WO2023102970A1

WO2023102970A1 - Use of parathyroid hormone in preparation of drug or health care product for treating male depression

Info

Publication number: WO2023102970A1
Application number: PCT/CN2021/137974
Authority: WO
Inventors: 张路; 刘念; 杨帆
Original assignee: 深圳先进技术研究院
Priority date: 2021-12-10
Filing date: 2021-12-14
Publication date: 2023-06-15
Also published as: CN113967249A

Abstract

Provided is the use of a parathyroid hormone in the preparation of a drug or health care product for treating male depression, wherein the parathyroid hormone is, for example, a recombinant human parathyroid hormone (1-34) or a parathyroid hormone-related protein. It is found for the first time that the parathyroid hormone has the probability of causing depression in females, but has an opposite effect in males, that is, the parathyroid hormone can improve organism metabolism and activity in males, thereby improving depression-related behaviors of males.

Description

Application of parathyroid hormone in preparation of medicine or health product for treating male depression

technical field

The invention belongs to the technical field of drugs for treating depression, and relates to the application of parathyroid hormone in the preparation of drugs or health products for treating male depression.

Background technique

Depression, also known as depressive disorder, is often seen clinically with low mood, slow thinking, decreased active speech, slow behavior, passive life, unwilling to interact with others, easy to shed tears and cry, and some cases have obvious anxiety and motor agitation, severe Patients may experience psychotic symptoms such as hallucinations and delusions. With the acceleration of the pace of life and the increase of life and work pressure, depression has become a common disease affecting human health. It is a disease with high morbidity, disability and mortality, which seriously endangers people's physical and mental health. Therefore, depression has become a research hotspot in the field of medicine today. The common ones are postpartum depression, senile depression, drug or disease-induced depression, endogenous depression, etc. The treatment methods usually include psychological counseling and drug therapy, but the effect is not satisfactory because of the complex etiology.

Parathyroid hormone (PTH) is an important calcium and phosphorus metabolism regulating hormone in the body. The main function of PTH in the body is to maintain blood calcium homeostasis by regulating renal tubular reabsorption and mobilizing bone cell function. Clinically, parathyroid hormone-related diseases are generally accompanied by neurological symptoms, which shows the role of PTH on the central nervous system.

Recombinant human parathyroid hormone (1-34) has been clinically used internationally to treat osteoporosis in elderly men and postmenopausal women. Among older men and postmenopausal women, depression and osteoporosis are frequent diseases. Previous studies have pointed to a correlation between the onset of osteoporosis and depression in older men and postmenopausal women.

Contents of the invention

In view of the deficiencies in the prior art, the technical problem to be solved by the present invention is to provide an application of parathyroid hormone in the preparation of medicine or health care product for treating male depression, so as to improve male depression symptoms.

In order to realize the above-mentioned purpose of the invention, the present invention provides a kind of application of parathyroid hormone in the medicine or the health product of preparation treatment male depression.

Specifically, the parathyroid hormone is recombinant human parathyroid hormone (1-34) or parathyroid hormone-related protein.

Another aspect of the present invention is to provide a medicine or health care product for treating male depression, the pharmaceutical composition or health care product contains parathyroid hormone or a pharmaceutically acceptable salt thereof as an active substance.

Specifically, the pharmaceutical composition is in the form of intravenous injection and oral administration.

Specifically, the dosage of the pharmaceutical composition is once a day, 300ng/kg-500ng/kg each time.

Specifically, the administration time period of the pharmaceutical composition is between 2:00 p.m. and 5:00 p.m. every day.

The application of the parathyroid hormone provided by the embodiment of the present invention in the preparation of a drug or a health product for treating male depression, specifically uses parathyroid hormone as an active substance of a drug or a health product for treating male depression. Parathyroid hormone can increase the body's metabolism and activity in men, thereby improving men's depression-related behaviors and improving men's depressive symptoms.

Description of drawings

Figures 1 to 3 are illustrations of the statistical results of open field experiments on experimental male mice in Example 1 of the present invention;

Fig. 4 is a graphical representation of the statistical results of the sugar water preference experiment on experimental male mice in Example 2 of the present invention;

Figures 5 to 7 are illustrations of statistical results of open field experiments on experimental male mice in Example 3 of the present invention;

Figures 8 to 10 are graphical representations of the statistical results of open field experiments on experimental male mice in Example 4 of the present invention;

Fig. 11 is a graphical representation of the statistical results of the sugar water preference experiment on experimental male mice in Example 5 of the present invention;

Figures 12 to 14 are illustrations of statistical results of open field experiments on experimental female mice in Example 6 of the present invention;

Fig. 15 is a graphical representation of the statistical results of tail suspension experiments on real female mice in Example 6 of the present invention;

Figures 16 to 18 are illustrations of statistical results of open field experiments on experimental female mice in Example 7 of the present invention;

Fig. 19 is a graphical representation of the statistical results of the tail suspension test on real female mice in Example 7 of the present invention.

Detailed ways

In order to make the object, technical solution and advantages of the present invention clearer, the specific implementation manners of the present invention will be described in detail below in conjunction with the accompanying drawings. Examples of these preferred embodiments are illustrated in the accompanying drawings. The embodiments of the invention shown in and described with reference to the drawings are merely exemplary, and the invention is not limited to these embodiments.

Here, it should also be noted that, in order to avoid obscuring the present invention due to unnecessary details, only the structures and/or processing steps closely related to the solution according to the present invention are shown in the drawings, and the related Other details are not relevant to the invention.

As mentioned above, the current clinical treatment methods for depression usually include psychological counseling and drug therapy, but due to the complexity of the etiology, the effect is not ideal. Therefore, the exploration of drugs for the treatment of depression is still a research field in the current medical field. hotspots. The present invention finds for the first time that parathyroid hormone has the probability of causing depression in women, but has the opposite effect in men. It can improve the metabolism and activity of men's bodies, thereby improving men's depression-related behaviors.

Based on the above findings, the embodiment of the present invention firstly provides an application of parathyroid hormone in the preparation of medicine or health care product for treating male depression. Specifically, the parathyroid hormone is recombinant human parathyroid hormone (1-34), namely rPTH (1-34), or parathyroid hormone-related protein PTHrP.

The embodiment of the present invention also provides a medicine or health care product for treating male depression, wherein the pharmaceutical composition or health care product contains parathyroid hormone or a pharmaceutically acceptable salt thereof as an active substance. Specifically, the parathyroid hormone is recombinant human parathyroid hormone (1-34), namely rPTH (1-34), or parathyroid hormone-related protein PTHrP.

In a preferred scheme, the pharmaceutical composition is in the form of intravenous injection or oral administration.

In a preferred scheme, the dosage of the pharmaceutical composition is once a day, 300ng/kg-500ng/kg each time, such as 300ng/kg, 310ng/kg, 330ng/kg, 350ng/kg, 380ng/kg kg, 400ng/kg, 420ng/kg, 450ng/kg, 480ng/kg or 500ng/kg. Continuous medication for no more than two years.

In a preferred scheme, the administration time period of the pharmaceutical composition is between 2:00 p.m. and 5:00 p.m. every day.

In order to illustrate that the medicine or health care product for treating male depression provided by the present invention can be used in relevant clinical research, the embodiment of the present invention provides a drug effect example of C57 mice.

Example 1

Take ordinary adult C57 male mice and divide them into two groups at random: one is the treatment group and the other is the control group.

(1), according to the following methods, the C57 male mice of the administration group and the control group were administered respectively:

Administration group: intraperitoneal injection of rPTH (1-34) within the time period of 2-5 p.m., the administration dose is 10 ng/30 g (333 ng/kg).

Control group: Compared with the administration group, the only difference is that the control group is injected with the same dose of normal saline.

(2), after administration is finished, open field experiment is carried out respectively to the male mice of administration group and matched group, record and count two groups of male mice's open field central residence time (central times), open field central entry times (central time) entries) and overall activity distance (Distance).

Fig. 1 is a graphical representation of the statistical results of the time spent in the center of the open field of two groups of male rats in this embodiment; Fig. 2 is a graphical representation of the statistical results of the number of times the center of the open field of the two groups of male rats entered in the present embodiment; Fig. 3 is a graphical representation of the statistical results of this embodiment The statistical results of the overall moving distance of the two groups of male rats in the examples are shown in a graphical representation.

As shown in Figures 1 to 3, the above experimental results show that compared with the control group, the dwell time in the center of the open field, the number of times of entering the center of the open field, and the overall moving distance of the male mice in the administration group were significantly increased, that is, after the administration, The activity level of male rats increased significantly.

Example 2

Administration group: intraperitoneal injection of rPTH(1-34) within the period of 2-5 p.m., the administration dose is 10ng/30g.

(2) After the administration was completed, the sugar water preference experiment was carried out on the male mice in the administration group and the control group respectively, and the sugar water preference ratio (ratio (sugar/water)) of the two groups of male mice was recorded and counted.

Fig. 4 is a graphical representation of the statistical results of the sugar water preference ratios of two groups of male mice in this embodiment.

As shown in Figure 4, the above experimental results show that compared with the control group, the male rats in the administration group showed a significant increase in their preference for sugar water.

Example 3

Normal adult C57 male mice were randomly divided into two groups: a depression group and a control group.

(1) The C57 male mice in the depression group were subjected to depression modeling for 10 days, and stress-stress depression was induced in the animals through restraint model; the male mice in the control group were not subjected to depression modeling treatment.

(2) After the depression modeling was completed, the open field experiment was carried out on the male mice of the depression group and the control group respectively, and the time spent in the center of the open field, the number of times of entering the center of the open field and the overall activity distance of the male mice of the two groups were recorded and counted.

Fig. 5 is a graphical representation of the statistical results of the time spent in the center of the open field of two groups of male rats in this embodiment, and Fig. 6 is a graphical representation of the statistical results of the number of times the center of the open field of the two groups of male rats entered in the present embodiment, and Fig. 7 is a graphical representation of the statistical results of this embodiment The statistical results of the overall moving distance of the two groups of male rats in the examples are shown in a graphical representation.

As shown in Figures 5 to 7, the above experimental results show that compared with the control group, the time spent in the center of the open field and the number of times of entering the center of the open field of male rats in the depression group were reduced, and the overall moving distance was significantly reduced, that is, the male rats in the depression group decreased significantly. Significantly reduced activity levels, characteristic of stress-induced depression.

Example 4

Take ordinary adult C57 male mice, carry out a period of 10 days of depression modeling to the C57 male mice according to the treatment method of the depression group in Example 3, and then divide them into two groups at random: one group is the treatment group, and one group is the control group Group.

(2) After the administration was completed, open field experiments were carried out on the male mice of the administration group and the control group respectively, and the time spent in the center of the open field, the number of times the center of the open field entered and the overall movement distance of the two groups of male mice were recorded and counted.

Fig. 8 is a graphical representation of the statistical results of the time spent in the center of the open field of two groups of male rats in this embodiment, and Fig. 9 is a graphical representation of the statistical results of the number of times of entry into the center of the open field of two groups of male rats in this embodiment, and Fig. The statistical results of the overall moving distance of the two groups of male rats in the examples are shown in a graphical representation.

As shown in Figures 8 to 10, the above experimental results show that for male mice with stress-induced depression symptoms, compared with the control group, the time spent in the center of the open field, the number of times of entering the center of the open field, and the overall activity of the male mice in the drug treatment group The distances were all significantly increased, that is, after the administration, the activity level of the male mice was significantly increased, and the symptoms of stress-induced depression were improved.

Example 5

(1) The C57 males of the administration group and the control group were obtained in the same manner as in Example 4, and the administration method was the same as in Example 4.

(2) After the administration was completed, the sugar water preference experiment was carried out on the male mice of the drug treatment group and the control group respectively, and the sugar water preference ratios of the two groups of male mice were recorded and counted.

Fig. 11 is a graphical representation of the statistical results of the sugar water preference ratios of two groups of male mice in this embodiment.

As shown in Figure 11, the above experimental results show that: for the male rats with stress-induced depression symptoms, compared with the control group, the male rats in the treatment group showed a significant increase in their preference for sugar water.

Example 6

Compared with Example 1, this example differs in that the test object is replaced by female mice, that is, ordinary adult C57 female mice are taken, and the test is carried out in the same manner as in Example 1.

Fig. 12 is a graphical representation of the statistical results of the time spent in the center of the open field by two groups of female mice in this embodiment, and Fig. 13 is a graphical representation of the statistical results of the number of times the center of the open field entered by two groups of female rats in this embodiment. The statistical results of the overall moving distance of the two groups of female mice in the examples are illustrated.

As shown in Figures 12 to 14, the above experimental results show that for ordinary adult C57 female mice, the time spent in the center of the open field, the number of times of entering the center of the open field, and the overall moving distance of the drug treatment group and the control group are roughly the same, and there is no significant change.

In this embodiment, the tail suspension test was also performed on the female mice in the administration group and the control group respectively, and the tail suspension immobility time (immobility) was recorded.

Fig. 15 is a graphical representation of the statistical results of tail suspension time of two groups of female mice in this embodiment.

As shown in Figure 15, the above experimental results show that compared with the control group, the tail-suspension time of the female mice in the administration group increased, but the difference was not significant.

Example 7

Compared with Example 6, this example differs in that the test object is replaced by a female mouse 4 weeks after ovariectomy, that is, after 4 weeks of ovariectomy of an ordinary adult C57 female mouse, the test is carried out in the same manner as in Example 6 .

Fig. 16 is a graphical representation of the statistical results of the time spent in the center of the open field by two groups of female mice in this embodiment, and Fig. 17 is a graphical representation of the statistical results of the number of times the center of the open field entered by two groups of female rats in this embodiment. The statistical results of the overall moving distance of the two groups of female mice in the embodiment are graphically illustrated, and FIG. 19 is a graphical representation of the statistical results of the tail suspension time of the two groups of female mice in this embodiment.

As shown in Figures 16 to 19, the above experimental results show that for the female mice 4 weeks after ovariectomy, compared with the control group, the time spent in the center of the open field, the number of times of entry into the center of the open field, and the overall moving distance of the female mice in the administration group were significantly lower than those in the control group. Significantly decreased, while tail suspension immobility time was significantly increased.

The experimental results of the above examples 1 to 5 show that the administration of parathyroid hormone injection can promote the body activity of male animals, significantly increase the preference for sugar water, and relieve the activity decline caused by long-term stress, The effect of depression-related symptoms such as decreased preference for sugar water, that is, parathyroid hormone can improve male body metabolism and activity, and can improve the effect of male depressive symptoms.

Examples 6 and 7 show that the administration of parathyroid hormone injection will reduce the physical activity of female animals, that is, parathyroid hormone has the probability of causing depression in females.

The above description is only the specific implementation of the present application. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present application, some improvements and modifications can also be made. It should be regarded as the protection scope of this application.

Claims

Application of parathyroid hormone in preparing medicine or health product for treating male depression.
The use according to claim 1, wherein the parathyroid hormone is recombinant human parathyroid hormone (1-34) or parathyroid hormone-related protein.
A medicine or health care product for treating male depression, wherein the pharmaceutical composition or health care product contains parathyroid hormone or a pharmaceutically acceptable salt thereof as an active substance.
The pharmaceutical composition or health product according to claim 3, wherein the parathyroid hormone is recombinant human parathyroid hormone (1-34) or parathyroid hormone-related protein.
The pharmaceutical composition or health care product according to claim 4, wherein the pharmaceutical composition is in the form of intravenous injection or oral administration.
The pharmaceutical composition or health product according to claim 5, wherein the dosage of the pharmaceutical composition is once a day, 300ng/kg-500ng/kg each time.
The pharmaceutical composition or health product according to claim 6, wherein the administration time period of the pharmaceutical composition is between 2:00 p.m. and 5:00 p.m. every day.