Composition for inhibiting gastrointestinal peristaltic movement, and method for inhibiting gastrointestinal peristaltic movement

Abstract

To provide a composition for inhibiting gastrointestinal peristaltic movement, comprising a compound capable of inhibiting gastrointestinal peristaltic movement even when administered as a single agent.SOLUTION: The foregoing problem is solved by a composition for inhibiting gastrointestinal peristaltic movement, comprising a Cav3.2 T-type calcium channel inhibitor.SELECTED DRAWING: None

Description

[Technical field]

[0001] Disclosed herein are compositions for inhibiting gastrointestinal peristalsis and methods for inhibiting gastrointestinal peristalsis. [Background technology]

[0002] It has been reported that the herbal medicine Keishikashakuyakuto has contributed to the improvement of abdominal pain in irritable bowel syndrome (IBS). In addition, it has been reported that the herbal medicines Shakuyaku and Glycyrrhiza have antispasmodic effects. Furthermore, it has been reported that Shakuyaku-kanzoto (SKT), which contains Shakuyaku and Glycyrrhiza, has an inhibitory effect on intestinal contraction during endoscopic examination (Non-Patent Documents 1 to 3). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Kimura M et al. Japan J Pharmacol. 1984; 36: 275-82 [Non-Patent Document 2] Maeda, T. et al. J. Pharmacobio-Dyn. 1983; 6: 153 [Non-Patent Document 3] Ai M et al. World J Gastroenterol. 2006; 12: 760-4 Summary of the Invention [Problem to be solved by the invention]

[0004] However, herbal medicines contain various ingredients, and Non-Patent Document 1 also describes that the combination of paeoniflorin and glycyrrhizin contained in Shakuyaku-kanzo-to has a blocking effect on the neuromuscular junction. An object of the present invention is to provide a composition for inhibiting gastrointestinal peristalsis, which comprises a compound capable of inhibiting gastrointestinal peristalsis even when administered alone. [Means for solving the problem]

[0005] The present invention may include the following embodiments. Item 1. A composition for inhibiting gastrointestinal peristalsis, comprising a Cav3.2 T-type calcium channel inhibitor. Item 2. The composition according to Item 1, wherein the Cav3.2 T-type calcium channel inhibitor is at least one selected from the group consisting of 3-arylcoumarin compounds and ascorbic acid compounds. Item 3. The composition according to item 2, wherein the 3-aryl coumarin compound is a compound represented by the following general formula (I) or a pharma- ceutically acceptable salt, glycoside, or ester thereof: [ka] (In the formula, R 1 represents a hydrogen atom, a hydroxyl group, a linear or branched alkoxy group having 1 to 3 carbon atoms, a linear or branched alkyl group having 1 to 6 carbon atoms, or a linear or branched alkenyl group having 2 to 6 carbon atoms, R 2 is a linear or branched alkenyl group having 2 to 6 carbon atoms, or a linear or branched alkyl group having 1 to 6 carbon atoms, R 3 is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or a linear or branched alkenyl group having 2 to 6 carbon atoms, m is an integer from 0 to 5. Item 4. The composition according to item 3, wherein the compound represented by general formula (I) is a compound represented by the following general formula (II): [ka] (In the formula, R 1 , R 2 , R 3 is the same as above.) Item 5. The composition according to item 3, wherein the compound represented by general formula (I) is a compound represented by the following general formula (III): [ka] (In the formula, R 1 , R 2 , R 3 is the same as above.) Section 6.R 2 Item 5. The composition according to item 4, wherein is a prenyl group. Item 7. The composition according to any one of items 1 to 5, wherein the prenyl group is a group represented by the following formula (IV): [ka] . Item 8. The composition according to item 1, wherein the compound represented by general formula (I) is glycyrrhetinic acid. Item 9. The composition according to any one of Items 1 to 5, wherein the ascorbic acid compound is one selected from the group consisting of ascorbic acid, ascorbic acid 2-phosphate, ascorbic acid 2-glucoside, 3-O-ethyl ascorbic acid, ascorbic acid 2-phosphate-6 palmitic acid, glyceryl octyl ascorbic acid, ascorbic acid monostearate, ascorbic acid monopalmitate, ascorbic acid dipalmitate, ascorbic acid tetraisopalmitate, and pharma- ceutically acceptable salts thereof. Item 10. A method for inhibiting gastrointestinal peristalsis, comprising the step of contacting a Cav3.2 T-type calcium channel inhibitor with an animal's gastrointestinal tissue in vitro. Effect of the Invention

[0006] A composition for inhibiting gastrointestinal peristalsis can be provided. [Brief description of the drawings]

[0007] [Figure 1] 1 shows an overview of a peristalsis observation system 100. [Diagram 2]1 shows the results of spatiotemporal mapping of peristalsis before and after addition of saline to the organ bath. [Diagram 3] 1 shows the results of spatiotemporal mapping of peristalsis before and after addition of SKT to the organ bath. [Figure 4] The PF, AUC, and PPA values ​​are shown when physiological saline and SKT were added to the organ bath. [Diagram 5] 1 shows the results of spatiotemporal mapping of peristalsis before and after addition of licorice powder to the organ bath. [Figure 6] The PF, AUC, and PPA values ​​are shown when physiological saline, peony powder, and licorice powder were added to the organ bath. [Figure 7] The results of spatiotemporal mapping of peristalsis before and after addition of GM to the organ bath are shown. [Figure 8] The PF, AUC, and PPA values ​​are shown when DMSO solution (control), GA, GM, and GAG were each added to the organ bath. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] 1. Composition for inhibiting gastrointestinal peristalsis One embodiment relates to a composition for inhibiting gastrointestinal peristalsis (hereinafter, also simply referred to as "composition"). The composition includes a Cav3.2 T-type calcium channel inhibitor.

[0009] Cav3(T)-type calcium ion channels are activated at a low threshold (approximately -60 mV). The channel pore of the T-type calcium ion channel is composed of only the α1 subunit and functions as a calcium ion channel. There are three subtypes of the α1 subunit: Cav3.1(α1G), Cav3.2(α1H) and Cav3.3(α1I). In this embodiment, a calcium channel inhibitor that inhibits Cav3.2 (also referred to as "Cav3.2 T-type calcium channel" in this specification) is added to a composition for inhibiting gastrointestinal peristalsis.

[0010] Inhibiting gastrointestinal peristalsis means stopping gastrointestinal peristalsis for a certain period of time after ingestion of the composition. A method for evaluating whether gastrointestinal peristalsis is inhibited or not will be described in the next section, "Method for inhibiting gastrointestinal peristalsis."

[0011] In this embodiment, the digestive tract refers to the esophagus, stomach, small intestine (duodenum, jejunum, and ileum), and large intestine (ascending colon, transverse colon, descending colon, sigmoid colon, and rectum). Preferably, the digestive tract is the large intestine, and more preferably the ascending colon.

[0012] The Cav3.2 T-type calcium channel inhibitor is preferably at least one selected from, for example, 3-arylcoumarin compounds and ascorbic acid compounds.

[0013] A 3-arylcoumarin compound is intended to mean a compound in which an aryl group is bonded to the third carbon of the coumarin skeleton.

[0014] As aryl groups, preferred examples include any of the following groups: [ka] .

[0015] More preferably, the 3-arylcoumarin compound is a compound represented by the following general formula (I), or a pharma- ceutically acceptable salt thereof: [ka] (In the formula, R 1 represents a hydrogen atom, a hydroxyl group, a linear or branched alkoxy group having 1 to 3 carbon atoms, a linear or branched alkyl group having 1 to 6 carbon atoms, or a linear or branched alkenyl group having 2 to 6 carbon atoms, R 2 is a linear or branched alkenyl group having 2 to 6 carbon atoms, or a linear or branched alkyl group having 1 to 6 carbon atoms, R 3is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or a linear or branched alkenyl group having 2 to 6 carbon atoms, and m is an integer from 0 to 5.

[0016] R 1 is preferably a hydrogen atom, a hydroxyl group, a linear or branched alkyl group having 1 to 3 carbon atoms, or a linear or branched alkenyl group having 2 to 3 carbon atoms, more preferably a hydrogen atom or a hydroxyl group, and even more preferably a hydroxyl group.

[0017] R 2 is preferably a linear or branched alkenyl group having 2 to 6 carbon atoms, and more preferably a prenyl group.

[0018] The prenyl group is preferably a group represented by the following formula (IV): [ka] It is.

[0019] R 3 is preferably a linear or branched alkyl group having 1 to 3 carbon atoms, more preferably an alkyl group having 1 to 2 carbon atoms, and further preferably a methyl group.

[0020] m is preferably an integer of 0 to 3, more preferably 1 or 2, and further preferably 2.

[0021] The compound represented by the general formula (I) is more preferably a compound represented by the following general formula (II): [ka] (In the formula, R 1 , R 2 , R 3 is the same as above.)

[0022] The compound represented by the general formula (I) is more preferably a compound represented by the following general formula (III): [ka] (In the formula, R 1 , R 2 , R 3 is the same as above.)

[0023] A specific example of the compound is glycyrrhetinic acid represented by the following formula (V): [ka] .

[0024] Pharmaceutically acceptable salts of the compound represented by general formula (I) include, but are not limited to, sodium salts, potassium salts, magnesium salts, calcium salts, and the like.

[0025] The compound represented by the general formula (I) may contain a pharma- ceutically acceptable glycoside, such as a monosaccharide glycoside such as glucose or galactose, or a disaccharide or oligosaccharide glycoside.

[0026] The compound represented by formula (I) may contain a pharma- ceutically acceptable ester such as acetate, propionate, phosphate, sulfate, etc.

[0027] The ascorbic acid compound may be one selected from the group consisting of ascorbic acid, ascorbic acid 2-phosphate, ascorbic acid 2-glucoside, 3-O-ethyl ascorbic acid, ascorbic acid 2-phosphate-6 palmitic acid, glyceryl octyl ascorbic acid, ascorbic acid monostearate, ascorbic acid monopalmitate, ascorbic acid dipalmitate, ascorbic acid tetraisopalmitate, and pharma- ceutically acceptable salts thereof.

[0028] The composition can be prepared by combining a suitable carrier or additive for formulation. Examples of the carrier or additive used in the preparation of the formulation include various types of carriers and additives commonly used in ordinary medicines depending on the dosage form of the formulation, such as excipients, binders, disintegrants, lubricants, colorants, flavorings, odorants, surfactants, etc.

[0029] When the composition is administered orally (including sublingually), the dosage form is not particularly limited, and examples include tablets, powders, granules, capsules (including hard capsules and soft capsules), liquids, pills, suspensions, jelly preparations, and emulsions. When the composition is administered parenterally, examples of the composition include injections, drip infusions, suppositories, nasal drops, and pulmonary preparations.

[0030] When the composition is prepared as an oral solid preparation such as a tablet, powder, granule, pill, or capsule, a carrier may be used, for example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, methylcellulose, glycerin, sodium alginate, or gum arabic; or binders such as simple syrup, glucose liquid, starch liquid, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, water, ethanol, or potassium phosphate. Combinations; disintegrants such as dried starch, sodium alginate, powdered agar, powdered laminaran, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc.; disintegration inhibitors such as sucrose, stearic acid, cocoa butter, hydrogenated oil, etc.; absorption promoters such as sodium lauryl sulfate, etc.; moisturizers such as glycerin, starch, etc.; adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, etc.; lubricants such as purified talc, stearates, powdered boric acid, polyethylene glycol, etc.

[0031] Here, tablets include oral tablets (plain tablets, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, multi-layered tablets, etc.), chewable tablets (including those that are taken by chewing in the oral cavity), lozenges (including those that are taken after dissolving in the oral cavity, such as lozenges), sublingual tablets, and buccal tablets.

[0032] When the composition is prepared as a solid oral preparation in the form of a pill, the following can be used as a carrier: excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, talc, etc.; binders such as powdered gum arabic, powdered tragacanth, gelatin, etc.; disintegrants such as laminaran, agar, etc.

[0033] When the composition is prepared as a solid oral preparation in the form of a capsule, the capsule is prepared by mixing the active ingredient with the various carriers exemplified above and filling the mixture into a hard capsule, a soft capsule or the like.

[0034] When the composition is a liquid, it may be in the form of a liquid, such as an aqueous or oily suspension, solution, syrup, elixir, or drink. The liquid is prepared by a conventional method using a conventional additive. The container in which the liquid is filled is not limited as long as it can be sealed, and may be a glass container, an aluminum container, or a plastic container.

[0035] When the composition is prepared as an injection, carriers that can be used include diluents such as water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc.; pH adjusters such as sodium citrate, sodium acetate, sodium phosphate, etc.; buffers such as dipotassium phosphate, trisodium phosphate, sodium hydrogen phosphate, sodium citrate, etc.; stabilizers such as sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid, etc.; and sugars such as mannitol, inositol, maltose, sucrose, lactose, etc., as molding agents for lyophilization. In this case, glucose or glycerin may be contained in the pharmaceutical preparation in an amount sufficient to adjust the solution to an isotonicity, and conventional solubilizers, pain relievers, local anesthetics, etc. may also be added. By adding these carriers, subcutaneous, intramuscular, and intravenous injections can be prepared by conventional methods.

[0036] When the composition is a drop preparation, it can be prepared by dissolving the compound to be administered in an isotonic electrolyte infusion preparation based on physiological saline, Ringer's solution, or the like.

[0037] The composition may include medicines, general foods (including beverages), health functional foods (including foods for specified health uses, foods with nutrient functions, and foods with functional claims), and the like.

[0038] The composition can be administered in a dose of, for example, 0.1 to 3000 mg / kg body weight, preferably 1 to 300 mg / kg body weight per day, calculated as a 3-arylcoumarin compound or an ascorbic acid compound, in one or several divided doses.

[0039] 2. Methods for inhibiting gastrointestinal peristalsis One embodiment relates to a method for inhibiting gastrointestinal peristalsis in vitro (hereinafter also simply referred to as "the method").

[0040] The method includes the step of contacting the Cav3.2 T-type calcium channel inhibitor described in 1. above with gastrointestinal tissue of an animal in vitro.

[0041] The animal can be, for example, a mouse, rat, rabbit, monkey, cow, sheep, goat, human, frog, etc. Preferably, the animal is a non-human animal. The digestive tract is as described in 1 above.

[0042] Contact of Cav3.2 T-type calcium channel inhibitors with animal gastrointestinal tissue in vitro can be carried out based on the literature Sugino S et al. (J Neurogastroenterol Motil 2022; 28: 693-705).

[0043] The peristaltic movement of the digestive tract in vitro can be observed using a peristaltic movement observation system 100 shown in FIG. 1. The peristaltic movement observation system 100 includes an organ bath 10, an organ bath lid 10a, a video camera 2, and a catheter pressure transducer 3. The organ bath 10 includes an input port 12a and an output port 12b for physiological saline. Both ports penetrate the organ bath lid 10a, enter the organ bath 10, and are held in the organ bath by the supports 13a and 13b of each port. The input port 12a and the output port 12b for physiological saline are discontinuous in the organ bath. By fitting a harvested digestive tract to both ports and ligating the fitting parts, physiological saline passes through the digestive tract from the input port 12a and is discharged from the output port 12b. Peristaltic movement can be induced by adjusting the height of the output port 12b. Krebs solution (indicated by reference symbol 11 in FIG. 1) is injected into the organ bath 10 through the input port 14a and discharged from the output port 14b. The output port 14b is placed at a higher position in the organ bath 10 than the input port 14a, and a certain amount of Krebs solution accumulates in the organ bath 10 due to the overflow principle.

[0044] A digestive tract of about 1 cm to 5 cm is taken from an animal and placed in an organ bath 10 (volume 100 mL). Krebs solution is perfused into the organ bath 10 at 34 to 35°C and a flow rate of about 3.5 mL / min while bubbling 95% oxygen and 5% carbon dioxide. Krebs solution can be prepared, for example, by dissolving 4.8 g of Krebs-Henseleit Buffer, 1.05 g of NaHCO3, and 0.1865 g of CaCl2·2H2O in 500 ml of distilled water and adjusting the pH to 7.5. The oral end and anal end of the digestive tract D in the organ bath 10 are respectively tied to the input port 12a and output port 12b of physiological saline (the ligated parts are indicated by symbols L1 and L2 in FIG. 1). At this time, the mucous membrane side of the digestive tract is on the inside, physiological saline circulates, and the serosal side comes into contact with the Krebs solution. To monitor intraluminal pressure (cmH2O), a pressure transducer 3, e.g., a Mikro-Tip catheter pressure transducer (SPR-524, Millar Instruments, Houston, TX, USA), is placed within the gastrointestinal lumen.

[0045] Peristalsis can be induced by applying a pressure within the digestive tract lumen of about 4 cmH2O by adjusting the height of the drain tube of the output port 12b of physiological saline.

[0046] The Cav3.2 T-type calcium channel inhibitor may be contacted with either the serosal membrane side or the digestive tract mucosa side, but is preferably contacted with the serosal membrane side. The Cav3.2 T-type calcium channel inhibitor can be added to Krebs solution to contact with the digestive tract tissue on the serosal membrane side. The Cav3.2 T-type calcium channel inhibitor can also be added to physiological saline to contact with the digestive tract tissue on the digestive tract mucosa side. The method may further comprise observing peristalsis of the gastrointestinal tissue within the organ bath.

[0047] Gastrointestinal peristalsis can be evaluated in vitro using a Mikro-Tip catheter pressure transducer (SPR-524, Millar Instruments, Houston, TX, USA), for example, according to the literature Sugino S et al. (J Neurogastroenterol Motil 2022; 28: 693-705). The peak frequency (PF), which is the number of high amplitude pressure peaks per minute, is counted. High amplitude pressure peaks are peaks with an amplitude of 8 mm or more, for example, by spatiotemporal mapping as described in the literature Kubota K et al. (Am J Physiol Gastrointest Liver Physiol 2015; 308: G579-90) and the literature Huizinga JD et al. (Front Neurosci 2011; 5: 93). Inhibiting peristalsis means that the ratio of PF within a certain period of time after administration of the composition to PF within a certain period of time before administration of the composition is less than 0.6%, preferably less than 0.5%. The certain period of time is, for example, about 20 to 25 minutes.

[0048] The peristaltic movement of the digestive tract tissue in the organ bath may be observed by spatiotemporal mapping as described in Kubota K et al. (Am J Physiol Gastrointest Liver Physiol 2015; 308: G579-90) and Huizinga JD et al. (Front Neurosci 2011; 5: 93). The peristaltic movement of the digestive tract tissue in the organ bath is captured by a video camera 2, and a spatiotemporal map is created from the captured video images.

[0049] For example, still images of the digestive tract are sampled from the video images every 5 seconds for 20 minutes. For each video frame, the width of the colon (image Y axis) at each point along the length of the colon (image X axis) (image intensity, coded as black to white) is measured using the Image J software program. In the spatiotemporal map, wide relaxations of the digestive tract are represented as white areas, and strong intestinal contractions are represented as dark diagonal stripes. EXAMPLES

[0050] The present invention will be described below with reference to examples, but the present invention should not be construed as being limited to these examples.

[0051] The animal experiments described in this example were approved by the Ethics Committee of Kyoto Prefectural University of Medicine and were performed in accordance with the 1964 Declaration of Helsinki and subsequent versions.

[0052] I. Materials and Methods 1.Animals Sprague-Dawley rats aged 7–12 weeks were obtained from Shimizu Laboratory (Kyoto, Japan). The rats were housed at 22°C under a 12-h day / night cycle and were provided with food and water and had free access to drinking water. Male rats were used in the experiments.

[0053] 2. Measurement of Intraluminal Pressure in the Ascending Colon of Rat and Mouse 2-1. Experimental protocol and test compounds The evaluation of peristalsis in vitro was performed based on the literature Sugino S et al. (J Neurogastroenterol Motil 2022; 28: 693-705). The test animals were fasted overnight, euthanized by decapitation, and placed in Krebs solution. A 2-3 cm portion of the ascending colon was immersed in Krebs solution in an organ bath (volume 100 mL) of the peristalsis observation system shown in Figure 1, and perfused with Krebs solution (Krebs-Henseleit Buffer 4.8 g, NaHCO3 1.05 g, CaCl2·2H2O 0.1865 g dissolved in 500 mL of distilled water: pH 7.5) in the organ bath at 34-35 °C at 3.5 mL / min while bubbling with 95% oxygen and 5% carbon dioxide. The oral and anal ends of the ascending colon in the organ bath were tied tightly with string to the saline input and output ports, respectively. A Mikro-Tip catheter pressure transducer (SPR-524, Millar Instruments, Houston, TX, USA) was placed in the intestinal lumen in the organ bath to monitor the ascending colon intraluminal pressure (cmH2O). By adjusting the height of the drain tube of the saline output port, the ascending colon intraluminal pressure was increased to approximately 4 cmH2O to induce peristalsis of the ascending colon. The pressure wave data in the intestinal lumen was collected using an MP100, BIOPAC Systems, Goleta, CA, USA, and analyzed using the same system to generate an intraluminal chart.

[0054] In addition, peristaltic movement was captured with a video camera (HDC-HS 100-K: Panasonic, Osaka, Japan), and a spatiotemporal map was created from the captured video images to analyze peristaltic movement. The analysis method was as follows: Kubota K et al. (Am J Physiol Gastrointest Liver Physiol 2015; 308: G579-90) and Huizinga JD et al. (Front Neurosci 2011; 5: 93).

[0055] Intestinal still images were sampled from the video every 5 seconds for 20 minutes. For each video frame, the width of the intestine (Y axis) at each point along the length of the colon (X axis) was measured using the Image J software program. In the spatiotemporal map, broad intestinal relaxation is represented as a white area, and strong intestinal contraction is represented as a dark diagonal stripe. The effects of the test compounds were verified as follows.

[0056] First, the peristaltic movement of the collected intestine was recorded for 20 to 25 minutes without adding a test compound to the organ bath, and then the test compound was added from the serosal side and the peristaltic movement was recorded for 20 to 25 minutes.

[0057] The test compounds used were Shakuyaku-kanzo-to extract (SKT) powder (Tsumura Co., Ltd., Tokyo), peony powder (Tsumura Co., Ltd., Tokyo), licorice powder (Tsumura Co., Ltd., Tokyo), glycyrrhetinic acid (GA) (Fujifilm Wako Pure Chemical Co., Tokyo, Japan), glycyrrhetinic acid 3-O-qlucuronide (GAG) (Nagara Science Co., Gifu, Japan), and glycycoumarin (GM) (Sigma Aldrich Chemical Co., USA), all purchased from Sigma. SKT (101 mg) was dissolved in 1 ml of saline, and peony powder and licorice powder (50.5 mg each) were dissolved in 1 ml of saline to prepare the test compound stock solutions. GA and GAG (0.5 mg each), and GM (1 mg each) were dissolved in 1 ml of dimethyl sulfoxide (DMSO) solution to prepare the test compound stock solutions. The entire amount of the test compound stock solution was added to the Krebs solution (100 mL) on the serosal side of the intestine in the organ bath. Using the measured intraluminal pressure waves and spatiotemporal mapping, the number of high amplitude pressure peaks (peaks of 8 mm or more measured by spatiotemporal mapping) per minute (peak frequency: PF), the area under the curve (AUC) exceeding the minimum pressure value in a certain time, and the peak pressure amplitude (PPA) calculated by subtracting the minimum value from the average pressure of the peaks per certain time were calculated. AUC = [integral value of intraluminal pressure chart] - ([minimum intraluminal pressure value during measurement time] x [measurement time]) PPA = [average of maximum intravenous pressure of each contraction wave] - [minimum intravenous pressure during measurement time]

[0058] The values ​​before and after administration of the test compound were measured and calculated, and the ratios of the values ​​after administration of the test compound to the values ​​before administration were calculated and expressed as PF (%), AUC (%), and PPA (%), respectively.

[0059] 2-2.Statistical analysis Data were obtained from multiple rats, and the mean and standard deviation were calculated. Statistical significance between two groups was evaluated by student's t-test, and statistical significance between three groups was evaluated by one-way analysis of variance (ANOVA). All analyses were performed using GraphPad Prism 7 (GraphPad Software, San Diego, CA, USA) on a Windows-based computer.

[0060] 3.Results The results of spatiotemporal mapping of peristalsis before and after adding saline to the organ bath are shown in Figure 2. No significant difference was observed in peristalsis.

[0061] The results of spatiotemporal mapping of peristalsis before and after adding SKT to the organ bath are shown in Figure 3. Peristalsis stopped about 5 minutes after adding SKT.

[0062] Figure 4 shows the values ​​of PF, AUC, and PPA when physiological saline and SKT were added to the organ bath. The number of mice was 5. Compared to the addition of physiological saline, the addition of SKT significantly reduced PF (P=0.0042, student t-test). On the other hand, no difference was observed in AUC and PPA. These results indicate that SKT has the effect of reducing the number of peristalsis.

[0063] The results of spatiotemporal mapping of peristalsis before and after adding licorice powder to the organ bath are shown in Figure 5. After adding licorice powder, peristalsis stopped.

[0064] Figure 6 shows the PF, AUC, and PPA values ​​when saline, peony powder, and licorice powder were added to the organ bath. n=5. PF was significantly decreased by the addition of licorice powder compared to the addition of saline and peony powder (P<0.01, ANOVA). On the other hand, no difference was observed in AUC and PPA. These results indicate that licorice powder has the effect of reducing the frequency of peristalsis.

[0065] Next, we added GA, GM, and GAG contained in licorice powder to the organ bath to examine whether peristalsis would stop. The results of spatiotemporal mapping of peristalsis before and after adding GM to the organ bath are shown in Figure 7. After adding GM, peristalsis stopped.

[0066] Figure 8 shows the values ​​of PF, AUC, and PPA when DMSO solution (control), GA, GM, and GAG were added to the organ bath. The number of animals was 3. PF was significantly decreased by the addition of GM compared to the control, GA, and GAG (P<0.01, ANOVA). On the other hand, no difference was observed in AUC and PPA. These results indicate that GM has the effect of reducing the number of peristalsis.

Claims

1. A composition for inhibiting gastrointestinal peristalsis, comprising a Cav3.2 T-type calcium channel inhibitor.

2. The composition according to claim 1, wherein the Cav3.2 T-type calcium channel inhibitor is at least one selected from the group consisting of 3-arylcoumarin compounds and ascorbic acid compounds.

3. The composition according to claim 2, wherein the 3-arylcoumarin compound is a compound represented by the following general formula (I), or a pharma- ceutically acceptable salt, glycoside, or ester thereof: 【Chemistry 1】 (In the formula, R １ is a hydrogen atom, a hydroxyl group, a linear or branched alkoxy group having 1 to 3 carbon atoms, a linear or branched alkyl group having 1 to 6 carbon atoms, or a linear or branched alkenyl group having 2 to 6 carbon atoms, R ２ is a linear or branched alkenyl group having 2 to 6 carbon atoms, or a linear or branched alkyl group having 1 to 6 carbon atoms, R ３ is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or a linear or branched alkenyl group having 2 to 6 carbon atoms, m is an integer from 0 to 5.

4. The composition according to claim 3, wherein the compound represented by general formula (I) is a compound represented by the following general formula (II): 【Chemistry 2】 (In the formula, R １ , R ２ , R ３ Same as above.)

5. The composition according to claim 3, wherein the compound represented by general formula (I) is a compound represented by the following general formula (III): 【Chemistry 3】 (In the formula, R １ , R ２ , R ３ Same as above.)

6. R ２ The composition of claim 4 , wherein is a prenyl group.

7. The composition according to claim 5, wherein the prenyl group is a group represented by the following formula (IV): 【Chemistry 4】 。

8. The composition according to claim 1, wherein the compound represented by the general formula (I) is a glycyrrhetinic acid ester.

9. The composition according to claim 1, wherein the ascorbic acid compound is one selected from the group consisting of ascorbic acid, ascorbic acid 2-phosphate, ascorbic acid 2-glucoside, 3-O-ethyl ascorbic acid, ascorbic acid 2-phosphate-6 palmitic acid, glyceryl octyl ascorbic acid, ascorbic acid monostearate, ascorbic acid monopalmitate, ascorbic acid dipalmitate, ascorbic acid tetraisopalmitate, and pharma- ceutically acceptable salts thereof.

10. A method for inhibiting gastrointestinal peristalsis, comprising the step of contacting a Cav3.2 T-type calcium channel inhibitor with gastrointestinal tissue of an animal in vitro.

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