JP2014074004A - Psychiatric symptom-improving agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a therapeutic agent for sleep disorder or depressive symptom, involving almost no adverse effect.SOLUTION: A therapeutic agent for sleep disorder or depressive symptom in a growth hormone secretion failure disease, particularly for sleep disorder or depressive symptom in a child growth hormone secretion failure disease contains growth hormone as an active ingredient.

Description

  The present invention relates to an agent for improving psychiatric symptoms, and more particularly to a therapeutic agent for sleep disorders or a therapeutic agent for depressive symptoms, particularly a therapeutic agent for sleep disorders in children, comprising human growth hormone as an active ingredient.

  Human growth hormone (hGH) is a peptide hormone composed of 191 amino acids. It is secreted mainly from the pituitary gland and promotes body growth and increases IGF-1 through receptors on the cell surface. Physiological activities such as action, body composition and lipid metabolism improvement are exhibited. hGH is produced for pharmaceutical use as recombinant human growth hormone (rhGH) using E. coli transformed with a gene encoding hGH, and various pharmaceutical preparations containing rhGH as an active ingredient, such as glow Preparations such as JECT (Nippon Chemical Research Co., Ltd.) have growth hormone deficiency short stature, Turner syndrome short stature, adult growth hormone secretory deficiency, SGA short stature, cartilage dystrophy short stature , Short stature in chronic renal failure, short stature in Praderwilly syndrome, and increased lean body mass in HIV infection are commercially available.

  Administration of human growth hormone has been reported to be effective for many diseases in addition to the above indications. For example, improvement of pulmonary function in lung diseases such as pulmonary dysfunction and pneumonia (Patent Document 1), improvement of liver function in cirrhosis accompanied by a decrease in blood concentration of IGF-1 (Patent Document 2), heart in congestive heart failure Improvement of function (patent document 3), improvement of renal function in undialyzed renal failure (patent document 4), improvement of liver function in acute liver failure due to fulminant hepatitis, acute alcoholic hepatitis, etc. (patent document 5), abdomen / Decrease in fat in visceral obesity (Patent Document 6), decrease in immune function and prevention of infection in hypothermia therapy (Patent Document 7), decrease in plasma cholesterol in familial hypercholesterolemia (Patent Document 8), Hematopoiesis after transplantation of hematopoietic stem cells and recovery of immune function (Patent Document 9), improvement of sexual dysfunction (Patent Document 10), improvement of pulmonary dysfunction (Patent Document 11), etc. It has been reported to have. These effects are mainly due to growth hormone anabolism.

  In addition, growth hormone improves the awareness of hypoglycemia in diabetes (Patent Document 12), improves nutritional status and psychiatric symptoms in anorexia nervosa (Patent Document 13), suppresses food intake (Patent Document 13) It has been reported that it has the effect of literature 14). That is, growth hormone is also effective in improving or adjusting human mental symptoms.

  The effect of growth hormone on the improvement or adjustment of human psychiatric symptoms is to promote sleep. When the concentration of growth hormone in blood during human sleep is measured, the concentration increases in synchrony with the deep sleep period, and there is a positive correlation between growth hormone secretion and sleep depth. In particular, growth hormone secretion peaks during non-REM sleep after falling asleep. In patients with narcolepsy characterized by repeated dozing during the day, growth hormone secretion during non-REM sleep after falling asleep is markedly reduced. In infants and children, failure to secure non-REM sleep after falling asleep results in a decrease in growth hormone secretion, resulting in delayed growth. Such a phenomenon is serious for children with obstructive sleep apnea syndrome, which appears at a frequency of 1 to 3%. This is because a child suffering from such a disease cannot secure sufficient non-REM sleep after falling asleep. Conversely, lack of growth hormone secretion may cause sleep disturbance.

  As means for improving such sleep disorders, there are documents suggesting that administration of a compound having growth hormone secretion promoting activity is effective (Patent Documents 15 to 17). However, these documents do not disclose data specifically showing the effects of these compounds. Moreover, since there is no safety data in these documents, it cannot be denied that these compounds may cause serious side effects when administered to the human body.

  On the other hand, in patients with growth hormone deficiency treated with growth hormone replacement therapy, it is suggested that growth hormone replacement therapy may reduce the percentage of deep sleep (Non-patent Document 1) There are many unclear points regarding the relationship between administration and improvement of sleep disorders, as well as improvement of psychiatric symptoms.

  In addition, there is a document that reported that depression symptoms were improved by growth hormone replacement therapy in patients with growth hormone deficiency short stature with depressive symptoms (Non-patent Document 2). This document shows that sleep disturbance has also been improved.

  For the treatment of depressive symptoms, selective serotonin reuptake inhibitors (SSRI), serotonin / noradrenaline reuptake inhibitors (SNRI), tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants Antidepressants such as monoamine oxidase inhibitors, noradrenergic / specific serotonergic antidepressants, noradrenaline / dopamine reuptake inhibitors are prescribed. Although these antidepressants are effective in alleviating anxiety and reduced motivation, they cause side effects such as malignant syndrome, serotonin syndrome, nausea, dysuria, and increased blood pressure. In addition, in the case of depression with sleep disorders such as insomnia, a sleep inducer is used in combination, but taking the sleep inducer has side effects such as transient amnesia.

JP-T-4-503359 JP 6-510292 A JP-T 9-512009 Japanese Patent Laid-Open No. 9-95455 JP-A-9-136840 Special table 2000-510451 gazette WO1998 / 016244 Special Table 2002-527486 JP 2000-178203 A Special table 2003-502379 WO1990 / 009189 JP-A-6-40941 WO1998 / 001152 Special table 2003-534237 gazette Japanese National Patent Publication No. 11-506471 JP 2004-043476 A Special table 2010-523466

Shintaro Yamashita et al., Brain and Development. 41. S308 (2009) Mahajan T. et al. et al. , Eur J Endocrinol. 151.345-32 (2004)

  In view of the above background, an object of the present invention is to provide a psychiatric symptom-improving agent having growth hormone as an active ingredient with few side effects, particularly a sleep disorder therapeutic agent and a depressive symptom therapeutic agent. To do.

In a study aimed at the above purpose, the present inventors have shown that administration of growth hormone improves depressive symptoms in children with growth hormone deficiency short stature (GHD) who have depressive symptoms, In addition, the present inventors have found that sleep disorders are improved in GHD patients with children who have sleep disorders. That is, the present invention provides the following.
(1) A therapeutic agent for sleep disorder or depressive symptom in a growth hormone secretory disease, comprising growth hormone as an active ingredient.
(2) A therapeutic agent for sleep disorders in a growth hormone secretory disorder, comprising growth hormone as an active ingredient.
(3) A therapeutic agent for depressive symptoms in a growth hormone secretory disease, comprising growth hormone as an active ingredient.
(4) The therapeutic agent according to the above (1) to (3), which is accompanied by an increase in cerebral blood flow.
(5) The therapeutic agent according to (1) to (4) above, wherein the growth hormone secretory disorder is growth hormone secretory short stature.
(6) Growth hormone is administered by intramuscular injection of 0.175 mg / kg body weight per week in 2-4 divided doses or administered subcutaneously in 6-7 divided doses. The therapeutic agent of (5).
(7) The therapeutic agent according to (6) above, wherein the growth hormone is administered within 1 hour before going to bed.
(8) The therapeutic agent according to (1) to (4) above, wherein the growth hormone secretory disorder is adult growth hormone secretory disorder.
(9) The therapeutic agent according to the above (8), wherein the growth hormone is administered by subcutaneously injecting 0.021 to 0.084 mg per kg body weight in 6 to 7 times per week.
(10) The therapeutic agent according to (9) above, wherein the growth hormone is administered within 1 hour before going to bed.

  According to the present invention, sleep disorders or depressive symptoms can be improved without side effects.

The figure which shows the change of (delta) wave of a patient (patient 1-patient 5) before and after growth hormone treatment start. The vertical axis represents the intensity of σ wave (μV), and the horizontal axis represents the time after going to bed. The left column (column A) shows the δ wave before the start of growth hormone treatment, and the right column (column B) shows the δ wave after the start of growth hormone treatment.

  In the present invention, the term “growth hormone” refers to human growth hormone. As long as it has growth hormone activity, the amino acid sequence includes one or more amino acids in addition to the natural type. Includes those that are lost, replaced, or inserted. Such growth hormone can be produced in large quantities as recombinant growth hormone using E. coli transformed with the human growth hormone gene. Growth hormone preparations marketed as therapeutic agents for growth hormone secretion deficiency short stature (for example, GROWJECT (registered trademark): Nippon Chemical Research Co., Ltd.) contain recombinant growth hormone as an active ingredient, It can be suitably used in the present invention.

  There is no particular limitation on the dosage form of the growth hormone preparation used in the present invention, but usually a freeze-dried product or a liquid product is used. The lyophilized product is used after being dissolved in a lysis solution at the time of use, and such a lysis solution is supplied as an attached lysis solution with the lyophilized product. The lyophilized product after dissolution is preferably a solution containing a stabilizer, a nonionic surfactant, an isotonic agent and a buffer. The solution likewise preferably includes a stabilizer, a nonionic surfactant, an isotonic agent and a buffer. The stabilizer used at this time is preferably an amino acid such as albumin, urea, arginine, histidine, or glycine, and more preferably an amino acid such as arginine, histidine, or glycine. The surfactant is preferably polysorbate, poloxamer or a combination thereof. Here, polysorbate 20 and polysorbate 80 are particularly suitable as the polysorbate, and poloxamer 188 (polyoxyethylene (160) polyoxypropylene (30) glycol) is particularly suitable as the poloxamer. The isotonic agent is not particularly limited as long as it is pharmaceutically acceptable, but sodium chloride, mannitol, and glycerin can be preferably used. The buffer is not particularly limited as long as it is pharmaceutically acceptable, but a phosphate buffer is preferable, and a sodium phosphate buffer is particularly preferable.

  The growth hormone preparation used in the present invention generally contains growth hormone for several days to one month in one vial, and it is common to use only the necessary amount for each administration. In general, growth hormone preparations of this type are provided with a piston wall that can be pushed with a piston rod at one end and a rubber wall that can be fitted with a double-ended needle at the other end for ease of use. The vial is filled and supplied to the injection apparatus as it is or with a dedicated holder. The injection device to which the vial is attached has a dial for adjusting the dose and a piston rod for pushing the piston in the vial forward so that a desired amount can be administered. After mounting the vial on the injection device, attach a double-ended needle to one side of the vial, adjust the dosage with a dial, and then push the piston in the vial forward with the piston rod, so that the growth hormone preparation filled in the vial The desired amount of solution containing is released from the double-ended needle. Examples of such growth hormone preparations and mechanism injection devices are disclosed in JP-A-11-267205, JP-A-2007-68630, JP-A-2007-143957, and the like. It can be used suitably.

  As described above, a growth hormone preparation containing growth hormones for several days to one month retains the drug solution in the vial after use, and therefore a preservative is added to prevent the growth of various bacteria. The preservative used at this time is preferably phenol, benzyl alcohol, m-cresol, or benzalkonium chloride.

  In the present invention, the term growth hormone secretion deficiency disease refers to a disease accompanied by a state in which the secretion of growth hormone is significantly lower than that of healthy individuals. Growth hormone secretion deficiency short stature and adult growth hormone secretion Insufficiency is typical, but this includes narcolepsy, closed sleep apnea syndrome, etc., in which the amount of growth hormone secretion decreases during sleep.

  In the present invention, when the growth hormone secretory disorder is pediatric growth hormone secretory short stature, the growth hormone preparation is intramuscularly divided into 2 to 4 doses of 0.175 mg per kg of body weight per week. It is administered by injecting into 5 to 7 times, or subcutaneously divided into 6 to 7 times. In the present invention, when the growth hormone secretion deficiency disease is adult growth hormone secretion deficiency, the growth hormone preparation is preferably divided into 6 to 7 doses per kg of body weight per week, preferably 0.021 to 0.084 mg. It is administered by injecting subcutaneously, and more preferably 0.021 mg is administered by injecting subcutaneously into 6 to 7 divided doses.

  In the present invention, the term psychiatric symptoms refers to a state of feeling depressed, irritated, strongly stressed, feeling hallucinations, or performing a behavior or thinking that is not considered normal when viewed by others. Psychiatric symptoms are a term that can be used as a broad concept that includes mental disorders, mental disorders, and the like. Depressive symptoms and sleep disorders are included in psychiatric symptoms.

  In the present invention, the term “depressive symptoms” refers to various symptoms observed in patients with depression and depression. Here, depression and depressive state are concepts including endogenous depression, reactive depression, degenerative depression, neurological depression, and brain matrix mental disorder depression. Although depression and depression cannot be clearly distinguished, depression is generally a condition in which sadness or despair has progressed to the point where the individual's social functions and / or activities of daily living are hindered. Depressive state means a depressive state that is sustained to a certain extent, mood disturbances characterized by sadness and / or anxiety, congestion in thought processes (difficulty of concentration and repeated thoughts) , A mental state with psychomotor suppression or irritability, psychosomatic symptoms, depressive delusions (psychiatry, poverty delusion, or guilt delusion). Whether or not you are depressed can be largely determined by the Barson Depression Trend Self-Assessment Scale (DSRSC) test. Depressive symptoms may be associated with sleep disturbances. In such a case, the sleep disorder becomes a treatment target with the therapeutic agent of the present invention as one symptom included in the depressive symptom.

  In the present invention, the sleep disorder is a general term for sleep disorders that interfere with all activities from the maintenance of life to social life, and includes insomnia, narcolepsy, nightmares, night wonders, sleepwalking, etc. It is a concept. Patients with sleep disorders can be roughly diagnosed by measuring their brain waves, since their brain waves during sleep are different from those of healthy people. What is the electroencephalogram measured here? Preferably, it is a δ wave associated with slow wave sleep. Since the δ wave is the brain wave that is detected most frequently during deep sleep, the depth of sleep can be determined by measuring the δ wave. Sleep disorders may be accompanied by depressive symptoms. In such cases, depressive symptoms may improve at the same time during the treatment of sleep disorders.

  In the present invention, the growth hormone preparation is preferably administered immediately before going to bed. By administering it immediately before going to bed, the growth hormone blood level immediately after going to bed can be increased, and the growth hormone secretion pattern of a healthy person whose growth hormone blood level becomes the maximum value immediately after going to bed can be simulated. it can.

  Hereinafter, the present invention will be described in more detail with reference to examples. However, it is not intended that the present invention be limited to the examples.

[Administration of human growth hormone for growth hormone deficiency short stature]
Whether 38-year-old or older children (27 boys, 11 girls) will be administered a commercially available hGH preparation by intramuscular injection of 0.175 mg per kg of body weight divided into 2 to 4 doses per week Or, it was administered by subcutaneous injection divided into 6 to 7 times. Table 1 shows the sex, weight, height, age at the start of treatment, and duration of hGH administration for the children who became the subjects. This study was conducted with the approval of the Juntendo University School of Medicine Ethics Review Board.

[Barson's Depression Trend Self-Filling Scale (DSRSC) Test]
A DSRSC test was performed before and after treatment on children with growth hormone deficiency short stature treated with the hGH preparation. DSRSC asks the 18 questions shown in Table 2, and answers these questions with three choices of “always seems to be”, “sometimes seems to be so” and “is not so”, items 1, 2, For 4,7,8,9,11,12,13 and 16, score "always so" with 0 points, "sometimes so" with 1 score, "not so" with 2 points, item 3, For 5, 6, 10, 14, 15, 17, and 18, score "always so" is 2 points, "sometimes seems so" is 1 point, "is not so" is 0 points, the total score is 16 It is determined that the person is in a depressed state (trend) above the point.

When the DSRSC test scores were compared before and after administration of human growth hormone, the score was 9.8 ± 5.8 before administration, but 7.0 ± 2.8 after administration, which is human growth hormone. It decreased significantly by administration.
Looking at individual cases, a girl with an age of 8 years and 3 months at the start of growth hormone administration took about an hour to go to bed before administration of growth hormone, but only a few minutes after administration of growth hormone. Interview results such as being able to go to bed, or a girl who was 7 years and 11 months old at the start of growth hormone administration, became deeply asleep due to the administration of growth hormone, and the time until bedtime was shortened. It was. DSRSC test and interview results show that growth hormone administration has the effect of improving depressive symptoms as well as sleep disorders. This suggests that the improvement of depressive symptoms caused by growth hormone administration is due to the improvement of sleep disorders.

[Measurement of cerebral blood flow]
Next, a [N, N'-ethylenedi-L-cysteinate (3-)] oxotechnetium ( ^99m Tc) diethyl ester injection was intravenously administered to a 6-year-old boy with growth hormone deficiency short stature. The change in cerebral blood flow before and after administration of growth hormone was measured by observing the cerebral blood flow scintigram using cerebral blood flow scintigraphy (gamma camera device Millennium MG, manufactured by GE). As a result, it was found that administration of growth hormone significantly increased cerebral blood flow (Table 3).

  Especially in the hippocampus, which has been associated with the onset of depression, an increase in blood flow of 30% or more was observed. This result suggests that the improvement of depressive symptoms and sleep disorders observed by growth hormone administration is due to the improvement of cerebral blood flow by growth hormone administration.

[Measurement of delta wave during sleep]
Next, we investigated the effect of growth hormone treatment on the pattern of δ waves during sleep in children with growth hormone deficiency short stature. When the δ wave pattern was measured before the start of growth hormone treatment and 6 months after the start of growth hormone treatment, it was found that the δ wave increased significantly with the administration of growth hormone (FIG. 1). An increase in δ waves indicates deep sleep. Thus, this result suggests that the growth of sleep hormone improves the quality of sleep.

[Side effects]
No side effects were observed in children receiving growth hormone. Selective serotonin reuptake inhibitors (SSRI), serotonin and noradrenaline reuptake inhibitors (SNRI), tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants Monoamine oxidase inhibitors, noradrenergic / specific serotonergic antidepressants, noradrenaline / dopamine reuptake inhibitors, etc. cause side effects such as malignant syndrome, serotonin syndrome, nausea, dysuria, and increased blood pressure. Moreover, sleep-improving agents used to improve sleep disorders, such as insomnia, cause side effects such as transient amnesia. Therefore, it can be said that growth hormone is remarkably superior in that no side effects are observed as a therapeutic agent for depressive symptoms or a sleep disorder improving agent.

  According to the present invention, it is possible to provide an agent for improving sleep disorder or a therapeutic agent for depressive symptoms, with almost no side effects.

Claims (10)

  A therapeutic agent for sleep disorder or depressive symptom in growth hormone deficiency disease comprising growth hormone as an active ingredient.   A therapeutic agent for sleep disorders in growth hormone deficiency diseases, comprising growth hormone as an active ingredient.   A therapeutic agent for depressive symptoms in a growth hormone secretory disorder, comprising growth hormone as an active ingredient.   The therapeutic agent of Claims 1-3 accompanying the increase in cerebral blood flow.   The therapeutic agent of Claims 1-4 whose growth hormone secretion deficiency disease is growth hormone deficiency short stature.   Growth hormone is administered by intramuscular injection of 0.175 mg / kg body weight per week in 2-4 divided doses or administered subcutaneously in 6-7 divided doses. The therapeutic agent according to claim 5.   The therapeutic agent according to claim 6, wherein the growth hormone is administered within 1 hour before going to bed.   The therapeutic agent of Claims 1-4 whose growth hormone secretion deficiency disease is adult growth hormone secretion deficiency.   The therapeutic agent according to claim 8, wherein the growth hormone is administered by subcutaneously injecting 0.021 to 0.084 mg per kg body weight in 6 to 7 times per week.   The therapeutic agent according to claim 9, wherein the growth hormone is administered within 1 hour before going to bed.

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