Agent for preventing or amelioriting nocturia

Abstract

An agent for preventing or ameliorating nocturia, containing rosmarinic acid or a salt thereof as an active ingredient.

Claims

1. A method of ameliorating or treating nocturia in a subject who wants or is in need of the ameliorating or treating, comprising administering or ingesting rosmarinic acid or a salt thereof to or by the subject.

2. The method according to claim 1, wherein the rosmarinic acid or the salt thereof is in an extract of a plant belonging to the Lamiaceae family containing rosmarinic acid or a salt thereof.

3. The method according to claim 2, wherein the plant is Perilla frutescens Britton var. acuta Kudo.

4. The method according to claim 2, wherein the ratio of rosmarinic acid or a salt thereof in the extract of the plant with respect to the extract solid content in terms of rosmarinic acid content is 0.1 mass % or more and 100 mass % or less.

5. The method according to claim 1, wherein the compound is ingested by the subject.

6. The method according to claim 5, wherein the age of the subject is 20 years old or older.

7. The method according to claim 1, wherein the amount of administration or intake of the rosmarinic acid or the salt thereof in terms of rosmarinic acid content for one (1) adult (body weight 60 kg) per one (1) day is 0.1 mg or more and 40,000 mg or less.

8. The method according to claim 1, wherein the blending amount or the content of the rosmarinic acid or the salt thereof in terms of rosmarinic acid content is 0.01 mass % or more and 100 mass % or less.

9. The method according to claim 1, wherein the blending amount or the content of the rosmarinic acid or the salt thereof in terms of rosmarinic acid content is 0.001 mass % or more and 50 mass % or less.

10. The method according to claim 1, wherein the rosmarinic acid or the salt thereof is ingested or administered once a day or divisionally several times a day or during an arbitrary period and at intervals.

11. The method according to claim 1, wherein the period of ingestion or administration of the rosmarinic acid or the salt thereof is one (1) day or more.

12. The method according to claim 1, wherein the rosmarinic acid or the salt thereof is in the form of a pharmaceutical composition.

13. The method according to claim 1, wherein the rosmarinic acid or the salt thereof is in the form of a food or drink.

14. The method according to claim 13, wherein the food or drink is a food or drink for the sick, a nutritionally functional food, a food for a specified health use, or a functional food.

15. The method according to claim 1, wherein a symptom of the nocturia is that the subject wakes up from sleep to urinate.

16. The method according to claim 15, wherein a symptom of the nocturia is that the subject wakes up from sleep more than once per night to urinate.

17. The method according to claim 1, wherein amelioration or treatment of the nocturia decreases the subject's urinary desire or feeling of abdominal tension during sleep and supports the subject's sound sleep.

18. The method according to claim 1, wherein amelioration or treatment of the nocturia reduces the subject's apprehension about urination during sleep.

19. The according to claim 1, wherein the salt is at least one kind of salt selected from the group consisting of alkali metal salts and alkali earth metal salts.

Description

EXAMPLES

(1) Hereinafter, the present invention will be described more in detail with reference to Examples, but the present invention is not limited thereto.

Test Example 1: How Oral Intake of Rosmarinic Acid Affected Urination Function in Rats

(2) For the test, Spontaneously Hypertensive Rats (SHRs, see American Journal of Physiology, 1998, vol. 275, p. R1279-1286 and Neurourology and Urodynamics, 2005, vol. 24, p. 295-300) (42-week-old, female, obtained from Japan SLC) were used.

(3) SHRs in the treatment group (n=12) ingested, for 8 weeks, a rosmarinic acid-containing feed (composition: 0.5 mass % rosmarinic acid (obtained from Carbosynth, Inc.), 66 mass % starch, 20 mass % casein, 5 mass % corn oil, 4 mass % cellulose, 3.5 mass % mineral, and 1 mass % vitamin). SHRs in the control group (n=12) ingested, for 8 weeks, a rosmarinic acid-free feed (composition: 66.5 mass % starch, 20 mass % casein, 5 mass % corn oil, 4 mass % cellulose, 3.5 mass % mineral, and 1 mass % vitamin). Then, their urination behavior was recorded in metabolic cages. Note that, before the recording in the metabolic cages, 4-day adaptation period was provided, and they were reared individually.

(4) The urination behavior recording (measurement of the urinary frequency and the urine volume) was carried out under conditions with free access to feed and water and under conditions with a 12/12-h light/dark cycle. The urine volume was weighed with an electronic balance while the urine was collected every urination. Note that a past report (see Neurourology and Urodynamics, 2017, vol. 36, p. 1034-1038) was consulted; the start time of a light period corresponding to a rest period of each rat was set to ZT0; the light period was divided into two periods of ZT0-6 and ZT6-12; and the urinary frequency during each period was defined as an indicator for nocturia. In addition, a dark period corresponding to an activity period was divided into two periods of ZT12-18 and ZT18-24; and the urinary frequency during each period was defined as an indicator for daytime frequent urination.

(5) Table 1 shows the urinary frequencies and Table 2 shows the urine volumes after intake of the test feed while data on the rest period and the activity period was tabulated every 6 hours. The results were means±standard errors. To compare the inter-group means, Student-t test was used.

(6) TABLE-US-00001 TABLE 1 <Mean urinary frequency (times/6 h) of rats during rest period and activity period> Rest period Activity period ZT0-6 ZT6-12 ZT12-18 ZT18-24 Control group 2.7 ± 0.1 3.3 ± 0.3 6.2 ± 0.9 5.9 ± 0.7 Treatment group 2.5 ± 0.2 2.4 ± 0.2 6.7 ± 1.1 6.0 ± 0.7 Significant difference N.S. P <0.05 N.S. N.S.

(7) TABLE-US-00002 TABLE 2 <Mean urine volume (mL/6 h) of rats during rest period and activity period> Rest period Activity period ZT0-6 ZT6-12 ZT12-18 ZT18-24 Control group 1.8 ± 0.1 1.4 ± 0.1 2.2 ± 0.3 2.4 ± 0.3 Treatment group 1.7 ± 0.1 1.1 ± 0.1 2.4 ± 0.4 2.4 ± 0.2 Significant difference N.S. N.S. N.S. N.S.

(8) As shown in Table 1, the mean urinary frequency during the rest period (ZT6-12) corresponding to a sleeping period in rats was significantly less in the treatment group than in the control group.

(9) By contrast, as show in Table 2, any significant difference in the mean urine volume during each time zone was undetected.

Test Example 2: How Oral Intake of Rosmarinic Acid-Containing Perilla Extract Affected Urination Function in Humans

(10) (1) Subjects

(11) Fourteen healthy males in the twenties to the fifties.

(12) The average age of the subjects at the start of this study was 38.6±2.8 years old and the average BMI was 21.8±0.6. In addition, the mean urinary frequency during daytime (other than during sleep) at the start of this study was 7.6±0.4 times and the mean urinary frequency during night (during sleep) was 0.24±0.11 times.

(13) (2) Preparation of Investigational Product

(14) A commercially available Perilla frutescens Britton var. acuta Kudo water extract (trade name: “NICHINO AkashisoEkisu” RA15P; manufactured by NICHINOKAGAKU, Co., Ltd.; containing rosmarinic acid in an amount of 15,400 mg/100 g) was filled into No. 2 capsules (trade name: gelatin capsule, manufactured by Qualicaps Co., Ltd.) at a rosmarinic acid content of 25 mg per capsule to prepare capsules encapsulating a rosmarinic acid-containing Perilla extract. Also prepared were rosmarinic acid-free placebo capsules into which instead of the rosmarinic acid-containing Perilla extract, an equivalent amount of starch was filled.

(15) (3) Study Design

(16) Two-group crossover study (washout period: 28 days or longer)

(17) (i) Treatment group (capsules encapsulating the rosmarinic acid-containing Perilla extract; 4 capsules/day; containing 100 mg rosmarinic acid)

(18) (ii) Control group (rosmarinic acid-free placebo capsules; 4 capsules/day)

(19) (4) How to Intake Capsule

(20) The respective capsules (2 capsules) were ingested with 100 mL of mineral water twice daily (within 30 min after breakfast and after dinner) for 28 days.

(21) (5) How to Evaluate Frequent Urination

(22) The situation of urination before and after the intake of capsules was recorded for 3 days, and the urinary frequencies (during daytime and during night) and the daily urine volume, for instance, were recorded.

(23) Note that during this study period, the study was conducted while attention was paid to the following points.

(24) (Important Points)

(25) (i) Beverages other than non-caffeine tee beverage and water were not drunk, and intake of caffeine was prohibited.

(26) (ii) Intake of Perilla-containing food was prohibited.

(27) (iii) Vigorous exercise with sweating was prohibited.

(28) (iv) Go to bed in a normal way (at 2 hours before or after their average bedtime).

(29) (v) Slept under the same sleep environment as usual (lighting, temperature and humidity settings, the opening/closing of window).

(30) (6) Statistical Test

(31) The results obtained for the urinary frequencies and the daily urine volumes were designated as means±standard errors. To compare the inter-group means, a paired t-test was used.

(32) A change in the urinary frequency during daytime or during night between before and after the intake of the investigational product was analyzed. Table 3 shows the results. Table 4 shows the results about a change in the daily urine volume between before and after the intake of the investigational product.

(33) TABLE-US-00003 TABLE 3 <Change in mean urinary frequency per day (times/day)> Inter-group Significant Control group Treatment group difference difference Change between During daytime 0.24 ± 0.21 −0.29 ± 0.29 −0.52 ± 0.35 N.S. before and after intake During night 0.17 ± 0.08 −0.07 ± 0.09 −0.24 ± 0.11 P <0.05

(34) TABLE-US-00004 TABLE 4 <Change in mean urine volume per day (mL/day)> Control Treatment Inter-group Significant group group difference difference Change between 84.0 ± 100.6 36.9 ± 106.0 −47.1 ± 159.1 N.S. before and after intake

(35) As shown in Table 3, when compared to the control group, a significant change in the mean urinary frequency during daytime was undetected in the treatment group (with a decrease of 0.52±0.53 times). By contrast, the mean urinary frequency during night was decreased significantly in the treatment group (with a decrease of 0.24±0.11 times, p<0.05).

(36) Meanwhile, as shown in Table 4, even when compared to the control group, a significant change in the daily mean urine volume was undetected in the treatment group.

(37) Note that there were no detected significant differences, between the control group and the treatment group, in the mean urinary frequency during daytime, the mean urinary frequency during night, and the daily mean urine volume before the intake of the investigational product.

(38) The above results have demonstrated that rosmarinic acid exerts an effect of preventing or ameliorating nocturia and the intake thereof makes it possible to prevent or ameliorate nocturia.

(39) Having described our invention as related to the present embodiments, it is our intention that the invention not be limited by any of the details of the description, unless otherwise specified, but rather be construed broadly within its spirit and scope as set out in the accompanying claims.

(40) This application claims priority on Patent Application No. 2018-101411 filed in Japan on May 28, 2018, which is entirely herein incorporated by reference.