JP2017149663A - Irritable bowel syndrome therapeutic agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new irritable bowel syndrome therapeutic agent.SOLUTION: An irritable bowel syndrome therapeutic agent comprises a material that inhibits one or two receptors selected from Aadenosine receptor and Aadenosine receptor as an active ingredient.SELECTED DRAWING: None

Description

  The present invention relates to a therapeutic agent for irritable bowel syndrome.

  Irritable bowel syndrome is an abdominal symptom centered on the lower abdomen such as abdominal pain and abdominal discomfort, and abnormal bowel movements such as constipation or diarrhea, and there is no functional disorder that causes the symptoms. Is a disease. Symptoms are classified into constipation type, diarrhea type, and alternating type that repeats both alternately. The causes are considered to be abnormalities of gastrointestinal motility centering on the large intestine, a decrease in the threshold for perception of the gastrointestinal tract, psychological factors such as stress, lifestyle distortion, and the like (Non-Patent Document 1).

  Treatment of irritable bowel syndrome includes lifestyle changes, diet, and medication. As the drug, antidiarrheal drugs (peristaltic movement suppression) such as loperamide and anticholinergic drugs, antidepressant drugs and the like are used. Recently, in addition to the antibacterial agent (rifaximin), μ opioid receptor agonist and δ opioid receptor antagonist erxadrine, antagonists for serotonin 3 (5-HT3) receptor (alosetron, ramosetron) have been used.

Glossary of medical terms, Japanese Society of Gastroenterology

  However, in conventional drug therapy, for example, ramosetron, which is a serotonin 3 receptor antagonist, is effective only for diarrhea-type irritable bowel syndrome, and has not been effective for other symptoms of irritable bowel syndrome.

  Accordingly, an object of the present invention is to provide a new therapeutic agent for irritable bowel syndrome.

  Therefore, as a result of various studies to develop a therapeutic agent for irritable bowel syndrome based on a new mechanism of action, the present inventor has found that a substance having a specific adenosine receptor inhibitory action, particularly theophylline or a salt thereof, is not only diarrhea. The present invention was completed by finding it useful as a therapeutic agent for irritable bowel syndrome that improves symptoms of visceral hypersensitivity.

  That is, the present invention provides the following [1] to [16].

[1] A therapeutic agent for irritable bowel syndrome comprising as an active ingredient a substance that inhibits one or two selected from A _2A adenosine receptor and A _2B adenosine receptor.
[2] The therapeutic agent for irritable bowel syndrome according to [1], wherein the substance that inhibits the receptor is theophylline or a salt thereof.
[3] The agent for improving irritable bowel syndrome according to [1] or [2], wherein the substance that inhibits the receptor is aminophylline.
[4] The therapeutic agent for irritable bowel syndrome according to any one of [1] to [3], wherein the irritable bowel syndrome is stool improvement and / or improvement of visceral hypersensitivity symptoms.
[5] Use of a substance that inhibits one or two selected from A _2A adenosine receptor and A _2B adenosine receptor for the preparation of a therapeutic agent for irritable bowel syndrome.
[6] The use according to [5], wherein the substance that inhibits the receptor is theophylline or a salt thereof.
[7] The use according to [5] or [6], wherein the substance that inhibits the receptor is aminophylline.
[8] The use according to any one of [6] to [7], wherein the irritable bowel syndrome is stool improvement and / or improvement of visceral hypersensitivity symptoms.
[9] A substance that inhibits one or two receptors selected from A _2A and A _2B adenosine receptors for treating irritable bowel syndrome.
[10] The substance according to [9], wherein the substance that inhibits the receptor is theophylline or a salt thereof.
[11] The substance according to [9] or [10], wherein the substance that inhibits the receptor is aminophylline.
[12] The substance according to any one of [9] to [11], wherein the irritable bowel syndrome is stool improvement and / or improvement of visceral hypersensitivity symptoms.
[13] A method for treating irritable bowel syndrome, comprising administering a substance that inhibits one or two receptors selected from an A _2A adenosine receptor and an A _2B receptor.
[14] The method according to [13], wherein the substance that inhibits the receptor is theophylline or a salt thereof.
[15] The method according to [13] or [14], wherein the substance that inhibits the receptor is aminophylline.
[16] The treatment method according to any one of [13] to [15], wherein the irritable bowel syndrome is stool improvement and / or improvement of visceral hypersensitivity symptoms.

  ADVANTAGE OF THE INVENTION According to this invention, the therapeutic agent effective not only for the stool improvement of the irritable bowel syndrome etc. but for the symptom of visceral hypersensitivity can be provided. In particular, theophylline or a salt thereof is a drug that has already been widely used as a bronchodilator, so its safety has been confirmed, and it is useful as a new therapeutic agent for irritable bowel syndrome.

The effect of aminophylline on the number and amount of stool in the restraint stress model (WRS) is shown. The effect of theophylline on the number of feces in a restraint stress model (WRS) is shown. The effect | action with respect to the quantity of feces of aminophylline when there is no restraint stress is shown. The effect | action of aminophylline with respect to the number of feces by new stress in each condition of the presence or absence of mother-child separation stress (MS) is shown. The effect of aminophylline on serum corticosterone concentration after restraint stress model (WRS) is shown. The effect of aminophylline on the increase in bronchial resistance caused by methacholine is shown. Figure 3 shows the effect of aminophylline on the number of feces in a mouse restraint stress (RS) model. The effects of A2A antagonist, A2B antagonist and A1 antagonist on the number of feces increased by restraint stress are shown. 2 shows the effect of aminophylline on visceral hypersensitivity (colorectal distension). Shows theophylline effects on visceral hypersensitivity (colorectal distension) The effect of aminophylline on visceral hypersensitivity (acetic acid administration) is shown. The effects of A2A antagonist, A2B antagonist and A1 antagonist on visceral hypersensitivity (colorectal distension) are shown. The effect | action of the A2A antagonist and A2B antagonist with respect to visceral hypersensitivity (MS) is shown. The effect | action of the A2A agonist and A2B agonist with respect to visceral hypersensitivity (no MS) is shown.

The active ingredient of the therapeutic agent for irritable bowel syndrome of the present invention is a substance that inhibits one or two receptors selected from A _2A adenosine receptor (A _2A AR) and A _2B adenosine receptor (A _2B AR). It is a component chosen from.

Examples of substances that inhibit A _2A AR include theophylline or a salt thereof, 8- (3-chlorostyryl) caffeine, ANR94, Istradefylline, SCH442416, SCH58261, TC-G1004, ZM241385, LuAA47070, MSX-3. Hydrate, CAY10680, CSC, Preladenant (SCH420814), STW5 (Iverogast, BAY98-7411), Tozadenant (SYN115), VER6947, VER7835, Bipadenant (BIIB014), 3,7-dimethyl-1-propargylxanthine (DMPX), (E ) -KF17837, MSX-2, MSX-4, BS-DMPX, CS-DMPX, DPMTX, CP-66713, SCH-63390, 5-amino-7 [4- (4-hydroxyphenyl) ethyl] -2- (2-furyl) pyrazolo [4,3-e] 1,2,4-triazolo [1,5-c] pyrimidine, 5-amino-7- [ 3- (4-hydroxyphenyl) propyl] -2- (2-furyl) pyrazolo [4,3-e] 1,2,4-triazolo [1,5-c] pyrimidine, VER-6623, caffeine, CGH2466 Dihydrochloride, CGS15943, XAC, diprofylline, 1,3-dipropyl-8- (p-sulfophenyl) xanthine, 1,3,9-trimethylxanthine, theobromine, 8- (p-sulfophenyl) theophylline hydrate, 8FB -PTP, 4-amino-6-benzylamino-1,2-dihydro-2-1,2,4-triazolo [4,3-a] quinoxaline- -One, ASP5854, ANR-152, MRS1595, N- (4-bromophenyl) -2- [4- (1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H- Pyrrolo [3,2-d] pyrimidin-6-yl) phenoxy] acetamide, 2-amino-6- (2-furyl) -3-methyl-5- (4-pyridyl) pyrimidin-4- (3H) -one Is mentioned.

Examples of substances that inhibit A _2B AR include theophylline or a salt thereof, GS6201, MRS1706, MRS1754, PSB0788, PSB1115, PSB603, MRE2029-F20, ATL-801, OSIP-339361, CVT-6883, MRE2028-F20, MRE-2030. -F20, LAS-38096, caffeine, CGH2466 dihydrochloride, CGS15943, XAC, diprofylline, 1,3-dipropyl-8- (p-sulfophenyl) xanthine, 1,3,9-trimethylxanthine, theobromine, 8- (P-sulfophenyl) theophylline hydrate, 8FB-PTP, 4-amino-6-benzylamino-1,2-dihydro-2-1,2,4-triazolo [4,3-a] quinoxaline -1-one, ASP5854, ANR-152, MRS1595, N- (4-bromophenyl) -2- [4- (1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro- 1H-pyrrolo [3,2-d] pyrimidin-6-yl) phenoxy] acetamide, 2-amino-6- (2-furyl) -3-methyl-5- (4-pyridyl) pyrimidine-4- (3H) -ON.

Of these receptor inhibitors, substances that inhibit A _2A AR and A _2B AR are preferred, and theophylline or a salt thereof is more preferred.

  Examples of theophylline salts include alkali metal salts such as sodium salts and potassium salts, and amine salts such as ethylenediamine salts. Of these theophylline salts, aminophylline which is theophylline / ethylenediamine salt is particularly preferred.

  Here, theophylline and aminophylline are widely known as bronchodilators, and are used as therapeutic agents for bronchial asthma, asthmatic bronchitis, chronic bronchitis and the like. Although the molecular mechanism of bronchodilation of theophylline and aminophylline is not completely clear, it has been reported that both phosphodiesterase inhibition and adenosine receptor antagonism are involved (Biochem. Pharmacol. 45 (4): 847 -851, Life Sci. 43 (5): 387-398).

As shown in Examples below, theophylline or a salt thereof, which is a representative example of a substance that inhibits A _2A AR and / or A _2B AR, improves various symptoms of irritable bowel syndrome, and a wide range of irritable bowel syndrome. It is useful as a therapeutic agent.

  As described above, irritable bowel syndrome is characterized by abdominal symptoms such as abdominal pain and abdominal discomfort, mainly in the lower abdomen, and abnormal bowel movements such as constipation or diarrhea. There is no functional disease of the intestinal tract. Symptoms are classified into constipation type, diarrhea type, and alternating type that repeats both alternately. The therapeutic agent for irritable bowel syndrome of the present invention is effective not only for diarrhea but also for visceral hypersensitivity, and is therefore effective for constipation type, diarrhea type and alternation type (particularly effective for diarrhea type).

  Examples of the dosage form of the therapeutic agent for irritable bowel syndrome of the present invention include injections, oral agents (tablets, granules, powders, capsules), ointments, creams, patches, suppositories and the like. Of these, oral preparations are particularly preferred. 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-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 dextran sulfate or a salt thereof.

  Further, the content of the active ingredient of the present invention in the pharmaceutical composition preparation of the present invention varies greatly depending on the form of the preparation and is not particularly limited, but is usually 0.01% with respect to the total amount of the composition. -100 mass%, preferably 1-100 mass%.

The dose of the therapeutic agent for irritable bowel syndrome of the present invention varies depending on the symptoms, age, and administration method of the patient to be administered, but as a substance that inhibits A _2A AR and / or A _2B AR, per day for an adult. It is preferable that it is 50-1000 mg. In addition, this dose can be divided into 2 to 4 times per day.

  EXAMPLES Next, an Example is given and this invention is demonstrated still in detail.

Example (Method)
(1) Measurement of visceral motor response (VMR) to colorectal dilatation (CRD)
Gut 55 (8): VMR against CRD was monitored with some modifications to the method described in 1090-1094. Rats were deeply anesthetized with a mixture of medetomidine hydrochloride (0.5 mg / kg), midazolam (2.5 mg / kg), butorphanol tartrate (2.5 mg / kg), and the electrodes (Star Medical, Tokyo, Japan) The abdominal external oblique muscle was sutured for electromyography (EMG) recording. The electrode lead was passed subcutaneously and exposed outside the body at the neck for future access. After surgery, rats were individually housed and allowed to recover for 6 days before being used for VMR measurements. Rats were restrained with a plastic conical tube (height 15 cm, diameter 6 cm) for 15 minutes before electromyogram recording. A polyethylene bag (2 cm in length) was inserted into the distal colon and placed 1 cm proximal from the rectum and a balloon catheter was connected. Balloon pressure and volume were controlled and monitored with a pressure controller timing device (G & J Electronics, Toronto, Canada, Diender Series II) connected to the balloon. Rats were repeated CRD (12 times at 80 mmHg, duration 30 seconds, stimulation interval 300 seconds) or transient CRD (10, 20, 40, 60, 80 mmHg, duration 20 seconds, stimulation interval for drug screening 150 seconds). Aminophylline or theophylline was dissolved in physiological saline and orally administered 2 hours before CRD. Other drugs (AR antagonist and AR agonist) were dissolved in 1% methylcellulose and administered intraperitoneally 15 minutes before CRD. Electromyogram (EMG) data was collected and analyzed using 8STAR software (Windows 6.0 version 6.0 to 19.2; Star Medical, Tokyo, Japan). The response elicited by contraction of the external oblique muscle was quantified by calculating the area under the curve (AUC) of the EMG amplitude of the voltage change graph. Baseline was determined by data collected for 20 seconds before CRD.

(2) Colonic hypersensitivity due to mother-child separation or acetic acid-induced CRD
Biol. Psychiary 65 (3): Newborn mother-child separation was performed with some modifications to the method described in 263-267. Late-pregnancy Wistar female rats were individually bred for about one week to give birth to children (10-15 rats / rat). The pups were separated from the mother for 180 minutes every day for 10 days (from day 2 to 12 after birth). Separation was performed between 9 am and 12 am in a plastic cage with a heater pad (30 ° C. to 33 ° C.) and placed in a room separated from the mother. Control rats were bred with their mothers. From day 12 onwards, both groups of rats were raised undisturbed every two days except for regular cage cleaning. CRD VMR was tested in both groups of rats at 5-6 weeks of age.
An acetic acid-induced colorectal hypersensitivity test was performed with some modifications to the method described in Nat. Commun. 4: 2686 (2013). On the 10th day after birth, the pups were given 0.2 mL of 0.5% acetic acid (in saline) intracolonically at a position 2 cm from the anus. Control rats received an equal volume of saline. CRD VMR was tested in both groups of rats at 5-6 weeks of age.

(3) Feces induced by stress
Gut 55 (8): 1090-1094, Neurogastroenterol Motil 20 (10): Induced by lap restraint stress (WRS), restraint stress (RS), new stress with some changes to the method described in 1147-1156 Monitored for stool. In monitoring WRS-induced stool in rats, aminophylline or theophylline was dissolved in physiological saline and administered orally (2 mL / kg) 2 hours before WRS. Other drugs (AR antagonist) were dissolved in 1% methylcellulose and administered intraperitoneally 15 minutes before WRS. Saline (2 mL / kg) was administered aminophylline or theophylline for 2 hours prior to oral WRS. Rats were subjected to WRS for 1 hour and the number of excreted feces or wet weight during this WRS period (1 hour) was measured. WRS was performed as described in Neurogastroenterol. Motil 20 (10): 1147-1156. Rats were lightly anesthetized with isoflurane and wrapped with paper tape to limit movement of the upper shoulders, forelimbs, and upper torso of the chest to prevent movement. Animals recovered from isoflurane within 2-5 minutes and immediately moved through the cage. Control animals were anesthetized with isoflurane but not restrained by paper tape.
To monitor RS-induced feces in mice, animals were placed individually in 50 mL Falcon tubes (Becton Dickinson, Franklin Lakes, NJ) for 1 hour. These tubes are small enough to keep the mouse from moving. It is therefore possible to breathe but not to move freely. Control mice were allowed to move freely within the cage. Aminophylline was dissolved in physiological saline and orally administered (10 mL / kg) 2 hours before RS. During this RS period (1 hour), the number of excreted feces or wet weight was measured.
The control and the mother-infant separated rat were tested for responsiveness to new stress. As in (2) above, new stress was induced by transferring rats from the home cage to a new cage of wire mesh with a white paper towel. Aminophylline was orally administered to rats 2 hours before subjecting to new stress. The animals were placed in a new cage for 1 hour and the number of feces excreted during this period was counted.

(4) Measurement of pulmonary airway resistance The measurement of pulmonary airway resistance was carried out by using a computer-controlled small animal ventilator (FlexiVent, SCIREQ, Montreal, Am. J. Physiol. Gastrointest. Liver Physiol. (Canada). Mice were anesthetized with chloral hydrate (500 mg / kg), a tracheotomy was performed, and an 8 mm metal tube was inserted into the trachea. Mice were mechanically ventilated at a respiratory rate of 150 breaths per minute using a tidal volume of 8.7 mL / kg and a positive end-expiratory pressure of 2-3 cm H ₂ O. To measure methacholine-induced increase in airway resistance, mice were nebulized with methacholine (1 mg / mL) five times for 20 seconds (at 40 second intervals). Airway resistance was measured after each methacholine exposure by the snapshot technique. Aminophylline was orally administered to mice 1 hour before the test. All data was analyzed using FlexiVent software.

(5) Measurement of corticosterone plasma concentration Plasma corticosterone concentration in rats was measured using an ELISA kit according to the manufacturer's instructions. After WRS, rats were sacrificed and blood was collected to measure plasma corticosterone levels.

(result)
(1) Influence of restraint stress model (WRS) on defecation quantity i) Restraint stress model (WRS)
Regarding the number and amount of stool increased with WRS, oral administration of aminophylline suppressed both the number and amount of stool in a dose-dependent manner (FIG. 1A). Similarly, oral administration of theophylline (molecular weight equivalent to theophylline in aminophylline) similarly suppressed the number of feces increased by WRS (FIG. 1B). On the other hand, in the absence of stress, oral administration of aminophylline did not affect stool volume even at 180 mg / kg (FIG. 1C).

  As a result, it was suggested that oral administration of aminophylline suppresses increase in defecation due to WRS, but does not affect normal defecation.

ii) Mother-child separation stress model (MS)
Without MS, the number of bowel movements due to new stress was not affected. With MS, the number of defecations increased due to new stress. Oral administration of aminophylline suppressed the increase in the number of defecations with MS + new stress (FIG. 1D).

iii) Serum corticosterone concentration after restraint stress model (WRS) Oral administration of aminophylline has no effect on serum corticosterone increased with WRS. That is, aminophylline suppresses the increase in defecation caused by WRS irrespective of corticosterone (FIG. 1E).

(2) Mechanism of defecation quantity suppression of aminophylline restraint stress model (WRS) Oral administration of aminophylline suppresses an increase in bronchial resistance caused by methacholine (particularly 180 mg / kg administration) (FIG. 2A). In the mouse RS (restraint stress) model, oral administration of aminophylline suppressed the number of feces (especially 180 mg / kg administration) (FIG. 2B).

  As a result, it was suggested that the suppression effect on the number of feces is mediated by a mechanism similar to the suppression effect on bronchial resistance in mice.

  A2B antagonist (MRS-1754) suppressed dose-dependently on stool count increased with WRS, whereas A1 antagonist (DPCPX) and A2A antagonist (Istadefylline) had no effect (FIG. 3).

  As a result, it was suggested that the suppressive action by oral administration of aminophylline is mediated by A2B inhibition in the increase in defecation by WRS.

(3) Effect of aminophylline on visceral hypersensitivity due to colorectal distension (CRD) Visceral hypersensitivity due to CRD increases in the maternal and child separation stress model (MS).
Oral administration of aminophylline suppressed the increase in visceral hypersensitivity by MS (suppressed to the same extent as without MS) (FIG. 4A).
On the other hand, without MS, oral administration of aminophylline did not affect visceral hypersensitivity even at 180 mg / kg.
Similarly, oral administration of theophylline (molecular weight equivalent to that of theophylline in aminophylline) similarly suppressed the increase in visceral hypersensitivity due to MS (suppressed to the same extent as without MS) (FIG. 4B).

(Influence of aminophylline on visceral hypersensitivity by acetic acid administration model)
Visceral hypersensitivity due to CRD is increased in the acetic acid administration model.
Oral administration of aminophylline suppressed the increase in visceral hypersensitivity caused by the administration of acetic acid (suppressed to the same extent as without MS) (FIG. 4C).

(4) Mechanism of inhibition of visceral hypersensitivity by colorectal dilatation (CRD) of aminophylline In a maternal and child separation stress model (MS), an A2A antagonist (Istadefylline) and an A2B antagonist (MRS-1754) suppressed an increase in visceral hypersensitivity ( Same as aminophylline).
On the other hand, the A1 antagonist (DPCPX) was not suppressed. Rather, higher doses promoted increased visceral hypersensitivity (FIG. 5A). In the mother-child separation stress model (MS), an A2A antagonist (ZM241385) and an A2B antagonist (PSB1115) different from FIG. 5B also suppressed the increase in visceral hypersensitivity (FIG. 5B). A2A agonist (CGS21680) and A2B agonist (BAY60-6583) promoted increased visceral hypersensitivity in the absence of MS (FIG. 5C).

Claims (4)

A therapeutic agent for irritable bowel syndrome comprising a substance that inhibits one or two receptors selected from A _2A adenosine receptor and A _2B adenosine receptor as an active ingredient.   The therapeutic agent for irritable bowel syndrome according to claim 1, wherein the substance that inhibits the receptor is theophylline or a salt thereof.   The therapeutic agent for irritable bowel syndrome according to claim 1 or 2, wherein the substance that inhibits the receptor is aminophylline.   The irritable bowel syndrome therapeutic agent according to any one of claims 1 to 3, wherein the irritable bowel syndrome is improvement of bowel movement abnormalities and / or visceral hypersensitivity symptoms.