CN113769065A - Application of cyclosporin A in preparation of medicine for improving embryo planting rate of patients with repeated embryo implantation failure - Google Patents

Application of cyclosporin A in preparation of medicine for improving embryo planting rate of patients with repeated embryo implantation failure Download PDF

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CN113769065A
CN113769065A CN202111103084.8A CN202111103084A CN113769065A CN 113769065 A CN113769065 A CN 113769065A CN 202111103084 A CN202111103084 A CN 202111103084A CN 113769065 A CN113769065 A CN 113769065A
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CN113769065B (en
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朱蕊
李红
李大金
杜美蓉
李明清
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
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    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis

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Abstract

The invention discloses an application of cyclosporine A in preparing a medicine for improving the embryo planting rate of a patient with repeated embryo implantation failure. The invention provides a method for improving embryo planting rate by using cyclosporin A as an immunosuppressant or a medicament for preventing miscarriage, particularly discloses a method for improving embryo planting rate of repeated embryo implantation failure patients in embryo transplantation, and is different from the prior art in research result.

Description

Application of cyclosporin A in preparation of medicine for improving embryo planting rate of patients with repeated embryo implantation failure
Technical Field
The invention belongs to the in vitro fertilization-embryo transplantation derivation technology, and particularly relates to application of cyclosporine A in preparation of a medicine for improving the embryo planting rate of a patient with repeated embryo implantation failure.
Background
Fertility disorders affect about 18-20% of fertile couple in our country, and become the third major disease beyond cancer and cardiovascular and cerebrovascular diseases. In recent years, ART level is increasingly improved and developed, the clinical pregnancy rate of In vitro fertilization-embryo transfer (IVF-ET) is improved to 50-60%, but the embryo planting rate still lingers In 30-40%. At present, embryo implantation failure is a bottleneck for further improving ART clinical pregnancy rate and live yield, and also brings great economic and mental pressure to patients, thus being a difficult problem and a research hotspot in the field of reproductive medicine at present.
The main factors affecting embryo implantation include embryonic factors, Endometrial Receptivity (ER), maternal diseases, and other complex factors. Embryo factors include chromosomal or genetic abnormalities, zona pellucida sclerosis, embryo culture conditions, and embryo transfer species and techniques. ER includes immune factors, infectious factors (flora), uterine cavity abnormalities or intima thinness, etc. Maternal diseases include endometriosis, hydrosalpinx, thrombophilia and autoimmune diseases.
Recurrent transplantation failure (RIF) refers to infertility patients who have undergone In Vitro Fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycle to transplant multiple high quality embryos without acquiring pregnancy. The diagnostic criteria of RIF are 13 in total since 2005, and at present, the definition of RIF is not unified, and controversial issues exist in the aspects of the number of transferred embryo cycles, the number and quality of transferred embryos, the period and cycle type of transferred embryos, the age and the like. The following 3 views are the mainstream: the number of high-quality embryo transplantation or accumulated transplantation embryos is more than 3 times and no pregnancy is obtained (combination of genetic diagnosis (PGD) before planting); after at least 2 fresh cycles or freeze-thaw cycles, no less than 4 good blastocysts or no less than 2 good blastocysts are co-transplanted without acquiring pregnancy (Polanski LT, Baumgarten MN, Quenby S, et al. at expressed do we mean by "pregnancy implantation failure" A systematic review and implantation. reproduced Online 2014;284(4): 409) 423); infertile patients under the age of 40 undergo at least 3 cycles of aspiration, fresh or frozen transfer cycles accumulating the transfer of at least 4 good quality embryos without acquiring pregnancy (Coughlan C, Ledger W, Wang Q, et a1. secure transfer failure: definition and management [ J ]. reproduced Biomed Online,2014;281 (1): 14-38). The literature reports that: monoblastocyst transfer had similar live yields to that of 2 cleavage stage embryos (Csokmay JM, Hill MJ, Chason RJ, et al, Experience with a patent friend, mandatory, single blast transfer polarity: the power of one [ J ] Fertil Steril,2011,96(3): 580-); one RIF cohort study found: the clinical pregnancy rate and the survival rate of embryo transplantation in the single-sac embryo stage in the freezing recovery period are obviously superior to those of embryo transplantation in the double cleavage stage (XD Zhang, Y Gao, WW Liu et al. hum Fertil (Camb), 2019 Jul 5; 1-6).
Normal physiological pregnancy is similar to allograft transplantation, and the immunological rejection of the embryo as a natural allograft by the mother is the only exception of immunological theory, actually reflecting the immunological tolerance of the mother to the embryo antigens. Cyclosporin A (CsA) is a macrolide immunosuppressant, is firstly used in clinic in the first 80 th of 20 th century, and is widely used for preventing and treating rejection reaction and autoimmune diseases after organ transplantation.
CsA is administered to patients with autoimmune diseases, and CsA (30-60 days after pregnancy, 50mg bid or tid) is added to 104 patients with Recurrent Spontaneous Abortion (RSA) caused by immune abnormality by treating immune diseases such as clinical pregnancy outcome and weekly faking. Currently, the therapeutic effect of CsA in embryo implantation failure patients is still lacked, and the application of cyclosporine in the reproductive field is also lacked evidence of evidence-based medicine.
Disclosure of Invention
The invention discloses an application of cyclosporine A in preparing a medicine for improving the embryo planting rate of embryo re-implantation of a patient with repeated embryo implantation failure.
In the present invention, embryo implantation refers to in vitro fertilization-embryo transfer into the mother's uterus.
In the invention, the repeated embryo implantation failure means that the number of embryo transplantation failures is more than or equal to 2, and more than or equal to 4 high-grade embryo in cleavage stage are transplanted or more than or equal to 2 high-grade blastocysts are transplanted; the scores were conventional techniques.
In the invention, the patient has no autoimmune system diseases, and is specifically judged to have the conventional medical standard.
In the invention, the patient takes the medicine from the day of embryo transplantation; the dosage of the medicine is calculated by cyclosporine A, and the blood concentration range is 40-400 ng/mL.
The invention discloses a medicine for improving the embryo planting rate of a patient with repeated embryo implantation failure, which comprises an active component of cyclosporine A.
The effect of cyclosporin A on mouse embryos is studied in the prior art, and researches on Dumet Rong and the like show that spleen CD4 in pregnancy period of CsA-treated spontaneous abortion model mice (CBA/J female mice mated with DBA/2 male mice) at pregnancy period+CD25+The proportion of tregs is significantly increased. In animal experiments, through research on a CBA/J female mouse multiplied by DBA/2 male mouse natural abortion mouse model, the CsA can promote proliferation of mouse trophoblasts and reduce apoptosis rate of the trophoblasts at 1-10 mg/kg, and pregnancy outcome is improved. On one hand, the prior art uses cyclosporin A to improve abortion, and has no effect connection with embryo transplantation, on the other hand, the effect of cyclosporin A on animals is opposite to that on human, for example, cyclosporin A has kidney protection effect on SLE mice, but has kidney toxicity on children, and is not suitable for SLE children.
As an immunosuppressant, cyclosporin A (cyclosporine A) can prevent and inhibit rejection reaction after organ transplantation and prevention and treatment of autoimmune diseases, the influence of CsA in pregnancy and the action mechanism thereof are further researched on the basis of immunosuppression in recent years, the CsA aims at abortion or pregnancy, for example, the CsA can improve trophoblastic biological behavior, and the appropriate dosage of CsA promotes proliferation of villus trophoblastic cells in 50-60 days of pregnancy to inhibit apoptosis in a concentration and time-dependent manner; and the combination of the CsA group is proved to achieve the effect of fetus protection. The effect of cyclosporin A on in vitro fertilization-embryo transplantation has not been seen so far, and particularly the effect of cyclosporin A on embryo planting in patients with repeated embryo implantation failure has not been seen. The invention discloses the effect of cyclosporin A on secondary embryo planting of a patient with recurrent embryo implantation failure for the first time, indicates that the use of cyclosporin A improves the embryo planting rate of secondary embryo transplantation of the patient with recurrent embryo implantation failure.
Detailed Description
The evaluation standard related to the invention is the current conventional medical standard; the cyclosporine A is a conventional commercial product; specific detection methodThe method is the conventional detection method. The statistical method comprises the following steps: statistical analysis is carried out on the research data by using an SPSS 22.0 statistical software package, the data accord with normal distribution, the measured data is expressed by (x +/-s), and the comparison among groups adopts t test; data rate (%) of counts and comparison between groups by χ２And (6) checking. P < 0.05 indicates that the difference is significant.
Examples
The invention discloses an application of cyclosporine A in preparing a medicine for improving the embryo planting rate of a patient with repeated embryo implantation failure. The invention indicates that the cyclosporine A can obviously improve the embryo planting rate of a patient with repeated embryo implantation failure for the first time; unlike pregnancy or abortion after pregnancy, the in vitro fertilization-embryo transfer into the mother's uterus is a different step and is affected by different factors.
Application examples
The patients who failed to repeatedly implant embryos and were treated by IVF-ET assisted pregnancy in Suzhou city hospital were divided into 105 cases in the treatment group and 285 cases in the control group according to whether cyclosporin A was used for the second time of embryo transfer. Inclusion criteria were: (1) the age is less than 40 years old; (2) the failure times of transplantation are more than or equal to 2 times, and more than or equal to 4 high-scoring embryo in cleavage stage is transplanted or more than or equal to 2 high-scoring blastocysts are transplanted. Exclusion criteria: (1) stage III-IV endometriosis or severe adenomyosis; (2) severe hydrosalpinx; (3) moderate and severe intrauterine adhesion; (4) merging uterine malformations; (5) recurrent abortion; (6) combined with autoimmune diseases. The general data of the treated group and the control group are compared in Table 1.
Figure 967175DEST_PATH_IMAGE001
Control patients used conventional treatment regimens: progesterone, folic acid drugs; in addition to the support of the conventional protocol, cyclosporin A50mg, q8h was orally administered from the transplantation day, during which CsA plasma concentration was measured weekly (C0 before administration and C2 2h after administration respectively reflect the effective dose and toxic dose of the drug), and dose-by-dose adjustment was performed according to the measured CsA plasma concentration, the CsA-effective plasma concentration ranged from 40 to 400ng/mL, and if C0 < 40 ng/mL, the increment dose was 75mg, q8 h. If C2 > 400ng/mL, the dosage is 50mg, q12 h. After the continuous administration for 14 days, the blood beta-HCG is measured, if the blood beta-HCG is positive, the administration is continued, and after 34 days of transplantation, the blood beta-HCG is more than 10 ten thousand mu/mL, and the embryo and the fetal heart can be detected by B ultrasonic examination, and CsA can be stopped.
Observation indexes are as follows: the embryo planting rate (%) is the number of the visible pregnancies of the B-ultrasonic wave 30-35 days after the transplantation/the total number of the transplanted embryos; clinical pregnancy rate (%) number of transplantation cycles of gestational sac seen by B-ultrasonic 30-35 days after transplantation/total number of transplantation cycles.
The clinical results of the secondary embryo transfer of the patients in the treatment group and the control group are shown in the table 2; the clinical results of the treatment group and the control group of patients who are transplanted with the embryo at the cleavage stage again are shown in the table 3; the clinical results of replanting blastocysts in the treated and control patients are shown in Table 4. It can be seen that, on the basis of basically similar baseline conditions, the planting rate of the second embryo transplantation of the patients with repeated embryo implantation failure is remarkably improved by adopting the treatment group of the cyclosporine A compared with the control group, and particularly the planting rate of the blastocyst is improved.
Figure 681053DEST_PATH_IMAGE002
Figure 585424DEST_PATH_IMAGE003
Figure 105267DEST_PATH_IMAGE004
Comparative application example
The patients who failed implantation of the first embryo in IVF-ET assisted pregnancy treatment in Suzhou city hospital were taken as samples, and were divided into 60 cases according to the application of cyclosporin A in the second (second) embryo transfer, and 240 cases were matched in the control group at a ratio of 1:4 without cyclosporin A. Inclusion criteria were: (1) the age is less than 40 years old; (2) the number of graft failures was 1. Exclusion criteria: (1) stage III-IV endometriosis or severe adenomyosis; (2) severe hydrosalpinx; (3) moderate and severe intrauterine adhesion; (4) merging uterine malformations; (5) recurrent abortion; (6) combined with autoimmune diseases. The treated group and the control group have no significant difference compared with the general data.
The clinical results of the previous transfer of the embryo from the patient with the previous transfer failure are shown in Table 5, and it can be seen that there is no difference in the embryo planting rate and the clinical pregnancy rate based on no significant difference in age, BMI, basal FSH, endometrial thickness, embryo quality, and cause of infertility.
Figure 575431DEST_PATH_IMAGE005
The embryo and endometrium entering the uterine cavity secrete related protein or (and) local factor according to a certain time-space sequence to achieve mutual recognition and mutual fusion, and then implantation is completed. The implantation process includes the positioning and adhesion of the hatched blastocyst until the whole embryo is embedded in endometrial stroma, and is a complex process of mutual recognition and mutual fusion of embryo and maternal stroma. How endometrial tissue changes in the endocrine environment, mainly progesterone, to adapt and limitedly allow the mechanisms of embryo fusion and implantation is not clear, which is the least obvious and most challenging subject in the field of reproductive medicine at present. Embryo implantation occurs in a very short "Window of implantation" (WOI), typically 6-8 days post-ovulation or 5-7 days post-fertilization, and the endometrium is in a state that allows the embryo to adhere, penetrate and implant, and is associated with endometrial thickness, blood flow, the number of pinocytosis in the Window of implantation, intimal microenvironment, etc. Currently accepted RIF is defined as an infertile female with an age of less than 40 years, with 3 cycles of transfer (including fresh embryo transfer and freeze-thaw embryo transfer), with more than 4 high-scoring cleavage stage embryos transferred or with more than 2 high-scoring blastocysts transferred, and with no pregnancy obtained; in this regard, there is a need for improvements in prior art treatment regimens. Cyclosporin A is a macrolide immunosuppressant, is first used in clinic in the beginning of the 20 th century and the 80 th year, and is widely applied to prevention and treatment of rejection reaction and autoimmune diseases after organ transplantation. In recent years, the influence of CsA in pregnancy and the action mechanism thereof are further researched on the basis of immunosuppression, and the CsA is a novel fetus-protecting medicine disclosed by the prior art. However, embryo implantation and pregnancy are different stages, have different influence factors, and no mutual teaching of technical effects exists. According to the invention, the cyclosporin A is creatively used for secondary embryo transplantation of a patient with repeated embryo implantation failure, and the unexpected discovery that the cyclosporin A remarkably improves the planting rate and even the pregnancy rate; provides powerful basis and technical guidance for guiding clinical application.

Claims (10)

1. Application of cyclosporin A in preparing medicine for increasing embryo planting rate of patient with repeated embryo implantation failure.
2. Use according to claim 1, wherein embryo implantation refers to in vitro fertilization-embryo transfer into the mother's uterus.
3. The use of claim 1, wherein the repeated embryo implantation failure is an embryo transfer failure of 2 or more times, and wherein 4 or more high scoring blastomeres are transferred or 2 or more high scoring blastocysts are transferred.
4. The use of claim 1, wherein the patient is free of autoimmune disease.
5. The use of claim 1, wherein the patient is taking medication from the day of embryo transfer; the dosage of the medicine taking is calculated by cyclosporine A, and the blood concentration range is 40-400 ng/mL.
6. Use according to claim 1, wherein cyclosporin A is used in the preparation of a medicament for increasing the embryo implantation rate in repeat embryo implantation failure patients who undergo embryo re-implantation.
7. A medicine for increasing the embryo planting rate of the patient with repeated embryo implantation failure contains cyclosporin A as active component.
8. Application of cyclosporin A in preparing medicine for increasing the clinical pregnancy rate of patients with recurrent embryo implantation failure.
9. A method for increasing the embryo implantation rate of a patient who has failed in implantation of repeated embryos for a non-therapeutic purpose, characterized in that the patient starts embryo transplantation again and takes cyclosporin A from the day of transplantation.
10. The method for increasing the embryo implantation rate of a patient with recurrent embryo implantation failure according to claim 9, wherein the blood concentration is in the range of 40-400 ng/mL.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115873937A (en) * 2022-08-15 2023-03-31 苏州市立医院 Biomarker for predicting occurrence of repeated planting failure and application thereof
CN115873937B (en) * 2022-08-15 2023-07-14 苏州市立医院 Biomarker for predicting occurrence of repeated planting failure and application thereof

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