WO2017119509A1 - Agent for improving taste disorder and/or appetite disorder, having glutamic acid as active ingredient - Google Patents

Abstract

The invention provides an agent for improving or treating taste disorders and/or appetite disorders that has glutamic acid or a salt thereof as an active ingredient. In particular, the invention is effective against taste disorders and/or appetite disorders that arise during chemotherapy in cancer patients and also effective in taste disorders and/or appetite disorders of patients in whom the taste receptor T1R3 has been attenuated by diabetes or nephritis.

Description

Taste disorder and / or appetite disorder improving agent containing glutamic acid as an active ingredient

The present invention relates to an improving agent or therapeutic composition containing glutamic acid or a salt thereof as an active ingredient for improving or treating taste disorders and / or appetite disorders. In particular, the present invention relates to a therapeutic agent or therapeutic composition for taste disorders and / or appetite disorders that occur in head and neck cancer patients and dialysis patients who are undergoing treatment.

Taste disorders and appetite disorders are major problems in the treatment of cancer-bearing patients, particularly in the treatment of head and neck cancer. Chemoradiation therapy (CRT) aimed at organ preservation is performed for the treatment of head and neck cancer. However, taste disorders and appetite disorders caused after chemoradiotherapy cause anorexia and worsen the patient's nutritional status. As a result, taste disorders and appetite disorders can cause prolonged hospitalization, delay in the timing of adjunct chemotherapy and resection, and affect the patient's QOL worsening and thus poor prognosis. Among head and neck cancers, especially in patients with oral cancer, pharyngeal cancer, and laryngeal cancer, lesions exist in the feeding route, and as a side effect of CRT or chemotherapy, oral and pharyngeal mucosal disorders such as stomatitis occur, In addition, it causes swallowing pain and decreased taste sensation, resulting in persistent anorexia after treatment. For this reason, a patient's QOL and prognosis deteriorate.
Until now, taste reduction and taste abnormalities have been left to recover spontaneously once anti-cancer drug treatment is completed. Therefore, oral intake of nutrients was often recommended and was not regarded as a serious treatment target.
However, the sense of taste is one of the five senses of animals, and is a sense that is recognized according to the substance to be consumed, and is an important sense that promotes appetite. Physiologically, sweetness, sourness, bitterness, salty taste, and umami taste are positioned as basic tastes. Taste cells sense the taste, and there are receptors on the surface that bind to the taste substances. The three taste substances, sweet, bitter and umami, bind to the G protein-coupled receptor, and the two taste substances, salty and sour, bind to the ion channel receptor. The sweet taste receptor is composed of T1R1 and T1R2, and the umami receptor is composed of a combination of T1R1 and T1R3. Bitterness is perceived by receptors of the T2R family. Therefore, by promoting the expression of these receptors and increasing the taste sensitivity, it can be expected that the patient's appetite is increased and the QOL is improved.

Glutamic acid, which is one of the non-essential amino acids, is a main taste quality such as soup stock, miso and soy sauce, which are widely used in Japanese diets, and is a substance exhibiting “umami”. In Western studies, it has been reported that free glutamic acid can be added to the diet of elderly people with reduced taste sensitivity to improve the amount of eating and the QOL of elderly people through the promotion of salivary secretion. In recent years, it has been confirmed from animal experiments that the receptor for free glutamate, which is an umami substance, exists not only in the oral cavity but also in the stomach, and that free glutamate ingested from foods causes T1R1 and T1R3 in the stomach to It has been shown that glutamate induces the response of the vagus nerve branch, increasing the expression of the glutamate receptor and its transporter.
Thus, glutamic acid has been found to have a nutritional physiological function in addition to umami (Non-Patent Document 1), and further discovery of unknown utility is expected. For example, sodium glutamate is known to have a wound healing effect (Patent Document 1), and is also known to have an immunostimulatory effect (Patent Document 2).
However, so far, there are no known therapeutic agents or pharmaceutical compositions for taste disorders that frequently occur in patients undergoing treatment with anticancer agents, and there are also known therapeutic agents and pharmaceutical compositions for taste disorders that frequently occur in dialysis patients. This is not the situation.

JP 2009-191015 A JP 2008-133265 A

An object of the present invention is to provide a pharmaceutical composition or a food additive composition containing glutamic acid or a salt thereof for improving or treating taste disorders and / or appetite disorders. In particular, in the present invention, a pharmaceutical composition or a composition for food addition for improving or treating taste disorders and / or appetite disorders, which are side effects at the time of treatment of cancer-bearing patients, particularly head and neck cancer patients, and diabetes It is to provide a pharmaceutical composition or a composition for food addition for improving or treating taste disorders frequently occurring in patients, nephritis patients, and patients with decreased T1R3.

As a result of intensive studies on the nutritional physiological function of glutamic acid or a salt thereof, the present inventors have found that glutamic acid or a salt thereof not only improves taste sensation and makes the meal feel delicious, but also helps smooth digestion. Also found that it can contribute to appetite improvement.
Therefore, the inventors further studied and found that glutamic acid or a salt thereof showed a marked improvement effect on anorexia during chemotherapy for head and neck cancer. That is, it has been found that as a new use of glutamic acid or a salt thereof, a marked improvement can be made for taste disorders and / or appetite disorders of cancer-bearing patients during chemotherapy.
When the present inventors mix and administer 1.8 g or more of glutamic acid or a salt thereof to a meal for one week, the umami receptor T1R3 that senses an umami component increases in cancer-bearing patients during chemotherapy. I found. In addition, administration of glutamic acid or a salt thereof at 1.8 to 2.7 g / day mixed with a meal for one week can suppress a decrease in food intake and weight loss, and can maintain expression of a taste receptor T1R3 gene. I found.
The present inventors have studied the contents of the composition such as sprinkles in order to ease the irritation unique to glutamic acid and make it easy to eat. As a result, in cancer-bearing patients at the time of chemotherapy, it was possible to suppress a decrease in taste receptor T1R3 and to find a pharmaceutical composition or a composition for food addition in which stimulation unique to glutamic acid was masked. The present inventors have completed the present invention based on these findings.

The gist of the present invention is as follows.
(1) An agent for improving or treating taste disorders and / or appetite disorders, comprising glutamic acid or a salt thereof as an active ingredient.
(2) A pharmaceutical composition or a composition for food addition containing the agent for improving or treating taste disorders and / or appetite disorders of (1) above.
(3) The pharmaceutical composition or food additive composition according to (2), wherein the taste disorder and / or appetite disorder is a disorder caused by a decrease in umami receptor T1R3.
(4) The pharmaceutical composition or food according to (2) or (3) above, wherein the taste disorder and / or appetite disorder is a disorder that occurs in cancer-bearing patients, diabetics, nephritis patients, and dialysis patients during chemotherapy. Composition for addition.
(5) The pharmaceutical composition or food additive composition according to (4) above, wherein the cancer-bearing patient is a head and neck cancer patient.
(6) The pharmaceutical composition or food additive composition according to any one of (2) to (5) above, wherein the glutamic acid or a salt thereof is a glutamic acid sodium salt.
(7) The pharmaceutical composition or food additive composition as described in (6) above, wherein the glutamic acid sodium salt is contained so as to have an intake of 1.8 to 2.7 g per day.
(8) The pharmaceutical composition or food additive composition according to the above (6), wherein the glutamic acid sodium salt is contained so as to have an intake of 2.0 to 2.7 g per day.

(9) An expression promoter for umami receptor T1R3 for cancer-bearing patients at the time of chemotherapy, diabetic patients, nephritis patients or dialysis patients who have decreased umami receptor T1R3, comprising sodium glutamate as an active ingredient.
(10) The expression promoter for umami receptor T1R3 according to (9), wherein the glutamic acid sodium salt is contained so as to have an intake of 1.8 to 2.7 g per day.
(11) The expression promoter for umami receptor T1R3 according to (9), wherein the glutamic acid sodium salt is contained so as to have an intake of 2.0 to 2.7 g per day.
(12) A pharmaceutical composition or food additive composition for improving suppression of gene expression of umami receptor T1R3 produced in cancer-bearing patients during chemotherapy, comprising sodium glutamate as an active ingredient.
(13) A pharmaceutical composition or food additive composition for improving gene expression of umami receptor T1R3, which is administered to a diabetic patient, a nephritis patient or a dialysis patient having reduced umami receptor T1R3, comprising sodium glutamate as an active ingredient object.
(14) The umami receptor T1R3 gene expression improving gene according to (12) or (13), wherein the glutamic acid sodium salt is contained so as to have an intake of 1.8 to 2.7 g per day. A pharmaceutical composition or a composition for food addition.
(15) The umami receptor T1R3 gene expression improving agent according to (12) or (13), wherein the glutamic acid sodium salt is contained so as to have an intake amount of 2.0 to 2.7 g per day. A pharmaceutical composition or a composition for food addition.

(16) The pharmaceutical composition or food additive according to any one of (2) to (8) and (12) to (15) above, wherein the pharmaceutical composition or food additive composition is a food additive composition Composition.
(17) The food additive composition as described in (16) above, wherein the food additive composition is sprinkled.
(18) The food additive composition as described in (17) above, wherein the sprinkle is a sprinkle for cooked rice.
(19) The composition for food addition according to (17) or (18), wherein the sprinkle contains bonito, soy sauce, and sesame.
(20) The food additive composition as described in any one of (17) to (19) above, wherein the sprinkle contains bonito, laver, sesame, sugar, soy sauce, and oil.
(21) The sesame content is 9 to 20% by weight, the oil content is 3 to 9% by weight, the bonito content is 3 to 16% by weight, the sugar content is 6 to 20% by weight, and the soy sauce content is 5 to 5%. The composition for food addition according to (20) above, wherein the content of chopped laver is 20 to 12% by weight and 3 to 12% by weight.

(22) A food composition for a mask with a taste of sodium glutamate, characterized by comprising sodium glutamate as an active ingredient and containing bonito, sesame seeds, and soy sauce.
(23) The food composition for masked taste of glutamic acid sodium salt according to (22) above, wherein sugar, laver and edible oil are further added.
(24) When the content of sodium glutamate is 24 to 30% by weight, it contains 8 to 16% by weight of bonito, 9 to 20% by weight of sesame, and 5 to 20% by weight of soy sauce, (22) Or the food composition for masks of the taste of the glutamic acid sodium salt as described in (23).
(25) The content of sodium glutamate is 1, and the bonito contains 0.27 to 0.56 parts by weight, sesame seeds 0.3 to 1.0 parts by weight, and soy sauce 0.15 to 0.66 parts by weight. A food composition for masks with a taste of sodium glutamate according to (22) or (23) above,
(26) Further comprising 0.33 to 0.66 parts by weight of sugar, 0.27 to 0.56 parts by weight of seaweed, and 0.11 to 0.45 parts by weight of edible oil, Food composition for masks with taste of sodium glutamate according to 22) or (23).
(27) The composition for food addition according to any one of the above (16) to (21), which is added to a food to give the food a function of improving or treating taste disorders and / or appetite disorders How to use.

The pharmaceutical composition or food additive composition of the present invention is not only effective in improving and treating taste disorders and / or appetite disorders in cancer-bearing patients, but also in diabetes, chronic glomerulonephritis, or dialysis patients. And / or effective in improving appetite disorders. For example, administration of sodium glutamate to cancer-bearing patients during chemotherapy for one week has improved taste disorders and / or appetite disorders. As a result, the effect on the amount of food intake during chemotherapy was reduced, and weight loss after chemotherapy was not observed (see FIG. 6).
When the expression level of the umami taste receptor T1R3 of the tongue was measured in a head and neck cancer patient who complained of abnormal taste at the time of chemotherapy, the expression level of T1R3 is the same as that at the start of chemotherapy in patients who have not been administered sodium glutamate. Both were significantly decreased after 2 weeks compared to before treatment. However, in the case of patients receiving glutamic acid sodium salt, the expression level of T1R3 was not significantly different from that before treatment both at the start of chemotherapy and after 2 weeks. Moreover, when the presence or absence of administration of glutamic acid sodium salt was compared, the amount of T1R3 expression was significantly increased in patients who received glutamic acid sodium salt (see FIG. 5). Thus, it became clear that administration of glutamic acid sodium salt can avoid and improve the decrease in expression of umami receptor T1R3 in cancer-bearing patients who have undergone chemotherapy.

Evaluation of satisfaction with the taste of food when 4 weeks of chemotherapy-induced head and neck cancer patients who had caused taste disorders were provided with a dietary supplement of sodium glutamate (MSG) (2.7 g of MSG) for 1 week FIG. When the satisfaction level of the taste of the meal was evaluated in five levels (1: unfavorable to 5: delicious, 3: no change), all the subjects answered that they were satisfied. It is the figure showing the result of having evaluated the satisfaction according to food in the satisfaction evaluation of the taste of the meal of FIG. Among the foods, foods that originally had soup stock, such as Koya tofu, brackish soup, udon, soba, and noodles, were highly evaluated. In addition, vinegar that was strongly stimulated by acidity was highly evaluated. It is a figure showing how meal intake changed by providing the meal which added MSG with respect to the cancer-bearing patient who caused the taste disorder at the time of chemotherapy (intervention). There was no difference in dietary intake before intervention between the non-intervention group and the intervention group. Regarding food intake at the time of intervention, there was an upward trend in the intervention group, but this was not a significant difference. However, the rate of change in food intake was significantly higher in the intervention group. Since there was a significant difference in the rate of change in dietary intake of cancer-bearing patients as shown in FIG. 3 depending on whether or not MSG was added, the effect of MSG on the oral energy intake per body weight was examined. It is a figure showing the change of the amount of oral intake energy per body weight by the presence or absence of addition of MSG with respect to the cancer bearing patient who caused the taste disorder. First, patients with head and neck cancer who have undergone chemoradiotherapy are divided into an MSG intervention group and a non-intervention group. The energy intake in the first course (non-intervention period) was almost the same as 21.13 ± 7.2 kcal / kg / day in the non-intervention group and 21.23 ± 2.06 kcal / kg / day in the intervention group. It was. However, the energy intake in the second course (intervention period) was 16.74 ± 7.86 kcal / kg / day in the non-intervention group, compared with 25.97 ± 3.73 kcal / kg / day in the intervention group. It was found to be significantly higher than the day and non-intervention groups. It is the figure which evaluated the change of the expression level of the umami receptor T1R3 by having eaten the meal which added MSG in the head and neck cancer patient who induced the taste disorder at the time of chemotherapy. Regarding the expression level of the umami receptor T1R3, in the first course (non-intervention period), the expression level at the start of chemotherapy and after 2 weeks was significantly decreased compared with that before treatment. On the other hand, in the second course (intervention period), there was no difference from before treatment at the start of chemotherapy and after 2 weeks. In addition, the expression level of T1R3 was significantly increased in the T1R3 expression level after 2 weeks of intervention compared to the T1R3 expression level after 2 weeks of non-intervention. It is a figure showing the change rate of the body weight by the presence or absence of MSG administration in the head and neck cancer patient (taste impaired person) under chemotherapy treatment. In the MSG administration group, the rate of decrease in body weight was significantly suppressed compared to the non-administration group. As a sensory test sample, the content of white sesame was changed as shown in Table 3 in a basic formula for 10 meals (white sesame 5 g, salad oil 2 g, bonito 5 g, MSG 9 g, sugar 3 g, soy sauce 6 g, chopped laver 2.5 g) It is the figure showing the result of having made the sprinkled and making the sensory test using this. If the amount of white sesame added increases, a mask with a taste of MSG can be made, but if the amount added increases, the texture becomes worse. As a result, a bell-shaped sensory curve as shown in the figure was shown. FIG. 8 is a diagram showing the results of sensory tests on samples prepared by changing the content of salad oil as shown in Table 4 in the same manner as FIG. 7. If the amount of salad oil added increases, a mask with a taste of MSG can be made, but if it increases, it becomes oily and the texture decreases. As a result, a bell-shaped sensory curve as shown in the figure was shown. FIG. 8 is a diagram showing the results of sensory tests performed by preparing samples with varying koji content as shown in Table 5, as in FIG. 7. FIG. 8 is a diagram showing the results of sensory tests performed by preparing samples in which the sugar content is changed as shown in Table 6, as in FIG. FIG. 8 is a diagram showing the results of producing a sample with the soy sauce content changed as shown in Table 7 and performing a sensory test in the same manner as FIG. 7. FIG. 9 is a diagram showing the results of sensory tests on samples prepared by changing the content of chopped laver as shown in Table 8 in the same manner as FIG. 7. During chemotherapy for cancer-bearing patients, the patients were randomly assigned to an intervention group (Umami (+) group) that took the sprinkles of the present invention and a non-intervention group (Umami (−) group) that did not take the patients, It is a figure showing the result of having measured the expression level of the T1R3 receptor at the time of chemotherapy and two weeks after the treatment, with the expression level of the T1R3 receptor before the start of treatment being 1. In the non-intervention group, the expression level of T1R3 receptor was significantly decreased 2 weeks after chemotherapy, whereas in the intervention group (sprinkle intake group), a decrease in the expression level of T1R3 receptor was observed. There wasn't.

The “glutamic acid and / or salt thereof” of the present invention may be any of those obtained by hydrolysis of natural proteins derived from animals or plants, those obtained by fermentation or chemical synthesis. As glutamic acid, D-form and L-form exist as optical isomers, but L-form which is a component of biological protein is desirable for use in the present invention. Glutamic acid may be used in various salt forms. As the salt, a salt with a base is mainly used because glutamic acid is acidic. Examples of the base include sodium, calcium, potassium and the like. A more preferred base is sodium.
The dosage of glutamic acid or a salt thereof can be appropriately adjusted according to symptoms such as taste disorders, but preferably the daily intake of cancer-bearing patients is 1.5 to 3.0 g as glutamic acid sodium salt. More preferably, 1.8 to 2.7 g can be mentioned. More preferably, 2.0 to 2.7 g can be mentioned.

The “chemotherapy” of the present invention is cancer chemotherapy, which is a treatment method that suppresses cancer growth and destroys cancer cells with a chemical substance (anticancer agent). It means chemoradiotherapy that combines chemotherapy and radiation therapy. Since normal cells are also destroyed when cancer cells are destroyed, it is considered inevitable that hair loss or bone marrow function is impaired. As a result, side effects common to cancer chemotherapy include gastrointestinal complications (eg, diarrhea, nausea, vomiting, loss of appetite and mucositis), taste disorders such as pain and abnormal taste, and decreased appetite resulting therefrom. Appetite disorders, bone marrow / hematological complications (eg leucopenia, neutropenia, anemia, bleeding and thrombocytopenia), fatigue and sleep disorders are caused.
In particular, persistent loss of appetite after chemotherapy may worsen the patient's nutritional status, resulting in delayed discharge and delayed additional chemotherapy and salvage surgery. In addition, in the case of head and neck cancers such as oral cancer, pharyngeal cancer, and laryngeal cancer where cancer lesions are present in the feeding route, the lesions are present in the feeding route, so stomatitis as a side effect of chemotherapy Mucous disorders of the oral cavity and pharynx are likely to occur, and at the same time, it causes swallowing pain and a decrease in taste, and anorexia after treatment continues. For this reason, the patient's QOL and prognosis often deteriorate.

The “cancer-bearing patient” of the present invention is a patient who has developed cancer, and the site where the cancer occurs is not particularly limited. For example, prostate cancer, breast cancer, uterine cancer, blood cancer, ovarian cancer, endometrial cancer, cervical cancer, colorectal cancer, testicular cancer, lymphoma, rhabdomyosarcoma, neuroblastoma, pancreatic cancer, lung cancer, brain tumor It refers to patients suffering from cancer including skin cancer, stomach cancer, oral cancer, liver cancer, laryngeal cancer, gallbladder cancer, thyroid cancer, liver cancer, kidney cancer, nasopharyngeal cancer and the like.
The “taste disorder and / or appetite disorder” of the present invention refers to gastrointestinal complications (eg, diarrhea, nausea, vomiting, loss of appetite and mucositis) caused by side effects during chemotherapy and chemoradiotherapy. Taste disorders such as abnormalities, and appetite disorders such as decreased appetite resulting therefrom.

The “improving agent or therapeutic agent” of the present invention refers to a preparation in which glutamic acid or a salt thereof is used in the form of a pharmaceutical, a food or a supplement depending on the purpose in order to improve or treat a taste disorder and / or an appetite disorder. It is possible to use glutamic acid or a salt thereof alone or as a mixture with a physiologically or pharmaceutically acceptable carrier or diluent. The administration form can be oral administration or parenteral administration, but oral, gastric or enteral administration is preferred. When these are orally administered as a pharmaceutical composition, they can be contained in a liquid component or take a solid form. For example, tablets, capsules, granules, powders, pills, troches, water for internal use Agents, suspensions, emulsions, syrups and the like. Furthermore, it can be used as a food composition such as supplements and sprinkles.
These various preparations include excipients, extenders, binders, wetting agents, disintegrants, lubricants, surfactants, dispersants, buffers, preservatives, solubilizers, preservatives, A flavoring agent, a soothing agent, a stabilizer, an isotonic agent and the like can be appropriately selected and produced by a conventional method.
The “pharmaceutical composition” of the present invention refers to a pharmaceutical composition containing the above-mentioned improving agent or therapeutic agent.
The “food additive composition” of the present invention is a food composition such as sprinkle, and preferred examples include sprinkle on cooked rice, topping applied on bread, mayonnaise, jam and the like.

The “umami receptor T1R3” of the present invention is one of receptors for sodium glutamate, which is an umami substance. The receptor for sodium glutamate is composed of T1R1 and T1R3 heterodimers. Therefore, an increase in the expression level of umami receptor T1R3 RNA can contribute to an increase in receptors that sense umami. As a result, it becomes easier to feel the umami of food, and the taste becomes sharper. Therefore, in order to ameliorate taste disorders caused by cancer chemotherapy, it is necessary to regenerate umami receptors damaged by chemotherapy.
The “expression promoter” of the present invention refers to the reduction of umami receptor T1R3 in cancer-bearing patients damaged by chemotherapy, and the expression of T1R3 receptor gene by the T1R3 receptor expression promoting effect of glutamate sodium salt. A formulation that increases the amount. For example, the dose of glutamic acid sodium salt, which is an active ingredient, is preferably 2.0 to 2.7 g per day for cancer-bearing patients who have undergone chemotherapy, and the T1R3 receptor gene can be administered by administration for 1 week. The expression level of is increasing. Thus, glutamate sodium salt can suppress the decrease of T1R3 receptor caused by chemotherapy, and further increase T1R3 receptor. Therefore, the taste disorder of patients due to chemotherapy is improved, and appetite disorders such as decreased appetite. Has been avoided and improved.
The “taste of glutamic acid sodium salt” in the present invention refers to a taste peculiar to glutamic acid. When the concentration of glutamic acid is high, the taste becomes an irritating taste, and many people avoid it.
The “food additive for mask” of the present invention is a food additive capable of masking the taste peculiar to glutamic acid. Examples thereof include sprinkles added to cooked rice, toppings added to bread and noodles, mayonnaise, jam and the like. be able to.

Next, the present invention will be further described with reference to examples, but the present invention is not limited thereto.

(Example 1) Glutamic acid sodium salt (MSG) improves gustatory disorder of cancer-bearing patients (1) Cancer-bearing patients Cancer-bearing patients are from Tokushima University Otolaryngology Department from October 2014 to August 2015. 10 patients (average age 63.6 ± 9.1 years old: 6 males, 4 females) who are hospitalized and treated, and their tumor sites are 1 laryngeal cancer and 1 hypopharyngeal cancer There were 1 oropharyngeal cancer, 1 nasopharyngeal cancer, 1 maxillary cancer, 1 parotid cancer, 1 submandibular gland cancer, 2 sinus cancer, and 1 tongue cancer. As a comparative study between 2 groups, 6 groups of glutamic acid sodium salt (MSG) intervention group and 4 groups of non-intervention group were divided.
In addition, the taste receptors T1R1, T1R2, T1R3, and T2R5 were analyzed for all the subjects.
This study was conducted for patients who had obtained consent from the Tokushima University Hospital Ethics Committee.
(2) Evaluation method In the treatment, radiation therapy (5 times a week, every day on weekdays) was continued for 2 months, chemotherapy was performed for 1 week (5 days a week), and a 3-week break was performed as 1 course. . After confirming a decrease in food intake and taste in the first course, MSG intervention was performed for one week from the second course. During the intervention period, the intervention group added 2.7 g / day of MSG (commercially available “Ajinomoto”) to the meal for 1 week, satisfaction of the taste of the meal (5-level evaluation, 1: tasteless to 5: delicious), The effects on food intake and oral energy intake were evaluated. In the non-intervention group, evaluation was performed with one week of one or two courses of chemotherapy as a comparison period.

(3) Method for evaluating expression level of umami receptor T1R3 a) Tongue cell sample collection Taste cells of head and neck cancer patients were collected by rubbing the leafy papillae of the tongue with the lid of the Eppendorf tube. To the collected sample of human taste cells, 500 μL of RNA later (registered trademark) (Ambion, Austin, TX, USA) was added and well shaken and stored at −20 ° C.
b) RNA Extraction RNA from human taste cell samples lysed in RNA later® (Ambion) from human taste cells was purified using RNAqueous® Kit (Ambion). According to the attached protocol, RNA was adsorbed onto the column with 64% ethanol, washed with the attached Wash Solution # 1, Wash Solution # 2/3, and eluted with 100 μL of the eluate. The concentration was measured using a spectrophotometer (NANODROP 8000, Thermo Scientific, Wilmington, DE).

c) cDNA synthesis cDNA was amplified from RNA extracted with RNAqueous Kit (registered trademark) using CellAmp (registered trademark) Whole Transliptome Amplification Kit (Takara, Japan).
CDNA was synthesized from mRNA by reverse transcription using an oligo dT adapter primer (RT dT Primer). Next, dA tail was added to the synthesized cDNA with TdT, and using this as a template, PCR method (95 ° C. × 1 minute, 50 ° C. × 1 minute, 72 ° C. × 3 minutes, 1 cycle, 95 ° C. × 30 seconds, 67 ° C.) The cDNA was amplified by 20 cycles of 72 ° C. × 10 minutes and 72 ° C. × 3 minutes). The concentration of the synthetic cDNA was confirmed by NANODROP 8000.

d) Real-time PCR analysis Real-time PCR was performed using a Step One ™ real-time PCR System (Applied Biosystems, Carsbad, CA, USA). Fast SYBER Green master Mix (registered trademark) (Applied Biosystems) 5 μL, cDNA 1 μL, Primer (final concentration 0.4 μM) were stirred in the plate, 95 ° C. × 20 seconds, 95 ° C. × 3 seconds, 60 ° C. × 30 Seconds were set at 60 cycles, 95 ° C. × 15 seconds, 60 ° C. × 1 minute, and 95 ° C. × 15 seconds. Artificial synthetic DNA was prepared as standard DNA (Invitrogen, Carsbad, CA, USA). The base sequences of the primers used are as shown in Table 1 below.

In the expression analysis, the Ct value of the target primer hT1R3 was corrected with the Ct value of GAPDH, which is an endogenous control. Furthermore, the degree of increase in expression (%) = [100-100 × (Ct correction value of collected sample / Ct value of GAPDH)] was calculated, and the increase / decrease in the expression level over time was evaluated.

e) Investigation regarding taste disorders of patients Disease name, treatment method, physical condition, biochemical examination (TP, Alb, ALT, AST, Cre, BUN, K, Na, Ca, P, CRP, RBC, WBC, PLT, Hb, Ht, MCH, MCV, MCHC), nutritional supplements, and dietary intake. Interviews were conducted on items not listed in the chart, such as those that are easy to ingest, tastes that are easy to feel, and tastes that are difficult to feel.

(4) Evaluation results a) Satisfaction of MSG intervention for cancer-bearing patients who have caused taste disorders during chemotherapy. Meal satisfaction by adding MSG is divided into 5 levels (1: tasteless to 5: delicious, 3: no change). When evaluated, all subjects answered that they were satisfied (FIG. 1). Looking at the level of satisfaction by food, foods that were originally soup-like, such as Koya tofu, brackish soup, udon, soba, and noodles, were highly rated. In addition, vinegar and the like that are strongly stimulated by acidity were also highly evaluated (FIG. 2).
b) Changes in dietary intake by MSG intervention for taste-impaired people We examined how much the addition of MSG affects dietary intake. There was no difference in dietary intake before intervention between the non-intervention group and the intervention group (FIG. 3A). Regarding the food intake at the time of intervention, there was an upward trend in the intervention group, but there was no significant difference (FIG. 3B). However, in terms of the rate of change in food intake, there was a significant increase in the intervention group (FIG. 3C).

c) Changes in oral energy intake per body weight due to MSG intervention for cancer-bearing patients who caused taste disorders during chemotherapy Since there was a significant difference in the rate of change in food intake, oral energy intake per body weight The effect on the amount was examined. The energy intake in the first course (non-intervention period) was almost the same as 21.13 ± 7.2 kcal / kg / day in the non-intervention group and 21.23 ± 2.06 kcal / kg / day in the intervention group. However, the energy intake in the second course (intervention period) was 16.74 ± 7.86 kcal / kg / day in the non-intervention group, compared with 25.97 ± 3.73 kcal / kg in the intervention group. / Day and significantly higher than those in the non-intervention group (FIGS. 4A and B). Also, looking at the rate of change in energy intake in the 1st and 2nd courses, the non-intervention group decreased to 77.3% compared to 1 course, while the intervention group increased to 117.6%. (FIG. 4C).
d) Changes in the expression level of umami receptor T1R3 by MSG intervention for cancer-bearing patients who caused taste disorder during chemotherapy In the head and neck cancer patients who complained of taste disorder, the expression level of umami receptor T1R3 was measured before chemotherapy. At the time of chemotherapy, 2 weeks after chemotherapy, during chemotherapy during MSG intervention, analysis was performed 2 weeks after MSG intervention. In the first course before the MSG intervention, the expression level at the start of chemotherapy and after 2 weeks was significantly decreased as compared to before treatment. On the other hand, in the second course in which MSG intervention was performed, there was no difference from before treatment at the start of chemotherapy and after 2 weeks. Moreover, compared with the T1R3 expression level after 2 weeks before MSG intervention, the direction after 2 weeks at the time of MSG intervention increased significantly (FIG. 5).

e) Changes in patient weight due to MSG intervention for cancer-bearing patients who caused taste disorders during chemotherapy Comparison of head and neck cancer patients who complained of abnormal taste in the non-intervention group and the intervention group The results are shown in FIG. Non-intervention group (N = 6, average age 66 ± 4.2 years old, 4 men, 2 women), intervention group (N = 4, average age 66 ± 11.0 years old, 2 men, 2 women)
In head and neck cancer patients undergoing chemotherapy (taste-impaired persons), when weight change after one week of MSG intervention was evaluated, suppression of weight loss was significantly observed for patients in the intervention group.

(Example 2) Manufacture of food additive composition for ingesting necessary amount of MSG (1) Purpose In the case of a taste disorder patient or a cancer-bearing patient under treatment, it is effective in promoting appetite and maintaining taste receptor T1R3 It is necessary to ingest about 0.9 g of MSG for which each meal is recognized. However, since MSG has a unique taste, it is necessary to mask it.
It is also necessary to mask the unique taste of MSG so that the necessary amount of MSG can be consumed even when the taste threshold is improved and increased.
In order to be able to ingest deliciously the cooked rice that is the main food of the above patients, there is a demand for an optimal composition for food addition. Therefore, preparation of a sprinkling with a good texture that enables the intake of the necessary amount of MSG is performed. It was.
(2) Preparation of sprinkles with a good texture Based on the previous studies on the composition of sprinkles, by adding seasonings such as bonito, seaweed, sesame seeds, sugar, etc., the taste unique to MSG can be masked, and even healthy people take it deliciously I found out that I can do it. Furthermore, in order to produce a sprinkle having a good texture, the following examination was performed.

(2-1) Composition Evaluation of Seasoning From the examination so far, it was found that sesame seeds, oil, bonito, sugar, soy sauce, and laver are useful seasonings for masking the taste of MSG. Therefore, in order to confirm which seasonings are essential, sprinkles of the composition (shown in g, 10 servings) in Table 2 below were prepared.

No. in Table 2 above. When the sensory test of Test Example 1 was conducted by preparing 1-7 sprinkles, it was shown that the taste of MSG was most masked by adding all the seasonings as shown by No. 1 sprinkling. It was. Moreover, from the results of Tables 5 and 6 below, it was suggested that bonito and sugar may be reduced.

(2-2) Evaluation of seasoning content As described above, it was found that there is room for weight reduction in the content of each seasoning, so optimization of the seasoning content was examined.
a) Effect of Sesame Content Sprinkles with varying contents of white sesame were prepared with the compositions shown in Table 3 below (g display, 10 servings). The result of the sensory test was also described.

As shown in Table 3, it was found that the taste of MSG can be masked when the content of sesame is 9% by weight or more. However, if the amount of sesame is too large to be 26% by weight or more, the texture becomes worse. Therefore, it is considered that the content of sesame is preferably 9 to 20% by weight, more preferably 9 to 16% by weight.
Alternatively, when MSG is set to 1 and sesame is present in an amount of 0.3 to 1.0, it has been clarified that the taste of MSG can be masked and the texture is good.

b) Influence of the content of dietary oils Various selections are possible as dietary oils. For example, salad oil is used, and the content is varied to change the composition ratio of Table 4 (g display, 10 servings) below. Samples were prepared and the mask effect and texture of MSG taste were evaluated.

Sprinkles with varying contents of white sesame were prepared with the compositions shown in Table 3 below (g display, 10 servings). The result of the sensory test was also described.
As shown in Table 4 above, when the content of salad oil is 3% by weight or more, the taste of MSG is masked. It was shown that if it was further added, an oily odor was obtained, and if it exceeds 14% by weight, the texture became worse.
From the above, it was found that if the content of salad oil is 3 to 9% by weight, MSG is 1 and sesame is 0.11 to 0.45 parts by weight, the taste of MSG can be masked and the texture is good. Furthermore, it was found that a salad oil content of 3 to 6.5% by weight is desirable. The same texture evaluation was obtained even when the dietary oil was switched from salad oil to sesame oil.

c) Effect of bonito content Samples having the composition ratio shown in Table 5 (g display, 10 servings) having different composition ratios of bonito were prepared, and the mask effect and texture of MSG taste by bonito were evaluated.

As shown in Table 5 above, the taste of MSG is masked when the bonito content is 3% by weight or more. Further, when koji was added and the content exceeded 20% by weight, the texture was shown to be poor. Therefore, it was found that when the bonito content is 3 to 16% by weight, the taste of MSG is masked and the texture is good. Further, it was found that 8 to 16% by weight is desirable. It was found that MSG is 1 and the knot is 0.27 to 0.56 parts by weight for the mask.

d) Influence of sugar content Samples having the composition ratios shown in Table 6 (g display, 10 servings) having different sugar composition ratios were prepared, and the masking effect and texture of MSG taste by sugar were evaluated.

As shown in Table 6 above, when the sugar content is 6% by weight or more, the taste of MSG is masked. Furthermore, when it added and it exceeds 23 weight%, it became sweet too much and it was shown that food texture worsens. Therefore, it was found that when the bonito content was 6 to 20% by weight, the taste of MSG was masked and the texture was good. Further, it was found that 9 to 17% by weight is preferable. It has been found that MSG is 1 and sugar is 0.33 to 0.66 parts by weight, which is good for a mask.

e) Effect of Soy Sauce Content Samples having the composition ratios shown in Table 7 (g display, 10 servings) shown below differing in the composition ratio of soy sauce were prepared, and the mask effect and texture of MSG taste by soy sauce were evaluated.

As shown in Table 7, the taste of MSG is masked when the content of soy sauce is 5% by weight or more, particularly 10% by weight or more. Furthermore, when it added and it exceeded 25 weight%, it became salty too much and it was shown that food texture worsens. Therefore, it was found that when the soy sauce content was 5 to 20% by weight, the taste of MSG was masked and the texture was good. Further, it was found that 10 to 19% by weight is preferable. It has been found that if MSG is 1 and soy sauce is 0.15 to 0.66 parts by weight, especially 0.33 to 0.66 parts by weight, it is good for the mask.

f) Influence of the content of chopped seaweed Samples having the composition ratio shown in Table 8 (g display, 10 servings) shown below differing in the composition ratio of chopped seaweed were used to evaluate the masking effect and texture of MSG taste by chopped seaweed. .

As shown in Table 8 above, when the content of chopped laver is 3% by weight or more, the taste of MSG is masked. Furthermore, when it added and it exceeded 14 weight%, it was shown that it becomes bulky and food texture worsens. Therefore, it was found that if the content of chopped seaweed is 3 to 12% by weight, the taste of MSG is masked and the texture is good. Further, it was found that the content of chopped laver is preferably 7 to 12% by weight. It was found that if MSG was 1 and the chopped seaweed was 0.27 to 0.56 parts by weight, it was good for the mask.

(Test Example 1)
(1) Samples In order to check that each food is necessary for masking a large amount of glutamic acid sodium salt and taking it deliciously, seven samples (one with no white sesame seeds, no salad oil, No bonito, no MSG, no sugar, no soy sauce, or chopped nori.
(2) Method The subjects of the sensory test are 12 healthy persons (average age 22.6 years, all women) and 20 healthy persons (average age 53.8 ± 12.2 years, male and female ratio 4: 1) It was.
The former was for young people with normal taste and sensitivity to taste, and the latter was the same in terms of the same generation as cancer patients and mainly men. Patients have not done this because they already have a taste disorder and do not know the taste.
The order of each sprinkle was fixed and they were eaten with white rice. Drinks were drinking water. We also interviewed MSG's past food experience.
The evaluation is anonymous, and a special evaluation sheet is created, and the appearance, flavor, sweetness, saltiness, MSG taste, good aftertaste (badness), compatibility with rice, texture, and overall evaluation, each in five stages We had you evaluate.
(3) Results Table 1 shows the results. From the results of the sensory test, we found that bonito, sesame seeds and soy sauce mainly function to mask the taste of MSG, and sugar, nori and edible oil function as a flavoring to enhance the mask effect. .
In addition, it turned out that it is good to add six types of seasonings from the result of Table 1. Furthermore, considering the results of Test Example 2, it was shown that bonito and sugar may be reduced.

(Test Example 2)
(1) Sample In order to show the basis for the amount of components such as sesame seeds added, sprinkles were prepared for each amount in the proportions shown in Tables 2-8.
(2) Method Subjects were 12 healthy people (average age 22.6 years, all women).
In the same manner as in Test Example 1, the order of each of the sprinkles was fixed and was eaten with white rice. Drinks were drinking water.
The evaluation is anonymous, and a special evaluation sheet is prepared. The taste is evaluated with 10 levels of VAS formula (delicious is -5, usually 0, delicious 5), and shown in Tables 2-8. The test results were scored out of 10 points. Also, whether the taste of MSG can be masked is evaluated on a 10-point scale, with MSG taste as -5 for "I feel very much", 0 for "I feel", and 5 for "I don't feel at all". In Tables 2 to 8, “completely masked” is shown as 100%.
(3) Results As shown in Tables 2 to 8 and FIGS. 7 to 13, the amount of each component necessary for masking the taste of MSG became clear.

(Example 3) Effect of sprinkling on abnormal taste patients (1) Target patients Five patients having taste disorders were selected in the following sensitivity test. The patient was a cancer-bearing patient who was hospitalized for the purpose of chemotherapy or CRT, and the average age was 63 years old, which was 4: 1.
[MSG sensitivity test]
When the taste of MSG is set to -5 for "I feel strongly" and +5 for "I don't feel" at all, the corresponding five patients have an average value of +4.5, and they almost do not feel the taste of MSG It is.
(2) Evaluation method In treatment, chemotherapy is performed for one week (five days a week), and a three-week rest is performed as one course. After confirming a decrease in food intake and taste in the first course, MSG intervention was performed for one week from the second course. During the intervention period, the intervention group is No. 2 in Example 2. Add 1 sprinkle to each meal (1.8 to 2.7 g / day) for 1 week to cooked rice. Satisfaction with the taste of the meal (10-level evaluation, 0: tasteless to 10: delicious), food consumption, oral The effect on the energy intake was evaluated. In the non-intervention group, the evaluation was performed using 2 weeks during 1 or 2 courses of chemotherapy as a comparison period.

(3) Evaluation results a) Satisfaction with sprinkle When evaluated based on the satisfaction with the taste of the meal (10-level evaluation, 0: tasteless to 10: delicious), the average value of 5 patients was 9.3. It became clear that the satisfaction of the meal became high by using. That is, the satisfaction of sprinkling was shown to be high.
b) Increase in dietary intake The amount of meal before and after the intervention was evaluated, and the change in the amount of meal due to the use of sprinkles was evaluated. As a result, it changed as follows.
(I) Average food intake before intervention (5 people): 250 kcal / day (ii) Average food intake after intervention (5 people): 530 kcal / day By using sprinkling as described above, The intake of cooked rice (including soft rice and whole rice bran) increased, leading to an increase in food intake about twice. Thus, it was suggested that the use of sprinkling is effective in increasing the food intake.
c) Evaluation method of expression level of umami receptor T1R3 Based on the evaluation method of expression level of umami receptor T1R3 in Example 1 (3), changes in expression level of T1R3 gene were evaluated.
When the gene expression level of T1R3 receptor before treatment was 1, as shown in FIG. 13, the expression of T1R3 receptor significantly decreased after 2 weeks of chemotherapy in the non-intervention group. However, in the group using sprinkling, no decrease in the expression of T1R3 receptor was observed.

According to the present invention, it is possible to provide an effective ameliorating agent or therapeutic agent for a taste disorder and / or appetite disorder, particularly a composition for food addition such as sprinkling. For example, it has become possible to provide an effective improving agent or composition for food addition against taste disorders and / or appetite disorders that occur during chemotherapy of cancer-bearing patients. In cancer-bearing patients, taste disorders and accompanying appetite disorders occur as side effects during chemotherapy, but the glutamic acid sodium salt of the present invention is used at a dosage of 1.8 to 2.7 g / adult, for example, in a sprinkled form. By administration, it was possible to improve / avoid taste disorders and accompanying appetite disorders. From this, the improvement agent or food additive composition of the present invention can be expected to be highly useful as a composition capable of ensuring physical fitness and QOL during chemotherapy for cancer-bearing patients.

Claims (22)

1. An agent for improving or treating taste disorders and / or appetite disorders, comprising glutamic acid or a salt thereof as an active ingredient.
2. A pharmaceutical composition or a composition for food addition, comprising the agent for improving or treating taste disorders and / or appetite disorders according to claim 1.
3. The pharmaceutical composition or food additive composition according to claim 2, wherein the taste disorder and / or appetite disorder is a disorder caused by a decrease in umami receptor T1R3.
4. The pharmaceutical composition or food additive composition according to claim 2 or 3, wherein the taste disorder and / or appetite disorder is a disorder that occurs in cancer-bearing patients, diabetics, nephritis patients, and dialysis patients during chemotherapy. .
5. The pharmaceutical composition or food additive composition according to claim 4, wherein the cancer-bearing patient is a head and neck cancer patient.
6. 6. The pharmaceutical composition or food additive composition according to any one of claims 2 to 5, wherein the glutamic acid or a salt thereof is glutamic acid sodium salt (MSG).
7. The pharmaceutical composition or composition for food addition according to claim 6, wherein the MSG is contained so as to have an intake of 1.8 to 2.7 g per day.
8. The pharmaceutical composition or the composition for food addition according to claim 6, wherein the MSG is contained so as to have an intake of 2.0 to 2.7 g per day.
9. An expression promoter for umami taste receptor T1R3 for cancer-bearing patients, umami receptor TIR3 diabetic patients, nephritis patients or dialysis patients with MSG as an active ingredient.
10. The expression promoter for umami receptor T1R3 according to claim 9, wherein the MSG is contained so as to have an intake of 1.8 to 2.7 g per day.
11. The expression promoter for umami receptor T1R3 according to claim 9, wherein the MSG is contained so as to have an intake of 2.0 to 2.7 g per day.
12. The pharmaceutical composition or food additive composition according to any one of claims 2 to 8, wherein the pharmaceutical composition or food additive composition is a food additive composition.
13. The food additive composition according to claim 12, wherein the food additive composition is sprinkled.
14. 14. The food additive composition according to claim 13, wherein the sprinkle is a sprinkle for cooked rice.
15. The food additive composition according to claim 13 or 14, wherein the sprinkle contains bonito, soy sauce, and sesame.
16. The composition for food addition according to claim 14 or 15, wherein the sprinkle contains bonito, seaweed, sesame, sugar, soy sauce, and oil.
17. The sesame content is 9-20% by weight, the oil content is 3-9% by weight, the bonito content is 3-16% by weight, the sugar content is 6-20% by weight, and the soy sauce content is 5-20% by weight. The composition for food addition according to claim 16, wherein the content of chopped laver is 3 to 12% by weight.
18. MSG taste mask food composition characterized by comprising MSG as an active ingredient and bonito, sesame seeds, and soy sauce.
19. The MSG-flavored mask food composition according to claim 18, further comprising sugar, nori and edible oil added thereto.
20. 20. The composition according to claim 18 or 19, characterized in that when the content of MSG is 24 to 30% by weight, it contains 8 to 16% by weight of bonito, 9 to 20% by weight of sesame and 5 to 20% by weight of soy sauce. MSG taste mask food composition according to the description.
21. The MSG content is 1, characterized in that it contains 0.27 to 0.56 parts by weight of bonito, 0.3 to 1.0 parts by weight of sesame and 0.15 to 0.66 parts by weight of soy sauce. The food composition for MSG taste mask according to claim 19.
22. The sugar-containing composition according to claim 21, further comprising 0.33 to 0.66 parts by weight of sugar, 0.27 to 0.56 parts by weight of laver, and 0.11 to 0.45 parts by weight of edible oil. MSG taste mask food composition.

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