CN111773221A

CN111773221A - Application of sinomenine and derivatives or pharmaceutically acceptable salts thereof in preparing medicine for treating breast diseases

Info

Publication number: CN111773221A
Application number: CN202010704260.2A
Authority: CN
Inventors: 李蕴麟
Original assignee: Individual
Current assignee: Individual
Priority date: 2020-07-21
Filing date: 2020-07-21
Publication date: 2020-10-16
Anticipated expiration: 2040-07-21
Also published as: CN111773221B

Abstract

The invention relates to the technical field of treatment of breast diseases, in particular to application of sinomenine and derivatives or pharmaceutically acceptable salts thereof in preparation of medicaments for treating breast diseases. In the medical treatment process, the inventor unexpectedly finds that the sinomenine has better curative effect on the mammary gland diseases, can effectively relieve the mammary gland pain symptom of the mammary gland hyperplasia patients for a long time, can gradually soften the mammary gland nodules of the mammary gland hyperplasia patients, and has short onset time.

Description

Application of sinomenine and derivatives or pharmaceutically acceptable salts thereof in preparing medicine for treating breast diseases

Technical Field

The invention relates to the technical field of treatment of breast diseases, in particular to application of sinomenine and derivatives or pharmaceutically acceptable salts thereof in preparation of medicaments for treating breast diseases.

Background

The hyperplasia of mammary glands is hyperplasia and degeneration of mammary glands, about 50-70% of the urban professional women suffer from hyperplasia of mammary glands with different degrees, and is one of the common diseases troubling the women, the expert consensus of the hyperplasia of mammary glands comprises ① hyperplasia of mammary glands is a benign mammary gland disease (BBD) caused by the abnormality of normal development and degeneration process (ANDI) of mammary glands, ② is essentially the normal structural disorder of mammary glands caused by hyperplasia of mammary glands with different degrees and subinvolution of mammary glands and involution insufficiency^[1]。

The current treatment principles are as follows: the combination of sufficient individual psychology and drug intervention, necessary biopsy and appropriate surgical excision is an effective treatment mode for hyperplasia of mammary glands. Different clinical manifestations and pathological types should be treated separately during treatment. Psychological persuasion and life habit change are mainly performed on patients with mild to moderate pain, and persistent severe breast painThe patient can be treated by medication. The therapeutic drug is: the hormone medicine, the iodine preparation and the tamoxifen can relieve pain, and are not preferred due to certain side effects^[1]. However, it should be noted that the drug treatment can not effectively relieve the pathological changes of the hyperplasia of mammary glands and can not play a radical role.

Disclosure of Invention

The invention aims to provide the application of sinomenine and derivatives or pharmaceutically acceptable salts thereof in preparing medicaments for treating breast diseases.

In order to achieve the above purpose of the present invention, the following technical solutions are adopted:

the use of sinomenine or its pharmaceutically acceptable salt, sinomenine derivative or its pharmaceutically acceptable salt in preparing medicine for treating mammary gland diseases is provided.

For breast diseases, the reason for the poor efficacy of the current conventional therapies is the excessive focus on the hyperplasia of the breast glands and neglecting the changes in the interstitial structure of the breast. In the medical treatment process, the inventor unexpectedly finds that the sinomenine has better curative effect on the mammary gland diseases, can effectively relieve the mammary gland pain symptom of the mammary gland hyperplasia patients for a long time, can gradually soften the mammary gland nodules of the mammary gland hyperplasia patients, and has short onset time.

Wherein, the sinomenine derivative still has the active group of sinomenine and may have the effect basically consistent with or better than that of the sinomenine. For example, the sinomenine derivative can be as described in application No.: sinomenine derivatives disclosed in CN201110453180.5, publication No.: sinomenine derivatives disclosed in WO2011098035A1, and the like.

The breast diseases in the present invention are not limited to humans, and may be other mammals.

Further, the breast disease is a disease caused by hyperplasia of mammary gland septal fibrous connective tissue.

Further, the breast disease includes hyperplasia of mammary glands.

Further, the hyperplasia of mammary glands comprises mastopathy and cystic hyperplasia of breast.

Clinically, breast diseases have different symptoms, i.e., each patient has more than one associated symptom.

Further, the mammary gland adenopathy comprises one or more of lobular hyperplasia type, fibroglandular disease type and sclerosing gonadal disease type;

the cystic hyperplasia of breast comprises one or more of cyst, ductal epithelial hyperplasia, caecal adenopathy, and hyperhidrosis adenosis.

Common symptoms of hyperplasia of mammary glands are periodic or aperiodic pain, breast nodules.

A method of treating a breast condition comprising administering to a subject an effective amount of sinomenine or a pharmaceutically acceptable salt thereof, a sinomenine derivative or a pharmaceutically acceptable salt thereof.

Or sinomenine or its pharmaceutically acceptable salt, sinomenine derivative or its pharmaceutically acceptable salt can be used for treating mammary gland diseases.

Wherein an effective amount is an amount of a therapeutic agent that treats, ameliorates, or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect. The precise effective amount for a subject will depend upon the size and health of the subject, the nature and extent of the symptoms, and the therapeutic agent and/or combination of therapeutic agents selected for administration. The administration may be oral, intramuscular, topical, intravenous, intracorporeal or transdermal, and the specific dosage and mode of administration may be determined by a physician in the light of the patient in need of treatment.

Further, the medicine also comprises pharmaceutically acceptable auxiliary materials.

Further, the auxiliary materials include any one or more of wetting agents, emulsifiers, diluents, excipients, fillers, disintegrants, binders, lubricants, surface active agents, flavoring agents, stabilizers and the like.

Further, the dosage forms of the medicine comprise oral preparations and injections.

Further, the oral preparation comprises tablets, granules, pills, capsules, paste and syrup.

Further, the injection includes a solution type and a powder type.

The pharmaceutical dosage form provided by the invention is prepared according to the conventional method in the field. For example, in order to prepare the sinomenine or pharmaceutically acceptable salt thereof, sinomenine derivative or pharmaceutically acceptable salt thereof as an active ingredient into a tablet, various pharmaceutically acceptable auxiliary materials known in the art, such as a diluent, a binder, a wetting agent, a disintegrant, a lubricant, a glidant and the like can be used; the diluent can be starch, dextrin, sucrose, lactose, mannitol, xylitol, microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, etc.; the disintegrant may be microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.

The tablets may be further formulated into coated tablets, such as film-coated tablets, enteric-coated tablets, sugar-coated tablets, or double-layer and multi-layer tablets.

Such as: in order to prepare the medicament into capsules, the effective component of the invention can be mixed with a diluent and a glidant, and the mixture is directly placed into hard capsules or soft capsules. Or mixing the effective components with diluent, binder, and disintegrating agent, making into granule or pellet, and placing into hard capsule or soft capsule. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compound tablets of the present invention may also be used to prepare capsules of the compound of the present invention.

For another example: in order to prepare the active ingredients of the invention into injection, water, ethanol, propylene glycol or the mixture of the water, the ethanol and the propylene glycol can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be lecithin, hydroxypropyl-beta-cyclodextrin and the like; the pH regulator can be acetate, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.

In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.

Further, the medicament is administered intravenously or intramuscularly or locally.

For example, intravenous drip is given for 1 time every day, and 7 days is a treatment course, and can be used for 2-3 treatment courses. The intravenous drip administration principle is that the medicine is slowly dripped from small dose, the first time is started from 100mg, the daily increment is 50mg, the maximum dose of the 1 st course is controlled to be 4-5mg/kg, and the maximum dose of the 2 nd to 3 rd courses is controlled to be 5-6 mg/kg.

In the present invention, the local injection is generally an injection into a joint or soft tissue. Intravenous administration and intramuscular injection are administered according to conventional medical regulations.

Compared with the prior art, the invention has at least the following beneficial effects:

(1) the invention discovers that the sinomenine or the pharmaceutically acceptable salt thereof and the sinomenine derivative or the pharmaceutically acceptable salt thereof have good curative effect on the breast diseases for the first time.

(2) The sinomenine is used for treating the mammary gland diseases, and the discovery shows that the pain of the mammary gland is obviously relieved, the mammary gland nodules are softened, and the recurrence is avoided after the follow-up visit for half a year.

Detailed Description

Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

About 50% -70% of urban occupational women suffer from different degrees of hyperplasia of mammary glands, one of the common conditions that afflict women.

1. Functional dissection of mammary gland

The mammary gland has 15-25 glandular lobes, each glandular lobe is divided into a plurality of glandular lobules, and the glandular lobules consist of small mammary ducts and acinus and are basic units of the mammary gland. The separate duct (duct) for transporting milk from each glandular lobe is formed by the convergence of a plurality of small ducts, and the ducts are radially opened at the nipple. The mammary gland lobes, lobules and acini of the breast have connective tissue spaces therebetween, and there are also fibrous bundles perpendicular to the skin between the lobes, which are called Cooper ligaments, above the superficial fascia superficial layer and below the superficial fascia deep layer. The composition of the mammary connective tissue compartment varies from site to site: the gland between mammary gland lobes and between gland lobules has a more compact connective tissue interval, and the gland lobules is the extension of the former, has less fibroblasts and more fibrous components; loose connective tissue is arranged in the lobules of the gland, the cell components are more, the collagen fiber is less, and the extension and the proliferation of the small mammary ducts and the acinus in the gestation and lactation period are facilitated.

From the functional point of view, the lactation function of the mammary gland is cooperatively completed by acinus, small mammary ducts, mammary ducts and nipples, the cell sources are epithelial tissues, the mammary gland mesenchyme is composed of dense connective tissues, loose connective tissues and fat cells, and structural support is provided for the radial distribution of glandular lobes.

The physiological function of the mammary gland is influenced by the secretion of hormones such as pituitary gland, ovary and adrenal cortex:

the hyperplasia of small mammary ducts and acini in the lactation period is obvious, the acini is filled with secretion, and the blood vessels in connective tissues are increased. If the ducts and ducts are unobstructed, the milk secreted by the acinus will be discharged in time without causing accumulation of secretions.

② the glandular lobular epithelial tissue in the resting stage can have periodic change along with the menstrual cycle: the epithelial basement membrane is thickened in the premenstrual period, the acinar cavity is increased in diameter and contains a small amount of secretion, and the interstitial connective tissue of the mammary gland is congested, edematous and infiltrated by lymphoid tissues and plasma cells, so that the volume of the mammary gland is increased; during the menstrual period, acinar epithelial cells degenerate and decrease, acinar cavities become narrow, acinar becomes a nearly solid cord, and the volume of mammary gland is reduced.

2. Pathology of hyperplasia of mammary glands

The hyperplasia of mammary glands is divided into two types of mastopathy and cystic hyperplasia of breast:

mammary gland acini and ductus of mammary gland hyperplasia, and have different degrees of connective tissue hyperplasia, lobule structure basically loses normal form. It is divided into 3 subtypes, namely lobular hyperplasia type, fibroglandular disease type and sclerosing gonadal disease type. Lobular hyperplasia type lobular ductus interna and acinus are hyperplastic, fibrous tissue is slightly hyperplastic, and can be seen in lymphocyte infiltration, and the lobular boundary is clear; fibroglandular ducts and fibrous tissues in lobular gland disease type further proliferate with lymphocyte infiltration, lobular structural disorder, glandular duct epithelial hyperplasia is in multilayer or forms papilla, sieve shape or even fills lumen, lobular ducts expand to form microcapsules; fibrous tissue in the hardened gonadal lobule is hyperproliferated to cause the atrophy and disappearance of the vacuole, the gland duct is extruded, distorted and deformed, the epithelial cell volume is reduced and deeply stained, but the cells have no abnormal shape^[1]。

The cystic hyperplasia of breast duct epithelial hyperplasia, the lumen enlarges, can form cysts of different sizes, and the cyst content is mostly yellowish, colorless or milk white serous fluid. It is divided into 4 subtypes, namely cyst, ductal epithelial hyperplasia, cecum adenopathy, and hyperhidrosis adenoids. Cysts are mainly formed by high expansion of a tail end catheter, and the wall of the cyst is lined with cubic epithelium; the duct epithelial hyperplasia is that the duct is thickened, epithelial cells are layered and the lumen is reduced; the cecum adenopathy is formed by the expansion of small ducts or peripheral ducts, and the lumen generally has no secretion; the lining epithelium of the large sweat gland-like cyst is in the shape of high column, large cell body, small and round nucleus, is positioned at the bottom of the cell, and the free edge can be seen as a small spherical bulge^[1]。

The above types can exist independently or simultaneously in the lobules of the mammary gland of the same patient, and the hyperplasia development of each lobule is not completely consistent^[1]。

3. Clinical manifestations

The main clinical manifestations of hyperplasia of mammary glands are mammary gland pain, nodular state or lump, and some patients have combined nipple discharge. Partial disease in early stage of diseaseThe pain that people complain about is the periodic pain associated with the menstrual cycle, most of which is aperiodic breast pain. Patients with cystic hyperplasia of the breast often have well-defined aperiodic pain. The breast nodule state includes granular nodules, funicular nodules, and localized or diffuse gonadal body thickening, etc., and there are usually a plurality of nodules which may involve bilateral mammary glands or single-shot mammary glands. The lump is generally small and irregular in shape, and can be enlarged, reduced or hardened and softened along with the periodic change of menstruation. 3.6-20.0% of the patients with nipple discharge, and the discharge is usually yellowish, colorless or milky serous fluid, with blood discharge rarely occurring^[1]。

4. The current therapeutic principle

The existing treatment of hyperplasia of mammary glands has three aspects, namely psychological treatment, hormone treatment and operative treatment.

The psychotherapy aims at intervening the functions of hypothalamus-pituitary-ovary axis through the activity of cerebral cortex, and has limited curative effect;

② the drug therapy anti-estrogen drugs inhibit the hyperplasia of mammary glands, tamoxifen (tamoxifen) is commonly used, but has more adverse reactions and is difficult to tolerate after long-term administration. These drugs do not alter the deformed lobular structure of the gland and have limited efficacy.

The operation treatment of the hyperplasia of mammary glands belongs to diffuse lesion, and the local surgical excision does not help to solve the fundamental problem.

And (4) conclusion: psychological, hormonal and surgical treatments recommended for hyperplasia of mammary glands have limited efficacy.

5. Analysis of causes of poor curative effect of hyperplasia of mammary glands

Functional understanding of mammary gland anatomy

From mammary gland anatomy, mammary gland interstitium is connective tissue, and dense connective tissue intervals are arranged between mammary gland lobes and between gland lobules, so that the gland lobes and the gland lobules are actually capsular bag-like structures formed by wrapping fibrous connective tissue membranes, and can be shrunk but can be slightly expanded.

Advantages of the pouch-like structure: firstly, providing structural support for the orderly arrangement of glandular lobes and glandular lobules to form a three-level tree-shaped branch structure of lactiferous ducts, lactiferous ducts and acini; secondly, the hyperproliferation of glands is limited, and structural tension is provided for acinus filled with secretion, so that milk is conveniently secreted; and thirdly, the compact fiber interval can prevent the lesion outside the structure from eroding into the structure, and vice versa.

Disadvantages of the pouch-like structure: firstly, the hyperproliferation and expansion of glands are limited from the outside, and mammary gland swelling pain is easily caused when acinus secretion is vigorous; ② the excessive proliferation of the fiber interval can extrude, distort or draw the mammary duct or tubule, leading to the obstruction of secretion discharge, namely the reduction of the smoothness of the mammary duct system or obstruction.

In lactation period, unsmooth duct discharge occurs, milk is deposited directly as a result, and mastitis is easily caused.

The clinical outcome of catheter malabsorption during the resting phase varies greatly depending on the course of the disease and the degree of compression. The initial stage of the disease is pain related to the menstrual cycle, the pathological manifestation is mainly lobular hyperplasia type, and the pathological mechanism is that the glandular ductus system is not completely blocked: increased secretion of glandular vesicles in the early period of menstruation, unsmooth catheter discharge, and increased internal pressure of glandular lobes or acini, manifested by distending pain of mammary glands; the acinus in menstrual period is atrophied, the secretion source is reduced, and the partial absorption of the secretion, the internal pressure of the glandular lobe or acinus is reduced, and the pain of mammary gland is relieved or disappeared. As the vessel becomes less open or obstructed, the secretions from the glandular lobes or acini accumulate and are not fully absorbed, and the high internal pressure is present for an extended period of time or continues, turning gradually into aperiodic pain. The lobular structure is disordered and the pathology is shown as fibroadenitis and/or sclerogonadal type due to hyperplasia caused by stimulation of glandular lobes and glandular lobular fiber intervals. When the mammary duct is completely blocked, secretion is not stopped because the hyperplastic change of acinus along the menstrual cycle is related to hormone level, and when the absorption speed is lower than the secretion speed, the secretion is continuously increased and gathered, and the pathological condition is cystic hyperplasia of breast, namely the cystic hyperplasia of breast which is clinically seen.

And (4) conclusion: the capsular bag-like structure of the mammary gland lobes is the structural basis that is prone to cause secretion obstruction.

The pathological manifestations can exist independently or simultaneously in different glandular lobes and lobules of the same patient, which indicates that the hyperplasia of mammary glands is the result of multifactorial diseases. Since the changes in the effects or morphological changes of the target organs due to hormonal changes are extensive and homogeneous, hormonal level changes cannot account for the differences in pathological manifestations in different parts of the same breast. The mammary gland is a lumen structure, and although secretion function is regulated by hormone level change, the realization of lactation must be the unobstructed state of a pipeline system, the two are harmonious and unified, and once the pipeline system is partially or completely blocked, partial or complete obstruction of secretion discharge is inevitably caused. From the viewpoint of obstruction, under the premise that the hormone level is relatively stable (during the childbearing age), the process of development from partial obstruction to complete obstruction is the process of gradual reduction of the patency of the mammary duct and the glandular tubule or even complete blockage, and is reflected in the pathological manifestation of the disease, namely the difference of the tissue structure related to the obstruction degree. Therefore, it can be said that the lobular hyperplasia, fibroglandular disease, sclerogonadal disease and cystic hyperplasia of breast seen in the pathological examination of hyperplasia of mammary glands are essentially different degrees and different stages of the same pathological process.

And (4) conclusion: hyperplasia of different pathological types occurring simultaneously in the mammary glands and lobules of the breast of the same patient cannot be considered to be caused by a single factor of hormonal level change, because the effect change or morphological change of the target organ caused by hormonal change is extensive and homogeneous.

And (4) conclusion: the difference of the pathological manifestations of hyperplasia of mammary glands is positively correlated with the degree of obstruction of the ducts and canaliculi of the mammary glands.

From the etiology of obstruction, there are only two possibilities, one is the hyperplasia of epithelial tissue on the inner wall of the duct caused by internal blockage, and the other is the hyperplasia of fibrous connective tissue on the periphery of the duct caused by squeezing and twisting the duct. The tissue and cell morphology seen in pathological expression have hyperplasia of different degrees, who gives priority to the disease after the disease is mature, and the rationality of the theory is verified by the only identification method through clinical treatment practice without accurate theory. The emphasis of current therapy is to inhibit the proliferation of glandular epithelium by hormonal drugs, but clinical practice has proven to be limited. Whether the treatment thought can be switched or not, and the curative effect can be obtained by inhibiting the chronic proliferation of the fibrous connective tissue, which is the key point of the invention.

6. Treatment method based on solving core pathological mechanism of hyperplasia of mammary glands

As mentioned above, the stationary breast acinus and lactiferous ducts are periodically proliferated and degenerated under the influence of menstrual cycle, and as long as the lactiferous ducts are unobstructed, a very small amount of secretion (including exfoliated epithelial cells) in the acinus can be naturally discharged, and the clinical manifestation is a small amount of secretion of the breast, which is a physiological phenomenon. If the milk delivery pipeline is unobstructed and limited, the secretion can not be discharged in time, which can cause hyperplasia of mammary glands with different pathological types. As the pathological analysis above, the chronic proliferative change of fibrous connective tissue can squeeze, twist or pull the milk duct, resulting in the limited patency of the milk duct, and it can be seen that the main cause of hyperplasia of mammary glands is the chronic proliferative change of fibrous connective tissue supporting the lobules and lobules of the mammary glands, so that the control and softening of the chronic proliferation of fibrous connective tissue is the core goal of treating hyperplasia of mammary glands.

It is considered that the pathological basis of controlling the chronic proliferative change of the mammary fibrosepta can not only prevent the occurrence and the development of the mammary hyperplasia, but also treat the mammary hyperplasia from the aspect of etiology.

And (4) conclusion: hyperplasia of fibrous connective tissue in the mammary gland space causes the patency of the ductal system of the mammary gland to be reduced or obstructed, which should be the core pathological mechanism of hyperplasia of mammary glands.

Examples of the experiments

The inventor surprisingly found that when the sinomenine is used for treating rheumatic diseases (inflammatory spondylopathy, spondyloarthropathy, rheumatoid arthritis and the like) and other antirheumatic drugs are combined, 16 female patients have the symptom of the combined hyperplasia of mammary glands and pain obviously improved. After further intensive research, the fact that another group of 5 patients with mammary gland hyperplasia are treated by sinomenine alone is found that the sinomenine also has obvious clinical curative effect, and the sinomenine is prompted to have definite therapeutic effect on the mammary gland hyperplasia.

The inventor summarizes 21 patients with neck, shoulder, waist and leg pain accompanied with hyperplasia of mammary glands in 2013 and 2020, wherein 7 patients are treated in Lanzhou city traditional Chinese medicine hospital, and 14 patients are treated in Western medicine of Zhuhai plum female disease in neck, shoulder, waist and leg pain clinic; women, age 31-49 years, are all associated with definite breast pain; periodic breast pain associated with the menstrual cycle was seen in 2 cases and aperiodic breast pain was seen in 19 cases. The pain is distending pain, aggravating in the menstrual period and multiple nodules when touched. 20 cases of bilateral mammary gland patients and 1 case of unilateral mammary gland patients. The diagnosis of 21 patients was confirmed by breast color ultrasound examination.

The treatment is as follows:

therapy 1

The local injection of sinomenine injection and the oral administration of sinomenine sustained release tablets are adopted for 12 patients (2 cases of periodic breast pain and 10 cases of aperiodic breast pain). The injection comprises sinomenine hydrochloride 35mg + 2% lidocaine 1 ml. The injection sites include cervical vertebra facet joints, thoracic vertebra facet joints and four-limb pathological change joints. Injecting 2-3 parts per day, and injecting one part every 40 minutes, wherein the dosage of sinomenine per part is 35mg, 7 days is a treatment course, and the interval period of the treatment course is 7 days, and 2-3 treatment courses are total. The sinomenine sustained release tablet is orally taken at intervals of the injection treatment course, 2 times a day, and each time is 120 mg.

Follow-up results

For 12 cases of patients treated by local injection of sinomenine and oral administration of sinomenine sustained release tablets, the pain of mammary gland is obviously relieved in 8 cases and 2 courses of treatment, the pain of mammary gland is obviously relieved in 3 cases and 3 courses of treatment, the breast nodules are gradually softened, and no obvious curative effect is obtained in 1 case. There was no recurrence in half a year of follow-up visit in 11 cases of respondents.

Therapy 2

9 patients received sinomenine intravenous injection treatment (4 cases are rheumatism diseases with hyperplasia of mammary glands, and 5 cases are simple hyperplasia of mammary glands). 7 days is a treatment course, and intravenous drip is carried out for 1 time every day for 2 treatment courses. The intravenous drip administration principle is slow drip from small dose, the maximum dose in the 1 st course is controlled at 4-5mg/kg, the maximum dose in the 2 nd to 3 rd courses is controlled at 5-6mg/kg, and the first dose is increased by 50mg from 100mg every day.

The specific daily dosage is as follows (taking 60kg patient as the 1 st course as an example):

day 1: 5% glucose injection and 100mg sinomenine hydrochloride intravenous drip;

day 2: 5% glucose injection and 150mg sinomenine hydrochloride intravenous drip;

day 3: 5% glucose injection and 200mg sinomenine hydrochloride intravenous drip;

day 4-7: 5% glucose injection and 250mg sinomenine hydrochloride intravenous drip.

The solution for diabetic patients is changed into normal saline.

The dropping speed during transfusion is as follows:

the dripping speed is controlled to be 20-30 drops/min in 0-10 min;

the dripping speed is controlled to be 30-40 drops/min in 11-20 min;

the dropping speed is controlled to be 40-50 drops/min in 21-30 min;

after 30 minutes, the maximum dropping speed is maintained at 50 drops/minute, and the dropping speed is not suitable to be increased randomly.

Adverse reactions and treatments (adverse reactions possibly occurring during infusion)

1) In the infusion process, if the dropping speed is too fast or the patient is sensitive in physique, transient skin redness, pruritus and wheal easily appear, which are normal phenomena, and after the dropping speed is reduced, symptoms disappear in 30 minutes mostly without special treatment.

2) If the skin is flush, itching, wheal and rash persist (more than 4 hours), the dosage of the former day should be reduced or maintained for continuous instillation until the symptoms disappear on the next day.

3) A few patients sustained flushing, itching, wheal, rash of the skin, and the symptoms disappeared after antihistamine treatment. If the symptoms continuously exist on the next day, the infusion is suspended and observed for 1 day, and if the symptoms disappear, the infusion is continued.

4) The occasional patients during transfusion have symptoms of dizziness, headache, nausea, vomiting and the like: dizziness and headache are mostly relieved within 30 minutes; most symptoms disappeared 0.5-2 hours after central antiemetic ondansetron was given to vomit patients.

5) Sometimes spastic abdominal pain occurs during transfusion, and the treatment such as histamine resistance and spasmolysis is given, and the symptoms are mostly relieved within 1 hour.

Clinical experience shows that according to the dosage and the dripping speed, no serious adverse reactions such as dyspnea, cyanosis, incontinence of urine and feces, rapid decrease of blood pressure, anaphylactic shock, coma and the like are found in the infusion process.

Follow-up results

After 9 patients are treated by sinomenine intravenous infusion for 2 courses of treatment, the symptoms of breast pain are obviously relieved, and breast nodules are gradually softened. The follow-up visit is half a year without relapse.

And (4) conclusion: the sinomenine can effectively relieve the symptoms of the breast pain of the patients with the hyperplasia of mammary glands for a long time, can gradually soften the breast nodules of the patients with the hyperplasia of mammary glands, and has short onset time.

In the present invention, the treatment of the patients is informed by the patients.

Reference documents:

1. the diagnosis and treatment experts of hyperplasia of mammary glands are in consensus. Journal of chinese utility surgery, 2016, 7 month, 36 th volume, 7 th phase.

While particular embodiments of the present invention have been illustrated and described, it would be obvious that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

Claims

1. The use of sinomenine or its pharmaceutically acceptable salt, sinomenine derivative or its pharmaceutically acceptable salt in preparing medicine for treating mammary gland diseases is provided.

2. The use according to claim 1, wherein the breast disorder is a disorder resulting from hyperplasia of the mammary gland septal connective tissue.

3. The use according to claim 1, wherein the breast disease comprises hyperplasia of mammary glands.

4. The use according to claim 3, wherein the hyperplasia of mammary glands comprises adenosis of mammary gland and cystic hyperplasia of breast.

5. The use of claim 4, wherein the breast adenopathy includes one or more of lobular hyperplasia, fibroglandular disease, sclerogonadal disease;

6. The use according to any one of claims 1 to 5, wherein the medicament further comprises a pharmaceutically acceptable excipient.

7. The use according to claim 6, wherein the adjuvants comprise any one or more of wetting agents, emulsifiers, diluents, excipients, fillers, disintegrants, binders, lubricants, surfactants, flavoring agents, stabilizers, and the like.

8. The use according to any one of claims 1 to 5, wherein the pharmaceutical dosage form comprises oral and injectable formulations.

9. The use according to claim 8, wherein the oral formulation comprises tablets, granules, pellets, capsules, pastes, syrups;

the injection includes a solution type and a powder type.

10. Use according to claim 9, wherein the medicament is administered intravenously or intramuscularly or topically.