CN102389425B - Application of nicotinic acid derivates in preparation of medicaments for promoting follicular development and maintaining ovarian functions - Google Patents
Application of nicotinic acid derivates in preparation of medicaments for promoting follicular development and maintaining ovarian functions Download PDFInfo
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- CN102389425B CN102389425B CN 201110146463 CN201110146463A CN102389425B CN 102389425 B CN102389425 B CN 102389425B CN 201110146463 CN201110146463 CN 201110146463 CN 201110146463 A CN201110146463 A CN 201110146463A CN 102389425 B CN102389425 B CN 102389425B
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Abstract
The invention discloses application of nicotinic acid derivates in the preparation of medicaments for promoting follicular development and maintaining ovarian functions. Experiment proves that the nicotinic acid derivates can promote follicular growth in the ovary, promote hormonogenesis and endometrial growth and enable women to form a regular period. The derivates have special treatment effects on promoting follicular development and maturing, treating ovarian hypofunction, recovering period and reducing climacteric symptoms. The invention compensates for the defects of the existing medicaments, and provides a new method for treating ovarian diseases, which is high in efficiency, convenient to use and low in cost.
Description
Technical field
The present invention relates to a kind of nicotinic acid class Xing biology, specifically the purposes of nicotinic acid class Xing biology in preparation treatment ovarian function disease medicament.
Background technology
Ovary is one of most important organ of human body women, is the place that stores oocyte, and the ovary state is directly determining the female fertility ability.All ovums are that form elementary, secondary follicle with static primordial follicle or growth conditions exists in the ovary.Ovarian function failure, dormancy follicle can not activate and reenter growth and can cause losing fertility, and premature ovarian failure also influences ovarian secretion progestogen, estrogen simultaneously, thereby influences sexual function, also can directly cause woman's aging.Make menopausal women recover physiological period again after now having had research with young ovary transplantation abroad, the function of visible ovary has very large relation for woman's health and young state.
Because not ovulating of causing of premature ovarian failure and because not ovulating of causing of other unknown causes has common characteristic, there is not dominant follicle ripe and discharge, there is not official holiday.These affect the women of child-bearing age's fertility, bring very big psychological burden to them, affect women's physical and mental health.
The growth of follicle is a very complicated process, is wrapped in by the cumulus cell of monolayer from the oocyte of resting state, just forms in 7 months from the mother and baby, can static decades.And be wrapped in oocyte static in the theca folliculi, if be subjected to Signal Regulation to recover growth, need just can grow up into secondary oocyte through 9 months slowly.The interior oocyte outside of follicle this moment has had multiple layer cumulus cell parcel to support.After this 3 months secondary ovum are increased rapidly by secretion signal regulation and control such as cumulus cell, to last 15 days (the preceding first quarter moon of menstruation just), can maturation be mature follicle, and discharge oocyte that theca folliculi etc. are organized the formation corpus luteum.Preceding first quarter moon in menstruation is influenced by the estrogen of follicle secretion, and endometrium constantly thickens, and estrogen and the progestogen of back first quarter moon corpus luteum secretion continue to make endometrial hyperplasia equally.Premenstrua, luteolysis, endometrium loses the hormone support, and at preceding 4～24 hours in the period, the inner membrance blood vessel was spastic contraction, make the inner membrance ischemic necrosis, diastole again after the vasoconstriction, thus it is hemorrhage to break, and forms the little hematoma of disperseing at theca interna, inner membrance is stripped off and hemorrhage, be menstrual onset.So menoxenia is the unbalance indirect reaction of ovary ovulation function.
Ovarian function treatment impaired and menoxenia is very difficult, up to the present, does not still have clear and definite therapy measure to recover or the protection ovarian function.At present, the main method for the treatment of is by hormone therapy, and the patient often needs a spot of estrogen, or female, progestogen cycle therapy.Though this method can be eliminated climacteric syndrome, majority are easily recurred after the drug withdrawal, and the side effect of hormone brings very big burden for too patient's body and mind.Recent American Women health association (Wommen ' s Health lnitiative, WHI) clinical research finds that hormone replacement therapy (HRT) is though reduced the danger of osteoporosis and fracture; But increased the sickness rate of breast carcinoma, carcinoma of endometrium and cardiovascular disease, apoplexy.
Integrate, many gynaecopathias all are because the termination of ovarian follicular growth or undesiredly carry out the growth of periodicity follicle and cause the undesired and ovarian function of official holiday to fail.Present Therapeutic Method can not be hormonal regulation from the radical change ovulation failure.
Summary of the invention
At the blank in the above-mentioned field, the present invention has carried out continuous research and has explored, found that nicotinic acid class Xing biology promoting follicular development, recover the ovary ovulation function, allowing women's physiological period good curative effect effect be arranged in normal, provides a kind of new drug new approaches for the treatment of ovarian disease simultaneously.
The application in the medicine of preparation treatment ovarian disease of nicotinic acid class Xing biology, its salt and precursor compound thereof, described nicotinic acid class Xing biology has suc as formula structure shown in (I):
Wherein R1 is the C1-10 alkyl, H, Cl, NH
2Or OH.
R2 is hydroxyl, the alkoxyl of C1-10, amido, secondary amine or quaternary amine base.
Described medicine is the ovarian function maintenance and repairs medicine, ovulation stimulants and adjusting menstrual cycle medicine.
Described alkoxyl, the alkyl in secondary amine, the quaternary amine base are straight chained alkyl, branched alkyl or the cycloalkyl with C1-C10.
Wherein R1 is H.
Described nicotinic acid class Xing biology is methyl nicotinate, ethyl nicotinate, nicotinic acid propyl ester, nicotinic acid n-butyl alcohol ester and nicotinic acid isobutyl alcohol ester, nicotinic acid pentyl ester, hexyl nicotinate or inositol niacinate.
Described nicotinic acid class Xing biology is nicotiamide, pyridine-3-carboxamide, pyridine-3-acetamide or pyridine-3-butyramide.
The precursor compound of described nicotinic acid class Xing biology is aluminum nicotinate, inositol niacinate, the own sweet fat of cigarette, niceritrol, tocopheryl nicotinate or piconol.
The dosage form of described medicine is tablet, capsule, injection, pill, colloid, unguentum, spray or granule.
Of the present invention experiment showed, the chemical compound with nicotinic acid class formation can promote follicular development, recover ovary ovulation function, allow women's physiological period recover normal.
The salt of niacin compound serving, and in the process of prodrug (comprising aluminum nicotinate, inositol niacinate, the own sweet fat of cigarette, niceritrol, tocopheryl nicotinate or piconol) metabolism in vivo, can obtain nicotiamide, therefore all can have the niacin compound serving identical functions, namely treat the effect of ovarian disease.
The nicotinic acid analog derivative, the C1-10 alkyl that is included on the pyridine ring replaces nicotiamide, nicotinate, wherein the amine in the niacinamide usp can be the C1-C10 amido, secondary amine, quaternary amine base (comprising the cyclammonium base), as nicotiamide, pyridine-3-carboxamide, pyridine-3-acetamide or pyridine-3-butyramide.Alcohol in the nicotinate can be C1-C10 alcohol or cyclic alcohol, as methyl nicotinate, ethyl nicotinate, nicotinic acid propyl ester, nicotinic acid n-butyl alcohol ester and nicotinic acid isobutyl alcohol ester, nicotinic acid pentyl ester, hexyl nicotinate or inositol niacinate.
Above-mentioned niacin compound serving can be mixed with various dosage forms with pharmaceutically acceptable any adjuvant, as tablet, capsule, injection, pill, colloid, unguentum, spray or granule mutually as active ingredient.Preferred oral agent or injection.
1, nicotinic acid
Formal name used at school: pyridine 3-carboxylic acid.
English name Nicotinic acid
Another name Niacin; 3-Pyridinecarboxylic acid; 3-Carboxypyridine.
Molecular formula: C6H5NO2, heat-resisting, can distil.
Chemical structural formula is:
The conventional purposes of nicotinic acid:
Nicotinic acid has another name called nicotinic acid, antipellagra factor.In human body, also comprise its derivant nicotiamide or niacin amide.It is one of 13 kinds of vitamin of needed by human, is a kind of water soluble vitamins, belongs to vitamin B complex.Nicotinic acid is converted into nicotiamide in human body, nicotiamide is nadide and coenzyme II ingredient, participates in the body lipid metabolism, the process that the oxidizing process of Tissue respiration and saccharide anaerobic are decomposed.
2, nicotiamide:
English name: nicotinamide
Another name: niacin amide
Chemical name: pyridine-3-carboxamide Pyridine-3-Carboxyamide
Molecular formula and molecular weight: C6H6N2O=122.13
Physicochemical property:
This product is white crystalline powder, odorless or odorless almost, and bitter in the mouth, easily molten in water or ethanol, in glycerol, dissolve.
Effect and purposes:
Vitamin drug participates in the internal metabolism process, is used for pellagra such as control pellagra.
Chemical structural formula:
3, inositol nicotinate (inositol niacinate)
Molecular formula: C42H30N6O12
Structural formula:
Purposes:
The auxiliary treatment that now is used for hyperlipemia, coronary heart disease, various peripheral vessel barrier property disease (as Arteriosclerosis obliterans, Raynaud's disease, cold injury, vascular migraine etc.) clinically.
The present invention has found that niacin compound serving has good curative effect effect in the ovulation function that promotes follicular development, recovery ovary, adjusting women's physiological period, and a kind of new drug new approaches for the treatment of ovarian disease are provided simultaneously.
Description of drawings
Ovary in Fig. 1 model group
The ovary of Fig. 2 after the nicotinic acid treatment
The ovary of Fig. 3 after the nicotiamide treatment
The ovary of Fig. 4 after the Inositol Hexanicotinate treatment
The specific embodiment:
Experiment material: implement used nicotinic acid, Inositol Hexanicotinate and nicotiamide and buy the cell culture rank from sigma reagent company.Oral nicotinic acid and nicotiamide can have been bought from pharmacy.Cyclophosphamide obtains from hospital.Nicotiamide intravenous injection liquid, physiological saline solution is used in configuration, is configured to 10mg/ml.The nicotinic acid solution concentration is 16mg/ml.The Inositol Hexanicotinate solution concentration is 20mg/ml.Cyclophosphamide is configured to 100mg/ml with normal saline.
Laboratory animal: 100 of Healthy female Kunming white mices, Mus 6 weeks of age, raise in temperature 23 and spend to 25 degree, relative humidity 50-60%, ad lib, water inlet, illumination every day 12 hours is carried out adaptability and is raised.
Experimental technique: after the animal adaptability is raised a week, be divided into 5 groups, be respectively the blank group, model group, nicotinic acid group, nicotiamide group, Inositol Hexanicotinate group.All the other four groups give the cyclophosphamide lumbar injection, and every mice per injection 0.1ml (100mg) injects 5 times continuously.Model group will not be treated, and every mice of nicotinic acid group gives nicotinic acid intravenous injection 2mg, injects continuously two days.Every mouse mainline nicotiamide of nicotiamide group 1mg.Injection is two days continuously.Every mice of Inositol Hexanicotinate group gives Inositol Hexanicotinate injection 4mg.
After the Drug therapy 2 days, fasting 12 hours, anesthetized animal, heart extracting blood, centrifugal back separation of serum is surveyed the short follicle of hormone and is generated plain FSH, estradiol E2 level.
Get after mice cervical vertebra dislocation method is put to death behind the blood, get ovary, give the scales/electronic balance weighing amount.
The follicle number of growing in the ovary is added up under stereoscope.
Weigh the back ovary with formalin fixed after, after the gradient alcohol dehydration, routine paraffin wax embedding, section, HE dyeing.Observe ovary tissue under the light microscopic and learn metamorphosis.
E2 in the mice serum, the FSH change of hormone contents sees Table 1.
Table 1
★ representative and blank group be P＜0.01 relatively, and ☆ representative and blank group be P＞0.05 relatively, and ▲ representative and model group be P＜0.01 relatively.
Ovary weight respectively organized by table 2 and the interior follicle quantity of ovary compares.
★ representative and blank group be P＜0.01 relatively, and ☆ representative and blank group be P＞0.05 relatively, and ▲ representative and model group be P＜0.01 relatively.
By to respectively organizing the ovary tissue morphological observation as seen, in the blank group destructing of ovary skin medullary substance clear, visible primordial follicle, primary follicle, secondary follicle, each phase follicle form, corpus luteum quantity are normal.Do not see follicular cyst or corpus luteum hematoma, a matter is not seen cell infiltration and fibrosis, rich blood vessel; Ovary volume-diminished in the model group, visible primordial follicle, hole vesicular ovarian follicles and corpus luteum, the follicle of cystic dilatation increases, and oocyte or corona radiata disappear in it, the artially follicular dysplasia, the distortion of follicle profile, with extending to matter between vicinity brokenly, the granular cell distortion reduces; Visible primordial follicle, primary follicle, secondary follicle in nicotinic acid group, Inositol Hexanicotinate group and the nicotiamide group, each phase follicle form, quantity approach normal mostly, accidental cystic dilatation, and the corpus luteum number is more, most stroma of ovary are not seen obvious fibrosis and hypertrophy, rich blood vessel.
Respectively organize data as can be seen from above, model group E2 level descends, and the FSH level rises, and follicle number and normal control group comparing difference are obvious in the ovary, P＜0.05; Ovary weight is compared with the blank group, and quality obviously alleviates, P＜0.01; The histology shows tangible pathological change, can think that by these results modeling is successful.Nicotinic acid group, Inositol Hexanicotinate group and nicotiamide group are treated after the modeling success, its E2 of interpretation of result, and FSH level and folliculus ovarii number return to relatively P＞0.05 of normal level and model group P＜0.01 and blank group.Ovary tissue is learned the approximate normal level of morphosis.
Clinical experiment
20 cases are adopted in clinical trial altogether, and cardinal principle situation such as the ovary of case fail, and adopt the medication standard is to take medicine nicotinic acid (10 example) 100mg or nicotiamide (10 example) 100mg at every turn, every day three times, the morning, noon and afternoon each once, each 100mg.Drug effect judges that effectively: recover ovulation function, official holiday is normal.Short follicle generates plain FSH and is down to below the 10IU/L, and effective percentage reaches 80%.
Specify clinical effectiveness of the present invention with following examples.
Typical menopause syndrome appears in √ case one, 42 years old, has a sleepless night 1 year.Official holiday reduces gradually.In JIUYUE, 2010 is measured FSH 40.6IU/L.Meet climacteric ovary degradation symptoms.Employing nicotiamide treatment, every day 300mg, each 100mg, one day three times, take 20 surplus day, come official holiday, amount is normal.Short follicle generates plain FSH and is down to 7IU/L, recovers women of child-bearing age's level.The expression ovarian function is good.
√ case two, 32 years old, official holiday is undesired more than 3 years, and after initial double dilatation and curettage, recover of uterus is good, but menstruation is from irregularly reducing at last not come.Adopt nicotinic acid curative every day 3 times, each 100mg.After taking 20 days, come official holiday.Hormone also returns to normal level.Short follicle generates plain FSH and is down to 3.8IU/L.
Claims (2)
1. nicotiamide or its salt application in the preparation promoting ovulation drug.
2. application according to claim 1, the dosage form of described medicine are tablet, capsule, injection, pill, colloid, unguentum, spray or granule.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110146463 CN102389425B (en) | 2011-06-01 | 2011-06-01 | Application of nicotinic acid derivates in preparation of medicaments for promoting follicular development and maintaining ovarian functions |
| HK12108669.9A HK1167828A1 (en) | 2011-06-01 | 2012-09-05 | Application of nicotinic acid derivates in preparation of medicaments for promoting follicular development and maintaining ovarian functions |
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| CN 201110146463 CN102389425B (en) | 2011-06-01 | 2011-06-01 | Application of nicotinic acid derivates in preparation of medicaments for promoting follicular development and maintaining ovarian functions |
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| CN104027339B (en) * | 2014-06-12 | 2017-01-18 | 王淑芳 | Vitamin composition and application thereof in regulating ovarian function |
| US20200368198A1 (en) * | 2017-07-31 | 2020-11-26 | Newsouth Innovations Pty Limited | Methods for increasing fertility |
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