Agent for suppressing increase in impulsivity and use thereof

Abstract

To provide a composition for preventing acceleration of impulsive symptoms.SOLUTION: To provide an agent for preventing acceleration of impulsive symptoms, containing D-allulose.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present specification relates to an agent for suppressing increased impulsivity and use thereof. [Background technology]

[0002] D-allulose is known as a food additive. It has been reported that oral administration of D-allulose to mice increased the expression of oxytocin and / or vasopressin mRNA in the hypothalamus, and that when mice were orally administered with allulose, their anxiety behavior in a novel environment was evaluated 30 minutes after administration, and that their anxiety behavior was alleviated, and that their social behavior was further enhanced 39 minutes after administration (Patent Document 1). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2019 / 146082 Summary of the Invention [Problem to be solved by the invention]

[0004] The alleviation of anxiety behavior and the enhancement of social behavior after administration of D-allulose cannot be correlated with the inhibitory effect on the enhancement of impulsive symptoms.

[0005] The present specification provides a technology for suppressing the exacerbation of impulsive symptoms using D-allulose. [Means for solving the problem]

[0006] In the course of various investigations into D-allulose, the present inventors have found through experiments using mice that continuous intake of a high-sucrose diet leads to significant symptoms of increased impulsivity.Therefore, when mice continuously ingesting a high-sucrose diet were administered D-allulose and the increase in impulsivity was evaluated, it was found that the increase in impulsivity was not observed.Based on these findings, the present specification provides an agent for preventing D-allulose-induced increased impulsivity and the use of this agent.

[0007] [1] An agent containing D-allulose for preventing the exacerbation of impulsive symptoms. [2] The agent described in [1], which prevents the exacerbation of impulsive symptoms associated with PET bottle syndrome. [3] A pharmaceutical composition containing D-allulose for preventing the exacerbation of impulsive symptoms. [4] A food composition containing D-allulose for preventing the exacerbation of impulsive symptoms. [5] A dietary supplement composition containing D-allulose for preventing the exacerbation of impulsive symptoms. [6] A food additive containing D-allulose for preventing the exacerbation of impulsive symptoms. [Brief explanation of the drawings]

[0008] [Figure 1] FIG. 1 shows the results of a cliff avoidance test in mice, showing the number of mice that jumped off the platform. [Figure 2] FIG. 1 shows the results of a cliff avoidance test in mice, showing the time it takes to jump off the platform (jump latency). DETAILED DESCRIPTION OF THE INVENTION

[0009] The technology disclosed in this specification relates to the prevention of exacerbation of impulsive symptoms by D-allulose. As mentioned above, D-allulose has been reported to alleviate anxiety behavior and enhance social behavior after administration of D-allulose, as disclosed in prior art documents. However, these anxiety-relieving effects and social behavior-enhancing effects cannot be associated with the effect of preventing exacerbation of impulsive symptoms. Furthermore, the anxiety-relieving effects and social behavior-enhancing effects disclosed in prior art documents are effects that occur immediately after administration of D-allulose (see Example 3: Behavioral Test in the prior art documents), whereas the inhibitory effect on exacerbation of impulsive symptoms disclosed in this specification was first discovered by continuous ingestion of D-allulose.

[0010] As used herein, "impulsive symptoms" refer to a pathological predisposition to hasty and unplanned reactions to internal or external stimuli, whether directed at the self or non-self, even if the reactions lead to negative consequences. Furthermore, "impulsive symptoms" refer to symptoms resulting in impulsive behavior. Specific examples of impulsive behavior include physical aggression, wandering, restlessness, agitation, irrational or deviant behavior, wandering, screaming, crying, verbal abuse, loss of motivation, repetitive questioning, stalking, suicide attempts or suicide, self-injury, threats, theft, overeating, intimidation, short-circuit reactions, panic reactions, damage to property, and putting on or taking off inappropriate clothing. Among these, impulsive symptoms may be agitation.

[0011] "Accelerated impulsive symptoms" refers to the progression of impulsive symptoms to a high degree. Accelerated impulsive symptoms can be evaluated, for example, in a cliff avoidance test using experimental animals such as mice, by measuring the number of individuals that jump (jump) from a prepared platform within a certain period of time or the time it takes to jump (jump latency). "Suppression of accelerated impulsive symptoms" can be evaluated, for example, in a cliff avoidance test, by measuring whether or not the experimental animals are inhibited from jumping from the platform and / or whether or not the jump latency is prolonged. The cliff avoidance test using experimental animals will be described in detail in the Examples.

[0012] Furthermore, as used herein, "preventing the exacerbation of impulsive symptoms" means, for example, that in the cliff avoidance test described above, when a single dose is administered to an individual at a predetermined dosage, the exacerbation of impulsive symptoms cannot be suppressed, for example, within 6 hours, 12 hours, 18 hours, or 24 hours after administration, but when the compound is administered continuously at a predetermined dosage for a certain period of time, for example, for at least 2 weeks, at least 3 weeks, or for example, at least 4 weeks, or for example, at least 5 weeks, the exacerbation of impulsive symptoms can be suppressed.

[0013] [Agent for preventing exacerbation of impulsive symptoms] D-allulose is contained in an agent for preventing the exacerbation of impulsive symptoms (hereinafter simply referred to as a preventive agent) disclosed in this specification. D-allulose is a type of monosaccharide classified as a hexose and a ketose. The origin and production method of D-allulose are not particularly limited, and various types of naturally-derived and chemically synthesized D-allulose can be used. D-allulose can also be used regardless of its degree of purification. For example, the D-allulose in the preventive agent may be a plant such as zeinosa that contains D-allulose, or a part thereof, or an extract thereof.

[0014] [Pharmaceutical composition for preventing the exacerbation of impulsive symptoms] The pharmaceutical composition disclosed herein contains D-allulose. The formulation form of the pharmaceutical composition is not particularly limited, and can be any known formulation such as tablets, capsules, granules, granules, fine granules, liquids, gels, etc. In formulating the pharmaceutical composition, a person skilled in the art can, for example, mix an appropriate amount of a pharmaceutically acceptable carrier, and, if necessary, add various additives such as stabilizers, excipients, binders, and disintegrants to produce the desired formulation.

[0015] The administration route is not particularly limited, and may be oral administration, intravenous administration by injection or the like, subcutaneous administration by subcutaneous injection or intramuscular injection, transdermal or transmucosal administration by patches or the like, or parenteral administration by various sprays such as intranasal administration. Oral administration may be effective as the administration route of the pharmaceutical composition.

[0016] The pharmaceutical composition may contain other ingredients as needed, for example, other known ingredients that suppress the exacerbation of impulsive symptoms.

[0017] [Nutritional supplement composition] The dietary supplement composition disclosed herein is a so-called supplement and contains D-allulose. The dietary supplement composition can be in the form of various oral administration formulations, among the formulation forms that can be used for the pharmaceutical compositions described above.

[0018] [Food composition] The food composition disclosed herein is a so-called functional food, and contains D-allulose. The food composition can be in various forms that can be orally ingested, such as food and beverages. Examples include, but are not limited to, confectioneries such as pudding, jelly, chocolate, bread, cake, and cookies; beverages such as functional drinks, lactic acid drinks, fruit juice drinks, and carbonated drinks; luxury items such as tea and coffee; various dairy products; and seasonings.

[0019] D-allulose has a refreshing sweetness that is 70% of that of fructose and is a zero-energy sugar. Therefore, food compositions can be in the form of a sweetener. Furthermore, food compositions can be in the form of foods containing D-allulose as a sweetener or as a part of the sweetener. In particular, food compositions can be in the form of beverages containing D-allulose. By including D-allulose as a sweetener or as a part of the sweetener in beverages that contain sucrose or the like and may cause PET bottle syndrome, it may be possible to prevent the exacerbation of impulsive symptoms associated with PET bottle syndrome.

[0020] D-allulose can also be provided in the form of liquid diets, elemental nutritional foods, nutritional drinks, various tube-fed nutritional foods, and the like.

[0021] [Food additives] D-allulose itself can be used in the above-mentioned dietary supplement composition and the above-mentioned food composition as an additive intended for food to prevent increased impulsivity.

[0022] [D-Allulose Dosage and Administration] The dosage and administration of D-allulose is not particularly limited, as long as the administration (in the case of dietary supplement compositions and food compositions, this refers to ingestion; the same applies hereinafter) of pharmaceutical compositions, dietary supplement compositions, and food compositions containing D-allulose provides a preventive effect against the exacerbation of impulsive symptoms. For example, in mice and rats, the daily dose is, for example, 1 g to 10 g, 2 g to 9 g, 3 g to 8 g, 4 g to 7 g, or 5 g to 6 g of D-allulose per kg of body weight. For humans, a lower dose than that used in mice and rats can be used, for example, about one-tenth the amount. For humans, the daily dose of D-allulose per kg of body weight is preferably 0.1 g to 0.8 g, more preferably 0.2 g to 0.7 g, even more preferably 0.3 g to 0.6 g, and even more preferably 0.4 g to 0.6 g. For example, the daily dose of D-allulose per adult (60 kg) may be, for example, 6 g to 48 g (0.1 g / kg to 0.8 g / kg), 12 g to 42 g (0.2 g / kg to 0.7 g / kg), 18 g to 36 g (0.3 g / kg to 0.6 g / kg), or 24 g to 36 g (0.4 g / kg to 0.6 g / kg). The dosage for humans is determined taking into consideration the subject's health condition, weight, age, and other conditions. The timing of administration is not particularly limited, and can be, for example, before meals, during meals, after meals, or between meals. For example, administration before meals may be preferable, and administration within one hour before meals is more preferable, and administration within 15 to 30 minutes before meals is even more preferable.

[0023] To prevent the exacerbation of impulsive symptoms, the drug is administered continuously at the above-mentioned dosage and administration for, for example, 2 weeks or more, 3 weeks or more, 4 weeks or more, 5 weeks or more, or 6 weeks or more. By administering continuously for a certain period of time, the exacerbation of impulsive symptoms can be suppressed. [Example]

[0024] Examples will be described below as specific examples to more specifically explain the disclosure of this specification. The following examples are intended to illustrate the disclosure of this specification, but are not intended to limit the scope thereof. [Example]

[0025] In this example, 5-week-old male C57BL / 6J mice purchased from Japan SLC Co., Ltd. were brought into a breeding room (room temperature 23°C, humidity 55%) at an animal testing facility and began breeding. After a one-week acclimation period, all groups were fed AIN-93G feed (see Table 1). At 6 weeks of age, the mice were divided into four groups (8 mice per group) and began breeding on the diets shown in Table 1. Five weeks later, a cliff avoidance test was conducted on 11-week-old mice.

[0026] The composition of the feeds is shown in Table 1. Each feed was prepared as follows, using AIN-93G feed as the basal diet. Example (HS + allulose): A high-sucrose diet containing D-allulose, with the sucrose content of 61% by mass and the D-allulose content of 3% by mass relative to the total mass of the feed, based on the AIN-93G feed. Comparative Example 1 (HS): A high-sucrose diet, with the sucrose content of the diet being 61% by mass relative to the total mass of the diet, based on the AIN-93G diet. Comparative Example 2 (allulose): A D-allulose-containing diet, in which the D-allulose content relative to the total weight of the diet was 3% by mass based on the AIN-93G diet. Control (AIN-93G): AIN-93G feed

[0027] [Table 1]

[0028] The average feed intake (g / day) of each group in the Example, Comparative Examples 1 and 2, and the Control Example was 4.5 g / day. The daily intake of D-allulose in the Example was 135 mg. The body weight of each mouse was 20 to 30 g.

[0029] [Cliff Avoidance Test] In the cliff avoidance test, a platform 11 cm in diameter and 14 cm high was prepared, and mice were placed on the platform at the top of the platform. The number of mice that jumped off the platform and the time it took to jump off (jump latency) were measured. The maximum measurement time was 90 seconds. The results are shown in Figures 1 and 2.

[0030] As shown in Figures 1 and 2, in Example 1, which was a D-allulose-containing high-sucrose diet, not a single mouse jumped off. Furthermore, in the control example of the basal diet and Comparative Example 2, which was a D-allulose-containing diet, not a single mouse jumped off during 90 seconds of observation. In contrast, in Comparative Example 1, which was a high-sucrose diet, 80% of the mice jumped off.

[0031] The cliff avoidance test is used to detect impulsive symptoms (Prostaglandin E receptor EP1 controls impulsive behavior under stress, PNAS, November 1, 2005, vol. 102, no. 44 16066-16071), and is particularly used as a test method for developing treatments for attention-deficit hyperactivity disorder (AD / HD) (Psychopharmacology, 2017, 234: 1853-1869).

[0032] As shown in the control group, healthy mice recognize the situation of being placed on the platform and feel the desire to escape (jump off), but they do not jump off and remain on the device. In other words, the exacerbation of impulsive symptoms was suppressed. However, the high sucrose diet group of Comparative Example 1 was unable to suppress the exacerbation of the impulsive symptoms of wanting to jump off, and jumped off within a short period of time.

[0033] In the D-allulose-containing high sucrose diet group (Example), mice were able to stay on the apparatus without jumping, just like healthy mice. In other words, impulsive symptoms were increased but suppressed.

[0034] These findings suggest that continued intake of D-allulose can suppress the exacerbation of impulsive symptoms. In other words, continuous intake of D-allulose can prevent the exacerbation of impulsive symptoms.

[0035] Increased impulsive symptoms are one of the symptoms (inattention, increased impulsivity, hyperactivity) of AD / HD, a psychiatric disorder. The inventors have confirmed that mice consuming a high-sucrose diet did not exhibit inattention or hyperactivity. Therefore, the mice in Comparative Example 1 are not AD / HD model mice, but are thought to exhibit irritability and shortness of breath (increased impulsive symptoms) associated with soft drink ketosis (PET bottle syndrome) (increased impulsive symptoms have also been reported in studies using rats in other countries). Therefore, continuous administration of D-allulose is thought to be effective in preventing increased impulsive symptoms and in preventing increased impulsive symptoms associated with PET bottle syndrome.

[0036] In addition, existing AD / HD treatment drugs (methylphenidate and atomoxetine) have shown an improving effect in AD / HD model mice with only a single administration (see Psychopharmacology, 2017), which differs from the preventive effect of D-allulose. Furthermore, the inventors have confirmed that a single administration of D-allulose does not suppress the exacerbation of impulsive symptoms in AD / HD model mice.

Claims

1. An agent for preventing the exacerbation of impulsive symptoms, comprising D-allulose.

2. The agent according to claim 1, which prevents the exacerbation of impulsive symptoms associated with PET bottle syndrome.

3. A pharmaceutical composition for preventing the exacerbation of impulsive symptoms, comprising D-allulose.

4. A food composition containing D-allulose for preventing the exacerbation of impulsive symptoms.

5. A dietary supplement composition containing D-allulose for preventing the exacerbation of impulsive symptoms.

6. A food additive containing D-allulose for preventing the exacerbation of impulsive symptoms.

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