JP2003081829A - Circadian rhythm regulator - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine composition or a food for regulating a circadian rhythm since a method effective as a prevention method or a treatment method in the case of modulation of circadian rhythm such as jet lag, etc., is needed. SOLUTION: This medicine composition or food comprises 5- hydroxytryptophan as an active ingredient as a circadian rhythm regulator.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition or food for regulating circadian rhythm. More specifically, the present invention relates to a pharmaceutical composition or food containing 5-hydroxytryptophan as an active ingredient for controlling the daily rhythm of the living body.

[0002]

2. Description of the Related Art All mammals including humans form rhythms such as sleep and wakefulness of one day by the action of an endogenous pacemaker called a body clock existing in the suprachiasmatic nucleus (SCN) of the hypothalamus. ing. A series of biological phenomena controlled by the body clock is called circadian rhythm. As examples of known circadian rhythms, in addition to sleep / wake rhythms, appetite, libido, systemic blood pressure and body temperature rhythms, endocrine rhythms such as corticosteroids, melatonin and growth hormone secretion, and immune system rhythms are known. (Falc
on J., Prog Neurobiol 1999 Jun; 58 (2): 121-62).

The circadian rhythm is originally determined on the basis of the repetition of daytime sunlight and nighttime darkness associated with the rotation of the earth, and nocturnal animals such as mice at nighttime and humans at daytime. Behavioral animals are systems designed to perform best in the daytime. For these reasons, it is considered most efficient for humans to work in the daytime under normal circumstances. However, in many cases, humans have to behave under an unusual time schedule, and in such a case, the circadian rhythm may reduce the efficiency of the action. For example, a traveler who crosses two or more time zones by aircraft in a short time may cause so-called jet-lag syndrome due to the difference in the daytime / nighttime cycle (time difference) between the departure place and the arrival place. Many. The jet lag disturbs the sleep / wake rhythm and reduces attention and concentration until the circadian rhythm is gradually adjusted to the time of arrival. In addition, the various rhythms described above are disturbed and a temporary physical condition is lost.

Further, the circadian rhythm disorder always occurs in the daily working environment. In shift workers who cycle between day and night shifts and so-called graveyard shifts that work from midnight to 8 am, temporary circadian rhythm disorder causes physical dysfunction, and as a result,
It is often difficult to adjust to shifts to work shifts.
In addition, such work not only poses a management problem from the viewpoint of reduced labor productivity, but may also cause problems regarding the safety of workers themselves (Hildebrandt G., Prog Clin.
Biol Res 1987; 227B: 377-90; Ashkenazi IE, Reinberg
AE, Motohashi Y., Chronobiol Int 1997 Mar; 14 (2): 9
9-113). Some of these workers may not be able to adapt to the new environment after a certain period of time and may cause illness such as psychosomatic disorder. Therefore, how to quickly adapt to environmental changes is very important from the viewpoint of industrial management and individual disease management, and there is a strong industrial demand for the development of drugs and foods that promote adaptation.

Further, it is recognized that congenital or acquired people who are totally blind suffer from free running of their circadian rhythm, which is not due to external environmental regulations. Furthermore, in elderly people, the synthesis of endogenous factors that regulate the body clock (eg, melatonin) is decreased, and there is concern that the maintenance of circadian rhythm may be decreased (Vitiello MV., Clin Corne
rstone 2000; 2 (5): 16-27; Mishima K. et al., Chronob
iol Int 2000 May; 17 (3): 419-32). Many problems associated with pineal gland dysfunction in the elderly are believed to result from it.

Light environment synchronization (light cycle synchronizatio
As a brain system involved in the formation process of n), melatonin (N-acetyl-5-methoxytryptamine), a hormone secreted by the pineal gland, is famous (Borjigin
J, Li X, Snyder SH., AnnuRev Pharmacol Toxicol 19
99; 39: 53-65). It has been suggested that the serotonin system is involved as another endogenous regulatory factor. For example, in rats, a decrease in brain serotonin causes a delay in synchronization (Miguez JM, J Pineal Res 1998,25,106.
-). In particular, there are many findings that the serotonin system in the central amygdala is important for light environment adaptation, stress, and feeding control (Davidson RJ, Science 2000,289,59-; Mark GP.
et al., Neuroscience 1996,74,767-, Maren S, Trend
S Neurosci 1999,22,561-).

It has been known that these two substances are synthesized from the essential amino acid tryptophan through a series of cellular metabolic processes of 5-hydroxytryptophan. Tryptophan, an essential amino acid, can only be taken from outside the body. In addition, ingestion of serotonin itself may cause oral absorption and adverse effects on digestive and circulatory systems (Hasler WL., Dig Dis Sci 1999 Aug; 44 (8 Supp
l): 108S-113S; van Zwieten PA, Blauw GJ, van Brumme
len P., Cardiovasc Drugs Ther 1990 Dec; 4 (6): 1443-
7). The use of melatonin in this area has already been tried, but the clear effect of melatonin is limited and side effects such as drowsiness are observed (ChalletE et al., J.
Biol Rhythms 1997,12,65-; Miguez JM, J Pineal Res
1998,25,106-; Esquifino AL et al., J Pineal Res 1
997,22,52-; Mrosovsky N & SalmonPA, Nature 1987,33
0,372-).

[0008] In addition, in a natural environment, in addition to the circadian rhythm within a relatively short period of time, humans are accustomed to the slower cycles of the moon and season. Despite the common use of air conditioning and artificial lighting today, the periodic depressive syndrome (SAD), which is still prevalent at the turn of the season in high latitude regions, remains a problem. It is Nelson RJ, Drazen DL. (Reprod Nutr Dev
1999 May-Jun; 39 (3): 383-98), Jepson TL, Ernst ME,
Kelly MW. (J Am Pharm Assoc (Wash) 1999 Nov-De
c; 39 (6): 822-9) and others.

Various efforts have been made to adjust the modulation of the circadian rhythm as described above. For example, CZEISLER CHARLES A & KRONAUER RICHARD and MICHIMORI AKIHIRO et al. Disclose that a circadian rhythm can be adjusted by irradiating light of sufficient brightness for a certain period of time (WO09616697, WO0971972).
0). In addition, melatonin (Samel), which is an endogenous hormone that regulates circadian rhythm, is used as a drug therapy.
A., Eur J Med Res 1999 Sep 9; 4 (9): 385-8) or the administration of melatonin derivatives has been attempted (Dubocovich
ML., FASEB J 1988 Sep; 2 (12): 2765-73; Tarzia G, Fa
rmaco 2000 Mar; 55 (3): 184-7). Furthermore, recently, Sh
ibata S et al. (EP0884049A1), Iflo SAS et al.
Searches for novel compounds and methods for adjusting circadian rhythm, such as JP-A-6-18968, Winoker, Andrew (Tokuhyo 11-515014). However,
Melatonin has actions other than circadian rhythm regulation such as hypnotic action and endocrine action (Monti JM, Cardinali DP., Bi
ol Signals Recept 2000, 9: 328-39; Reiter RJ., Ann
Med 1998, 30: 103-8), and the safety of new compounds is still unproven. Thus, despite these efforts, there is still a strong demand from society for a method of effectively adjusting the circadian rhythm.

Several experimental systems for investigating the drug effect on the circulatory action of the circadian rhythm associated with changes in the light environment have been reported so far, including experiments in humans (Deacon S, Aren.
dt J., Physiol Behav 1996 Apr-May; 59 (4-5): 665-73;
Depres-Brummer P et .al., Am J Physiol 1995 May; 26
8 (5 Pt 2): R1111-6). As an application of these systems, the present inventors constructed a new experimental system in which the appetite rhythm and the serotonin concentration rhythm in the brain, particularly the amygdala, were used as indicators.
That is, a rat is allowed to perform learning that combines a bar pushing action and feeding, a microdialysis tube is embedded in the brain of the rat, and the behavior until becoming accustomed to a new light environment is observed with a day-night reversal paradigm. An experimental method to grasp the circadian rhythm adjustment effect of 5-hydroxytryptophan was devised and used in the study.

[0011]

The problem to be solved by the present invention is to provide a pharmaceutical composition or food for regulating circadian rhythm. Targets to which the pharmaceutical composition or food according to the present invention is applied are: 1) Humans at risk of falling into circadian rhythm disorder, namely shift workers and overseas travelers 2) Psychological insomnia (sleep phase delay syndrome; Delayed Phase
Those who have sleep disorders such as Sleep Syndrome) 3) Those who may have desynchronized circadian rhythm due to blindness, etc. 4) Elderly people who easily fall into circadian rhythm disorder 5) Seasonal Affecive Disorder;
Those suffering from SAD) are envisioned, but are not limited to these.

[0012]

Means for Solving the Problems As a result of intensive studies for solving the above problems, the present inventors have found that administration or ingestion of 5-hydroxytryptophan rapidly adjusts the circadian rhythm. Heading out, the present invention has been completed. The present invention includes the following items. (1) A pharmaceutical composition or food for regulating circadian rhythm, which comprises 5-hydroxytryptophan as an active ingredient. (2) The pharmaceutical composition or food according to (1), wherein the adjustment of the circadian rhythm is improvement of jet lag and psychological insomnia. (3) The pharmaceutical composition or food according to (1) or (2), wherein the intake or dose of 5-hydroxytryptophan is 0.01 to 300 mg / kg body weight per day. (4) The pharmaceutical composition or food according to (1) or (2), wherein the intake or dose of 5-hydroxytryptophan is 0.1 to 100 mg / kg body weight per day. (5) The pharmaceutical composition or food according to (1) to (3), wherein the form of ingestion or administration is a granule, a tablet, or an injection.

If necessary, auxiliary components such as vitamins and minerals that are usually contained in foods and pharmaceuticals can be added to the above-mentioned pharmaceutical composition or food.

The mechanism by which 5-hydroxytryptophan is effective is presumed as follows. That is, ingested 5-hydroxytryptophan migrates into the brain, is taken up by serotonin nerve cells, becomes a substrate for metabolic amino acid (aromatic amino acid decarboxylase), is converted into serotonin, and when serotonin is needed. It can be used without exhaustion. Also, 5-hydroxytryptophan taken up in the pineal gland is similarly metabolized and converted into serotonin, and then se
rotoninn N-acetyl-transferase, 5-hydroxyindole-Om
Converted to melatonin by ethyltransferase.
It is considered that the rhythm can be improved early by enhancing the supply of these two substances, serotonin and melatonin, when necessary for rhythm adjustment.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the present invention will be described below. The pharmaceutical composition or food according to the present invention,
If it is expected that the circadian rhythm will become irregular, for example, when overseas travel or nighttime work is expected to cause circadian rhythm modulation, pre-administration or ingestion
Time disorders such as jet lag and sleep phase delay syndrome (chronopath
are expected to be prevented or treated.
Moreover, the pharmaceutical composition or food may be administered or ingested after circadian rhythm modulation such as jet lag has occurred. An effective dose or intake for humans is 0.01 to 3 per day as the amount of 5-hydroxytryptophan.
00 mg / kg body weight, preferably 0.1-100 mg /
A weight of kg / day is suitable.

A pharmaceutical composition or food containing 5-hydroxytryptophan as an active ingredient according to the present invention is
The following forms are possible.

Examples of the form of the pharmaceutical composition include granules, tablets, capsules, syrups, suspensions, injections and the like. In order to manufacture these dosage forms, various substances for manufacturing preparations such as excipients, disintegrants, binders, lubricants, flavors, sweeteners and the like can be used.

The form of the food may be granules, tablets, confectionery, juice, etc., but is not limited thereto.

When the pharmaceutical composition or food produced in these forms is expected to have circadian rhythm modulation, it is expected that the circadian rhythm will be adjusted promptly by pre-administration or ingestion. Of.

[0020]

The present invention will be more specifically illustrated by the following examples, but the present invention is not limited thereto.

Example 1 Male Wistar rats (body weight
250-280 g; Charles River Japan) was used for the experiment. Individual preliminary breeding was performed with free drinking water and feeding in a hanging cage (12-hour light-dark cycle, dark period: 19: 00-7: 00). A guide cannula for a microdialysis probe for brain amines (Acom, Tokyo) was placed in the central part of the left amygdala according to a standard method, and a recovery period was set for one week. Then, move to the operant box, Smriga M, et al., J. Nutrition 130, 20
According to the method of 00, 1641, the training for bar-press learning was carried out for one week so that one tablet of bait (50 mg) could be obtained by pressing the bar once. After training, the rats were divided into a normal diet tablet (Muromachi Kikai, Tokyo) group and a normal diet tablet to which 5-hydroxytryptophan was added (270 μg / tablet) (5-HTRP diet tablet) group, and each tablet was used. After breeding for 3 days, the light-dark cycle was reversed, and changes in the bar-pressing behavior rhythm and changes in brain serotonin concentration rhythm were measured. The amount of serotonin in the brain was detected by a usual HPLC / ECD system (Acom, Tokyo) by inserting a dialysis probe (outer diameter 0.22mm, major axis 2mm; Acom, Tokyo) into a guide cannula inserted in the amygdala.

(Effect of 5-Hydroxytryptophan on Feeding Behavior Rhythm) First, a change in food intake due to bar pushing behavior by light / dark reversal is used as an index of rhythm modulation.
The effect of breeding with 5-HTRP food tablets was examined.
Fig. 1 shows a typical pattern of changes in bar pushing behavior before and after reversal of the light-dark cycle and 7 days after reversal. Before light / dark reversal, the rat was pushing the bar during the dark period (19: 00-7: 00). This means that rats, which are nocturnal animals, mostly eat during the active, dark period.
Immediately after the reversal of light and dark, neither the normal diet tablet group nor the 5-HTRP diet tablet group could adapt to light, and the bar was pressed in the light period. However, the number of days until the adjustment was completed was 6.9 ± 0.6 days (N = 5) in the normal diet group, and 4.5 ± 1.0 days in the 5-HTRP diet tablet group (N = 6).

(Effect of 5-hydroxytryptophan on amygdala serotonin rhythm) Before light / dark reversal (A1, B
1), on the day of reversal (A2, B2), and one week after reversal (A3, B3), normal diet tablets (A1, A2, A3), 5-HTRP diet tablets (B1, B2, B3)
The effect when the animals were bred in Japan was examined (Fig. 2). Also, B1, B
The white circles in B2 and B3 are the results of the normal diet tablet group of A1. The microdialysis probe is inserted at 8:00 am on each measurement day, and the measurement is from 13:00 to 14: 0 of the next day.
I went to 0. Each value shows the average value ± SEM (N = 6). The normal diet tablet group before the light-dark reversal is in the dark period (19: 0
0) had a diurnal rhythm where the serotonin concentration peaked (arrow A1), but the rhythm disappeared (A2) on the day of the light-dark reversal, and one week later, a serotonin peak was observed again during the dark period. (Figure A3 arrow). On the other hand, in 5-HTRP diet tablets, the absolute value of serotonin increased, but the amount of serotonin release before the reversal of light and dark peaked during the dark period and the diurnal rhythm was maintained (B1). Furthermore, the 5-HTRP diet tablet group retained the serotonin release rhythm on the day of light-dark reversal (B2). That is, in the normal diet tablet, the serotonin peak disappeared on the first day and night, but the peak was confirmed one week later. This seems to mean that the reversal of the day and night caused the disappearance of the serotonin rhythm and the rhythm formation from the zero to the new environment. On the other hand, the 5-HTRP food tablet shows that the serotonin peak is maintained even on the first day of the day-night reversal. This means that the 5-HTRP diet tablet does not lose the serotonin rhythm and maintains
It means responding to a new environment by causing a time shift of the rhythm. These facts
It means that pre-addition of 5-hydroxytryptophan to a normal diet accelerates adaptation to a new light-dark rhythm. The problem with jet lag is physical condition deficiency caused by the loss of rhythm itself. Therefore, the rhythm shift has an improving effect.

(Effect of 5-hydroxytryptophan on food intake) FIG. 3 shows changes in food intake on the day before and one week after switching to daytime and nighttime reverse lighting, showing the normal diet tablet breeding group and the 5-HTRP diet tablet breeding group. Compared with. A shows the results of the normal diet tablet group, and B shows the results of the 5-HTRP diet tablet group. In the normal diet group, a decrease in daily food intake was observed after switching to day-night reversal lighting, but in the 5-HTRP diet group, there was no such decrease tendency. That is, the intake of 5-hydroxytryptophan was found to have an effect of preventing or treating anorexia caused by day-night reversal stress.

[0025]

From the above, it is clear that the circadian rhythm regulator provided by the present invention is remarkably effective for regulating circadian rhythm modulation such as jet lag. In addition, since 5-hydroxytryptophan, which is an active ingredient, is highly safe and has almost no side effects, the pharmaceutical composition or food of the present invention is advantageous without any problems in use.

[0026]

[Brief description of drawings]

FIG. 1 is a diagram showing the effect of a 5-HTRP food tablet on eating behavior rhythm.

FIG. 2 shows the effect of 5-HTRP diet tablets on amygdala serotonin rhythm.

FIG. 3 is a graph showing the effect of a 5-HTRP food tablet on food intake.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 25/02 A61P 25/02 25/20 25/20 25/24 25/24 F term (reference) 4B018 LE01 LE02 MD19 ME14 4C076 AA11 AA31 AA36 BB01 BB11 CC01 4C086 AA01 AA02 BC14 MA01 MA04 MA16 MA35 MA41 MA52 MA66 NA14 ZA03 ZA05

Claims (5)

[Claims] 1. A pharmaceutical composition or food containing 5-hydroxytryptophan as an active ingredient for controlling circadian rhythm. 2. The pharmaceutical composition or food according to claim 1, wherein the adjustment of circadian rhythm is improvement of jet lag and psychological insomnia. 3. The intake or dose of 5-hydroxytryptophan is 0.01 to 300 mg / day k
The pharmaceutical composition or food according to claim 1 or 2, which is g. 4. The intake or dose of 5-hydroxytryptophan is 0.1 to 100 mg / kg body weight per day.
The pharmaceutical composition or food according to claim 1 or 2. 5. The pharmaceutical composition or food according to any one of claims 1 to 3, wherein the ingested or administered form is a granule, a tablet, or an injection.