Application of Dan'e Fukang preparation in preparation of medicine for treating polycystic ovarian syndrome

Abstract

The invention belongs to the technical field of traditional Chinese medicines, and particularly relates to application of a Dan'e Fukang preparation in preparation of a medicine for treating polycystic ovarian syndrome. The invention provides application of a Dan'e Fukang preparation in preparation of a medicine for treating polycystic ovarian syndrome. Animal experiments are carried out on a polycystic ovarian syndrome mouse model by adopting the Dan'e Fukang decoction, and the Dan'e Fukang decoction is proved to be capable of treating insulin resistance, effectively recovering regular estrus cycle, improving ovarian function state, improving high male symptom and promoting ovulation; and more medication choices are provided for clinical treatment of polycystic ovarian syndrome diseases.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of traditional Chinese medicine, and particularly relates to application of Dan'e Fukang preparation in preparation of a medicine for treating polycystic ovary syndrome. BACKGROUND

[0002] Polycystic ovary syndrome (PCOS) is an endocrine disorder syndrome with coexisting abnormal reproductive and metabolic functions. It is mainly manifested in menstrual disorder, no or rare ovulation, high androgen level, and polycystic-like change of ovary. Polycystic ovary syndrome causes symptoms such as reduced fertility, menstrual disorder, obesity and the like in women of childbearing age, and has significant metabolic influence. Hyperandrogenism and insulin resistance are typical clinical symptoms.

[0003] At present, the treatment of polycystic ovary syndrome mainly includes surgical treatment and drug treatment. The surgery is ovary puncture, but it has poor curative effect, many complications, and affects ovary reserve, and is rarely used at present; the drug treatment mainly uses oral hormone drugs, such as: hyperandrogenism treated by diane-35; oral contraceptive for adjusting menstrual cycle; metformin for treating insulin resistance; and citrate clomiphene for promoting ovulation. Since each drug is only symptomatic treatment, the curative effect is poor, and there are many complications, so at present, there is lack of effective comprehensive treatment drug for polycystic ovary syndrome.

[0004] Dan'e Fukang decoction is derived from a Yi medicine formula, which is prepared from Radix Salviae Miltiorrhizae, Curcuma zedoary, Bupleurum smithii, Panax notoginseng, Radix Paeoniae Rubra, Angelica sinensis, Sparganium stoloniferum, Rhizoma Cyperi, Corydalis, and Glycyrrhiza, and has the effects of activating blood and resolving stasis, soothing liver and regulating qi, regulating menstruation and relieving pain, and softening and resolving accumulation. It is used for treating menstrual disorder, dysmenorrhea, and menstrual discomfort caused by blood stasis and obstruction in women. At present, there is no relevant report on Dan'e Fukang decoction for treating polycystic ovary syndrome. SUMMARY

[0005] The application aims to provide a new medical use of Dan'e Fukang preparation.

[0006] The application provides application of Dan'e Fukang preparation in preparation of a medicine for treating polycystic ovary syndrome.

[0007] Further, the Dan'e Fukang preparation is Dan'e Fukang decoction.

[0008] Further, the polycystic ovary syndrome is hyperandrogenism-induced polycystic ovary syndrome.

[0009] Further, the polycystic ovary syndrome is insulin resistance-induced polycystic ovary syndrome.

[0010] The ingredients of Dan'e Fuke Kang decoction are purple salvia miltiorrhiza, curcuma, bupleurum, panax notoginseng, red peony root, angelica, sparganium, cyperus, corydalis, and licorice.

[0011] Purple salvia miltiorrhiza is the dried root of Salvia przewalskii Maxim. or Salvia przewalskii Maxim. var. mandarinorum (Diels) Stib. of Labiatae. It tastes bitter and cold, and returns to the heart and liver meridians. It can activate blood and resolve stasis, regulate menstruation and relieve pain, and clear the heart and relieve restlessness. It is used for irregular menstruation, amenorrhea and painful menstruation, accumulation of masses, chest and abdominal pain, heat and pain, restlessness and insomnia, and abscesses and sores.

[0012] Curcuma phaeocaulis Val., Curcuma kwangsiensis S.G.Lee et C.F.Liang or Curcuma wenyujin Y.H.Chen et C.Ling of Zingiberaceae. It has the effects of promoting blood flow and resolving stasis, and removing accumulation and relieving pain. It tastes bitter and warm, and returns to the liver and spleen meridians. It is used for accumulation of masses, blood stasis and amenorrhea, chest pain, and food accumulation and abdominal pain.

[0013] Dried whole grass of Bupleurum marginatum Wall. ex DC., Bupleurum microcephalum Diels. and Bupleurum tenue Buch.-Ham. ex D.Don of Umbelliferae. It tastes bitter and cold, and returns to the liver and gallbladder meridians. It can resolve the exterior and interior, soothe the liver, and raise yang. It is used for cold and heat, chest and abdominal pain, irregular menstruation, uterine prolapse, and prolapse of the anus.

[0014] Panax notoginseng (Burk.) F.H.Chen of Araliaceae. It tastes bitter and warm, and returns to the liver and stomach meridians. It can stop bleeding, remove stasis, and relieve pain. It is used for hemoptysis, hematemesis, metrorrhagia, uterine bleeding, external trauma, chest and abdominal pain, and contusion and pain.

[0015] Red peony root is the dried root of Paeonia lactiflora Pall. or Paeonia veitchii Lynch of Ranunculaceae. It tastes bitter and cold, and returns to the liver meridian. It can clear heat and cool blood, and remove stasis and relieve pain. It is used for heat entering the blood, warm toxin and rash, hemoptysis and hematochezia, red and swollen eyes, liver stagnation and hypochondriac pain, amenorrhea and painful menstruation, abdominal masses, contusion and pain, abscesses and sores.

[0016] Angelica sinensis (Oliv.) Diels is the dried root of Angelica sinensis (Oliv.) Diels. It is sweet and pungent, and warm. It belongs to the liver, heart and spleen channels. It can tonify blood, regulate menstruation, relieve pain, moisten the intestines and relieve constipation. It is used for blood deficiency, dizziness, palpitation, irregular menstruation, amenorrhea, dysmenorrhea, cold abdominal pain, rheumatism, sprains, carbuncles and sores.

[0017] Sparganium stoloniferum Buch.-Ham. is the dried tuber of Sparganium stoloniferum Buch.-Ham. It is pungent and bitter, and neutral. It belongs to the liver and spleen channels. It can break blood, move qi, resolve accumulation and relieve pain. It is used for masses, dysmenorrhea, blood stasis, chest pain, food accumulation and abdominal pain.

[0018] Cyperus rotundus L. is the dried rhizome of Cyperus rotundus L. It is pungent, bitter and slightly sweet, and neutral. It belongs to the liver, spleen and Sanjiao channels. It can soothe the liver, relieve stagnation, regulate qi and relieve pain. It is used for liver stagnation, chest and hypochondriac pain, hernia pain, breast pain, spleen and stomach qi stagnation, abdominal distension and pain, irregular menstruation and dysmenorrhea.

[0019] Corydalis yanhusuo W.T.Wang is the dried tuber of Corydalis yanhusuo W.T.Wang. It is pungent and bitter, and warm. It belongs to the liver and spleen channels. It can invigorate blood, move qi and relieve pain. It is used for chest and abdominal pain, chest pain, dysmenorrhea, postpartum blood stasis and sprains.

[0020] Glycyrrhiza uralensis Fisch., Glycyrrhiza inflata Bat. or Glycyrrhiza glabra L. is the dried root and rhizome of Glycyrrhiza uralensis Fisch., Glycyrrhiza inflata Bat. or Glycyrrhiza glabra L. It is sweet and neutral. It belongs to the heart, lung, spleen and stomach channels. It can tonify the spleen and invigorate qi, clear heat and resolve toxins, relieve cough and relieve pain, and harmonize various drugs. It is used for spleen and stomach weakness, fatigue, palpitation, cough and phlegm, abdominal and limb pain, carbuncles and sores, and drug toxicity and virulence.

[0021] The Dan'e Fukang decoction can be purchased from commercially available products, or it can be prepared by the method of national drug standard WS-10227 (ZD-0227) 2002-2012Z-2016. The Dan'e Fukang decoction is used for animal experiments on polycystic ovary syndrome mouse models, and the Dan'e Fukang decoction has obvious therapeutic effect on polycystic ovary syndrome mice. The application finds that the Dan'e Fukang decoction not only can treat insulin resistance, but also can effectively restore regular estrous cycle, improve ovarian function, improve hyperandrogenism, and promote ovulation, thereby providing more drug selection for the clinical treatment of polycystic ovary syndrome. Detailed Implementation

[0022] The present invention will be further described in detail below through specific embodiments. All drugs and reagents involved in the specific embodiments are commercially available.

[0023] Example 1

[0024] The Dan'e Fuke Decoction was prepared according to the national drug standard WS-10227(ZD-0227)2002-2012Z-2016, as follows: 450g of Salvia miltiorrhiza, 250g of Curcuma zedoaria, 250g of Bupleurum chinense, 150g of Panax notoginseng, 250g of Paeonia lactiflora, 250g of Angelica sinensis, 175g of Sparganium stoloniferum, 150g of Cyperus rotundus, 175g of Corydalis yanhusuo, and 100g of Glycyrrhiza uralensis.

[0025] The above ten herbs—Salvia miltiorrhiza, Curcuma zedoaria, Panax notoginseng, Angelica sinensis, and Corydalis yanhusuo—were soaked in 70% ethanol for 24 hours. The mixture was then percolated at a rate of 2–4 mL per minute, collecting approximately 5800 mL of the percolate. The ethanol was recovered under reduced pressure and concentrated to a thick paste with a relative density of 1.30–1.35 (50°C). The dregs were then decocted twice with the remaining five herbs, including Bupleurum chinense, for 2 hours each time. The decoctions were combined, filtered, and the filtrate was concentrated to a thick paste with a relative density of 1.30–1.35 (50°C). The two thick pastes were combined, and an appropriate amount of refined honey-refined sugar (100:165) and 3 g of potassium sorbate were added. The mixture was stirred until it reached 1000 g, which is the final product.

[0026] Example 2: Pharmacological Experiment

[0027] 1. Experimental Materials

[0028] 1.1 Laboratory Animals

[0029] Female C57 mice (Beijing Vital River Laboratory Animal Technology Co., Ltd.) were housed in an SPF-grade animal facility. The facility was maintained at an ambient temperature of 22–24°C and a humidity of 55%–65%. The lighting environment consisted of alternating 12-hour light and 12-hour dark cycles. The mice had free access to food and water.

[0030] 1.2 Experimental reagents and materials:

[0031] Dan'e Fuke Decoction (Yunnan Shengke Pharmaceutical Co., Ltd., National Drug Approval Number: Z20025253, Specification: 150g / bottle), Modeling Drug: Dehydroepiandrosterone (Shaanxi Huicheng Biotechnology Co., Ltd., 10g / bottle, Batch No.: 20200813, Content ≥99.5%), is prepared according to the ratio of 45mg dehydroepiandrosterone to 10mL sesame oil. It is used after the drugs are completely dissolved.

[0032] 2. Experimental Methods

[0033] To induce polycystic ovary syndrome, 3-week-old female prepubertal C57 mice were injected subcutaneously with 6 mg / 100 g dehydroepiandrosterone daily for 21 days to successfully model the mice. The successful modeling of polycystic ovary syndrome mice was marked by irregular estrous cycles, high androgens, polycystic ovaries, anovulation, and symptoms of glucose tolerance and insulin resistance.

[0034] Ten normal non-modeled mice were taken as a blank control group; the successfully modeled polycystic ovary syndrome mice were randomly divided into four groups, namely, a model group, a low-dose Dan'e Fujun group, a medium-dose Dan'e Fujun group, and a high-dose Dan'e Fujun group, each group having 10 mice. The blank control group and the model group were given normal saline by gavage; the human clinical dosage was 10-15 g at a time, twice a day, and the highest daily dosage for humans was 30 g, which was equivalent to 4.55 g / kg for mice (dose conversion mice: human = 9.1: 1), and the equivalent dose was set as the medium dose, 1 / 2 of the medium dose was the low dose, and 2 times the medium dose was the high dose. Therefore, the low-dose Dan'e Fujun group (2.275 g / kg), the medium-dose Dan'e Fujun group (4.55 g / kg), and the high-dose Dan'e Fujun group (9.1 g / kg) were administered to the mice by gavage. After 21 days of continuous gavage, the fasting blood glucose value of each mouse was detected, and the estrous cycle was determined by vaginal smear test; four mice from each group were injected intraperitoneally with PMSG and HCG, then sacrificed by cervical dislocation, and the number of MII oocytes in the ampulla was counted; the remaining mice were taken for serum sex hormone level detection, and the ovaries were embedded with paraffin, and the number of corpus luteum and cysts was counted after slicing and HE staining.

[0035] The values in all the following tables are mean + standard error, * statistically significant compared with the control group; ** statistically significant compared with the control group; *** extremely statistically significant compared with the control group; # statistically significant compared with the model group, ## statistically significant compared with the model group, ### extremely statistically significant compared with the model group.

[0036] 3. Experimental results

[0037] (1) General condition: The blank control group, the model group, and the low-, medium-, and high-dose Dan'e Fujun groups all developed well, with shiny fur, no obvious differences in behavior characteristics, and sensitive reactions.

[0038] (2) Estrus cycle test: After intragastric administration of Dan'e Fukang decoction, the estrus cycle disorder caused by polycystic ovary syndrome was improved. According to the different estrus cycle time, there was a significant difference between the low, medium and high dose groups of Dan'e Fukang and the placebo group. The experimental data is shown in Table 1.

[0039] Table 1 Effect of Dan'e Fukang decoction on estrus cycle of polycystic ovary syndrome mice

[0040]

[0041] (3) Ovulation statistics: As shown in Table 2, the number of oocytes in mice with polycystic ovary syndrome decreased significantly after intragastric administration of Dan'e Fukang decoction.

[0042] Table 2 Effect of Dan'e Fukang decoction on ovulation number of polycystic ovary syndrome mice

[0043] Group n Number of ovulation Control group 4 22±6 Model group 4 5±3*** Dan'e Fukang low-dose group 4 6±4 Dan'e Fukang medium-dose group 4 8 ± 2 # ]] Dan'e Fukang high-dose group 4 16 ± 2 ## ]]

[0044] (4) Fasting blood glucose value determination:

[0045] After fasting for 12 hours, the mice were injected with 2g / kg of glucose, and the blood glucose value was measured at 0min, 15min, 30min, 60min, and 90min. It was found that the glucose tolerance of polycystic ovary syndrome mice was significantly improved by Dan'e Fukang decoction. After 3 days, the mice were fasted for 12 hours, and then injected with 1IU / kg of insulin. The blood glucose value was measured at 0min, 15min, 30min, 60min, 90min, and 120min. Dan'e Fukang decoction could improve the symptoms of insulin resistance in polycystic ovary syndrome mice. The results are shown in Tables 3 and 4.

[0046] Table 3 Effect of Dan'e Fukang decoction on glucose tolerance of polycystic ovary syndrome mice

[0047]

[0048] Table 4 Effect of Dan'e Fukang decoction on insulin tolerance of polycystic ovary syndrome mice

[0049]

[0050]

[0051] (5) Ovary follicle count: As shown in Table 5, compared with the blank control group, the number of cysts increased and the number of corpus luteum decreased significantly in the model group. Compared with the model group, the number of cysts decreased and the number of corpus luteum increased in each dose group of Dan'e Fukang decoction, which could effectively improve the polycystic ovary of polycystic ovary syndrome mice.

[0052] Table 5 Effect of Dan'e Fuke Kang Decoction on the number of cysts and corpus luteum in mice with polycystic ovary syndrome

[0053] Group n Number of cysts Number of corpus luteum Control group 10 0 7.24±1.31 Model group 10 4.35±0.62** 3.62±1.38*** Dan'e Fukang low-dose group 10 2.37 ± 0.43 # ]] 4.88 ± 0.28 # ]] Dan'e Fukang medium-dose group 10 1.61 ± 0.69 ## ]] 6.18 ± 0.46 ### ]] Dan'e Fukang high-dose group 10 1.89 ± 0.37 ## ]] 5.34 ± 0.23 ## ]]

[0054] Example 3 Clinical trial

[0055] 1. Clinical data: 36 patients with polycystic ovary syndrome were collected from January 2021 to May 2022 in the gynecological clinic of Chengdu High-tech Good Doctor First Hospital. The patients were aged 25-38 years, and the disease duration was 1-5 years.

[0056] 2. Inclusion criteria: (1) meet the relevant diagnostic criteria for polycystic ovary syndrome in Western medicine, long-term anovulation, biochemical examination shows that the body's androgen level is increased, and the ovary shows polycystic changes. (2) meet the standard of TCM kidney deficiency type, the main symptoms are soreness of waist and knees, black spicule skin, irregular menstruation or amenorrhea, obesity; secondary symptoms are chest and abdominal distension, edema, aversion to cold, pale and dark menstrual color, body fatigue; tongue is dim and pale, greasy fur, and slow pulse. Main symptoms > 2, secondary symptoms 23, combined with tongue and pulse can be diagnosed. (3) Age 20-40 years old. (4) Have normal sex life, and the male reproductive function is normal. (5) Infertility for 21 years. (6) Complete clinical data.

[0057] 3. Exclusion criteria: other high androgen causes, infertility caused by immune, tubal obstruction, congenital physiological defects, deformities, etc., combined with endocrine diseases such as thyroid, pituitary, adrenal glands, liver and kidney dysfunction, drug contraindications, blood system diseases.

[0058] 4. Drug treatment: 36 patients with polycystic ovary syndrome used Dan'e Fuke Kang Decoction (Yunnan Shengke Pharmaceutical Co., Ltd., National Drug Standard Code: Z20025253, specification: 150g / bottle), oral, 15g each time, 2 times a day, continuous treatment for 30-45 days, diagnosis and observation of patient treatment.

[0059] 5. Efficacy evaluation criteria:

[0060] Effective: high androgen related symptoms disappeared, and menstruation returned to normal;

[0061] Marked effect: high androgen related symptoms were significantly improved and controlled, and menstrual status was significantly improved;

[0062] No effect: compared with before treatment, the symptoms were not improved or the improvement was not obvious.

[0063] The results showed that among the 36 patients with polycystic ovary syndrome, 22 were cured, 11 were effective, 3 were ineffective, and no accidents occurred. The treatment effect was significant and safe and effective.

[0064] 6. Typical cases

[0065] Patient Zhang, female, 27 years old, irregular menstruation, cycle 45-60 days, menstrual period 4-6 days, little amount of menstruation, dark red color, no pain, hair loss, more body hair on chest and arms, acne on face, diagnosed with polycystic ovary syndrome. After using the Dan'e Fukang decoction of the application for continuous treatment for 30 days, the facial acne was obviously controlled, the menstruation returned to normal, no recurrence after 6 months of follow-up, the hair loss symptoms were obviously controlled, and the treatment effect was obvious.

[0066] Patient Li, female, 30 years old, obese, more leg hair. The patient had menarche at 14 years old, and since then, the menstruation came once every 2-3 months. The patient had been trying to get pregnant for three years since marriage, but failed. The vaginal ultrasound examination showed that the endometrial thickness was 5mm, the left ovary was 4.4cm x 2.3cm x 2.6cm, the right ovary was 5.3cm x 4.1cm x 2.1cm, and more than 12 2-9mm small follicles were found in the bilateral ovaries, which was diagnosed as polycystic ovary syndrome. After continuous use of the Dan'e Fukang decoction of the application for 60 days, the menstrual cycle was basically normal, and after another 2 months of continuous use, the B-ultrasound showed that the size of the bilateral ovaries was normal. After follow-up, the patient got pregnant 6 months after stopping the drug.

Claims

1. Application of Dan'e Fujun preparation in the preparation of a drug for treating polycystic ovary syndrome.

2. Use according to claim 1, characterized in that: The Dan'e Fujun preparation is Dan'e Fujun decoction.

3. Use according to claim 1, characterized in that: The polycystic ovary syndrome is high androgen-induced polycystic ovary syndrome.

4. Use according to claim 1, characterized in that: The polycystic ovary syndrome is insulin resistance-induced polycystic ovary syndrome.

Images