Specification
Technical Field. The present invention relates to an agent for the prophylaxis or improvement of a functional gastrointestinal disorder. Wore particularly, the present invention relates to an agent for the prophylaxis or improvement of functional
gastrointestinal disorders (FGIDs), particularly, upper gastrointestinal dysfunctions such as functional dyspepsia (FD) (e.g., abdominal pain, heavy stomach, heartburn and the like), gastro esophageal reflux disease (GERD) and the like, a gastrointestinal motility function promoter, an agent for the prophylaxis or improvement of dysphasia and a serotonin and/or nitric oxide release promoter. The present invention also relates to a food for the prophylaxis or improvement of a functional gastrointestinal disorder and’ the like.
Background Art Even with the advancement in endoscope diagnosis, there are many cases where a complaint of the upper gastrointestinal symptoms such as upper abdominal pain, discomfort, postprandial heavy stomach, nausea, vomiting and the like cannot be fully explained. Such condition where a complaint of gastrointestinal symptom is reported but no organic disease is found by a general checkup including endoscopes examination, and no finding to elucidate the symptom is available is referred to as an FD [functional dyspepsia: non-ulcer dyspepsia (NUD): upper abdominal indefinite complaint). According to The American Gastroenterological Association, FD is defined to be a pathology where organic diseases such as peptic
ulcer and cancer symptoms are not observed, but upper abdomina1 indefinite complaint continues for 4 weeks or longer, such as feeling of fullness .in the abdomen, nausea. ■ vomiting, upper abdominal pain, anorexia, abnormal bowel movement and the like, based on the retention of contents in the stomach.
On the other hand, in Japan, such case has been determined to be "upper abdomen gastrointestinal complaint associated with chronic gastritis" :.respective of organic findings, and, in clinical situations, diagnosed conventional],y as "gastritis" or "chronic gastritis". Currently, the subtype of FD includes an ulcer symptom type, a gastrointestinal dysmotility type and non-specific type, which include conventional gastroatonia, nervous dyspepsia and gastric neurosis.
Even in cases where an organic disease (reflux esophagi is, peptic ulcer, acute gastritis, gastrointestinal cancer, pancreas ■ bleary disease etc.) is clearly observed, abdominal pain, discomfort, postprandial heavy stomach, nausea-vomiting and the like are also found. Accordingly, there is an urgent need for the improvement of such discomfort able feeling to ensure better QOL of patients. When NUD is joined with lower admen indefinite complaint such as defecation difficulty, unrelieved feeling after defecation, abdominal pain, feeling of fullness in the abdomen and the like due to constipation, about 30%-50% of the total population of Japan is assumed to have experienced some gastrointestinal indefinite complaint, The development of abdominal indefinite complaint is considered to be influenced by sex, aging, stress or overweight due to the western style diet, and is a disease representing the modern society along with the lifestyle-related diseases. Even though it is such a
serious disease, the etiology of the gastrointestinal indefinite complaint is merely suggested to involve various diseases (chronic gastritis, diabetes, overweight, constipation etc.), and the only suggested mechanism of its onset is degraded gastrointestinal motility function.
In addition, many of the patients with a progressive degenerative disease of the brain such as Parkinson's disease, Huntington chorea, olivopontocerebellar atrophy and the like, cerebral apoplexy and the like also develop gastrointestinal motility dysfunction, and improvement of QOL by the improvement of gastrointestinal motility function is Considered to be necessary. It is considered that many of these patients cannot report indefinite complaint by themselves due to logopathy, disturbance of consciousness and the like. Thus, a care that removes a disturbance of sensation such as indefinite complaint and the like simultaneously with a care of organic dysfunction leads to the improvement of QOL in a t rue sense.
S-HT'^ receptor agonists and the like have heretofore been used for the treatment of FD, For example, cisalpine and metoclopramide have a hyperanakinesia action on tlie stomach and intestines, and have been used for the treatment of the symptoms and the like of chronic gastritis, feeling of fullness in the abdomen, reflux esophagi is, abdominal indefinite complaint and pseudoileus. However, metoclopramide shows a side effect of extra pyramidal symptoms caused by the action on dopamine D2 receptors in the central nervous system, and cisapride has also been clarified to show Parkinson an symptoms, While misapplied etc. have also been used, the effect is not always sufficient, and side effects such as feeling of
fullness in the abdomen and the like appear. While H2 antagonists and proton pump inhibitors have been used for the treatment of gastroesophageal reflux disease (GERD), since the safety of long-term administration has not laeen established, a periodic examination is necessary. Therefore, it is difficult to expect a treatment effect of these existing pharmaceutical agents while ensuring sufficient safety.
Moreover, therapeutic drugs for FD and gastrointestinal indefinite complaint accompanying a gastrointestinal organic disorder, partial 5-HT3 receptor agonist, nitroglycerol, nitric oxide {hereinafter NO)-releasing drugs such as nitrate etc. and the like are known. However, since 5-HT receptors and neoteric proteins, which are the target of these pharmaceutical agents, are distributed in not only the gastrointestinal mucous membrane but also organs in the body including brain, the agents show various physiological activities. To be specific, when a 5-HT3 antagonist is used as an anathematic agent, a non-specific 5-HT3 receptor agonist particularly induces nausea and vomiting. It is also known that nonspecific HO release in the systemic circulation induces low blood pressure. Therefore, it is necessary to develop a safe and highly effective pharmaceutical agent that can be acted on these targets limited in the gastrointestinal organs.
On the other hand, glutamine has been reported to show an effect of Improving organic gastrointestinal diseases such as ulcer and the like without expressing a side effect [Elia M, Lunn PC, Nutrition. 1997 Jul-Aug; 13(7-8); 743-7). However, glutamine has low solubility, is highly unstable in an aqueous solution, and lacks convenience. A report has documented that addition of monosodium glutamate alone, and both
glutamic acid and sodium Iodinate, to diet can enhance gastric secretion in an experiment model of atrophy gastriti.s, which is aiso one of tiie organic diseases (Vasllevskaia LS, et al., Vopr Pitan. 1993 May~Jun; (3): 29-33r Rymshina MV & Vasiievskaia LS., Vopr Pitan. 1996; (1): 9-11). Monosodium glutamate has been confirined to enhance gastric secretion in atrophy gastritis patients, and moreover, glutamic acid and sodium inosinate show a potential to be digestion promoters in atrophy gastritis patients (Kochetkov AM, Vopr Pitan. 1992 Sep~Dec; [ 5-6) : 19-22, Shlygin GK, Klin Med (Mosk). 1991 Aug; 69{8): 66-70). However, a treatment effect of glutamic acid and sodium inosinate has not been suggested yet for the sensory abnormality {indefinite complaint) associated with NUD and digestive trouble.
In addition, there are reports on several attempts to improve gastrointestinal function and increase efficiency of nutrition support in patients with organic disorder in the gastrointestinal tract or patients with lower function caused thereby, by enteral administration of a glutamic acid-containing composition for the purpose of protecting the mucous membrane and improving the motility of the lower gastrointestinal tract {DE-B-4133366, US patent application publication Ho. 2003/138476, EP-B~0316446, JP-A-56-57385, CA-B-2404005, JP-A-49-30593). In these cases, however, maintenance of gastrointestinal barrier by protection of the mucous membxane, improvement of the motility of the lower gastrointestinal tract and the like are desired by addition of glutamic acid to a nutritional composition such as amino acid, protein and the like^ and a treatment effect on FD is not suggested.
Disclosure of the Invention
As mGntioned above, 5-HT agonists and NO releasing agents have conventionally been used as therapeutic agents for FD. While serotonin and NO are systemically distributed, they are particularly abundantly present in the gastrointestinal tract. Particularly, it is considered thai: about, 80% of serotonin is present in the gastrointestinal mucosal epithelium. There are abundant findings relating to the physiological activities of NO and serotonin in the gastrointestinal tract. NO in the gastrointestinal raucQUij membrane is considered to relate tn receptive relaxation upon food intake, promotion of mucus secretion, repair of disordered mucous membrane, enhancement of gastrointestinal immunity, sterilisation of gastrointestinal lumen, improvement of microcirculation by increased mucosal blood flow and to antiplatelet aggregation effect, and the like, and plays an important role for the maintenance of gastrointestinal function. In addition, serotonin is a main physiologically active substance of the gastrointestinal tract, which is responsible for gastrointestinal motility regulation, gastrointestinal exocrine regulation (gastric-acid secretion, pancreatic exocrine secretion etc.). When the action of these substances is artificially inhibited, the gastrointestinal function is prevented, which causes ulcer, gastrointestinal bleeding, and abnormal motility.
Therefore, a gastrointestinal indefinite complaint can be taken as a warning from the gastrointestinal tract, and it is easily assumed that a gastrointestinal indefinite complaint can be caused by a nonorganic gastrointestinal dysfunction of a mild level which is pathologically difficult to judge, not
to mention an event of gastrointestinal organic pathology. Therefore, 5-HT agonists that promote serotonin release and NO releasing agents that promote NO have conventionally been used. However, these pharmaceutical agents are problematic in terms of systemic side effects and safety as mentioned above. Hence, there is a demand for the development of a pharmaceutical agent that specifically promotes release of serotonin and NO in the gastrointestinal tract and improves various conditions associated with FD and the like.
The present invention has been made in this situation and aims at providing a pharmaceutical agent or a food capable of improvement of upper gastrointestinal dysfunction such as functional gastrointestinal disorders, particularly functional dyspepsia, esophageal reflux and the like, promotion of gastrointei^tinal moi-jlity function, and prophylaxis or improvement of dysphagia. Moreover, the pre sent invention aims at providing a pharmaceutical agent or a food for specifically promoting a release of serotonin and/or NO in the gastrointestinal tract.
The present inventors have conducted intensive studies in an attempt to solve the above-mentioned problems and found that when at least one kind of glutamic acid, 5'-nucleotide and a salt thereof is administered to the subject of administration, the concentration of NO and serotonin increases only in the gastrointestinal tract to promote gastrointestinal motility function, and therefore, functional gastrointestinal disorders and dysphagia can be improved without inducing systemic side effects, which resulted in the completion of the present invention.
Here, with regard to the absorbability of monosodium glutamate and 5'-nucleotide, for example, it
has been reported that when monosodium glutamats and sodium inosinate are orally taken, not less than 90% of glutamic acid taken is completely oxidized on the gastrointestinal mucous membrane into carbon dioxide and water and the remaining 10% or less is converted to alanine and lactic acid, and thus, the amount of glutamic acid that transfers into blood is extremely small (PJ. Reeds, DG Burin, B Stoll, Jahoor, J. Nutrition 130: 978S (2000)]. Moreover, the study of Niijima et al. affords the finding that administration of monosodium glutamate into the stomach and duodenum activates the vagus nerve afferent pathway, but intravenous and intraportal administration of monosodium glutamate does not activate the vagus nerve (Niijima A., et al., Physiol Behav. 1991 May; 49(5): 1025-8, Niijima A., et al., J Nutr. 2000 Apr; 130 [4S Suppl): 971S-33), From these findings, it is considered that even if a part of glutamic acid is absorbed and transferred to the systemic circulation, glutamic acid does not directly activate the vagus nerve afferent pathway in the body.
From these findings, the action mechanism of improvement of functional gastrointestinal disorders by the pharmaceutical agent of the present invention is assumed to be as follows. That is, when the pharmaceutical agent of the present invention is administered to the subject of administration, release of NO and/or serotonin is promoted only in the stoij>ach mucous membrane. As a result, the concentration of NO and/or serotonin increases only in such topical environment, and gastrointestinal motility function is promoted. Thus, the indefinite complaint associated with functional gastrointestinal disorders such as FD and the like can be improved safely and effectively. In addition, since the amount of active Ingredient
transferred to blood is extremely low, systemic side effects are seldom induced.
The present invention encornpasses the following.
(I) An agent for the prophylaxis or improvement of a
functional gastrointestinal disorder, which comprises,
as an active ingredient;, at least one ki.nd selected
from the group consisting of glutamic acid, 5'-
nucleotide and a salt thereof.
(2} The agent of (1), wherein the aforementioned 5'-nucleotide is selected from the group consisting of 5'-inosinic acid, S'-guanylic acid, S'-adenyl acid, 5'-cytidylic acid, 5'-uridylic acid and 5'-xanthylic acid.
(3) The agent of (1), wherein the aforement ioned 5'-
nucleotide is selected from 5'-inosinic acid and 5'-
guanylic acid.
(4) The agent of any one of (1) to (3), wherein the aforementioned salt is a salt with basic amino acid.
(5) The agent of (4), wherein the basic amino acid is selected from the group consisting of arginine, lysine and orni thine.
(6) The agent of (4), wherein the basic amino acid is arginine,
(7) The agent of (1], wherein the aforementioned active ingredient is an arginine salt with glutamic acid.
(B) The agent of any one of {!) to (7), wherein the aforementioned functional gastrointestinal disorder is upper gastrointestinal dysfunction.
(9) The agent of (8), wherein the. aforementioned upper
gastrointestinal dysfunction is functional dyspepsia or
gastroesophageal reflux disease.
(10) The agent of any one of (1) to (9), wherein a
daily dose of the aforementioned active ingredient to
an adult is 0.01 g to 20 g.
(II) An agent for the promotion of gastrointestinal
motility function, which comprises, as an active
ingredient, at least one kind selected from the group consisting of glutamic acid, 5'~nucleotide and a salt thereof.
(12) An agent for the prophylaxis or improvement of dysphagia, which comprises, as an active ingredient, at least one ki.nd selected from the group consisting of glutamic acid, 5'-nucleotide and a salt thereof.
(13) An NO and/or serotonin release promoter specific to the gastrointestinal tract, which comprises, as an active ingredient, at least one kind selected from the group consisting of glutamic acid, 5'-nucleotide and a salt tliereof.
(14) The release promoter of (13), wherein the aforementioned gastrointestinal tract is stomach, (15} A food for promoting gastroi/itestinal motility function, which comprises at least one kind of compound selected from the group consisting of glutamic acid, 5'-nuc].eotide and a salt thereof,
(16) A food for the prophylaxis or improvement of dysphagia, which comprises at least one kind of compound selected from the group consisting of glutamic acid, 5'"nucleotide and a salt thereof.
(1"7) A food for promoting release of NO and/or serotonin specific to the gastrointestinal tract, which comprises at least one kind of compound selected from the group consisting of glutamic acid, 5'-nucleotide and a salt thereof.
(18) The food of (17), wherein the aforementioned gastrointestinal tract is stomach.
(19) A food for the prophylaxis or improvement of a functional gastrointestinal disorder, which compri ses at least one kind of compound selected from the group consisting of glutamic acid, 5'-nucleotide and a salt thereof.
(20) The food of (19), wherein the aforementioned 5'-
nucleotide is selected from the group consisting of 5'-inosinic acid, 5'-guanylic acid, 5'-adenyl acid, 5'-cytidylic acid, 5'-uridylic acid and 5'-xanthylic acid.
(21) The food of (191, wherein the aforementioned 5'-nucleotide is selected from 5'~inosinic acid and 5'-guanylic acid.
(22) The food of any one of (19) to (21), wherein the aforementioned salt is a salt with basic amino acid,
(23) The food of (22), wherein the basic amino acid is selected from the group consisting of arginine, lysine and ornithine.
(24) The food of (22), wherein the basic amino acid is arginine.
(25) The food of (19), wherein the aforementioned compound is an arginine salt with glutamic acid.
(26) The food of any one of (19) to (25), wherein the aforementioned functional gastrointestinal disorder is upper gastrointestinal dysfunction.
(27) The food of (26), wherein the aforementioned upper gastrointestinal dysfunction is functional dyspepsia or gastroesophageal reflux disease.
(28) The food of any one of (19) to (27), wherein a daily dose of the aforementioned compound to an adult is 0. Olg - 20 q.
(29) The food of any one of (lb) to (28), wherein the content of the aforementioned compound is 0,01 wt% to 10 wt%.
(30) The food of (29), which is a food with health claims or a dietary supplement.
(31) The food of (30), wherein the aforementioned food with health claims is a food ior specified health us as or a food with nutrient function claims,
(32} A commercia1 package comprising a composition comprising at least one kind selected from the group consisting of glutamic acid, 5'-nucleotide and a salt
thereof, and a written matter stating that the compos it ion can or should be used for at least one kind selected from prophylaxis or improvement of a functional gastrointestinal disorder, promotion of gastrointestinal motility function and prophylaxis or improvement of dysphagia.
(33) A commercial package compris ing a composition comprising at least one kind selected from the group consisting of glutamic acid, 5'-nucleotide and a salt thereof, and a written matter stating that the composition can or should be used for promoting release of NO and/or serotonin specific to the gastrointestinal tract.
(34) The commercial package of (33), wherein the a£oreitiBntioned gastrointestinal tract is stomach,
(35) A commercial package comprising a food comprising at least one kind of compound selected from the group consisting of glutamic acid, 5'--nucleotide and a salt thereof, and a written matter associated therewith, the written matter stating that the food can or should be used for at least one kind selected from prophylaxis or improvement of a functional gastrointestinal disorder, promotion of gastrointestinal motility function and prophylaxis or improvement of dysphagia.
(36) A commercial package comprising a food comprising at least one kind of compound selected from the group consisting of glutamic acid, 5'-nucieotide and a salt thereof, and a written matter associated therewith, the written matter stating that the food can or should be used for promoting release of NO and/or serotonin specific to the gastrointestinal tract,
(37) The commercial package of (36), wherein the aforementioned gastrointestinal tract is stomach.
(38) Use of glutamic acid, 5'-nucleotide or a salt thereof for the production of an agent for the
prophylaxis or improveraent of a funct.i onal gastrointestinal disorder, which comprises, as an active ingredient, at least one kj.nd seJ.ectecl from 1:he group consisting of glutamic acid, 5'-nucleotide and a salt thereof.
(39) The use of (38), wherein the aforementioned salt is a salt with basic amino acid.
{40) The use of (39), wherein the basic amino acid is selected from the group consisting of arginine, lysine and ornithine.
(^31) The use of (39), wherein the basic amino acid is arginine.
(42) The use of (38), wherein the aforementioned active ingredient is an arginine salt with glutamic acid.
(43) The use of any one of (38) to (42), wherein the aforementioned functional gastrointestinal disorder is upper gastrointestinal dysfunction.
(44) The use of (43), wherein the aforementioned upper gastrointestinal dysfunction is functional dyspepsia or gastroesophageal reflux disease.
(45) The use of any one of (38} to (44), wherein a daily dose of the aforementioned active ingredient to an adult is 0.01 g to 20 g.
(46) Use of glutamic acid, 5'-nucleotide or a salt thereof for the production of an agenl for the promotion of gastrointestinal motility function, which comprises, as an active ingredient, at least one kind selected from the group consisting of glutamic acid,
5'-nucleotide and a salt thereof.
(47) Use of glutamic acid, 5'-nucleotide or a salt
thereof for the production of an agent for the
prophylaxis or improvement of dysphagia, which
comprises, as an active ingredient, at least one kind
selected from the group consisting of glutamic acid,
5'-nucleotide and a salt thereof.
58) Use of glutamic acid, 5'-nucleotlde or a salt lereof for the production of an NO and/or serotonin 2lease promoter in the gastrointestinal tract, which comprises, as an active ingredient, at least one kind selected from the group consisting of glutamic acid, 5'-nucleotide and a salt thereof,
(49) The use of (48), wherein the aforementioned gastrointestinal tract is stomach.
(50) Use of glutamic acid, 5'-nucleotide or a salt thereof for the production of a food for promoting gastrointestinal motility function, which comprises at least one kind of coinpound selected from the gro\ip consisting of glutamic acid, 5'-nucleotide and a salt thereof.
(51) Use of glutamic acid, 5'-nucleotide or a salt thereof for tlie production of a food for the prophylaxis or Improvement of dysphagia, which comprises at least one kind of compound selected froru the group consisting of glutamic acid, 5'-nucleotide and a salt thereof,
(52) Use of glutamic acid/ 5'-nucleotide or a salt thereof for the production of a food for promoting release of NO and/or serotonin specific to the gastrointestinal tract, which comprises at least one )
Documents
Application Documents
| # |
Name |
Date |
| 1 |
1395-chenp-2009 form-18 06-08-2009.pdf |
2009-08-06 |
| 2 |
1395-chenp-2009 correspondence others 06-08-2009.pdf |
2009-08-06 |
| 3 |
1395-CHENP-2009 POWER OF ATTORNEY.pdf |
2012-07-30 |
| 4 |
1395-CHENP-2009 FORM-5.pdf |
2012-07-30 |
| 5 |
1395-CHENP-2009 FORM-3.pdf |
2012-07-30 |
| 6 |
1395-CHENP-2009 FORM-1.pdf |
2012-07-30 |
| 7 |
1395-CHENP-2009 DRAWINGS.pdf |
2012-07-30 |
| 8 |
1395-CHENP-2009 DESCRIPTON (COMPLETE).pdf |
2012-07-30 |
| 9 |
1395-CHENP-2009 CORRESPONDENCE OTHERS.pdf |
2012-07-30 |
| 10 |
1395-CHENP-2009 CLAIMS.pdf |
2012-07-30 |
| 11 |
1395-CHENP-2009 ABSTRACT.pdf |
2012-07-30 |
| 12 |
1395-CHENP-2009 CORRESPONDENCE OTHERS 21-04-2015.pdf |
2015-04-21 |
| 13 |
1395-CHENP-2009_EXAMREPORT.pdf |
2016-07-02 |