of cholecystokinin include cholecystokinin 8, cholecystokinin 8S (sulfate adduct of cholecystokinin 8) and the like.
  • Intrathecal administration is preferred for administration of cholecystokinin and the subject.
  • the scratching behavior was observed by placing the mouse in a cage, recording the scratching behavior on the video for 180 minutes without an experimenter in the observation room, and playing each video to create the seizure of the scratching behavior.
  • a series of actions of raising, scratching and lowering the rear leg is defined as a seizure of one scratching action. Movements such as grooming, licking, and biting should be considered scratching behavior.
  • the score is a total of the presence or absence of scratching behavior by five mechanical stimuli, with an aronesis score of one point.
  • the evaluation of the inhibitory effect may be whether or not the scratching behavior and the aronesis score are reduced when cholecystokinin or the like and the subject are administered compared to when only cholecystokinin or the like is administered. .
  • Example 1 DNA microarray analysis was performed using dorsal root ganglia (DRG) of NC / Nga mice that did not develop atopic dermatitis and NC / Nga mice that developed atopic dermatitis. That is, RNA extraction from DRG was performed using RNeasy Micro Kit (Qiagen), and after extraction, the absorbance of RNA was measured using NanoDrop 1000. The quality of the extracted RNA was confirmed using Agilent 2100 BioAnalyzer series II. Next, cDNA synthesis, cRNA labeling and amplification were performed using Low Input Quick Amp Labeling kit (Agilent Technologies).
  • DRG dorsal root ganglia
  • RNA extraction from DRG was performed using RNeasy Micro Kit (Qiagen), and after extraction, the absorbance of RNA was measured using NanoDrop 1000. The quality of the extracted RNA was confirmed using Agilent 2100 BioAnalyzer series II.
  • the labeled cRNA was purified using RNeasy mini spin columns (Qiagen) and the quality of the labeled cRNA was confirmed using Agilent 2100 BioAnalyzer series II. Next, hybridization was performed using Gene Expression Hybridization Kit (Agilent Technologies), and the slide glass was washed with Gene Expression Wash Buffer (Agilent Technologies). Thereafter, the slide glass was scanned using an Agilent Technologies Microarray Scanner. Next, each spot was digitized and normalized using the Agilent Feature Extraction 12.0.3.1 software, and FoldChange was analyzed. Table 1 shows the genes (mRNA) whose expression was increased more than 2-fold in the atopic dermatitis-onset NC / Nga DRG as compared to the atopic non-onset NC / Nga DRG.
  • mRNA cholecystokinin gene
  • Example 2 0.5 nmol of cholecystokinin 8S (CCK8 sulfate adduct) was injected into the medullary cavity of C57BL / 6J mice, and the scratching behavior was observed. The scratching behavior was observed and measured as follows (Kuraishi Y, Nagasawa T, Hayashi K, Satoh M. Scratching behavior induced by pruritogenic but not algesiogenic agents in mice. 1995, 275 (3) : 229-33). The hair on the rostral back of each mouse was shaved with an electric shaver. Mice were individually placed in acrylic cages consisting of 4 chambers (13 x 9 x 35 cm).
  • a video camera (HC-W850M; Panasonic, Osaka, Japan) was placed on the top of the cage using a tripod, and the scratching behavior was recorded. Mice were acclimated for at least 1 hour prior to imaging, then physiological saline (solvent), 0.5 nmol CCK8S was administered intrathecally under sevoflurane (Marui Pharmaceutical Co., Osaka, Japan) anesthesia. Immediately after intrathecal injection, the mouse was placed in a cage and the scratching behavior was recorded with a video camera for 3 hours in the absence of an experimenter in the observation room. The number of seizures of scratching behavior was counted by playing each video. FIG. 1 shows the number of attacks of 3 hours of scratching behavior, and FIG. 2 shows the time course of the scratching behavior. 1 and 2, the intrathecal administration of CCK8S significantly increased the scratching behavior of mice, suggesting that cholecystokinin may be a neurotransmitter of pruritus.
  • Example 3 The aronesis assay was based on previously reported literature (Akiyama T, Carstens MI, Ikoma A, Cevikbas F, Steinhoff M, E. Carstens. Mouse model of touch-evoked itch (alloknesis). J Invest Dermatol. 2012, 132 (7): 1886-1891, Bourane S, Duan B, Koch SC, Dalet A, Britz O, Garcia-Campmany L, Kim E, Cheng L, Ghosh A, Ma Q, Goulding M. Gate control of mechanical itch by a subpopulation of spinal cord interneurons. Science. 2015 Oct 30; 350 (6260): 550-4.).
  • FIG. 3 shows the results of 0.5 nmol or 1.0 nmol CCK8S administered intrathecally and subjected to an aronesis assay. As shown in FIG. 3, allonesis was induced by intrathecal administration of CCK8S in a time-lapse and dose-dependent manner after administration.
  • Example 4 In the aronesis assay of Example 3, together with CCK8S, SR27897 (1 nmol) which is a CCK-1R antagonist or L-365260 (1 nmol) which is a CCK-2R antagonist was intrathecally administered, and the scratching behavior of mice was observed. It was measured. As a result, as shown in FIGS. 4 and 5, the CCK-1R antagonist did not suppress the CCK8S-induced alonosis, but the CCK-2R antagonist administration significantly suppressed the CCK8S-induced alonosis.
  • Example 5 L-365260, PD135158, and LY-288513, which are known as CCK-2 receptor antagonists, were used to examine the aronesis inhibitory action.
  • (1) Determination of dose C57BL / 6J mice (male, 6-8 weeks old) were habituated in a photographing cage for 1 hour.
  • a CCK-2 receptor antagonist (L-365260, PD135158, LY-288513), which is known to have central migration, was orally administered. Spontaneous momentum was measured for 2.5 hours using the SCLABA-Real system.
  • the group composition was as follows.
  • L-365260 was administered at 10 mg / kg
  • PD135158 was administered at 10 mg / kg
  • LY-288513 was administered at 20 mg / kg.
  • L-365260, PD135158, and CY-288513 all inhibited cholecystokinin 8S-induced alonosis at doses that did not affect the locomotor activity.
  • Example 6 The back of C57BL6 / J mice (10 weeks old, male) was shaved (at least 3 days before the start of the experiment) and AEW treatment (7 days, morning, evening, twice) was performed to prepare dry skin model mice.
  • AEW treatment an AE solution in which acetone (A) and diethyl ether (E) were mixed at a ratio of 1: 1 was soaked into cotton and applied to the shaved portion for 15 seconds. Next, sterilized water was soaked into cotton and applied for 30 seconds (AEW group). The control group was coated with sterilized water for 45 seconds (W group).
  • FIG. 8 shows changes in TEWL and SC hydration in the skin of an AEW dry skin model mouse.
  • An increase in transepidermal water transpiration (TEWL value) and a decrease in stratum corneum water retention (SC hydration) were observed in AEW-treated mice as compared to W-treated control mice. From this, it was confirmed that dry skin was induced in the AEW mice used in this experiment.
  • FIG. 9 shows spontaneous scratching behavior in an AEW dry skin model mouse. Spontaneous scratching behavior associated with dry skin was observed with repeated AEW treatments.
  • FIG. 10 shows the effect of a CCK2 receptor antagonist on aronosis in AEW dry skin model mice. From FIG. 10, oral administration of 1 mg / kg and 10 mg / kg L-365260 significantly suppressed aronosis in AEW dry skin mice.

Abstract

Provided are a novel itching neurotransmitter and a therapeutic means for itchiness. A prophylactic or therapeutic drug for itching skin diseases, said drug comprising a cholecystokinin-2 receptor antagonist as an active ingredient.

Description

掻痒性皮膚疾患の予防又は治療薬Preventive or therapeutic agent for pruritic skin disease
　本発明は、アトピー性皮膚炎等の掻痒性皮膚疾患の予防又は治療薬に関する。 The present invention relates to a preventive or therapeutic agent for pruritic skin diseases such as atopic dermatitis.
　かゆみを伴う皮膚疾患には、アトピー性皮膚炎、接触皮膚炎、乾癬、乾皮症等の原因が判明している限局性掻痒症以外に、肝硬変、腎不全、悪性リンパ腫等の内臓疾患による全身性の皮膚掻痒症がある。このうち、アトピー性皮膚炎等においては、強いかゆみを引き起こすため、掻いてしまうことで症状を悪化させてしまうことが問題となっている。かゆみのメカニズムは明確にされていない。 For itchy skin diseases, systemic pruritus, such as atopic dermatitis, contact dermatitis, psoriasis, psoriasis, etc., as well as systemic pruritus such as cirrhosis, renal failure, malignant lymphoma, etc. Sexual pruritus is present. Among these, in atopic dermatitis and the like, it causes a strong itch, so that it is a problem that the symptoms are worsened by scratching. The mechanism of itching has not been clarified.
　最近の研究によって、後根神経節（ＤＲＧ）－脊髄間でいくつかの神経伝達物質がかゆみの情報伝達に関与することが示された。すなわち、末梢ＤＲＧで放出された脳性ナトリウム利尿ペプチド（ＢＮＰ）やガストリン放出ペプチド（ＧＲＰ）が、脊髄内のＢＮＰ受容体（Ｎｐｒａ）やＧＲＰ受容体（ＧＲＰＲ）を介してかゆみの情報伝達をしていることが報告された（非特許文献１、２）。 Recent studies have shown that several neurotransmitters are involved in the transmission of itching between the dorsal root ganglion (DRG) and the spinal cord. That is, brain natriuretic peptide (BNP) and gastrin-releasing peptide (GRP) released by peripheral DRG transmit itch information through BNP receptor (Npra) and GRP receptor (GRPR) in the spinal cord. (Non-Patent Documents 1 and 2).
　しかしながら、ＢＮＰやＧＲＰだけではかゆみの神経伝達を解明したとは言えず、更なる新たな神経伝達物質の解明が望まれている。
　従って、本発明の課題は、かゆみの新たな神経伝達物質を見出し、新たなかゆみの治療手段を提供することにある。 However, it cannot be said that BNP and GRP alone have clarified itching neurotransmission, and further elucidation of new neurotransmitters is desired.
Therefore, an object of the present invention is to find a new itching neurotransmitter and provide a new means of treating itching.
　そこで本発明者は、アトピー性皮膚炎発症ＮＣ／Ｎｇａマウス（ＡＤ／ＮＣ／Ｎｇａマウス）を用いてかゆみの新たな神経伝達物質の探索を行ったところ、ＡＤ－ＮＣ／Ｎｇａマウスにおいて、アトピー性皮膚炎未発症ＮＣ／Ｎｇａマウスに比べて、後根神経節（ＤＲＧ）でコレシストキニン遺伝子の発現が強く発現しており、コレシストキニンがかゆみの神経伝達物質である可能性を見出した。さらに、研究を続けたところ、コレシストキニン８Ｓの髄腔内投与によりマウスの掻破行動が増加し、コレシストキニン８Ｓは、アトピー性皮膚炎の特徴的な症状であるアロネーシスも誘発することを見出し、コレシストキニン８Ｓがかゆみの神経伝達物質であることを確認した。そしてさらに研究を続けたところ、コレシストキニン受容体のうち、コレシストキニン－２受容体（ＣＣＫ－２Ｒ）拮抗剤が、コレシストキニン８Ｓによる掻痒性皮膚疾患の予防又は治療薬として有用であることを見出し、本発明を完成した。 Therefore, the present inventor conducted a search for a new iterative neurotransmitter using NC / Nga mice (AD / NC / Nga mice) with atopic dermatitis. In AD-NC / Nga mice, The expression of cholecystokinin gene was strongly expressed in dorsal root ganglia (DRG), compared with NC / Nga mice without dermatitis, and it was found that cholecystokinin is an itching neurotransmitter. Furthermore, as a result of further research, it was found that intrathecal administration of cholecystokinin 8S increased the scratching behavior of mice, and cholecystokinin 8S also induced alonosis, a characteristic symptom of atopic dermatitis. Cholecystokinin 8S was confirmed to be an itchy neurotransmitter. As a result of further research, a cholecystokinin-2 receptor (CCK-2R) antagonist among cholecystokinin receptors is useful as a preventive or therapeutic agent for pruritic skin diseases caused by cholecystokinin 8S. As a result, the present invention has been completed.
　すなわち、本発明は、次の〔１〕～〔５〕を提供するものである。 That is, the present invention provides the following [1] to [5].
〔１〕コレシストキニン－２受容体拮抗剤を有効成分とする掻痒性皮膚疾患予防又は治療薬。
〔２〕掻痒性皮膚疾患が、アロネーシスを伴う掻痒性皮膚疾患である〔１〕記載の予防又は治療薬。
〔３〕コレシストキニン－２受容体拮抗剤が、Ｌ－３６５２６０、ＹＭ０２２、ＣＩ－９８８、Ｚ－３６０、プログルミド、ＣＩ－１０１５、ＰＤ１３５１５８、ＬＹ２２５９１０、ＹＦ４７６、ＬＹ－２８８５１３又はＲＰ－６９７５８である〔１〕又は〔２〕記載の予防又は治療薬。
〔４〕掻痒性皮膚疾患予防薬又は治療薬製造のための、コレシストキニン－２受容体拮抗剤製造のための使用。
〔５〕掻痒性皮膚疾患が、アロネーシスを伴う掻痒性皮膚疾患である〔４〕記載の使用。
〔６〕コレシストキニン－２受容体拮抗剤が、Ｌ－３６５２６０、ＹＭ０２２、ＣＩ－９８８、Ｚ－３６０、プログルミド、ＣＩ－１０１５、ＰＤ１３５１５８、ＬＹ２２５９１０、ＹＦ４７６、ＬＹ－２８８５１３又はＲＰ－６９７５８である〔４〕又は〔５〕記載の使用。
〔７〕掻痒性皮膚疾患を予防又は治療するための、コレシストキニン－２受容体拮抗剤。
〔８〕掻痒性皮膚疾患が、アロネーシスを伴う掻痒性皮膚疾患である〔７〕記載のコレシストキニン－２受容体拮抗剤。
〔９〕コレシストキニン－２受容体拮抗剤が、Ｌ－３６５２６０、ＹＭ０２２、ＣＩ－９８８、Ｚ－３６０、プログルミド、ＣＩ－１０１５、ＰＤ１３５１５８、ＬＹ２２５９１０、ＹＦ４７６、ＬＹ－２８８５１３又はＲＰ－６９７５８である〔７〕又は〔８〕記載のコレシストキニン－２受容体拮抗剤。
〔10〕コレシストキニン－２受容体拮抗剤の有効量を投与することを特徴とする掻痒性皮膚疾患の予防又は治療方法。
〔11〕掻痒性皮膚疾患が、アロネーシスを伴う掻痒性皮膚疾患である〔１０〕記載の方法。
〔12〕コレシストキニン－２受容体拮抗剤が、Ｌ－３６５２６０、ＹＭ０２２、ＣＩ－９８８、Ｚ－３６０、プログルミド、ＣＩ－１０１５、ＰＤ１３５１５８、ＬＹ２２５９１０、ＹＦ４７６、ＬＹ－２８８５１３又はＲＰ－６９７５８である〔１０〕又は〔１１〕記載の方法。
〔13〕被検体のコレシストキニン－２受容体に対する拮抗作用を測定することを特徴とする掻痒性皮膚疾患予防又は治療薬のスクリーニング方法。
〔14〕被検体のコレシストキニン－２受容体に対する拮抗作用の測定が、コレシストキニン又はその部分ペプチド類及び被検体を投与した非ヒト動物の掻破行動を測定するものである〔１３〕記載のスクリーニング方法。 [1] A prophylactic or therapeutic agent for pruritic skin diseases comprising a cholecystokinin-2 receptor antagonist as an active ingredient.
[2] The prophylactic or therapeutic agent according to [1], wherein the pruritic skin disease is a pruritic skin disease accompanied by aronosis.
[3] The cholecystokinin-2 receptor antagonist is L-365260, YM022, CI-988, Z-360, proglumide, CI-1015, PD135158, LY225910, YF476, LY-288513 or RP-69758 [ The prophylactic or therapeutic agent according to [1] or [2].
[4] Use for the production of a cholecystokinin-2 receptor antagonist for the manufacture of a prophylactic or therapeutic drug for pruritic skin diseases.
[5] The use according to [4], wherein the pruritic skin disease is pruritic skin disease accompanied by aronesis.
[6] The cholecystokinin-2 receptor antagonist is L-365260, YM022, CI-988, Z-360, proglumide, CI-1015, PD135158, LY225910, YF476, LY-288513 or RP-69758 [ Use of 4] or [5].
[7] A cholecystokinin-2 receptor antagonist for preventing or treating pruritic skin diseases.
[8] The cholecystokinin-2 receptor antagonist according to [7], wherein the pruritic skin disease is a pruritic skin disease accompanied by aronesis.
[9] The cholecystokinin-2 receptor antagonist is L-365260, YM022, CI-988, Z-360, proglumide, CI-1015, PD135158, LY225910, YF476, LY-288513 or RP-69758 [ 7] or [8] a cholecystokinin-2 receptor antagonist.
[10] A method for preventing or treating pruritic skin diseases, comprising administering an effective amount of a cholecystokinin-2 receptor antagonist.
[11] The method according to [10], wherein the pruritic skin disease is pruritic skin disease accompanied by aronesis.
[12] The cholecystokinin-2 receptor antagonist is L-365260, YM022, CI-988, Z-360, proglumide, CI-1015, PD135158, LY225910, YF476, LY-288513 or RP-69758 [ [10] or [11].
[13] A screening method for a prophylactic or therapeutic drug for pruritic skin disease, which comprises measuring an antagonistic action of a subject against cholecystokinin-2 receptor.
[14] The measurement of the antagonistic action of a subject on cholecystokinin-2 receptor measures the scratching behavior of a non-human animal to which cholecystokinin or a partial peptide thereof and the subject have been administered [13] Screening method.
　本発明によれば、全く新しい機序による掻痒性皮膚疾患の予防又は治療薬が提供される。 According to the present invention, a prophylactic or therapeutic drug for pruritic skin disease by a completely new mechanism is provided.
コレシストキニン８Ｓ投与後３時間の掻破行動の発作回数を示す。The number of seizures of scratching behavior 3 hours after administration of cholecystokinin 8S is shown. コレシストキニン８Ｓ投与後３時間までの掻破行動のタイムコースを示す。The time course of scratching behavior up to 3 hours after administration of cholecystokinin 8S is shown. コレシストキニン８Ｓ投与後のアロネーシススコアのタイムコースを示す。The time course of the aronesis score after administration of cholecystokinin 8S is shown. コレシストキニン８Ｓ（０．５ｎｍｏｌ）投与後のアロネーシススコアに対するＣＣＫ１Ｒアンタゴニスト及びＣＣＫ２Ｒアンタゴニストの作用を示す。The effect | action of the CCK1R antagonist and the CCK2R antagonist with respect to the aronosis score after cholecystokinin 8S (0.5 nmol) administration is shown. コレシストキニン８Ｓ（１．０ｎｍｏｌ）投与後のアロネーシススコアに対するＣＣＫ１Ｒアンタゴニスト及びＣＣＫ２Ｒアンタゴニストの作用を示す。The effect | action of the CCK1R antagonist and the CCK2R antagonist with respect to the aronesis score after cholecystokinin 8S (1.0 nmol) administration is shown. ＣＣＫ２受容体拮抗剤の自発運動量に及ぼす作用を示す。2 shows the effect of a CCK2 receptor antagonist on the amount of spontaneous movement. コレシストキニン誘発性アロネーシスに対するＣＣＫ２受容体拮抗剤経口投与の作用を示す。The effect | action of the CCK2 receptor antagonist oral administration with respect to a cholecystokinin induction aronesis is shown. ドライスキンモデルマウスの皮膚における経表皮水分蒸散量（ＴＥＷＬ）及びＳＣ　ｈｙｄｒａｔｉｏｎの変動を示す。The fluctuation | variation of transepidermal water transpiration (TEWL) and SC hydration in the skin of a dry skin model mouse is shown. ドライスキンモデルマウスにおける自発的掻破行動を示す。Fig. 4 shows spontaneous scratching behavior in a dry skin model mouse. ドライスキンモデルマウスのアロネーシスに対するＣＣＫ２受容体拮抗剤経口投与の作用を示す。The effect | action of the CCK2 receptor antagonist oral administration with respect to aronesis of a dry skin model mouse | mouth is shown.
　本発明は、コレシストキニン８Ｓ（ＣＣＫ８Ｓ）がかゆみの神経伝達物質であるとともにアロネーシスを誘発する神経ペプチドであることを見出し、さらにＣＣＫ－２受容体（ＣＣＫ－２Ｒ）拮抗剤が掻痒性皮膚疾患の予防又は治療薬として有用であることを見出したものである。 The present invention has found that cholecystokinin 8S (CCK8S) is an itching neurotransmitter and a neuropeptide that induces aronesis, and further, a CCK-2 receptor (CCK-2R) antagonist is an itching skin disease Has been found to be useful as a prophylactic or therapeutic drug.
　本発明の掻痒性皮膚疾患の予防又は治療薬の有効成分は、コレシストキニン－２受容体拮抗剤（ＣＣＫ－２Ｒアンタゴニスト）である。 The active ingredient of the preventive or therapeutic agent for pruritic skin diseases of the present invention is a cholecystokinin-2 receptor antagonist (CCK-2R antagonist).
　コレシストキニンは、ガストリンファミリーに属するペプチドであり、ＣＣＫ－２受容体拮抗剤は、従来、胃運動亢進作用を有すること、及び痛覚消失作用又は痛覚消失増強作用を有することは知られているが、かゆみに対する作用は全く知られていない。ＣＣＫ－２Ｒ拮抗剤としては、例えば次の既知化合物が挙げられる。 Cholecystokinin is a peptide belonging to the gastrin family, and CCK-2 receptor antagonists are conventionally known to have a gastric motility enhancing action and an analgesic action or an analgesic enhancing action. No effect on itching is known. Examples of the CCK-2R antagonist include the following known compounds.
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
　（Ｒ）－（－）－３－［３－（１－ｔｅｒｔ－ブチルカルボニルメチル－２－オキソ－５－シクロヘキシル－１，３，４，５－テトラヒドロ－２Ｈ－１，５－ベンゾジアゼピン－３－イル）ウレイド］安息香酸またはその薬学的に許容される塩（Ｚ－３６０） (R)-(−)-3- [3- (1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine-3- Yl) ureido] benzoic acid or a pharmaceutically acceptable salt thereof (Z-360)
　ＣＣＫ－２受容体拮抗剤は、後記実施例に示すように、コレシストキニンの部分ペプチドであるコレシストキニン８Ｓにより生じるアロネーシスを抑制し、ヒトを含む哺乳動物における掻痒性皮膚疾患の予防又は治療薬として有用である。アロネーシスとは、本来かゆみをもたらさない刺激によりかゆみを生じることをいう。掻痒性皮膚疾患としては、掻痒を伴なうアトピー性皮膚炎、接触皮膚炎などのアレルギー性皮膚炎、乾癬、乾皮症、ドライスキン等が挙げられる。
　また、これらのＣＣＫ－２受容体拮抗剤は、中枢作用を示さない投与量において、コレシストキニン８Ｓにより生じるアロネーシスを抑制することから、安全性も高い。 The CCK-2 receptor antagonist, as shown in Examples below, suppresses allonosis caused by cholecystokinin 8S, which is a partial peptide of cholecystokinin, and prevents or treats pruritic skin disease in mammals including humans. Useful as a medicine. Aronesis means that itching is caused by a stimulus that does not inherently cause itching. Examples of pruritic skin diseases include atopic dermatitis with pruritus, allergic dermatitis such as contact dermatitis, psoriasis, psoriasis, and dry skin.
In addition, these CCK-2 receptor antagonists are highly safe because they suppress allonesis caused by cholecystokinin 8S at doses that do not exhibit central effects.
　本発明の医薬は、ＣＣＫ－２受容体拮抗剤を有効成分として含有する各種の剤形の医薬組成物とすることができる。当該剤形としては、錠剤、顆粒剤、細粒剤、粉末剤、カプセル剤、液剤等の経口投与用製剤、静脈投与用製剤等の注射剤、経皮投与用製剤、経直腸投与用製剤等が挙げられるが、経口投与用製剤が特に好ましい。 The medicament of the present invention can be made into pharmaceutical compositions of various dosage forms containing a CCK-2 receptor antagonist as an active ingredient. The dosage forms include tablets, granules, fine granules, powders, capsules, liquid preparations for oral administration, intravenous injection preparations, transdermal preparations, rectal administration preparations, etc. However, oral preparations are particularly preferred.
　これらの医薬組成物の形態とするには、薬学的に許容される担体とともに製剤化することができる。そのような担体としては、例えば、乳糖、ブドウ糖、Ｄ－マンニトール、澱粉、結晶セルロース、炭酸カルシウム、カオリン、デンプン、ゼラチン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、エタノール、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム塩、ステアリン酸マグネシウム、タルク、アセチルセルロース、白糖、酸化チタン、安息香酸、パラオキシ安息香酸エステル、デヒドロ酢酸ナトリウム、アラビアゴム、トラガント、メチルセルロース、卵黄、界面活性剤、白糖、単シロップ、クエン酸、蒸留水、エタノール、グリセリン、プロピレングリコール、マクロゴール、リン酸－水素ナトリウム、リン酸二水素ナトリウム、リン酸ナトリウム、ブドウ糖、塩化ナトリウム、フェノール、チメロサール、パラオキシ安息香酸エステル、亜硫酸水素ナトリウム等があり、製剤の形に応じて、グリシル－Ｌ－アラニル－Ｌ－ヒスチジン又はその塩と混合して使用される。 These pharmaceutical compositions can be formulated with a pharmaceutically acceptable carrier. Examples of such carriers include lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, ethanol, carboxymethylcellulose, carboxymethylcellulose calcium. Salt, magnesium stearate, talc, acetylcellulose, saccharose, titanium oxide, benzoic acid, p-hydroxybenzoate, sodium dehydroacetate, gum arabic, tragacanth, methylcellulose, egg yolk, surfactant, sucrose, simple syrup, citric acid, distillation Water, ethanol, glycerin, propylene glycol, macrogol, sodium phosphate-sodium hydrogen, sodium dihydrogen phosphate, sodium phosphate, grape , Sodium chloride, phenol, thimerosal, p-hydroxybenzoic acid ester, there are sodium hydrogen sulfite, depending on the form of the preparation, are used in admixture with glycyl -L- alanyl -L- histidine or a salt thereof.
　さらに、本発明の医薬組成物中における本発明の有効成分の含有量は、製剤の形によって大きく変動し、特に限定されるものではないが、通常は、組成物全量に対して０．０１～１００質量％、好ましくは１～１００質量％である。 Further, the content of the active ingredient of the present invention in the pharmaceutical composition of the present invention varies greatly depending on the form of the preparation and is not particularly limited, but is usually 0.01 to the total amount of the composition. 100% by mass, preferably 1 to 100% by mass.
　本発明の医薬の投与量は、投与する患者の症状、年齢、投与方法によって異なるが、ＣＣＫ－２受容体拮抗剤として、成人に対して１日あたり１０～２０００ｍｇであるのが好ましい。またこの投与量は１日に１～４回に分けて投与することもできる。 The dose of the medicament of the present invention varies depending on the symptom, age and administration method of the patient to be administered, but it is preferably 10 to 2000 mg per day as an CCK-2 receptor antagonist for adults. The dose can be divided into 1 to 4 times per day.
　本発明の掻痒性皮膚疾患予防又は治療薬のスクリーニング方法は、被検体のＣＣＫ－２受容体に対する拮抗作用を測定することにより実施できる。ＣＣＫ－２受容体拮抗作用は、ＣＣＫ－２受容体を有する細胞又は組織を用いて、ＣＣＫ又はその部分ペプチド類と被検体との拮抗作用を測定することにより検討することができる。また、掻痒作用を直接評価するには、コレシストキニン又はその部分ペプチド類及び被検体を投与した非ヒト動物の掻破行動を測定することによって行うこともできる。また、ドライスキンモデル動物の掻破行動を測定することによっても行うことができる。 The screening method for a prophylactic or therapeutic drug for pruritic skin disease of the present invention can be carried out by measuring the antagonistic action of a subject against CCK-2 receptor. CCK-2 receptor antagonism can be examined by measuring antagonism between CCK or a partial peptide thereof and a subject using cells or tissues having CCK-2 receptor. In addition, the pruritic action can be directly evaluated by measuring the scratching behavior of a non-human animal to which cholecystokinin or a partial peptide thereof and a subject have been administered. It can also be performed by measuring the scratching behavior of a dry skin model animal.
　より具体的には、マウスやラット等の非ヒト動物にコレシストキニン又はその部分ペプチド類を投与して誘発されるアロネーシスを、被検体を投与した場合に抑制するか否かを検討すればよい。コレシストキニンの部分ペプチド類としては、コレシストキニン８、コレシストキニン８Ｓ（コレシストキニン８の硫酸付加物）等が挙げられる。コレシストキニンや被検体の投与は、髄腔内投与が好ましい。また、掻破行動の観察は、以前報告された方法に従い、マウスをケージに置き、観察室に実験者がいない状態で１８０分間ビデオに掻破行動を記録、各ビデオを再生することによって掻破行動の発作の数を計測することにより行うのが好ましい（Kuraishi Y, Nagasawa T, Hayashi K, Satoh M. Scratching behavior induced by pruritogenic but not algesiogenic agents in mice. 1995, 275(3):229-33）。計測の際に、後脚を上げ、掻破し、下す一連の行動を１回の掻破行動の発作として定義する。グルーミング（毛づくろい）、舐める、噛むなどの動きは掻破行動とはみなさい。アロネーシスの観察は、以前報告された方法に従い、無作為に選んだ５つの部位にｖｏｎ　Ｆｒｅｙフィラメント（０．１６ｇ）を用いて１０秒ごとに５回の機械刺激を与え、次の刺激をマウスに与える前に、各刺激について掻破行動の有無を観察することにより行うのが好ましい（Akiyama T, Carstens MI, Ikoma A, Cevikbas F, Steinhoff M, E. Carstens. Mouse model of touch-evoked itch (alloknesis). J Invest Dermatol.2012, 132(7): 1886-1891、Bourane S, Duan B, Koch SC, Dalet A, Britz O, Garcia-Campmany L, Kim E, Cheng L, Ghosh A, Ma Q, Goulding M. Gate control of mechanicalitch by a subpopulation of spinal cord interneurons. Science. 2015 Oct 30;350(6260):550-4）。１回の機械刺激によって掻破行動が認められたら場合、アロネーシススコアを１点とし、５回分の機械刺激による掻破行動の有無を合計した点数で評価する。抑制作用の評価は、コレシストキニン等のみを投与した場合に比べて、コレシストキニン等と被検体を投与した場合に掻破行動及びアロネーシススコアが低下しているか否かを評価すればよい。 More specifically, it is only necessary to examine whether or not aronesis induced by administering cholecystokinin or a partial peptide thereof to a non-human animal such as a mouse or a rat is suppressed when the subject is administered. . Examples of partial peptides of cholecystokinin include cholecystokinin 8, cholecystokinin 8S (sulfate adduct of cholecystokinin 8) and the like. Intrathecal administration is preferred for administration of cholecystokinin and the subject. In addition, according to the method reported previously, the scratching behavior was observed by placing the mouse in a cage, recording the scratching behavior on the video for 180 minutes without an experimenter in the observation room, and playing each video to create the seizure of the scratching behavior. (Kuraishi Y, Nagasawa T, Hayashi K, Satoh M. Scratching behavior induced by pruritogenic but not algesiogenic agents in mice. 1995, 275 (3): 229-33). When measuring, a series of actions of raising, scratching and lowering the rear leg is defined as a seizure of one scratching action. Movements such as grooming, licking, and biting should be considered scratching behavior. According to a previously reported method, aronesis was observed by giving 5 mechanical stimuli every 10 seconds to 5 randomly selected sites using von Frey filament (0.16 g), and the next stimulus was given to the mice. Before giving, it is preferable to observe the presence or absence of scratching behavior for each stimulus (Akiyama T, Carstens MI, Ikoma A, Cevikbas F, Steinhoff M, E. Carstens. . J Invest Dermatol. 2012, 132 (7): 1886-1891, Bourane S, Duan B, Koch SC, Dalet A, Britz O, Garcia-Campmany L, Kim E, . Gate control of mechanicalitch by a subpopulation of spinal cord interneurons. Science. 2015 Oct 30; 350 (6260): 550-4). If scratching behavior is recognized by one mechanical stimulus, the score is a total of the presence or absence of scratching behavior by five mechanical stimuli, with an aronesis score of one point. The evaluation of the inhibitory effect may be whether or not the scratching behavior and the aronesis score are reduced when cholecystokinin or the like and the subject are administered compared to when only cholecystokinin or the like is administered. .
　次に実施例を挙げて本発明を更に詳細に説明する。 Next, the present invention will be described in more detail with reference to examples.
実施例１
　アトピー性皮膚炎未発症のＮＣ／Ｎｇａマウスとアトピー性皮膚炎発症のＮＣ／Ｎｇａマウスの後根神経節（ＤＲＧ）を用いて、ＤＮＡマイクロアレイ解析を行った。すなわち、ＤＲＧからのＲＮＡ抽出は、ＲＮｅａｓｙ　Ｍｉｃｒｏ　Ｋｉｔ（Ｑｉａｇｅｎ社）を用いて行い、抽出後、ＲＮＡの吸光度をＮａｎｏＤｒｏｐ　１０００を用いて測定した。抽出したＲＮＡの品質はＡｇｉｌｅｎｔ　２１００　ＢｉｏＡｎａｌｙｚｅｒ　ｓｅｒｉｅｓ　ＩＩを使用して確認した。次に、Ｌｏｗ　Ｉｎｐｕｔ　Ｑｕｉｃｋ　Ａｍｐ　Ｌａｂｅｌｉｎｇ　ｋｉｔ（Ａｇｉｌｅｎｔ　Ｔｅｃｈｎｏｌｏｇｉｅｓ）を使用し、ｃＤＮＡ合成、ｃＲＮＡのラベルと増幅を行った。ＲＮｅａｓｙ　ｍｉｎｉ　ｓｐｉｎ　ｃｏｌｕｍｎｓ（Ｑｉａｇｅｎ社）を使用しラベル化ｃＲＮＡを精製し、Ａｇｉｌｅｎｔ　２１００　ＢｉｏＡｎａｌｙｚｅｒ　ｓｅｒｉｅｓ　ＩＩを使用してラベル化ｃＲＮＡの品質を確認した。次に、Ｇｅｎｅ　Ｅｘｐｒｅｓｓｉｏｎ　Ｈｙｂｒｉｄｉｚａｔｉｏｎ　ｋｉｔ（Ａｇｉｌｅｎｔ　Ｔｅｃｈｎｏｌｏｇｉｅｓ）を用いてハイブリダイゼーションを行い、スライドガラスをＧｅｎｅ　Ｅｘｐｒｅｓｓｉｏｎ　Ｗａｓｈ　Ｂｕｆｆｅｒ（Ａｇｉｌｅｎｔ　Ｔｅｃｈｎｏｌｏｇｉｅｓ）で洗浄した。その後、Ａｇｉｌｅｎｔ　Ｔｅｃｈｎｏｌｏｇｉｅｓ　Ｍｉｃｒｏａｒｒａｙ　Ｓｃａｎｎｅｒを用いてスライドガラスをスキャンした。次に、Ａｇｉｌｅｎｔ　Ｆｅａｔｕｒｅ　Ｅｘｔｒａｃｔｉｏｎ　１２．０．３．１ソフトを用いて各スポットの数値化、ノーマライズを行い、ＦｏｌｄＣｈａｎｇｅの解析を行った。
　アトピー性皮膚炎発症ＮＣ／ＮｇａのＤＲＧにおいて、アトピー性未発症ＮＣ／ＮｇａのＤＲＧに比べて２倍以上発現が上昇していた遺伝子（ｍＲＮＡ）を表１に示す。 Example 1
DNA microarray analysis was performed using dorsal root ganglia (DRG) of NC / Nga mice that did not develop atopic dermatitis and NC / Nga mice that developed atopic dermatitis. That is, RNA extraction from DRG was performed using RNeasy Micro Kit (Qiagen), and after extraction, the absorbance of RNA was measured using NanoDrop 1000. The quality of the extracted RNA was confirmed using Agilent 2100 BioAnalyzer series II. Next, cDNA synthesis, cRNA labeling and amplification were performed using Low Input Quick Amp Labeling kit (Agilent Technologies). The labeled cRNA was purified using RNeasy mini spin columns (Qiagen) and the quality of the labeled cRNA was confirmed using Agilent 2100 BioAnalyzer series II. Next, hybridization was performed using Gene Expression Hybridization Kit (Agilent Technologies), and the slide glass was washed with Gene Expression Wash Buffer (Agilent Technologies). Thereafter, the slide glass was scanned using an Agilent Technologies Microarray Scanner. Next, each spot was digitized and normalized using the Agilent Feature Extraction 12.0.3.1 software, and FoldChange was analyzed.
Table 1 shows the genes (mRNA) whose expression was increased more than 2-fold in the atopic dermatitis-onset NC / Nga DRG as compared to the atopic non-onset NC / Nga DRG.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　表１から、コレシストキニン遺伝子（ｍＲＮＡ）は、アトピー性皮膚炎発症ＮＣ／Ｎｇａマウスにおいて有意に増加していた。 From Table 1, the cholecystokinin gene (mRNA) was significantly increased in NC / Nga mice with atopic dermatitis.
実施例２
　Ｃ５７ＢＬ／６Ｊマウスの髄腔内にコレシストキニン８Ｓ（ＣＣＫ８硫酸付加物）０．５ｎｍｏｌを注射し、掻破行動を観察した。掻破行動は、以前報告された方法に従い、下記のように観察・測定した（Kuraishi Y, Nagasawa T, Hayashi K, Satoh M. Scratching behavior induced by pruritogenic but not algesiogenic agents in mice. 1995, 275(3):229-33）。各マウスの吻側背部の毛を電気シェーバーで剃毛した。マウスを個々に４つの部屋（１３×９×３５ｃｍ）からなるアクリル製ケージに入れた。ケージの上部に三脚を用いてビデオカメラ（ＨＣ－Ｗ８５０Ｍ；Ｐａｎａｓｏｎｉｃ、Ｏｓａｋａ、Ｊａｐａｎ）を配置し、掻破行動を録画した。マウスは撮影前に、少なくとも１時間、馴化させ、その後セボフルラン（Ｍａｒｕｉｓｈｉ　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｃｏ．，大阪、日本）麻酔下で、生理食塩水（溶媒）、０．５ｎｍｏｌ　ＣＣＫ８Ｓを髄腔内投与した。髄腔内注射の直後に、マウスをケージに置き、観察室に実験者がいない状態で３時間ビデオカメラにて掻破行動を記録した。各ビデオを再生することによって掻破行動の発作の数を計測した。
　３時間の掻破行動の発作回数を図１に、掻破行動のタイムコースを図２に示す。
　図１及び図２より、ＣＣＫ８Ｓの髄腔内投与により、マウスの掻破行動が有意に増加し、コレシストキニンが掻痒の神経伝達物質である可能性が示唆された。 Example 2
0.5 nmol of cholecystokinin 8S (CCK8 sulfate adduct) was injected into the medullary cavity of C57BL / 6J mice, and the scratching behavior was observed. The scratching behavior was observed and measured as follows (Kuraishi Y, Nagasawa T, Hayashi K, Satoh M. Scratching behavior induced by pruritogenic but not algesiogenic agents in mice. 1995, 275 (3) : 229-33). The hair on the rostral back of each mouse was shaved with an electric shaver. Mice were individually placed in acrylic cages consisting of 4 chambers (13 x 9 x 35 cm). A video camera (HC-W850M; Panasonic, Osaka, Japan) was placed on the top of the cage using a tripod, and the scratching behavior was recorded. Mice were acclimated for at least 1 hour prior to imaging, then physiological saline (solvent), 0.5 nmol CCK8S was administered intrathecally under sevoflurane (Marui Pharmaceutical Co., Osaka, Japan) anesthesia. Immediately after intrathecal injection, the mouse was placed in a cage and the scratching behavior was recorded with a video camera for 3 hours in the absence of an experimenter in the observation room. The number of seizures of scratching behavior was counted by playing each video.
FIG. 1 shows the number of attacks of 3 hours of scratching behavior, and FIG. 2 shows the time course of the scratching behavior.
1 and 2, the intrathecal administration of CCK8S significantly increased the scratching behavior of mice, suggesting that cholecystokinin may be a neurotransmitter of pruritus.
実施例３
　アロネーシスアッセイは以前の報告された文献に基づき行った（Akiyama T, Carstens MI, Ikoma A, Cevikbas F, Steinhoff M, E. Carstens. Mouse model of touch-evoked itch (alloknesis). J Invest Dermatol. 2012, 132(7): 1886-1891、Bourane S, Duan B,Koch SC, Dalet A, Britz O, Garcia-Campmany L, Kim E, Cheng L, Ghosh A, Ma Q, Goulding M. Gate control of mechanical itch by a subpopulation of spinal cord interneurons.　Science. 2015 Oct 30;350(6260):550-4.）。すなわち、Ｖｏｎ　Ｆｒｅｙ　フィラメントを用いて軽微な機械的刺激をＣ５７ＢＬ／６Ｊマウスの皮膚に与え、刺激直後に掻破行動が生じるか否かを解析するアローネシスアッセイを行った。アロネーシスアッセイを実施する３日前にマウスの吻側背部を剃毛した。各マウスの髄腔内に生理食塩水５μＬを溶媒とした０．５または１．０ｎｍｏｌのＣＣＫ８Ｓを溶解した溶液を投与し、髄腔内投与５分、３０分、６０分、９０分、１２０分、１５０分、１８０分後にアロネーシスアッセイを行った。無作為に選んだ５つの部位でｖｏｎ　Ｆｒｅｙフィラメント（０．１６ｇ）を用いてマウスに１０秒間隔で５回のＶｏｎ　Ｆｒｅｙ刺激を与え、そのうちマウスが刺激した場所を掻破した回数をスコア化し、評価した。０．５ｎｍｏｌ又は１．０ｎｍｏｌＣＣＫ８Ｓはを髄腔内投与し、アロネーシスアッセイを行った結果を図３に示す。
　図３より、ＣＣＫ８Ｓの髄腔内投与により、投与後の時間経過及び投与量依存的にアロネーシスを誘発した。 Example 3
The aronesis assay was based on previously reported literature (Akiyama T, Carstens MI, Ikoma A, Cevikbas F, Steinhoff M, E. Carstens. Mouse model of touch-evoked itch (alloknesis). J Invest Dermatol. 2012, 132 (7): 1886-1891, Bourane S, Duan B, Koch SC, Dalet A, Britz O, Garcia-Campmany L, Kim E, Cheng L, Ghosh A, Ma Q, Goulding M. Gate control of mechanical itch by a subpopulation of spinal cord interneurons. Science. 2015 Oct 30; 350 (6260): 550-4.). That is, a slight mechanical stimulus was applied to the skin of C57BL / 6J mice using Von Frey filament, and an Arronesis assay was performed to analyze whether or not scratching behavior occurred immediately after the stimulus. The rostral back of the mice was shaved 3 days prior to performing the aronesis assay. A solution in which 0.5 or 1.0 nmol of CCK8S using 5 μL of physiological saline as a solvent is administered into the medullary cavity of each mouse, and intrathecal administration 5 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes , 150 minutes, 180 minutes later, an aronesis assay was performed. Mice were given 5 Von Frey stimuli at 10 second intervals using von Frey filaments (0.16 g) at 5 randomly selected sites, and the number of times the mice were stimulated was scored and evaluated. did. FIG. 3 shows the results of 0.5 nmol or 1.0 nmol CCK8S administered intrathecally and subjected to an aronesis assay.
As shown in FIG. 3, allonesis was induced by intrathecal administration of CCK8S in a time-lapse and dose-dependent manner after administration.
実施例４
　実施例３のアロネーシスアッセイにおいて、ＣＣＫ８Ｓとともに、ＣＣＫ－１Ｒ拮抗剤であるＳＲ２７８９７（１ｎｍｏｌ）又はＣＣＫ－２Ｒ拮抗剤であるＬ－３６５２６０（１ｎｍｏｌ）を髄腔内投与し、マウスの掻破行動を測定した。
　その結果、図４及び図５に示すように、ＣＣＫ－１Ｒ拮抗剤ではＣＣＫ８Ｓ誘発性アロネーシスが抑制されなかったが、ＣＣＫ－２Ｒ拮抗剤投与によりＣＣＫ８Ｓ誘発性アロネーシスが有意に抑制された。 Example 4
In the aronesis assay of Example 3, together with CCK8S, SR27897 (1 nmol) which is a CCK-1R antagonist or L-365260 (1 nmol) which is a CCK-2R antagonist was intrathecally administered, and the scratching behavior of mice was observed. It was measured.
As a result, as shown in FIGS. 4 and 5, the CCK-1R antagonist did not suppress the CCK8S-induced alonosis, but the CCK-2R antagonist administration significantly suppressed the CCK8S-induced alonosis.
実施例５
　ＣＣＫ－２受容体拮抗剤として知られているＬ－３６５２６０、ＰＤ１３５１５８及びＬＹ－２８８５１３を使用してアロネーシス抑制作用を検討した。
（１）投与量の決定
　Ｃ５７ＢＬ／６Ｊマウス（雄、６－８週齢）を１時間撮影ケージで馴化した。中枢移行性があることが知られているＣＣＫ－２受容体拮抗剤（Ｌ－３６５２６０、ＰＤ１３５１５８、ＬＹ－２８８５１３）を経口投与した。ＳＣＬＡＢＡ－Ｒｅａｌシステムを用いて、２．５時間、自発運動量を測定した。 Example 5
L-365260, PD135158, and LY-288513, which are known as CCK-2 receptor antagonists, were used to examine the aronesis inhibitory action.
(1) Determination of dose C57BL / 6J mice (male, 6-8 weeks old) were habituated in a photographing cage for 1 hour. A CCK-2 receptor antagonist (L-365260, PD135158, LY-288513), which is known to have central migration, was orally administered. Spontaneous momentum was measured for 2.5 hours using the SCLABA-Real system.
　群構成は、以下の通りとした。
群構成（１）
１．溶媒(0.5% メチルセルロース)                    投与群(N=9)
２．10mg/kg p.o. L-365260(ベンゾジアゼピン誘導体)  投与群(N=5)
３．10mg/kg p.o. PD135158(ペプチド誘導体)          投与群(N=6)
４．10mg/kg p.o. LY-288513(ピラゾリジン誘導体)     投与群(N=9)
群構成（２）
１．溶媒(0.5%メチルセルロース)                       投与群(N=9)
２．20mg/kg p.o. L-365260(ベンゾジアゼピン誘導体)  　投与群(N=4)
３．20mg/kg p.o. PD135158(ペプチド誘導体)            投与群(N=4)
４．20mg/kg p.o. LY-288513(ピラゾリジン誘導体) 　　　投与群(N=8) The group composition was as follows.
Group structure (1)
1. Solvent (0.5% methylcellulose) administration group (N = 9)
2. 10 mg / kg po L-365260 (benzodiazepine derivative) administration group (N = 5)
3. 10 mg / kg po PD135158 (peptide derivative) administration group (N = 6)
4. 10 mg / kg po LY-288513 (pyrazolidine derivative) administration group (N = 9)
Group composition (2)
1. Solvent (0.5% methylcellulose) administration group (N = 9)
2. 20 mg / kg po L-365260 (benzodiazepine derivative) administration group (N = 4)
3. 20 mg / kg po PD135158 (peptide derivative) administration group (N = 4)
4. 20 mg / kg po LY-288513 (pyrazolidine derivative) administration group (N = 8)
　その結果、図６に示すように、Ｌ－３６５２６０は１０ｍｇ／ｋｇ投与で、ＰＤ１３５１５８は１０ｍｇ／ｋｇ投与で、またＬＹ－２８８５１３は２０ｍｇ／ｋｇ投与で、自発運動量に影響しないことが判明した。 As a result, as shown in FIG. 6, it was found that L-365260 was administered at 10 mg / kg, PD135158 was administered at 10 mg / kg, and LY-288513 was administered at 20 mg / kg.
（２）ＣＣＫ２受容体拮抗剤のコレシストキニン８Ｓ誘発性アロネーシスに対する作用
　Ｃ５７ＢＬ／６Ｊマウス（雄、６－８週齢）を１時間アッセイ用のケージで馴化した。前記のＣＣＫ２受容体拮抗剤を経口投与した。
　ＣＣＫ２Ｒ受容体拮抗剤の経口投与３０分後に、髄腔内にＣＣＫ８Ｓ（１ｎｍｏＬ／５μＬ）を投与した。ＣＣＫ８Ｓ投与後５，３０，６０，９０，１２０分で、ｖｏｎ　Ｆｒｅｙフィラメント（０．１６ｇ）を用いてアロネーシスアッセイを行った。 (2) Effect of CCK2 receptor antagonist on cholecystokinin 8S-induced alonosis C57BL / 6J mice (male, 6-8 weeks old) were habituated in a cage for 1 hour assay. The CCK2 receptor antagonist was orally administered.
Thirty minutes after oral administration of the CCK2R receptor antagonist, CCK8S (1 nmoL / 5 μL) was administered intrathecally. At 5, 30, 60, 90, and 120 minutes after CCK8S administration, an aronesis assay was performed using von Frey filament (0.16 g).
　群構成を以下に示す。
１．Veh(p.o. 0.5% メチルセルロース)→ i.t. saline　　　　　(N=9)
２．Veh(p.o. 0.5% メチルセルロース)→ i.t. CCK8S (1 nmoL)　(N=9)
３．10mg/kg p.o. L-365260→i.t. CCK8S (1 nmoL)             (N=9)
４．10mg/kg p.o. PD135158→i.t. CCK8S(1 nmoL)　　　　　　　(N=8)
５．20mg/kg p.o. LY-288513→i.t. CCK8S(1 nmoL)　　　　　　 (N=7) The group structure is shown below.
1. Veh (po 0.5% methylcellulose) → it saline (N = 9)
2. Veh (po 0.5% methylcellulose) → it CCK8S (1 nmoL) (N = 9)
3. 10mg / kg po L-365260 → it CCK8S (1 nmoL) (N = 9)
4. 10mg / kg po PD135158 → it CCK8S (1 nmoL) (N = 8)
5. 20mg / kg po LY-288513 → it CCK8S (1 nmoL) (N = 7)
　その結果、図７に示すように、Ｌ－３６５２６０、ＰＤ１３５１５８及びＣＹ－２８８５１３は、いずれも自発運動量に影響を及ぼさない投与量でコレシストキニン８Ｓ誘発性アロネーシスを抑制した。 As a result, as shown in FIG. 7, L-365260, PD135158, and CY-288513 all inhibited cholecystokinin 8S-induced alonosis at doses that did not affect the locomotor activity.
実施例６
（方法）
　Ｃ５７ＢＬ６／Ｊマウス（１０週齢、雄）の背部を剃毛し（少なくとも実験開始３日前）、ＡＥＷ処置（７日間、朝・夕・２回）を行い、ドライスキンモデルマウスを作製した。
　ＡＥＷ処置は、アセトン（Ａ）とジエチルエーテル（Ｅ）を１：１で混ぜたＡＥ溶液をコットンに染み込ませ、剃毛部に１５秒間塗布した。次に滅菌水をコットンに染み込ませ、３０秒間塗布した（ＡＥＷ群）。コントロール群には、滅菌水で４５秒間塗布した（Ｗ群）。
　最後のＡＥＷ処理から１６～２０時間後にスクラバを用いて２時間（内、１時間は馴化のため）、掻破行動を録画した。スクラバ解析後、下記の行動試験を開始した。
　１時間ケージで馴化中に、ＡＥＷドライスキンモデルマウスにＣＣＫ２Ｒ拮抗薬（Ｌ－３６５２６０）をアロネーシスアッセイ開始３０分前に経口投与した。
　アロネーシスアッセイは、ｖｏｎ　Ｆｒｅｙ　ｆｉｌａｍｅｎｔ　０．１６ｇを用いて行った。計６回、Ｖｏｎ　Ｆｒｅｙ　ｆｉｌａｍｅｎｔで刺激した。
　アロネーシスアッセイ後、経表皮水分蒸散量（ＴＥＷＬ）及びＳＣ　ｈｙｄｒａｔｉｏｎの測定し、試験を終了した。
群構成
１．Ｗ処理マウス　＋　溶媒（０．５％メチルセルロース）（ｎ＝８）
２．ＡＥＷ処理マウス　＋　溶媒（０．５％メチルセルロース）（ｎ＝８）
３．ＡＥＷ処理マウス　＋　１ｍｇ／ｋｇ　Ｌ－３６５２６０（ｎ＝８）
４．ＡＥＷ処理マウス　＋　１０ｍｇ／ｋｇ　Ｌ－３６５２６０（ｎ＝８） Example 6
(Method)
The back of C57BL6 / J mice (10 weeks old, male) was shaved (at least 3 days before the start of the experiment) and AEW treatment (7 days, morning, evening, twice) was performed to prepare dry skin model mice.
In the AEW treatment, an AE solution in which acetone (A) and diethyl ether (E) were mixed at a ratio of 1: 1 was soaked into cotton and applied to the shaved portion for 15 seconds. Next, sterilized water was soaked into cotton and applied for 30 seconds (AEW group). The control group was coated with sterilized water for 45 seconds (W group).
16-20 hours after the last AEW treatment, the scratching behavior was recorded for 2 hours (of which 1 hour was for habituation) using a scrubber. After the scrubber analysis, the following behavioral test was started.
While acclimatized for 1 hour in the cage, a CCK2R antagonist (L-365260) was orally administered to AEW dry skin model mice 30 minutes before the start of the aronosis assay.
The aronesis assay was performed using 0.16 g of von Frey filament. Stimulated with Von Frey filament six times in total.
After the aronesis assay, transepidermal water transpiration (TEWL) and SC hydration were measured and the test was terminated.
Group structure W-treated mouse + solvent (0.5% methylcellulose) (n = 8)
2. AEW-treated mouse + solvent (0.5% methylcellulose) (n = 8)
3. AEW treated mouse + 1 mg / kg L-365260 (n = 8)
4). AEW-treated mice + 10 mg / kg L-365260 (n = 8)
（結果）
　図８に、ＡＥＷドライスキンモデルマウスの皮膚におけるＴＥＷＬ及びＳＣ　ｈｙｄｒａｔｉｏｎの変動を示す。Ｗ処理コントロールマウスと比較して、ＡＥＷ処理マウスにおいて経表皮水分蒸散量（ＴＥＷＬ値）の増加と角層水分保持量（ＳＣ　ｈｙｄｒａｔｉｏｎ）の低下が認められた。このことから、本実験で用いたＡＥＷマウスにおけるドライスキンが誘発されたことを確認した。
　図９に、ＡＥＷドライスキンモデルマウスにおける自発的掻破行動を示す。ＡＥＷ反復処理により、ドライスキンに伴う自発的掻破行動が観察された。
　図１０に、ＡＥＷドライスキンモデルマウスのアロネーシスに対するＣＣＫ２受容体拮抗薬の作用を示す。図１０から、１ｍｇ／ｋｇ及び１０ｍｇ／ｋｇ　Ｌ－３６５２６０の経口投与は、ＡＥＷドライスキンマウスのアロネーシスを有意に抑制した。 (result)
FIG. 8 shows changes in TEWL and SC hydration in the skin of an AEW dry skin model mouse. An increase in transepidermal water transpiration (TEWL value) and a decrease in stratum corneum water retention (SC hydration) were observed in AEW-treated mice as compared to W-treated control mice. From this, it was confirmed that dry skin was induced in the AEW mice used in this experiment.
FIG. 9 shows spontaneous scratching behavior in an AEW dry skin model mouse. Spontaneous scratching behavior associated with dry skin was observed with repeated AEW treatments.
FIG. 10 shows the effect of a CCK2 receptor antagonist on aronosis in AEW dry skin model mice. From FIG. 10, oral administration of 1 mg / kg and 10 mg / kg L-365260 significantly suppressed aronosis in AEW dry skin mice.

Claims (14)

  1. 　コレシストキニン－２受容体拮抗剤を有効成分とする掻痒性皮膚疾患予防又は治療薬。 An agent for the prevention or treatment of pruritic skin diseases comprising a cholecystokinin-2 receptor antagonist as an active ingredient.
  2. 　掻痒性皮膚疾患が、アロネーシスを伴う掻痒性皮膚疾患である請求項１記載の予防又は治療薬。 The prophylactic or therapeutic agent according to claim 1, wherein the pruritic skin disease is an itching skin disease accompanied by aronosis.
  3. 　コレシストキニン－２受容体拮抗剤が、Ｌ－３６５２６０、ＹＭ０２２、ＣＩ－９８８、Ｚ－３６０、プログルミド、ＣＩ－１０１５、ＰＤ１３５１５８、ＬＹ２２５９１０、ＹＦ４７６、ＬＹ－２８８５１３又はＲＰ－６９７５８である請求項１又は２記載の予防又は治療薬。 The cholecystokinin-2 receptor antagonist is L-365260, YM022, CI-988, Z-360, Proglumide, CI-1015, PD135158, LY225910, YF476, LY-288513 or RP-69758 2. The preventive or therapeutic agent according to 2.
  4. 　掻痒性皮膚疾患予防薬又は治療薬製造のための、コレシストキニン－２受容体拮抗剤製造のための使用。 Use for the manufacture of a cholecystokinin-2 receptor antagonist for the manufacture of a prophylactic or therapeutic drug for pruritic skin diseases.
  5. 　掻痒性皮膚疾患が、アロネーシスを伴う掻痒性皮膚疾患である請求項４記載の使用。 The use according to claim 4, wherein the pruritic skin disease is a pruritic skin disease accompanied by aronosis.
  6. 　コレシストキニン－２受容体拮抗剤が、Ｌ－３６５２６０、ＹＭ０２２、ＣＩ－９８８、Ｚ－３６０、プログルミド、ＣＩ－１０１５、ＰＤ１３５１５８、ＬＹ２２５９１０、ＹＦ４７６、ＬＹ－２８８５１３又はＲＰ－６９７５８である請求項４又は５記載の使用。 The cholecystokinin-2 receptor antagonist is L-365260, YM022, CI-988, Z-360, Proglumide, CI-1015, PD135158, LY225910, YF476, LY-288513 or RP-69758 5. Use according to 5.
  7. 　掻痒性皮膚疾患を予防又は治療するための、コレシストキニン－２受容体拮抗剤。 Cholecystokinin-2 receptor antagonist for preventing or treating pruritic skin diseases.
  8. 　掻痒性皮膚疾患が、アロネーシスを伴う掻痒性皮膚疾患である請求項７記載のコレシストキニン－２受容体拮抗剤。 The cholecystokinin-2 receptor antagonist according to claim 7, wherein the pruritic skin disease is a pruritic skin disease accompanied by aronesis.
  9. 　コレシストキニン－２受容体拮抗剤が、Ｌ－３６５２６０、ＹＭ０２２、ＣＩ－９８８、Ｚ－３６０、プログルミド、ＣＩ－１０１５、ＰＤ１３５１５８、ＬＹ２２５９１０、ＹＦ４７６、ＬＹ－２８８５１３又はＲＰ－６９７５８である請求項７又は８記載のコレシストキニン－２受容体拮抗剤。 The cholecystokinin-2 receptor antagonist is L-365260, YM022, CI-988, Z-360, Proglumide, CI-1015, PD135158, LY225910, YF476, LY-288513 or RP-69758 9. The cholecystokinin-2 receptor antagonist according to 8.
  10. 　コレシストキニン－２受容体拮抗剤の有効量を投与することを特徴とする掻痒性皮膚疾患の予防又は治療方法。 A method for preventing or treating pruritic skin diseases, comprising administering an effective amount of a cholecystokinin-2 receptor antagonist.
  11. 　掻痒性皮膚疾患が、アロネーシスを伴う掻痒性皮膚疾患である請求項１０記載の方法。 The method according to claim 10, wherein the pruritic skin disease is a pruritic skin disease accompanied by aronesis.
  12. 　コレシストキニン－２受容体拮抗剤が、Ｌ－３６５２６０、ＹＭ０２２、ＣＩ－９８８、Ｚ－３６０、プログルミド、ＣＩ－１０１５、ＰＤ１３５１５８、ＬＹ２２５９１０、ＹＦ４７６、ＬＹ－２８８５１３又はＲＰ－６９７５８である請求項１０又は１１記載の方法。 The cholecystokinin-2 receptor antagonist is L-365260, YM022, CI-988, Z-360, proglumide, CI-1015, PD135158, LY225910, YF476, LY-288513 or RP-69758 11. The method according to 11.
  13. 　被検体のコレシストキニン－２受容体に対する拮抗作用を測定することを特徴とする掻痒性皮膚疾患予防又は治療薬のスクリーニング方法。 A screening method for an agent for the prevention or treatment of pruritic skin diseases, which comprises measuring the antagonistic action of a subject against cholecystokinin-2 receptor.
  14. 　被検体のコレシストキニン－２受容体に対する拮抗作用の測定が、コレシストキニン又はその部分ペプチド類及び被検体を投与した非ヒト動物の掻破行動を測定するものである請求項１３記載のスクリーニング方法。 14. The screening method according to claim 13, wherein the measurement of the antagonistic action on the cholecystokinin-2 receptor of the subject is to measure the scratching behavior of a non-human animal administered with cholecystokinin or a partial peptide thereof and the subject. .
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JP7478895B1 (en) 2022-11-30 2024-05-07 花王株式会社 Agent for preventing or improving itching

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JP7478894B1 (en) 2022-11-30 2024-05-07 花王株式会社 Agent for preventing or improving itching
JP7478895B1 (en) 2022-11-30 2024-05-07 花王株式会社 Agent for preventing or improving itching

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