Application of medicine for nourishing yin and soothing liver in preparation of medicine for preventing and treating multi-system decline lesion caused by POI (Point of Interest)

Abstract

The invention belongs to the field of traditional Chinese medicine, and particularly relates to application of a yin-nourishing and liver-soothing medicine in preparation of a medicine for preventing and treating multisystem decline lesions caused by POIs, and the yin-nourishing and liver-soothing medicine is prepared from, by weight, 10-30 parts of radix rehmanniae, 10-30 parts of radix paeoniae alba, 5-30 parts of radix bupleuri, 10-30 parts of radix curcumae, 5-30 parts of rhizoma cyperi, 10-30 parts of Chinese yam and 10-30 parts of radix paeoniae rubra. The invention finds that the medicine for nourishing yin and soothing liver can be used for protecting the ovarian function and also can be used for better improving the psychological and nervous system degenerative lesion symptoms, such as insomnia, anxiety, low emotion, irritability, fright and hypomnesis, caused by POI (Point of Interest); cardiovascular system decline lesion symptoms such as dyslipidemia, precardiac oppression, shortness of breath, weakness and palpitation, and related symptoms such as immune system hypofunction.

Description

Technical Field

[0001] The present invention belongs to the field of traditional Chinese medicine, and in particular relates to the use of a yin-nourishing and liver-soothing drug in preparing a drug for preventing and treating multi-system degenerative lesions caused by POI. Background Art

[0002] Premature ovarian insufficiency (POI) is a female endocrine disease. POI not only leads to infrequent menstruation or amenorrhea, significantly increased follicle-stimulating hormone and decreased estrogen levels, which seriously affect women's reproductive health, but also leads to multiple system degenerative lesions such as mental and nervous system degenerative lesions and cardiovascular system degenerative lesions. Among them, mental and nervous system degenerative lesions are mainly manifested as changes in mood and memory function, including insomnia, anxiety, depression, irritability, panic, memory loss, etc.; cardiovascular system degenerative lesions are mainly dyslipidemia, and cardiovascular symptoms include precordial tightness, shortness of breath, fatigue, palpitations, etc.

[0003] Traditional Chinese medicine has few adverse reactions and definite efficacy, and has great advantages in treating POI. For example, patent application CN110179947A discloses a Yin-nourishing and liver-soothing medicine, whose active ingredients are composed of Radix Rehmanniae, Radix Paeoniae Alba, Radix Bupleuri, Radix Curcumae, Rhizoma Cyperi, Rhizoma Dioscoreae, and Radix Paeoniae Rubra, which can effectively increase the number of basal antral follicles and improve ovarian blood flow in POI patients, and improve menstrual disorders and ovarian function in POI patients.

[0004] Xu Xiaolu (Clinical Observation on Yishen Yangluan Decoction for the Treatment of Premature Ovarian Insufficiency of Kidney Deficiency, Liver Depression and Blood Stasis Type [D]. Guangxi University of Chinese Medicine, 2018: 31-34.) used the following prescription to treat POI of kidney deficiency, liver depression and blood stasis type: cooked rehmannia, yam, cornus officinalis, wolfberry, cinnamon twig, poria, tangerine peel, bupleurum, red peony root, angelica, white peony root and dodder seed. This prescription can effectively improve the clinical symptoms of patients with premature ovarian insufficiency of kidney deficiency, liver depression and blood stasis type, promote the development of antral follicles in the ovaries, and effectively improve hormone levels in the body.

[0005] However, the existing Chinese medicines for the treatment of POI are basically aimed at improving symptoms related to ovarian function such as oligomenorrhea or amenorrhea, follicle-stimulating hormone levels, and estrogen levels caused by POI. For systemic degenerative lesions such as mental and nervous system degenerative lesions and cardiovascular system degenerative lesions caused by POI, hormone replacement therapy is usually used clinically, and hormones are rejected by some patients due to their large side effects. Therefore, the value of traditional Chinese medicine in the treatment of multi-system degenerative lesions caused by POI still needs to be further explored. Summary of the invention

[0006] The purpose of the present invention is to provide a new use of a Yin-nourishing and liver-soothing drug, namely, use of the Yin-nourishing and liver-soothing drug in the preparation of a drug for preventing and treating multi-system degenerative lesions caused by POI.

[0007] According to the first aspect of the present invention, there is provided an application of a Yin-nourishing and liver-soothing drug in the preparation of a drug for preventing and treating multi-system degenerative lesions caused by POI, wherein the raw material composition of the Yin-nourishing and liver-soothing drug includes, by weight: 10-30 parts of Radix Rehmanniae, 10-30 parts of Radix Paeoniae Alba, 5-30 parts of Radix Bupleuri, 10-30 parts of Radix Curcumae, 5-30 parts of Rhizoma Cyperi, 10-30 parts of Rhizoma Dioscoreae, and 10-30 parts of Radix Paeoniae Rubra. Specifically, multi-system degenerative lesions include reproductive endocrine disorders of kidney deficiency and liver depression POI, degenerative lesions of the mental and nervous system, degenerative lesions of the cardiovascular system, and decreased immune system function. More specifically, Yin-nourishing and liver-soothing drugs for the treatment of kidney deficiency and liver depression POI reproductive endocrine disorders include improving irregular menstruation, Chinese medicine symptoms, improving FSH and AMH hormone levels, increasing the number of antral follicles and mature follicles, etc.; mental and nervous system degenerative lesions include insomnia, anxiety, depression, irritability, panic, memory loss and other symptoms; cardiovascular system degenerative lesions include dyslipidemia, precordial tightness, shortness of breath, fatigue, palpitations; and immune system dysfunction and other symptoms.

[0008] The present invention believes that among the Yin-nourishing and liver-soothing drugs, white peony root and raw rehmannia root nourish the liver and kidney, restrain Yin and stop sweating, and are the main drugs; bupleurum, curcuma, and cyperus rotundus soothe the liver qi, relieve depression to suit the liver nature, and are compatible with white peony root to soften the liver body to harmonize the liver, and can promote and improve the symptoms related to the degenerative lesions of the mental and nervous system such as insomnia, anxiety, depression, irritability, panic, and memory loss, and are the minister drugs; Chinese yam strengthens the spleen and replenishes qi, can make the spleen healthy without being invaded by the liver, and can make the spleen transform qi and blood to nourish Chong and Ren, and can be used together with raw rehmannia root to nourish the acquired and nourish the innate; red peony root promotes blood circulation and removes blood stasis, assists bupleurum, curcuma, and cyperus rotundus to remove blood stasis and relieve pain, is beneficial to preventing and treating abnormal blood lipid metabolism, and improves the symptoms of degenerative lesions of the cardiovascular system such as precordial tightness, shortness of breath, fatigue, palpitations, etc., and is the adjuvant drug. Looking at the whole prescription, it embodies the method of treating the liver, spleen and kidney simultaneously with the emphasis on nourishing Yin and soothing the liver. The whole prescription can be used together to nourish Yin and soothe the liver, nourish the internal organs, and regulate multiple organs. While protecting ovarian function, it can also improve the symptoms related to multi-system degenerative diseases caused by POI, and prevent and treat multi-system degenerative diseases.

[0009] The sources of raw materials for Yin-nourishing and liver-soothing drugs are as follows:

[0010] Rehmannia: The dried root of Rehmannia glutinosa Libosch., a perennial herb of the Scrophulariaceae family.

[0011] White peony root: the dried root of Paeonia lactiflora Pall., a plant of the Ranunculaceae family.

[0012] Bupleurum: The dried root of Bupleurum chinense DC., a plant of the Umbelliferae family.

[0013] Curcuma: The dried tuberous root of Curcuma wenyujinY.H.Chen et C.Ling, a plant of the Zingiberaceae family.

[0014] Cyperus rotundus: The dried rhizome of Cyperus rotundus L., a plant of the Cyperaceae family.

[0015] Huaishan: The dried rhizome of Dioscorea opposita Thunb., a plant of the Dioscoreaceae family.

[0016] Red peony root: the dried root of Paeonia veitchii Lynch, a plant of the Ranunculaceae family.

[0017] In some embodiments, the syndrome type of POI is kidney deficiency and liver depression type.

[0018] In some embodiments, the raw material composition of the Yin-nourishing and liver-soothing medicine includes, by weight: 10-30 parts of Radix Rehmanniae, 10-20 parts of Radix Paeoniae Alba, 5-15 parts of Radix Bupleuri, 10-15 parts of Radix Curcumae, 5-15 parts of Radix Cyperi, 10-30 parts of Radix Chinese Yams, and 10-15 parts of Radix Paeoniae Rubra. Preferably, the raw material composition of the Yin-nourishing and liver-soothing medicine includes, by weight: 12 parts of Radix Rehmanniae, 15 parts of Radix Paeoniae Alba, 10 parts of Radix Bupleuri, 12 parts of Radix Curcumae, 9 parts of Radix Cyperi, 15 parts of Radix Chinese Yams, and 15 parts of Radix Paeoniae Rubra.

[0019] In some embodiments, the cyperus rotundus is the cyperus rotundus obtained by vinegar moxibustion. The processing method of cyperus rotundus is: remove hair and impurities, cut into thick slices or crush. Take cyperus rotundus slices (granules), and fry them dry according to the vinegar roasting method (Chinese Pharmacopoeia 2015 Edition Four General Rules 0213). The cyperus rotundus obtained by vinegar moxibustion can lead the medicine into the liver, enhance the effect of soothing the liver, regulating qi and relieving pain, and can be used in combination with bupleurum and curcuma to promote the improvement of insomnia, anxiety, depression, irritability, panic, memory loss and other symptoms manifested by degenerative lesions of the mental and nervous system, and symptoms such as precordial stuffiness manifested by degenerative lesions of the cardiovascular system. It can be used in combination with white peony root and red peony root to improve dyslipidemia, precordial stuffiness, shortness of breath, fatigue, palpitations and other symptoms manifested by degenerative lesions of the cardiovascular system.

[0020] In some embodiments, the dosage form of the Yin-nourishing and liver-soothing drug is capsule, granule, tablet, powder, granule or decoction.

[0021] In some embodiments, the Yin-nourishing and liver-soothing drug further comprises a pharmaceutically acceptable excipient.

[0022] In some embodiments, the auxiliary material is at least one of a sustained-release agent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption enhancer, an adsorption carrier, a surfactant, and a lubricant.

[0023] The Yin-nourishing and liver-soothing medicine of the present invention can be prepared by using the corresponding existing preparation method according to the specification requirements of the specific preparation.

[0024] Compared with the prior art, the beneficial effects of the present invention include:

[0025] The present invention finds that the Yin-nourishing and liver-soothing drugs can protect ovarian function and can also well improve the mental and nervous system degenerative lesions symptoms such as insomnia, anxiety, depression, irritability, panic, memory loss, etc. caused by POI, as well as the cardiovascular system degenerative lesions and immune system dysfunction symptoms such as dyslipidemia, precordial tightness, shortness of breath, fatigue, palpitations, etc. Therefore, the Yin-nourishing and liver-soothing drugs can be used to prepare drugs for preventing and treating multi-system degenerative lesions caused by POI. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is a line graph of the menstrual scores of the treatment group and the control group in the experiment on the effect of Yangyin Shugan Capsule on the reproductive endocrine system of POI; blue represents the control group; red represents the treatment group.

[0027] Figure 2 This is a line graph of data analysis of the TCM syndrome scale for the treatment group and the control group in the experiment on the effect of Yangyin Shugan Capsule on the reproductive endocrine system of POI; blue represents the control group; red represents the treatment group.

[0028] Figure 3 This is a line graph of the data analysis of the SDS scale of the treatment group and the control group in the experiment on the effects of Yangyin Shugan Capsule on the psychoneurological system of POI; blue represents the control group; red represents the treatment group.

[0029] Figure 4 This is a line chart of the SAS scale data analysis of the treatment group and the control group in the experiment on the effects of Yangyin Shugan Capsule on the psychoneurological system of POI; blue represents the control group; red represents the treatment group.

[0030] Figure 5 This is a line graph of the total Green scale scores of the treatment group and the control group in the experiment on the effects of Yangyin Shugan Capsule on cardiovascular system symptoms and vasoactive substances; blue represents the control group; red represents the treatment group. DETAILED DESCRIPTION

[0031] The present invention is further described in detail below in conjunction with specific embodiments. It is worth noting that the following embodiments are only for better explanation of the present invention and are not intended to limit the scope of protection of the present invention. The undisclosed process steps in the embodiments are prior art. Unless otherwise specified, the following raw materials are commercially available.

[0032] In the following examples, the cyperus rotundus is the cyperus rotundus obtained by vinegar moxibustion. The processing method of cyperus rotundus is: remove hair and impurities, cut into thick slices. Take the cyperus rotundus slices, and stir-fry them dry according to the vinegar moxibustion method (Chinese Pharmacopoeia 2015 Edition Four General Rules 0213).

[0033] Example 1

[0034] The Yin-nourishing and liver-soothing drug is used to prepare a drug for preventing and treating multi-system degenerative lesions caused by POI, and the preparation method thereof is as follows:

[0035] (1) Take 12g of Radix Rehmanniae, 15g of Radix Paeoniae Alba, 10g of Radix Bupleuri, 12g of Radix Curcumae, 9g of Rhizoma Cyperi, 15g of Rhizoma Dioscoreae, and 15g of Radix Paeoniae Rubra, and set aside;

[0036] (2) Take the above components, grind and mix them with carriers and excipients to make dry powder, then make them into granules and encapsulate them to make Yangyin Shugan Capsules. When taking, each person takes 4 capsules each time, 3 times a day, with an interval of 4-6 hours between each time.

[0037] Example 2

[0038] The Yin-nourishing and liver-soothing drug is used to prepare a drug for preventing and treating multi-system degenerative lesions caused by POI, and the preparation method thereof is as follows:

[0039] (1) Take 10g of Radix Rehmanniae, 15g of Radix Paeoniae Alba, 5g of Radix Bupleuri, 10g of Radix Curcumae, 9g of Rhizoma Cyperi, 15g of Rhizoma Dioscoreae, and 10g of Radix Paeoniae Rubra, and set aside;

[0040] (2) Take the above components, add water and decoct twice, add 10 times the amount of water for the first time, decoct for 2 hours, add 8 times the amount of water for the second time, decoct for 1.5 hours, filter, and concentrate the filtrate under reduced pressure to a clear paste with a relative density of 1.20 (measured at 60°C), filter, and use the clear paste for later use. Take 10% of the total mass of the raw material maltodextrin, dissolve it in hot water, combine the solution with the above clear paste, adjust the relative density to 1.16 (measured at 60°C), spray dry, and obtain a dry paste powder. Add an appropriate amount of maltodextrin to the dry paste powder, mix well, granulate with 90% ethanol, and dry to obtain Yangyin Shugan Granules.

[0041] Example 3

[0042] The Yin-nourishing and liver-soothing drug is used to prepare a drug for preventing and treating multi-system degenerative lesions caused by POI, and the preparation method thereof is as follows:

[0043] (1) Take 15g of Radix Rehmanniae, 15g of Radix Paeoniae Alba, 10g of Radix Bupleuri, 15g of Radix Curcumae, 9g of Rhizoma Cyperi, 20g of Rhizoma Dioscoreae, and 10g of Radix Paeoniae Rubra, and set aside;

[0044] (2) Take the above components, add water and boil twice, add 10 times the amount of water for the first time, boil for 2 hours, filter, add 8 times the amount of water for the second time, boil for 1.5 hours, filter, combine the decoctions obtained from the two decoctions, and obtain a nourishing yin and soothing liver decoction.

[0045] Example 4

[0046] The Yin-nourishing and liver-soothing drug is used to prepare a drug for preventing and treating multi-system degenerative lesions caused by POI, and the preparation method thereof is as follows:

[0047] (1) Take 20g of Radix Rehmanniae, 15g of Radix Paeoniae Alba, 10g of Radix Bupleuri, 15g of Radix Curcumae, 9g of Cyperus Rhizoma, 20g of Chinese Yam, and 15g of Radix Paeoniae Rubra, and set aside;

[0048] (2) The above components are taken, crushed, and uniformly mixed with carriers and excipients to form dry powder to obtain Yangyin Shugan Powder, which can be taken with water.

[0049] Example 5

[0050] The Yin-nourishing and liver-soothing drug is used to prepare a drug for preventing and treating multi-system degenerative lesions caused by POI, and the preparation method thereof is as follows:

[0051] (1) Take 25g of Radix Rehmanniae, 10g of Radix Paeoniae Alba, 10g of Radix Bupleuri, 10g of Radix Curcumae, 9g of Rhizoma Cyperi, 20g of Rhizoma Dioscoreae, and 15g of Radix Paeoniae Rubra, and set aside;

[0052] (2) Take the above components, add water and decoct twice, add 10 times the amount of water for the first time, decoct for 2 hours, add 8 times the amount of water for the second time, decoct for 1.5 hours, filter, and concentrate the filtrate under reduced pressure to a clear paste with a relative density of 1.20 (measured at 60°C), filter, and use the clear paste for later use. Take 10% of the total mass of the raw material drug maltodextrin, dissolve it in hot water, combine the solution with the above clear paste, adjust the relative density to 1.16 (measured at 60°C), spray dry, and obtain dry paste powder, add appropriate amount of maltodextrin to the dry paste powder, mix well, granulate with 90% ethanol to obtain wet granules, and then compress the above wet granules by tableting to obtain Yangyin Shugan Tablets.

[0053] Example 6

[0054] The Yin-nourishing and liver-soothing drug is used to prepare a drug for preventing and treating multi-system degenerative lesions caused by POI, and the preparation method thereof is as follows:

[0055] (1) Take 10g of Radix Rehmanniae, 10g of Radix Paeoniae Alba, 5g of Radix Bupleuri, 10g of Curcuma, 5g of Rhizoma Cyperi, 10g of Rhizoma Dioscoreae, and 10g of Radix Paeoniae Rubra, and set aside;

[0056] (2) The above components are taken, crushed, and uniformly mixed with carriers and excipients to form dry powder, which is then granulated and encapsulated to form Yangyin Shugan Capsules.

[0057] Example 7

[0058] The Yin-nourishing and liver-soothing drug is used to prepare a drug for preventing and treating multi-system degenerative lesions caused by POI, and the preparation method thereof is as follows:

[0059] (1) Take 30g of Radix Rehmanniae, 20g of Radix Paeoniae Alba, 15g of Radix Bupleuri, 15g of Radix Curcumae, 15g of Rhizoma Cyperi, 30g of Rhizoma Dioscoreae, and 15g of Radix Paeoniae Rubra, and set aside;

[0060] (2) The above components are taken, crushed, and uniformly mixed with carriers and excipients to form dry powder, which is then granulated and encapsulated to form Yangyin Shugan Capsules.

[0061] Example 8

[0062] The Yin-nourishing and liver-soothing drug is used to prepare a drug for preventing and treating multi-system degenerative lesions caused by POI, and the preparation method thereof is as follows:

[0063] (1) Take 30g of Radix Rehmanniae, 30g of Radix Paeoniae Alba, 30g of Radix Bupleuri, 30g of Radix Curcumae, 30g of Rhizoma Cyperi, 30g of Rhizoma Dioscoreae, and 30g of Radix Paeoniae Rubra, and set aside;

[0064] (2) The above components are taken, crushed, and uniformly mixed with carriers and excipients to form dry powder, which is then granulated and encapsulated to form Yangyin Shugan Capsules.

[0065] The following is a test to verify the effect of the Yin-nourishing and liver-soothing drug of the present invention in preparing a drug for preventing and treating multi-system degenerative lesions caused by POI. The drug used in the test is the Yin-nourishing and liver-soothing capsule prepared in Example 1.

[0066] 1. Experimental research methods

[0067] (1) Clinical research

[0068] A prospective, randomized, double-blind controlled clinical trial was conducted, and 60 patients with premature ovarian insufficiency (POI) of kidney deficiency and liver depression type who met the diagnostic criteria, inclusion criteria and exclusion criteria and visited the gynecology outpatient clinic of the Second Clinical Medical College of Guangzhou University of Chinese Medicine from 2020 to 2022 were selected as the research subjects. They were randomly divided into the Yangyin Shugan Capsule treatment group (referred to as the "treatment group") and the placebo control group (referred to as the "control group"). The treatment group was treated with Yangyin Shugan Capsule (in-hospital preparation), and the control group was given placebo capsules. The observation time point was the first visit and the 12th week of treatment. The efficacy indicators were measured at each time point, including the menstrual score sheet, Chinese medicine syndrome scale, depression scale (SDS), anxiety scale (SAS), Green scale, serum sex hormones, serum anti-Mullerian hormone (AMH), transvaginal B-ultrasound monitoring of basal antral follicles (AFC), and safety indicators (including blood and urine routine, liver function, renal function, and electrocardiogram). At the same time, adverse events and adverse drug reactions were closely observed and recorded during the study. The obtained data were statistically analyzed using SPSS26.0 software.

[0069] (2) Animal Experimental Research

[0070] SD rats were selected, and VCD + chronic stress stimulation was used to create a POI rat model of kidney deficiency and liver depression. After the model was established, 58 rats were randomly divided into 6 groups, namely, a blank control group, a model control group, a medium-, low-, and high-dose group of Yangyin Shugan Capsule, and a western medicine group of Bujiale. The proposed clinical dose of Yangyin Shugan Capsule for adults is 45.0g of crude drug / day, which is converted into a clinical equivalent dose of rats according to body surface area: rat equivalent dose = 45×0.018×5 = 4.05g crude drug / kg, and the low, medium, and high doses of Yangyin Shugan Capsule are set to 1 / 2, 1, and 2 times of the clinical equivalent dose of Yangyin Shugan Capsule; the proposed clinical dose of Bujiale group for adults is 1.0mg / day, which is converted into a clinical equivalent dose of rats according to body surface area: rat equivalent dose = 1×0.018×5 = 0.09mg crude drug / kg. The dose of Bujiale group was set to 1 times the clinical equivalent dose of Bujiale. According to the above algorithm combined with the literature and previous experimental results, this experiment used low, medium and high doses of Yangyin Shugan Capsule set at 2.1, 4.2, 8.4g crude drug / kg, and the dose of Progynova was 0.09mg / kg for the experiment. The model control group did not intervene, the drug group was given different drugs by gavage, and the blank control group was given normal saline by gavage once a day. After 4 consecutive weeks of administration, the safety of rats and the effects on multiple systems (including reproductive endocrine system, mental nervous system, cardiovascular system, and immune system) were observed and tested to explore the mechanism of action of Yangyin Shugan Capsule in treating multiple system symptoms of POI rats with kidney deficiency and liver depression, and provide a reference for clinical trials.

[0071] 2. Research and analysis on the effects of Yangyin Shugan Capsule on multiple systems of POI with kidney deficiency and liver depression

[0072] 1. Analysis of the effects of Yangyin Shugan Capsule on the reproductive endocrine system of POI

[0073] (1) Clinical research

[0074] The intergroup comparison results of menstrual efficacy were as follows Figure 1 As shown in Table 1, the two-factor repeated measures variance analysis was performed on the four evaluation points of the total menstrual score of the treatment group and the control group (initial diagnosis, 4 weeks of treatment, 8 weeks, and 12 weeks). The results showed that the difference in sphericity test was extremely significant (P < 0.01), so the GG model was selected for correction. The results showed that there was an extremely significant difference in the observation time points (P < 0.01), and the interaction between the grouping and the observation time point was extremely significant (P < 0.01). There was no statistically significant difference between different groups (P = 0.052). Comparison between the two groups at different time periods showed that the differences between the two groups at the end of the 4th, 8th, and 12th weeks of treatment were extremely significant (P < 0.01).

[0075] Table 1 Comparison of the total scores of the four evaluation points of the two groups

[0076]

[0077] Comparison of the efficacy of TCM syndrome scale between groups Figure 2 As shown in Table 2, two-factor repeated measurement variance analysis was performed on the four evaluation points of the total score of the TCM syndrome scale in the treatment group and the control group. The results showed that the difference in sphericity test was statistically significant (P<0.000), so the GG model was selected for correction. The results showed that there was a significant difference in the observation time points (P<0.01), the interaction between grouping and observation time points was statistically significant (F(2.257, 130.921)=39.833, P<0.01), and the differences between different groups were statistically significant (P<0.01). Comparison between the two groups at different time periods showed that the differences between the two groups at the 4th, 8th and 12th weekends of treatment were significant and statistically significant (P<0.000), and the treatment group was better than the control group.

[0078] Table 2 Comparison of the total scores of the four evaluation points of the TCM syndrome scale between the two groups

[0079]

[0080] The inter-group comparison of the efficacy of bFSH, AMH and AFC is shown in Table 3. At the end of the 12th week of treatment, the treatment group had a significantly better down-regulating effect on the abnormally elevated bFSH level than the control group, and the difference between the groups was extremely significant (P < 0.00); it had a significant effect on improving the reduced AMH level, and the efficacy of the treatment group was significantly better than that of the control group, and the difference between the groups was statistically significant (P < 0.002); it could increase the number of AFCs, and the independent sample rank sum test showed that the difference between the groups was statistically significant, and the treatment group was better than the control group (P < 0.00).

[0081] Table 3 Comparison of bFSH, AMH and AFC between the two groups

[0082]

[0083] (2) Results of animal experiments

[0084] The intergroup comparison of FSH levels is shown in Table 4. Compared with the blank control group, the FSH concentration of the model control group increased significantly (P<0.01). Compared with the model control group, the FSH concentration of the western medicine Bujiale group was extremely significantly reduced (P<0.01), the FSH concentration of the high- and medium-dose groups of Yangyin Shugan Capsule was significantly reduced (P<0.05), and the FSH concentration of the low-dose group of Yangyin Shugan Capsule was not statistically different (P>0.05). Compared with the western medicine Bujiale group, the FSH concentration of the high- and medium-dose groups of Yangyin Shugan Capsule was not much different from that of the Bujiale group, and there was no statistical difference (P>0.05). It shows that the effect of the high- and medium-dose groups of Yangyin Shugan Capsule in downregulating abnormally elevated FSH levels is consistent with that of the western medicine Bujiale group.

[0085] The inter-group comparison of AMH levels is shown in Table 4. Compared with the blank control group, the AMH concentration in the model control group was significantly reduced (P<0.01). Compared with the model control group, the AMH concentration in the high-dose group of Chinese medicine Yangyin Shugan Capsule increased significantly (P<0.01), and the AMH concentration in the western medicine Bujiale group and the medium and low-dose groups of Chinese medicine Yangyin Shugan Capsule increased (P<0.05). Compared with the western medicine Bujiale group, the high-dose group of Yangyin Shugan Capsule was significantly better than the western medicine Bujiale group in improving the AMH level (P<0.05). It shows that the high-dose group of Yangyin Shugan Capsule is better than the western medicine group in improving the AMH level.

[0086] Table 4 Effects of Yangyin Shugan Capsule on serum FSH, E2 and AMH in rats ( n=10)

[0087]

[0088] Note: Compared with the blank control group, * indicates P < 0.05, ** Indicates P < 0.01; compared with the model control group, # indicates P<0.05, ## Indicates P<0.01.

[0089] The inter-group comparison of AFC number is shown in Table 5. For the number of primordial follicles, compared with the blank control group, the primordial follicles in the model control group were significantly reduced (P<0.01). Compared with the model control group, the western medicine Bujiale group increased significantly (P<0.05), and the high and medium doses of Yangyin Shugan Capsule increased significantly (P<0.01). Compared with the western medicine Bujiale group, the high and medium doses of Yangyin Shugan Capsule were significantly better than the western medicine Bujiale group in increasing the number of AFC (P<0.05). For the number of mature follicles, compared with the blank control group, the model control group had a significant decrease in mature follicles (P<0.01), the Bujiale group had a significant decrease (P<0.01), and the Yangyin Shugan Capsule dose groups had a significant decrease (P<0.05). Compared with the model control group, the number of mature follicles in the high-dose Yangyin Shugan Capsule group increased significantly (P<0.05), and the western medicine Bujiale group had no significant increase, indicating that the high-dose Yangyin Shugan Capsule group had a significantly better effect on increasing the number of mature follicles than the western medicine control group.

[0090] Table 5 Effect of Yangyin Shugan Capsule on the number of follicles in rats ( n=10)

[0091]

[0092] Note: Compared with the blank control group, * indicates P < 0.05, ** Indicates P < 0.01; compared with the model control group,# indicates P<0.05, ## Indicates P<0.01.

[0093] Tips: Yangyin Shugan Capsule can effectively improve and protect ovarian function, improve the reproductive endocrine system of POI with kidney deficiency and liver depression, including improving menstruation, TCM syndrome, bFSH, AMH, AFC, primordial follicles, and the number of mature follicles, and the effect is significantly better than that of the control group.

[0094] 2. Analysis of the effect of Yangyin Shugan Capsule on the psychoneurological system of POI

[0095] (1) Clinical research results

[0096] The intergroup comparison of SDS efficacy is shown in Tables 6-7 and Figure 3 The two-factor repeated measurement variance analysis of the four evaluation points of the SDS total score between the treatment group and the control group showed that the difference in sphericity test was extremely significant (P < 0.000), so the GG model was selected for correction. The results showed that the comparison of the observation time points was extremely significant (P < 0.01), the interaction between the group and the observation time point was extremely significant (P < 0.01), and the difference between different groups was not statistically significant (P = 0.051). The comparison between the two groups at different time periods showed that the difference between the two groups at the 4th and 8th weekends of treatment was extremely significant (P < 0.05), and the difference between the two groups at the 12th weekend of treatment was extremely significant (P < 0.000).

[0097] Table 6 Comparison of SDS scores at different time points between the two groups

[0098]

[0099] Table 7 Comparison of the dimensions of the two groups of SDS scales

[0100]

[0101] Note: # In case of non-normal distribution, the Wilcoxon Mann-Whitney test (non-parametric test) was used.

[0102] The intergroup comparison of SAS efficacy is shown in Tables 8-9 and Figure 4The two-factor repeated measurement variance analysis was performed on the four evaluation points of the SAS scale between the treatment group and the control group. The results showed that the difference in sphericity test was statistically significant (P < 0.000), so the GG model was selected for correction. The results showed that the comparison of observation time points was extremely statistically significant (P < 0.000), the interaction between groups and observation time points was extremely statistically significant (P < 0.000), and the difference between different groups was not statistically significant (P = 0.091). The comparison between the two groups at different time periods showed that the differences between the two groups at the 4th and 8th weekends of treatment were extremely statistically significant (P < 0.01), and the differences between the two groups at the 12th weekend of treatment were extremely statistically significant (P < 0.01).

[0103] Table 8 Comparison of SAS scales at different time points between the two groups

[0104]

[0105] Table 9 Comparison of the dimensions of the two groups of SAS scales

[0106]

[0107] The inter-group comparison of neurotransmitter levels is shown in Tables 10-12. The serum DA, NE and 5-HT levels in the treatment group were significantly higher than those in the control group, and the difference was statistically significant (P<0.01, 0.05), indicating that the Yangyin Shugan treatment group can significantly improve the serum DA, NE and 5-HT levels.

[0108] Table 10 Comparison of serum DA (ng / ml) levels between groups (M (P25, P75)

[0109]

[0110] Table 11 Comparison of serum NE (pg / ml) levels between groups (M (P25, P75))

[0111]

[0112] Table 1 Comparison of serum levels of 25-HT (ng / ml) between groups (M (P25, P75))

[0113]

[0114] (2) Animal Experiment Results

[0115] The results of serum 5-HT test are shown in Table 13. Compared with the blank control group, the 5-HT concentration in the model control group was significantly reduced (P < 0.01). Compared with the model control group, the 5-HT concentration in the Progynova group was significantly increased (P < 0.01), and the 5-HT concentration in the high- and medium-dose Yangyin Shugan Capsule groups was significantly increased (P < 0.05). Compared with the Progynova group, the effect of the high-dose Yangyin Shugan Capsule group on improving 5-HT was not statistically different from that in the Progynova group (P > 0.05), indicating that the two groups had comparable efficacy.

[0116] The results of NE detection are shown in Table 13. Compared with the blank control group, the NE concentration in the model control group was significantly increased (P < 0.01). Compared with the model control group, the NE concentration in the Progynova group was significantly increased (P < 0.01), and the NE concentration in the high- and medium-dose Yangyin Shugan Capsule groups was significantly increased (P < 0.05). Compared with the Progynova group, there was no statistical difference in the NE concentration in the high- and medium-dose Yangyin Shugan Capsule groups (P > 0.05), indicating that the two groups had equivalent therapeutic effects.

[0117] The DA test results are shown in Table 13. Compared with the blank control group, the DA concentration in the model control group was significantly reduced (P < 0.01). Compared with the model control group, the DA concentration in the Progynova group was significantly increased (P < 0.01), and the DA concentration in the high- and medium-dose Yangyin Shugan Capsule groups was significantly increased (P < 0.05). Compared with the Progynova group, the DA concentration in the high- and medium-dose Yangyin Shugan Capsule groups was not much different, with no statistical difference (P > 0.05), indicating that the two groups had equivalent therapeutic effects.

[0118] The results of hippocampal ER-a detection are shown in Table 13. Compared with the blank control group, the average optical density of ER-a in the model control group was significantly reduced (P<0.01). Compared with the model control group, the average optical density of ER-a in the high-dose Yangyin Shugan Capsule group was significantly increased (P<0.01), while there was no statistical difference in the average optical density of ER-a between the Bujiale group and the medium- and low-dose Yangyin Shugan Capsule groups (P>0.05). Compared with the Bujiale group, the average optical density of ER-a in the high-dose Yangyin Shugan Capsule group was significantly higher than that in the Bujiale group (P<0.01).

[0119] Table 13 Effects of Yangyin Shugan Capsule on 5-HT, NE, DA, and ER-a density in hippocampus

[0120]

[0121] Note: Compared with the blank control group, * indicates P < 0.05, ** Indicates P < 0.01; compared with the model control group, # indicates P<0.05, ## Indicates P<0.01.

[0122] Tip: Yin-nourishing and liver-soothing drugs can protect ovarian function while also significantly improving symptoms of mental and nervous system decline such as insomnia, anxiety, depression, irritability, panic, and memory loss caused by ovarian dysfunction. They can also effectively improve the levels of neurotransmitter indicators and delay the decline of hippocampal ER-a density, which is significantly better than the control group.

[0123] 3. Analysis of the effect of Yangyin Shugan Capsule on cardiovascular system symptoms and vasoactive substances

[0124] (1) Clinical research results

[0125] The intergroup comparisons of the Green scale are shown in Tables 14-15 and Figure 5 The two-factor repeated measurement variance analysis was performed on each evaluation point of the Green scale in the treatment group and the control group. The results showed that the sphericity test showed significant statistical differences (P<0.000), so the GG model was selected for correction. The results showed that there was a very significant statistical difference in the observation time points (P<0.000), the interaction between the group and the observation time point was statistically significant (P<0.000), and the difference between different groups was statistically significant (P=0.033). The two groups were compared at different time periods. The difference between the two groups at the 4th weekend of treatment was statistically significant (P<0.05), and the difference between the two groups at the 8th and 12th weekends of treatment was extremely significant (P<0.01); especially for the precordial stuffiness, palpitations, shortness of breath, fatigue and other cardiovascular system degenerative lesions in the physical dimension of the Green scale.

[0126] Table 14 Comparison of Green Scale between the two groups at different time points

[0127]

[0128] Table 15 Comparison of Green Scale between the two groups

[0129]

[0130] The comparison of blood trilipid between the two groups is shown in Table 16. After treatment, the low-density lipoprotein in the treatment group decreased compared with that before treatment, and the difference was statistically significant (P < 0.05). There was no statistically significant difference in cholesterol, triglycerides, and high-density lipoprotein (P > 0.05). After treatment, the triglycerides in the control group increased compared with that before treatment, and the difference was statistically significant (P < 0.05). There was no statistically significant difference in cholesterol, high-density lipoprotein, and low-density lipoprotein (P > 0.05). The comparison of blood trilipid between the treatment group and the control group showed that cholesterol decreased in the treatment group after treatment, while it increased in the control group. The difference between the two groups after treatment and before treatment was statistically significant (P = 0.044). This shows that the effect of Chinese medicine Yangyin Shugan group in lowering cholesterol is better than that of the control group.

[0131] Table 16 Comparison of blood trilipids between the two groups

[0132]

[0133] Note: * P<0.05 for comparison within the Chinese medicine treatment group; ** P<0.05 for comparison within the control group; # For non-normal distribution, the Wilcoxon Mann-Whitney test (nonparametric test) was used; ## Comparison between groups was P<0.05.

[0134] (2) Animal Experiment Results

[0135] The results of glutathione peroxidase (GSH-PX) detection are shown in Table 17. Compared with the blank control group, the GSH-PX concentration in the model control group was significantly reduced (P < 0.01). Compared with the model control group, the GSH-PX concentrations in the high- and medium-dose Yangyin Shugan Capsule groups were significantly increased (P < 0.05), while there was no statistical difference in the GSH-PX concentrations in the Bujiale group and the low-dose Yangyin Shugan Capsule group (P > 0.05). Compared with the Bujiale group, the GSH-PX concentration in the high-dose Yangyin Shugan Capsule group was better than that in the western medicine Bujiale group (P < 0.05).

[0136] The results of malondialdehyde (MDA) test are shown in Table 17. Compared with the blank control group, the MDA concentration of the model control group was significantly increased (P < 0.05). Compared with the model control group, the MDA concentration of the high-dose Yangyin Shugan Capsule group was significantly reduced (P < 0.05), and there was no statistical difference in the MDA concentration between the Bujiale group and the medium- and low-dose Yangyin Shugan Capsule groups (P > 0.05), indicating that the high-dose Yangyin Shugan Capsule group was significantly better than the control group in improving the MDA concentration.

[0137] The results of ER-a expression in the thoracic aorta are shown in Table 17. Compared with the blank control group, the ER-a expression in the model control group was significantly decreased (P < 0.01). Compared with the model control group, the ER-a expression in the Bujiale group and the Yangyin Shugan Capsule high-dose group was significantly increased (P < 0.01), and there was no statistical difference in the ER-a expression between the Yangyin Shugan Capsule medium-dose and low-dose groups (P > 0.05). Compared with the Bujiale group, the ER-a gene expression in the Yangyin Shugan Capsule high-dose group was not much different from that in the Bujiale group, with no statistical difference (P > 0.05), indicating that the two groups had equivalent effects.

[0138] Table 17 Effect of Yangyin Shugan Capsule on serum vasoactive substance index concentration

[0139]

[0140] Note: Compared with the blank control group, * indicates P < 0.05,** Indicates P < 0.01; compared with the model control group, # indicates P < 0.05, ## Indicates P<0.01.

[0141] Tip: Yin-nourishing and liver-soothing drugs can protect ovarian function while also effectively improving cardiovascular system symptoms such as precordial tightness, palpitations, shortness of breath, fatigue, etc. caused by ovarian dysfunction. They can also improve the levels of serum cholesterol, blood lipids, low-density lipoprotein, MDA, GSH-PX and other indicators, and delay the expression of ER-a in the thoracic aorta, thereby protecting cardiovascular function.

[0142] 4. Analysis of the effect of Yangyin Shugan Capsule on the immune system

[0143] The results of CD4 detection are shown in Table 18. Compared with the blank control group, the CD4 concentration in the model control group was significantly reduced (P < 0.01). Compared with the model control group, the CD4 concentration in the Progynova group was significantly increased (P < 0.01), and the CD4 concentration in the high-dose and medium-dose Yangyin Shugan Capsule groups was significantly increased (P < 0.01). Compared with the Progynova group, there was no statistical difference in the CD4 concentration in the high-dose Yangyin Shugan Capsule group (P > 0.05), and the therapeutic effects of the two groups were comparable.

[0144] The results of TH-17 detection are shown in Table 18. Compared with the blank control group, the TH-17 concentration in the model control group was significantly increased (P < 0.05). Compared with the model control group, the TH-17 concentration in the Progynova group and the Yangyin Shugan Capsule high-dose group was significantly reduced (P < 0.05), and the therapeutic effects of the two groups were comparable.

[0145] The results of interleukin-6 (IL-6) test are shown in Table 18. Compared with the blank control group, the IL-6 concentration in the model control group was significantly increased (P < 0.05). Compared with the model control group, the IL-6 concentration in the high-dose Yangyin Shugan Capsule group was significantly reduced (P < 0.05), while there was no statistical difference in IL-6 concentration between the Bujiale group and the medium- and low-dose Yangyin Shugan Capsule groups (P > 0.05), indicating that the Yangyin Shugan group can improve the level of the immune indicator IL-6 better than the hormone control group.

[0146] Table 18 Effect of Yangyin Shugan Capsule on CD4 and TH-17 concentrations in serum

[0147]

[0148] Note: Compared with the blank control group, * indicates P < 0.05, ** indicates P < 0.01; compared with the model control group, # indicates P < 0.05, ## indicates P < 0.01.

[0149] Tip: Yin-nourishing and liver-soothing drugs can protect ovarian function while also better protecting the immune system dysfunction caused by ovarian dysfunction, improving immune-related indicators, and are helpful in improving the body's immunity and disease resistance.

[0150] 5. Security Analysis

[0151] (1) Clinical safety testing: Before and after treatment, both groups of patients were tested for safety indicators such as blood, urine, liver function (alanine aminotransferase), kidney function (urea, creatinine), and electrocardiogram. The results showed that there were no obvious abnormalities in the safety indicators of both groups of patients; no adverse events occurred (see Tables 19-20 for details).

[0152] (2) Safety testing of animal experiments: No abnormalities were found in the urine routine, blood routine and blood biochemistry (liver and kidney function) tests of all experimental rats after treatment.

[0153] This suggests that Yangyin Shugan Granules are safe in clinical application.

[0154] Table 19 Effect of Yangyin Shugan Capsule on the number of abnormal urine indicators in rats

[0155]

[0156] Table 20 Effects of Yangyin Shugan Capsule on various blood indexes of rats

[0157]

[0158] The above are only some specific embodiments of the present invention. For those skilled in the art, several modifications and improvements can be made without departing from the creative concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. Application of Yin-nourishing and liver-soothing drugs in the preparation of drugs for preventing and treating multi-system degenerative lesions caused by POI, wherein: The raw materials of the Yin-nourishing and liver-soothing medicine include, by weight: 10-30 parts of raw rehmannia, 10-30 parts of white peony root, 5-30 parts of bupleurum, 10-30 parts of curcuma, 5-30 parts of cyperus, 10-30 parts of yam, and 10-30 parts of red peony root.

2. The use according to claim 1 or 2, characterized in that: The raw materials of the Yin-nourishing and liver-soothing medicine include, by weight: 10-30 parts of raw rehmannia, 10-20 parts of white peony root, 5-15 parts of bupleurum, 10-15 parts of curcuma, 5-15 parts of cyperus, 10-30 parts of yam, and 10-15 parts of red peony root.

3. The use according to claim 1 or 2, characterized in that: The multi-system degenerative lesions include reproductive endocrine system disorders, mental and nervous system degenerative lesions, cardiovascular system degenerative lesions, and immune system dysfunction.

4. The use according to claim 3, characterized in that: The degenerative lesions of the mental and nervous system include insomnia, anxiety, depression, irritability, panic, and memory loss.

5. The use according to claim 3, characterized in that: The degenerative lesions of the cardiovascular system include dyslipidemia, precordial tightness, shortness of breath, fatigue, and palpitations.

6. The use according to claim 1 or 2, characterized in that: The syndrome type of the POI is kidney deficiency and liver depression.

7. The use according to claim 1 or 2, characterized in that: The Cyperus rotundus is obtained by vinegar moxibustion.

8. The use according to claim 1 or 2, characterized in that: The dosage form of the yin-nourishing and liver-soothing medicine is capsule, granule, tablet, powder, granule or decoction.

9. The use according to claim 1 or 2, characterized in that: The yin-nourishing and liver-soothing medicine also includes pharmaceutically acceptable excipients.

10. The use according to claim 1 or 2, characterized in that: The auxiliary material is at least one of a sustained-release agent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption promoter, an adsorption carrier, a surfactant, and a lubricant.

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