CN102895227A - Applications of 3,3-2 indole methane in preparing medicament for treating mastalgias - Google Patents
Applications of 3,3-2 indole methane in preparing medicament for treating mastalgias Download PDFInfo
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- CN102895227A CN102895227A CN2012103711504A CN201210371150A CN102895227A CN 102895227 A CN102895227 A CN 102895227A CN 2012103711504 A CN2012103711504 A CN 2012103711504A CN 201210371150 A CN201210371150 A CN 201210371150A CN 102895227 A CN102895227 A CN 102895227A
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Abstract
The invention provides applications of 3,3-2 indole methane in preparing a medicament for treating mastalgias. An animal experiment of an experimental animal breast hyperplasia model shows that the compound 3,3-2 indole methane has favorable treatment effect for mastalgias, wherein the structure formula of 3,3-2 indole methane is as shown in the specification.
Description
Technical field
The present invention relates to the application of 3,3'-Diindolylmethane in the medicine of preparation treatment mastalgia, belong to medical technical field.
Background technology
Mastalgia all can have generation in all ages women, and discovery rate is higher, and the most direct and the most common symptom is exactly mastalgia, comprises persistence and interim pain.The generation of mastalgia symptom usually and environment, stress, diet, the many factors such as menarche, motherhood and emotion are relevant.The main pathogenic factor of mastalgia may be ovarian dysfunction, causes estrogen level too high, and progesterone level is lower.High-caliber estrogen makes the local histamine of mammary gland, catecholamine, 5-hydroxy tryptamine increased content, latex dust congestion and edema, epithelial proliferation, acinus hypertrophy, and then stimulate, oppress the intrinsic teleneuron of latex dust, form breast nodule state and pain.High-caliber estrogen also can make lactotropin raise, and same purpose causes that in mammary gland tissue tissue morphology changes, and causes pain.In addition, human body increases estrogen-sensitive, and estrogen receptor is crossed expression, also is the major incentive of mastalgia.Some patient who suffers from mastalgia can increase lump in breast, the symptoms such as nipple discharge by concurrent breast.
Studied the substantial connection that exists of finding mastalgia and breast carcinoma, the Etiological of mastalgia is cyclomastopathy, and mastalgia patient pain degree becomes positive correlation with incidence of breast cancer.The genesis of breast carcinoma has generally been followed normally-this evolution of hypertrophy-atypical hyperplasia-cancer in situ-infiltrating carcinoma.The formation and development, particularly atypical hyperplasia of mastalgia found in research, may promote the generation of breast carcinoma, and just its probability that cancerates depends on the degree of preneoplastic lesions.
Do not find at present the method at the basis radical cure mastalgia that keeps breast, for a mastalgia symptom of finding and occuring, the patient normally the patient of means and the requirement, particularly some mild of seeking some property alleviated, does not cause enough attention to disease.Because external influence factors is a lot, and be in continuous change, so the generation of mastalgia also can show as interim symptom, have been reported with disclosed treatment means and mostly be some Chinese medicines (oral or external application) or naturopathy, come relief of symptoms by the conditioning to system or local organization.Can say, for the mastalgia disease that a variety of causes causes, in clinical treatment, also can't accomplish real effective treatment at present.
3,3 '-di-indole methyl hydride (diindolylmethane, DIM) be the dimeric forms of Indole-3-carbinol (I3C), research to the medical usage of this chemical compound is many, for example, DIM is used for the treatment of age related hearing loss (CN200980105668.X), and DIM can suppress purposes in treatment hepatic disease and rheumatoid arthritis of increasing the weight of of diabetes and DIM (can referring to CN201010258545.4 and CN200810243556.8) etc.About 3,3'-Diindolylmethane and the treatment mastalgia and and the mastalgia relevant disease between relation, have no relevant research and report.
Summary of the invention
Technical problem underlying solved by the invention has been to propose the application of 3,3'-Diindolylmethane in the medicine of preparation treatment mastalgia, thereby provides new means for the treatment mastalgia and with the mastalgia relevant disease.
Studies confirm that estrogen is the main inducing that breast carcinoma occurs.When estrogen increases unusually, make the normal breast epithelial cell proliferation, and inhibition cellular immunization, make self repair ability reduction, the cell of hypertrophy promotes ER by the hormone receptor system, PR is synthetic to be increased, and has improved breast epithelium to estrogenic sensitivity, thereby further stimulation causes the growth of galactophore epithelial cell and enlivening of cell function.The Growth of Cells that estrogen causes and function are active, can show as mitochondrion quantity significantly increases, promote mammary gland tissue cell survival and growth, mitochondrion release apoptosis inducible factor transmits apoptotic signal, make the depleted aging cell death of nonfunctional, and when the overexpression of mammary gland tissue cell Mitochondria, just produce self dysfunction, affecting the metabolism harmful substance can't remove, body abnormal even histiocyte sudden change.In addition, estrogen also can cause the PR that represents the ER activity to increase, and when this PR overexpression, the ability of sticking of mammoplasia's cell descends, and the inducing cell form changes.PR induces special somatomedin (startup methylates) high expressed in breast tissues, cause the reaction of galactophore epithelial cell progestogen disorderly, promoted the hypertrophy of mammary gland tissue interstitial collagen fiber, make mammary gland not change recovery over to by propagation, cause the mammary gland normal configuration disorderly, thereby impel the generation of cyclomastopathy to cause mastalgia, for the development of breast carcinoma hides some dangers for.
The estrogen main metabolic pathway is the hydroxide approach, that is, estradiol is converted into estrone phenol, and at C2,16 hydroxylatings of C4 or C, different estrogen metabolism products show different estrogen activitys.A little less than wherein 2-hydroxyestrone (2-OHE1) conjugated estrogen hormone is subjected to ability of immigrants, can promote differentiation and the apoptosis of cell, be considered to have estrogenic antagonist.16 α-hydroxyestrone (16 α-OHE1) also are the oestrogen-like hormone chemical compounds, and strong estrogen action is arranged, can with the estrogen receptor covalent bond, activate ER, inducing cell abnormal differentiation and mammary glandular cell propagation.In addition, 16 α-OHE1 also has the function that block cell DNA repairs.
3,3'-Diindolylmethane (diindolylmethane, DIM) is the dimeric forms of Indole-3-carbinol (I3C).1975, Wattenberg finds that first Indole-3-carbinol has antitumaous effect (Loub WD, Wattenberg LW, Davis DW:Aryl hydrocarbon hydroxylase induction in rat tissues by naturally occurring indoles of cruciferous plants.J Natl Cancer Inst1975,54 (4): 985-988).Its structure as shown in Equation 1, this material is present in the catabolite that the glucosinolate(s)s of various brassicaceous vegetables produces under the effect of plant tissue myrosinase, is the present composition of maximum brassicaceous vegetable of research.
I3C has unstability, easily forms polymer under sour environment, comprises dimer 3,3'-Diindolylmethane (diindolylmethane, DIM); Wire trimer 2-(indol-3-yl methyl)-3,3-di-indole methyl hydride (2-(indol-3-ylmethyl)-3,3-diindoly-lmethane, LTR-1); Cyclic trimer 5,6,11,12,17,18-six hydrogen cyclononane [1,2-b:4,5-b:7,8-b] three Yin (5,6,11,12,17,18-hexahydrocy-clonona[1,2-b:4,5-b ': 7,8-b :] tri-indole, CTR); Indole [3,2-b] and carbazole (indolo[3,2b], carbazole, ICZ) and ascorbic acid etc.The 3,3'-Diindolylmethane structure is suc as formula 2:
At present research finds that at aspects such as adjusting estrogen metabolisms, DIM shows the effect more favourable than I3C.For example, the DIM treatment can improve 2-OHE1 level (the Dalessandri KM of the postmenopause with breast carcinoma of early stage medical history, Firestone GL, Fitch MD, Bradlow HL, Bjeldanes LF:Pilot study:effect of 3,3'-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer.Nutr Cancer 2004,50 (2): 161-167); There is zoopery to show, than I3C, DIM has less hepatotoxicity (Leibelt DA, Hedstrom OR, Fischer KA, Pereira CB, Williams DE:Evaluation of chronic dietary exposure to indole-3-carbinol and absorption-enhanced3,3'-diindolylmethane in sprague-dawley rats.Toxicol Sci2003,74 (1): 10-21); Research is in recent years also found, DIM can suppress the AKT(protein kinase B, a kind of serine/threonine protein kitase) phosphorylation (Gao N, Cheng S, Budhraja A, Liu EH, Chen J, Chen D, Yang Z, Luo J, Shi X, Zhang Z:3,3'-Diindolylmethane exhibits antileukemic activity in vitro and in vivo through a Akt-dependent process.PLoS One2012,7 (2): e31783), thus the cyclin D1 in downward modulation hormone receptor level and its downstream of inhibition, CDK4 and CDK6, cell death inducing (Garikapaty VP, Ashok B T, Tadi K, Mittelman A, Tiwari RK:Synthetic dimer of indole-3-carbinol:second generation diet derived anti-cancer agent in hormone sensitive prostate cancer.Prostate 2006,66 (5): 453-462).
But present research more still concentrates on I3C and the DIM impact in breast cancer treatment, especially for making a definite diagnosis and find to suffer from the situation of breast carcinoma the application of I3C and DIM.Have no the report of any relevant 3,3'-Diindolylmethane treatment mastalgia aspect.
The inventor's research is found, use 3 for the hyperplasia of mammary gland model rat, 3 '-di-indole methyl hydride, can obviously dwindle breast diameter, the height of nipples of suffering from the cyclomastopathy rat, so, the present invention proposes 3, a kind of novel medical use of 3 '-di-indole methyl hydride, that is, the application of 3,3'-Diindolylmethane in the medicine for the treatment of for the preparation of mastalgia.
Mastalgia described in the present invention refers to the mastalgia that a variety of causes causes, has comprised various physiological mastalgias and/or pathologic mastalgia.This type of disease to some extent concurrent breast increases lump in breast, the symptoms such as nipple discharge.
On clinical symptoms, the Symptoms of mastalgia described in the present invention can comprise periodically mastalgia and/or aperiodicity mastalgia.
The symptom of mastalgia of the present invention can comprise the mastalgia that causes because of pure breast epithelium hypertrophy, adenosis of breast or cystic hyperplasia of breast.
According to the solution of the present invention, the medicine of described treatment treatment mastalgia comprises 3 for the treatment of effective dose, the acceptable pharmaceutical adjuvant of 3 '-di-indole methyl hydride and pharmaceutics, pharmaceutical dosage form can comprise oral agents, intravenous administration formulation, nasal feeding preparation, rectally preparation, vagina administration preparation, dosing eyes preparation or other local administration preparation etc.
According to the solution of the present invention, for the mastalgia patient in the normal type scope, with 3,3'-Diindolylmethane as effective ingredient, the dosage of the medicine of described treatment mastalgia (take 3,3'-Diindolylmethane as effective ingredient) can be the 100-1000 mg/day.
Although multiple different factor all may cause mastalgia, the common clinical examination index of mastalgia all shows owing to the disorderly generation that impels cyclomastopathy of mammary gland normal configuration, thereby causes mastalgia.In the present invention program, the inventor adopts the method for estradiol benzoate associating Progesterone intramuscular injection to copy cyclomastopathy rat model and Rabbit Model, and use 3,3 '-di-indole methyl hydride carries out the administration experiment, the result shows, 3,3'-Diindolylmethane can obviously reduce to suffer from breast diameter, the height of nipples of cyclomastopathy rat and rabbit.So, the animal experiment of experimental animal models hyperplasia of mammary gland model is shown the chemical compound 3,3'-Diindolylmethane has good therapeutical effect to mastalgia.
The specific embodiment
Below describe the solution of the present invention in detail by concrete experimentation.
The present invention proposes the novel medical use of 3,3'-Diindolylmethane, that is, and the application of 3,3'-Diindolylmethane in the medicine for the treatment of for the preparation of mastalgia.
According to the solution of the present invention, the medicine of described treatment mastalgia comprises 3 for the treatment of effective dose, the acceptable pharmaceutical adjuvant of 3 '-di-indole methyl hydride and pharmaceutics, pharmaceutical dosage form can comprise oral agents, intravenous administration formulation, nasal feeding preparation, rectally preparation, vagina administration preparation, dosing eyes preparation or other local administration preparation etc.
The test of experimental example 1 experimental rat hyperplasia of mammary gland model
Laboratory animal adopts SD rat, Female Rats, body weight 150-200g.Laboratory temperature 18-28 ℃, water is freely ingested, taken the photograph to forage feed.
Confirm 48 of the normal Healthy female Mus of mammary gland index, after weighing, be divided at random DIM low dose group, DIM high dose group, model group and Normal group, 12 every group.
Adopt the mode of estradiol benzoate associating Progesterone intramuscular injection to copy the cyclomastopathy rat model: DIM low dose group, DIM high dose group, model group laboratory animal give intramuscular injection estradiol benzoate injection 0.5mg/kg.w, once a day, injection is 25 days continuously, rose in the 26th day and use intramuscular injection Progesterone 5mg/kg.w instead, once a day, injection is 5 days continuously, confirms that the cyclomastopathy symptom all appears in each treated animal, finishes modeling.
Normal group intramuscular injection normal saline 0.2ml/ only once a day, injected 30 days continuously.
After the modeling, respectively organize about the 2nd pair two breast diameter of rat and height of nipples with the accurate measurement of slide gauge.
Normal group and model group animal gavage normal saline 2ml/ time, once a day, and continuous 30 days.DIM is low, high dose group gavages the DIM aqueous solution by the dosage of 1mg/kg.w/day and 5mg/kg.w/day respectively, gavages total amount of liquid every day to be
Continuous 30 days.
DIM is on the impact of breast diameter and height of nipples:
Respectively organized about the 2nd pair two breast diameter of rat (Normal group and model group gavage normal saline) and height of nipples after again accurately measuring above-mentioned administration with slide gauge on the 31st day, identical before measuring position and the administration implemented anesthesia to animal in case of necessity.
Measurement result Macro or mass analysis to each treated animal is as follows:
Table 1.DIM is to the effect (successive administration 30 days) of experimental rat breast diameter and breast height
##: compare P＜0.01 with Normal group; *: compare P＜0.01 with model group
Experimental rat mammary gland tissue pathology form:
The mammary gland tissue lobule that paraffin section is observed visible normal rat changes without hypertrophy, and acinus is few, and lobule is not obvious, and fatty tissue is more, and breast duct is without expansion;
Model group rat nipple occurs red and swollen and increases, and the acinus number increases in the lobule, and branch is many, and connective tissue reduces between acinus, and lumen of gland enlarges, and a large amount of secretions appear in intracavity;
DIM high and low dose group rat mammary gland lobule number and acinus number obviously reduce than model group, and the luminal sectetion thing also reduces.
Conclusion: 3,3'-Diindolylmethane can obviously reduce acinus number in rat breast diameter, height of nipples and the lobules of mammary gland, and 3,3'-Diindolylmethane has preferably therapeutical effect to the rat mammary gland hypertrophy.
The test of embodiment 2 Experimental Rabbit hyperplasia of mammary gland model
Laboratory animal adopts rabbit, Female rabbits, body weight 2-3kg.Laboratory temperature 18-28 ℃, water is freely ingested, taken the photograph to the standard particle forage feed.
Confirm 40 of the normal Healthy female rabbit of mammary gland index, after weighing, be divided at random DIM low dose group, DIM high dose group, model group and Normal group, 10 every group.
Adopt the mode of estradiol benzoate associating Progesterone intramuscular injection to copy the cyclomastopathy Rabbit Model: DIM low dose group, DIM high dose group, model group laboratory animal give intramuscular injection estradiol benzoate injection 0.5mg/kg.w, once a day, injection is 25 days continuously, rose in the 26th day and use intramuscular injection Progesterone 5mg/kg.w instead, once a day, injection is 5 days continuously, confirms that the cyclomastopathy symptom all appears in each treated animal, finishes modeling.
Normal group rabbit intramuscular injection normal saline 1.0ml/ only once a day, injected 30 days continuously.
After the modeling, respectively organize about the 2nd pair two breast diameter of rabbit and height of nipples with the accurate measurement of slide gauge.
Normal group and model group animal gavage normal saline 20ml/ time, once a day, and continuous 30 days.DIM is low, high dose group gavages the DIM aqueous solution by the dosage of 1mg/kg.w/day and 5mg/kg.w/day respectively, 20ml/ time/only, and once a day, continuous 30 days.
Respectively organized about the 2nd pair two breast diameter of rabbit (Normal group and model group gavage normal saline) and height of nipples after again accurately measuring above-mentioned administration with slide gauge on the 31st day, identical before measuring position and the administration implemented anesthesia to animal in case of necessity.
Table 2.DIM is to the effect (successive administration 30 days) of Experimental Rabbit breast diameter and breast height
#: compare P＜0.05 with normal group; ##: compare P＜0.01 with normal group;
*: compare P＜0.05 with model group; *: compare P＜0.01 with model group;
Experimental rabbit mammary gland tissue pathology form:
Paraffin section is observed visible normal group rabbit breast lobule, and mammary gland is in the quiescent stage state, sexually revises without hypertrophy, and acinus is few, and lobule is not obvious, and fatty tissue is more, and the breast duct chamber is without expansion;
Model group rabbit nipple occurs red and swollen and increases, and the acinus number increases in the lobule, and branch is many, and connective tissue reduces in the acinus, and lumen of gland enlarges, and a large amount of secretions appear in intracavity;
DIM high and low dose group rabbit lobule number and acinus number obviously reduce than model group, and the luminal sectetion thing also reduces.
Conclusion: 3,3'-Diindolylmethane can obviously reduce acinus number in rabbit breast diameter, height of nipples and the lobules of mammary gland, and 3,3'-Diindolylmethane has preferably therapeutical effect to the rabbit cyclomastopathy.
Claims (6)
1.3, the application of 3 '-di-indole methyl hydride in the medicine of preparation treatment mastalgia, the structural formula of described 3,3'-Diindolylmethane is as follows:
2. application according to claim 1, wherein, described mastalgia comprises physiological mastalgia and/or pathologic mastalgia.
3. application according to claim 1 and 2, wherein, the Symptoms of described mastalgia comprises periodically mastalgia and/or aperiodicity mastalgia.
4. application according to claim 1 and 2, wherein, the symptom of described mastalgia comprises the mastalgia that causes because of pure breast epithelium hypertrophy, adenosis of breast or cystic hyperplasia of breast.
5. according to claim 1-4 each described application, the pharmaceutical dosage form of described treatment mastalgia comprises oral agents, intravenous administration formulation, nasal feeding preparation, rectally preparation, vagina administration preparation or dosing eyes preparation.
6. use according to claim 1 or 5, wherein, as effective ingredient, the dosage of the medicine of described treatment mastalgia is the 100-1000 mg/day with 3,3'-Diindolylmethane.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114984006A (en) * | 2022-06-13 | 2022-09-02 | 华中农业大学 | Application of 3,3' -diindolylmethane in preparation of medicine for treating feline infectious peritonitis |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001020990A1 (en) * | 1999-09-23 | 2001-03-29 | Bioresponse L.L.C. | Phytochemicals for treatment of mastalgia and endometriosis |
| CN102153500A (en) * | 2011-03-02 | 2011-08-17 | 河北大学 | Method for synthesizing diindolylmethane derivative |
| CA2797558A1 (en) * | 2010-04-26 | 2011-11-03 | Vsevolod Ivanovich Kiselev | Medication on the basis of 3,3'-diindolylmethane (dim) with high-bioavailability and its use in treatment of human hyperplastic and inflammatory diseases |
| CN102335168A (en) * | 2011-10-25 | 2012-02-01 | 合肥博太医药生物技术发展有限公司 | Application of indole-3-carbinol, diindolyl methane and derivatives thereof in preparation of medicaments for treating osteoporosis |
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- 2012-09-28 CN CN2012103711504A patent/CN102895227A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001020990A1 (en) * | 1999-09-23 | 2001-03-29 | Bioresponse L.L.C. | Phytochemicals for treatment of mastalgia and endometriosis |
| CA2797558A1 (en) * | 2010-04-26 | 2011-11-03 | Vsevolod Ivanovich Kiselev | Medication on the basis of 3,3'-diindolylmethane (dim) with high-bioavailability and its use in treatment of human hyperplastic and inflammatory diseases |
| CN102153500A (en) * | 2011-03-02 | 2011-08-17 | 河北大学 | Method for synthesizing diindolylmethane derivative |
| CN102335168A (en) * | 2011-10-25 | 2012-02-01 | 合肥博太医药生物技术发展有限公司 | Application of indole-3-carbinol, diindolyl methane and derivatives thereof in preparation of medicaments for treating osteoporosis |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114984006A (en) * | 2022-06-13 | 2022-09-02 | 华中农业大学 | Application of 3,3' -diindolylmethane in preparation of medicine for treating feline infectious peritonitis |
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Application publication date: 20130130 |