CN101953824B - Application of taurine and pharmaceutically acceptable salt thereof in preparing uterine contraction inhibition drug - Google Patents
Application of taurine and pharmaceutically acceptable salt thereof in preparing uterine contraction inhibition drug Download PDFInfo
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- CN101953824B CN101953824B CN2009100894291A CN200910089429A CN101953824B CN 101953824 B CN101953824 B CN 101953824B CN 2009100894291 A CN2009100894291 A CN 2009100894291A CN 200910089429 A CN200910089429 A CN 200910089429A CN 101953824 B CN101953824 B CN 101953824B
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Abstract
The invention discloses novel application of taurine and a pharmaceutically acceptable salt thereof to preparing a tocolytic agent or a health product for protecting a pregnant woman and/or normal development of a fetus. The taurine or the pharmaceutically acceptable salt fulfills the regulation function of smooth muscle contraction of mother uterusn, is beneficial to the reducing of early abortin and has the advantages of low cost, good effect without side drug effects.
Description
Technical field
The present invention relates to the new medicine field of taurine; Be particularly related to taurine and pharmaceutically acceptable salt thereof and suppress the purposes in the uterine contraction medicine in preparation, and as tocolytic agent and health product in human pregnancy's phase and improve the application aspect the human supplementary reproduction efficient.
Background technology
Tocolytic agent that uses to the anemia of pregnant woman on the domestic market at present and health product are very rare.International reproductive medicine bound pair is more and more paid attention in some important nutraceutical new purposes, is forcing to carry out " folic acid+biotin " like Japan and is being this state anemia of pregnant woman's oral ingesta.
The chemical name of taurine is 2-aminoethyl sulfonic acid (Taurine writes a Chinese character in simplified form Tau), is commonly called as taurine, taurine etc., gains the name because of from Fel Bovis seu Bubali, separating first.Taurine content in natural marine organisms is the highest, is a kind of directly small-molecule substance of extraction or synthetic from animals and plants.In recent years research shows: taurine is a human body conditionality essential amino acids, has biological action widely, is the important active substances of regulating the body normal physiological function.The physiologic function of taurine mainly comprises: stabilizing cell membrane biochemical characteristic, antioxidation, removing oxygen-derived free radicals, regulate the Premeabilisation of cells equilibrium, keep effects such as intracellular Ca2+ stable state, nervous system regulation.Taurine is used for prophylactic treatment cardiovascular disease, alcoholic liver, diabetes etc. clinically.But, do not see both at home and abroad the report that taurine uses in gravid woman and animal as tocolytic agent and health product so far as yet.
Summary of the invention
The object of the invention provides the new purposes of a kind of taurine and pharmaceutically acceptable salt thereof.
The new purposes of taurine provided by the present invention or its pharmaceutically acceptable salt is that taurine or its pharmaceutically acceptable salt suppress the application in the uterine contraction medicine in preparation.
Because taurine or its pharmaceutically acceptable salt can suppress uterine contraction, so taurine or its pharmaceutically acceptable salt also can be used for preparing tocolytic agent, and/or trimester of pregnancy protection anemia of pregnant woman's health product, and/or, the health product of fetus normal development.
Taurine or its pharmaceutically acceptable salt can be used as tocolytic agent or health product are applied to also can be added in the embryo in-vitro culture solution and operation liquid of auxiliary procreation technology use in trimester of pregnancy anti-current product medicine, tocolytic agent, the health product.
The present invention can be any dosage form that is fit to medicine and health product, can add the material that one or more other trimester of pregnancy need replenish.Be used for when oral, can be made into conventional solid preparation, like tablet, capsule, dispersible tablet, oral liquid, granule, chewable tablet, oral cavity disintegration tablet, drop pill, slow releasing tablet, controlled release tablet, controlled release capsule; Process liquid preparation such as water or oil-suspending agent or other liquid preparation as, syrup, oral liquid, injection etc., preferred dosage form is oral formulations or injection, like sheet, capsule, granule, minute hand, liquid drugs injection, transfusion etc.
Said medicine can adopt the conventional method production in the existing pharmaceutical field, adds the medicine acceptable auxiliary, comprises filler, binding agent, disintegrating agent, lubricant and fluidizer, pH value regulator and the solvent of solid preparation.
Taurine or its taking dose 0.5-4000mg/ day pharmaceutically acceptable salt day, be preferably 500-4000mg/ day.Embryo in-vitro culture solution adds concentration at 2.5mM-10mM.
Vivo and vitro experiment proof taurine or its pharmaceutically acceptable salt help the growth of embryo and fetus, therefore can be used for the pregnant early embryonic development stage.Taurine or its pharmaceutically acceptable salt shrink the parent uterine smooth muscle has regulating action, the efficient that helps to reduce the generation of miscarriage and improve human supplementary reproduction.The cost of taurine or its pharmaceutically acceptable salt is low and effective, and is without any side effects.
Description of drawings
Fig. 1 is the influence of taurine to mice embryonic extracorporeal culturing embryo blastaea rate.
Fig. 2 penetrates the influence of different concentration of taurine transport inhibitors Beta-alanine to implantation for the 4th day Mouse Uterus subscript of gestation.
Fig. 3 is the influence that taurine shrinks the isolated mouse uterine smooth muscle.
The specific embodiment
Be conventional method like no specified otherwise method therefor among the following embodiment, agents useful for same all can obtain from commercial sources.
Embodiment 1, taurine are used to prepare the health product of tocolytic agent or trimester of pregnancy protection anemia of pregnant woman and/or fetus normal development
1) taurine is to the ectogenetic influence of embryo
With the immigration of well-developed kunming mice germ cell spend the night (table 1 is seen in the constituent of mKSOM culture fluid culture fluid) in the equilibrated mKSOM culture fluid that contains different final concentration taurines (0mM, 5mM, 10mM), 10mM taurine and 10mM Beta-alanine (taurine transporter inhibitor), 10mM Beta-alanine; Every culture fluid is put 6～10 germ cell; Place 37 ℃, 5%CO
2Be cultured to blastula stage in the incubator of saturated humidity, cultivate statistics blastaea rate after 112 hours.With Hochest 33342 (5 μ g/ml) blastaea is dyeed, statistics blastomere sum is estimated taurine to the ectogenetic influence of mice embryonic.
The composition of table 1.mKSOM (mice embryonic culture fluid)
Ectogenetic in three kinds of culture fluid to influence the result as shown in table 2 to the kunming mice embryo for taurine.
Table 2. taurine is to the ectogenetic influence of kunming mice embryo
Table
Middle b representes meansigma methods ± standard error,
*Representative compare with matched group significant difference (
*, P＜0.05,
*, P＜0.01); The mKSOM culture fluid of any material is not added in "-" expression in first row and the secondary series; " 5 " are illustrated in and add this material in the mKSOM culture fluid; Making its final concentration is 5mM, and " 10 " are illustrated in the mKSOM culture fluid and add taurine, and making its final concentration is 10mM;
Situation when Fig. 1 is each processed group fetal development to blastaea.Among Fig. 1, con representes not add the mKSOM culture fluid of any material, and 10mM Tau is illustrated in the mKSOM culture fluid and adds taurine, and making its final concentration is 10mM; 10mM β-ala is illustrated in the mKSOM culture fluid and adds Beta-alanine, and making its final concentration is 10mM; 10mM Tau+ β-ala adds taurine and Beta-alanine in the mKSOM culture fluid, make their final concentration be 10mM.
Above-mentioned experimental result shows, adds the 10mM taurine and can significantly improve embryo's ectogenesis 4-cell rate, blastaea rate, the total cell number of blastaea.
2) taurine is to the influence of embryo nidation
10 female Mus of kunming mice are divided into 2 groups, experimental group and matched group, 5 every group.
Give female Mus superovulation, see that bolt was designated as the 1st day (D1) of gestation on the 1st day.Control group mice is only drunk tap water, and experimental mice is added taurine in drinking-water, to concentration be 1.5% (quality percentage composition).The 8th day (D8) statistics embryo number.Taurine is as shown in table 3 to the influence of embryo nidation.Show that adding 1.5% (quality percentage composition) taurine in pregnant female Mus drinking-water can significantly improve mice embryonic implantation number (P＜0.01).
Table 3. is drunk taurine to be influenced the female Mus D8 of gestation embryo number purpose
3) taurine is to the influence of mice embryonic implantation
The female Mus of pregnant Kunming white of superovulation carries out suppressing in the body experiment through the selective transport inhibitor Beta-alanine that an Aconitum carmichaeli Debx. palace subscript is penetrated taurine in gestation the 4th day (D4) morning.
20 of the female Mus of pregnant D4 Kunming white of superovulation are divided into 4 groups, are respectively experimental group 1, experimental group 2, experimental group 3 and matched group 1,5 every group.
Experimental group 1: mice on the right side cornua uteri to inject 3 μ l concentration be the Beta-alanine of 2 μ g/ml, the left side cornua uteri is injected the normal saline of same dosage;
Experimental group 2: mice on the right side cornua uteri to inject 3 μ l concentration be the Beta-alanine of 20 μ g/ml, the left side cornua uteri is injected the normal saline of same dosage;
Experimental group 3: mice on the right side cornua uteri to inject 3 μ l concentration be the Beta-alanine of 200 μ g/ml, the left side cornua uteri is injected the normal saline of same dosage;
Contrast: the both sides cornua uteri of mice is all injected the normal saline of same dosage.
Experiment repetition 3 times.
Animal subject cuts open inspection in gestation the 9th day (D9), gathers the uterus, embryo's number of adding up every side cornua uteri implantation.Beta-alanine influences result such as table 4 to what implant phase mice embryonic implantation.
Table 4. Beta-alanine is to implanting the influence (individual) of phase mice embryonic implantation
Visible by table 4, pregnant D4 cornua uteri is injected the selective transport inhibitor Beta-alanine of taurine, is the embryo number of the pregnant D9 implantation of remarkable reduction of dose dependent.When Beta-alanine during at 200 μ g/ml, the right side cornua uteri does not have embryo nidation.
A among Fig. 2, B, C is respectively the uterus, right side that experimental group 1, experimental group 2, experimental group 3 pregnant D9 collect; D is uterus, matched group right side.
4) effect of medicine is produced in the taurine anti-current
Every of the female Mus of natural mating gestation Kunming white is in gestation subcutaneous injection 75ug RU486 in the 4th day afternoon (miscarriage medicine: mifepristone), carry out miscarriage protection experiment in the body through lumbar injection various dose taurine.Animal subject cuts open inspection in gestation the 9th day (D9), adds up embryo's number of every side cornua uteri implantation.
20 of the female Mus of natural mating gestation Kunming white are divided into 4 groups, are respectively experimental group 1, experimental group 2, experimental group 3 and matched group, 5 every group.
Experimental group 1: every of the female Mus of natural mating gestation Kunming white is in gestation subcutaneous injection 75ugRU486 in the 4th day afternoon
Experimental group 2: every of the female Mus of natural mating gestation Kunming white is in gestation subcutaneous injection 75ugRU486 in the 4th day afternoon and 37.5mg taurine (Tau).
Experimental group 3: every of the female Mus of natural mating gestation Kunming white is in gestation subcutaneous injection 75ugRU486 in the 4th day afternoon and 75mg taurine (Tau).
Contrast: the female Mus of natural mating gestation Kunming white is not injected any medicine.
Experiment repetition 3 times.
The embryo number of table 5. implantation (individual)
Experimental result shows, when lumbar injection 37.5mg or 75mg taurine, reduces to 75% or 46.1% by the abortion ratio that miscarriage medicine mifepristone (RU486) causes from 85.49%.It is thus clear that taurine has the certain protection effect to the miscarriage that miscarriage medicine mifepristone causes.
5) taurine is to the influence of isolated mouse smooth muscle contraction
To anaesthetize back cervical vertebra dislocation method and put to death mice, and open the abdominal cavity, the clip uterus places buffer immediately rapidly, carefully removes periuterine mesentery and connective tissue, gets the both sides body of uterus and is about one section of 1.0-1.5cm as BIAO and BEN.Open RM B6240 bio signal acquisition system (Chengdu Instruement Factory), zeroing, calibration.Ligation is distinguished with silk thread in the two ends of BIAO and BEN, and the lower end lies on the L type hook fixing, places the thermostatic bath that fills the 6ml locke solution, and the upper end connects tonotransducer.Temperature in the thermostatic bath remains (37 ± 0.5) ℃, feeds gaseous mixture (60～80 bubble/minute) simultaneously.BIAO and BEN load 0.94g; Balance 30 minutes, treat that experimental system is stable after, begin to trace 10 minutes normal uterus smooth muscle self-discipline curves; (it is 10mM that elder generation's adding taurine makes its final concentration in the uterine smooth muscle bath of setting up the rule uterine contraction is housed, to add taurine (Tau) with the mode that adds up; Adding taurine after 20 minutes again, to make its final concentration be 20mM, adds taurine after 20 minutes again, and making final concentration is 30mM.Do not change liquid between each concentration replacement; Directly add storage liquid); Other one group is 30mM taurine and 30mM transport inhibitors guanidine radicals ethyl sulfonic acid (Guanidinoethane sulfonate, GES) interpolation jointly simultaneously, record uterus muscle bar contraction situation; Change conventional locke solution into after each all administration experiments finish, observe the uterus and whether can recover normal contraction.
The influence that table 6. taurine shrinks the isolated mouse uterine smooth muscle
(
*, P＜0.01, expression difference is extremely remarkable;
* * *, P＜0.0001, the expression difference utmost point is extremely remarkable; Contrast is the preceding uterus of administration).
The influence that table 7. guanidine radicals ethyl sulfonic acid shrinks the isolated mouse uterine smooth muscle
Table 6 is that table 7 is to the data statistics of scheming B, C in the accompanying drawing 3 to the data statistics of figure A in the accompanying drawing 3.
The data of table 6 and table 7 are the mean+SD of 3 BIAO and BEN.
Experimental result such as table 6,7 and shown in Figure 3; Show that taurine suppresses the mice isolated uterine with dosage dependence mode and shrinks; The 10mM taurine can obviously suppress shrinkage amplitude, but contraction frequency is not seen obvious influence, when concentration almost completely suppresses to shrink (extremely remarkable with contrast difference) during to 30mM; Administration changes normal locke solution into after finishing, and uterine contraction can return to the normal contraction state again.Final concentration is taurine and its inhibitor-guanidine radicals ethyl sulfonic acid (GES) of 30mM when adding jointly, and taurine can not be brought into play and suppress uterotonic effect, adds 30mM GES separately to uterine contraction not influential (not remarkable with contrast difference).Explain that taurine can suppress the contraction of isolated uterine really.
Among Fig. 3, A is the influence that taurine shrinks the mice isolated uterine; B is that final concentration is that taurine and the 30mM taurine transporter inhibitor-guanidine radicals ethyl sulfonic acid (GES) of 30mM adds uterotonic influence jointly; C is that final concentration is that 30mM GES is to uterotonic influence.Among Fig. 3 A, it is that to represent the taurine cumulative concentration be that to represent the taurine cumulative concentration be 30mM for 20mM, " 30 " for 10mM, " 20 " that the taurine cumulative concentration is represented in " 10 ".Among Fig. 3 B, " 30+30 " represents the taurine cumulative concentration is that the final concentration of 30Mm and guanidine radicals ethyl sulfonic acid is 30mM.Among Fig. 3 C, it is 30mM that the final concentration of guanidine radicals ethyl sulfonic acid is represented in " 30 ".
Claims (1)
1. taurine or its pharmaceutically acceptable salt suppress the application in the uterine contraction medicine in preparation.
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|---|---|---|---|---|
| CN101306015A (en) * | 2007-05-17 | 2008-11-19 | 黄胜先 | Composition for increasing embryo quality and preventing and curing defect baby from generating |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101306015A (en) * | 2007-05-17 | 2008-11-19 | 黄胜先 | Composition for increasing embryo quality and preventing and curing defect baby from generating |
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