A medicine for preventing or treating a scarred pregnancy

Abstract

The application relates to a medicine for preventing or treating a scar pregnancy. The scar pregnancy is a high-risk form of ectopic pregnancy, and the existing treatment method has limited effect, is prone to cause uterine rupture and massive hemorrhage, and seriously threatens the life safety of a patient. The existing technology mainly focuses on drug treatment and surgical intervention, but these methods have certain limitations and side effects. The medicine of the application can safely and effectively reduce the incidence of the scar pregnancy in the early pregnancy period.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and particularly relates to a medicine for preventing or treating a scarred pregnancy. BACKGROUND

[0002] Scarred pregnancy (CSP) refers to a very rare form of pregnancy in which the embryo implants on the scar of the uterus, which is mostly left by previous cesarean section surgery. If the uterine incision does not heal completely or heals poorly, it can cause the uterine wall to thin and form a scar. If the embryo implants on these scars, it can form a scarred pregnancy. This situation is very dangerous because the scar tissue is much harder and has much less carrying capacity than the normal uterine wall, and it is extremely likely to cause uterine rupture, posing a serious threat to the mother and fetus. The incidence of scarred pregnancy is very low, but it has increased with the rise in the rate of cesarean section. The diagnosis of scarred pregnancy usually requires ultrasound examination to confirm, and the treatment methods may include drug treatment (such as lauromacrogol or methotrexate, etc.), surgical intervention, and in some cases, hysterectomy may be required to prevent serious complications. These treatment methods often have high risks and complications. Therefore, finding effective methods to prevent and treat scarred pregnancy has become an important direction of current medical research.

[0003] Cell blebbing refers to the local swelling of the cell membrane to form a bubble-like structure, which is usually related to physiological activities such as cell migration, division and apoptosis. Studies have shown that when cells are under compression, the stretching and unfolding of the nuclear membrane triggers calcium release and the activation of cytoplasmic phospholipase A2 (cPLA2). cPLA2 is a key signal and metabolic regulatory molecule, and its activation further catalyzes the production of arachidonic acid (ARA), which in turn promotes the contractile activity of myosin II, triggering active contraction of the cell and causing cell membrane blebbing, helping the cell to quickly escape from the compression environment. In certain pathological conditions, such as cancer and inflammation, cell membrane blebbing can also significantly increase, leading to abnormal cell behavior and disease progression. By using cell blebbing inhibitors, these processes can be regulated, thereby providing new therapeutic means to address diseases such as cancer and inflammation. Typical cell blebbing inhibitors include AACOCF3, Y-27632, Blebbistatin or Latrunculin A, etc. SUMMARY

[0004] The technical problem to be solved by the present application is to overcome the shortcomings of the prior art and provide a method for improving embryo implantation on the scarred part of the uterus using cell blebbing inhibitors, in order to reduce the incidence of scarred pregnancy, thereby providing more options for the clinical treatment of scarred pregnancy.

[0005] The present application provides the use of a cell blebbing inhibitor in the preparation of a composition for preventing or treating a scarred pregnancy.

[0006] The present application also provides a use of a cell blebbing inhibitor in the preparation of a composition for reducing or avoiding implantation of an embryo at a scarred tissue.

[0007] In some embodiments, the composition is a medicament.

[0008] In some embodiments, the composition further comprises other drugs or agents for preventing or treating a scarred pregnancy.

[0009] In some embodiments, the other drugs or agents for preventing or treating a scarred pregnancy comprise one or more of lauromacrogol, methotrexate, mifepristone, potassium chloride, fluorouracil (5-Fu), or Trichosanthes kirilowii Maxim.

[0010] In some embodiments, the cell blebbing inhibitor comprises an inhibitor of cytoplasmic phospholipase A2, a Rho kinase inhibitor, a non-myosin II ATPase inhibitor, or an actin depolymerizing agent.

[0011] In some embodiments, the inhibitor of cytoplasmic phospholipase A2 is AACOCF3; or the Rho kinase inhibitor is Y-27632; or the non-myosin II ATPase inhibitor is Blebbistatin; or the actin depolymerizing agent is Latrunculin A.

[0012] In some embodiments, the composition is administered non-invasively (e.g. uterine perfusion or hysteroscopic perfusion) or invasively; locally or systemically.

[0013] In some embodiments, the composition is a lotion, suppository, spray, ointment, patch, paste, pill, suppository, emulsion, capsule, oral agent, or injection.

[0014] In some embodiments, the composition is administered in the early stage of pregnancy, preferably within 3 days, 10 days, 1-2 weeks, 3-4 weeks, 5-6 weeks, 7-8 weeks, 9-10 weeks, or 11-12 weeks after fertilization; more preferably, the composition is administered within one week of the development of the embryo.

[0015] Advantages of the present application:

[0016] (1) Efficient inhibition of cell blebbing: the cell blebbing inhibitor efficiently reduces the cell blebbing phenomenon.

[0017] (2) Potential for reducing scarred pregnancy: by improving the inhibition of embryo implantation in scarred tissue, the incidence of scarred pregnancy is reduced.

[0018] (3) Reduced side effects: compared to traditional drug therapy and surgical intervention, the present method reduces the risk of systemic side effects by using the cell blebbing inhibitor locally.

[0019] (4) Easy operation: Through a simple uterine perfusion method, effective intervention of embryo implantation in scar tissue can be achieved, which is easy to operate and highly feasible. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 , schematic diagram of drug infusion operation.

[0021] Figure 2 , Uterine morphology and embryo implantation location diagram. The left uterus is the model uterus, the lower 1 / 2 of the model uterus is the scar, and the right uterus is the healthy uterus.

[0022] Figure 3 The implantation rates of the lower 1 / 2 of the healthy side and the scar on the modeling side were compared between the NS group and the AA group.

[0023] Figure 4 The total number of implantations in the healthy side uterus of the NS group and the AA group. DETAILED DESCRIPTION

[0024] Scar pregnancy occurs in the uterine scar, the site of embryo implantation, and its incidence increases with the number of previous cesarean sections. The exact pathogenesis of scar pregnancy remains unclear, but the mechanical properties of uterine scars differ significantly from those of other parts of the body. Ultrasound elastography has shown that the stiffness of uterine scars is significantly increased compared to the intact myometrium of the uterus, which may also affect embryo implantation. Furthermore, the stiffness of the endometrium under pathological conditions is significantly higher than that under normal conditions. The inventors have discovered that, in the context of the characteristics of normal and pathological human endometrial tissue (differences in stiffness), the mechanobiological regulation of trophoblast migration and attachment may play a key role in the implantation process. Current treatments for scar pregnancy primarily rely on medication and surgical intervention, but these methods often carry high risks and complications. For example, drug therapy may have adverse effects on the mother and fetus, while surgical intervention may cause uterine damage or other complications. Furthermore, existing preventive measures have not effectively reduced the incidence of scar pregnancy. Therefore, there is an urgent need for new, safe and effective methods to prevent and treat scar pregnancy.

[0025] To solve this problem, the present application proposes to use a cell blebbing inhibitor to improve the problem of embryo implantation at the site of scar by inhibiting cell blebbing. The inventors found that mouse embryos tend to move to areas with higher stiffness in an in vitro environment, and the stiffness of uterine scar tissue is significantly higher than that of healthy uterine tissue. The difference in stiffness between the uterine scar and the healthy tissue can induce the embryo to migrate from the original implantation site to the scar, thereby causing a scar pregnancy. The cell blebbing inhibitor can block a series of reactions in the cell compression response, affecting cell blebbing and cell migration, thereby effectively reducing the embryo implantation at the site of scar and reducing the incidence of scar pregnancy. This method not only has clear biological mechanism support, but also can provide a new non-invasive treatment option, reduce the risk and complications in the treatment process, and has a wide clinical application prospect.

[0026] Terms and definitions

[0027] AACOCF3 (Arachidonyl trifluoromethyl ketone), also known as eicosapentaenoic acid trifluoromethyl ketone, is a fluorine-containing compound. Its structure contains an arachidonic acid group and a trifluoromethyl ketone group, which makes AACOCF3 have high lipophilicity and chemical stability. AACOCF3 belongs to a cell blebbing inhibitor and is used as an inhibitor of cytoplasmic phospholipase A2 (cPLA2). The introduction of the trifluoromethyl group enhances its inhibitory ability to cPLA2, mainly affecting the active center of the enzyme through the electron attraction effect. The activation of cPLA2 is an important step in the process of cell blebbing, and AACOCF3 binds to the active site of cPLA2 to inhibit its catalytic activity, thereby preventing the release of arachidonic acid, and inhibiting cPLA2 can reduce cell blebbing. Therefore, by inhibiting cPLA2, AACOCF3 can effectively block the cell blebbing process and reduce the blebbing behavior of cells under pressure. AACOCF3 has shown extensive potential in the treatment of various diseases: by inhibiting the activity of cPLA2, it effectively slows down the calcification of vascular smooth muscle cells and reduces lipid deposition in arterial plaques in cardiovascular diseases; in brain glioblastoma, by reducing ATP and adenosine levels, it inhibits tumor cell proliferation and metastasis; in the treatment of liver fibrosis, AACOCF3 can significantly alleviate liver fibrosis by inhibiting the activity of cPLA2; cPLA2 is a key molecule in the generation of lipid droplets (LDs), and the application of AACOCF3 can inhibit LDs generation and promote autophagy, reducing the progression of fibrosis; in anticancer research, AACOCF3 reduces the generation of ATP in tumor cells by inhibiting the activity of cPLA2, thereby inhibiting the proliferation and migration of tumor cells. In summary, AACOCF3 has shown significant therapeutic effects in cardiovascular diseases, cancer, inflammation, and neuroprotection, and other medical fields.

[0028] Y-27632 is a selective Rho kinase (ROCK) inhibitor that reduces the phosphorylation of myosin light chain, thereby decreasing the contractile activity of myosin II and inhibiting cell membrane blebbing by inhibiting ROCK; Blebbistatin is a specific non-myosin II ATPase inhibitor that directly inhibits the contractile function of myosin II, preventing the formation of blebbing; Latrunculin A (LatA) is a toxin extracted from the red sea sponge Latrunculia magnifica, which is widely used as an actin depolymerizing agent in live cell experiments. Latrunculin A inhibits the formation of actin filaments by binding to G-actin with high affinity, preventing its polymerization into F-actin. This binding leads to the disruption of the cytoskeleton, affecting the formation and dynamics of cell membrane blebbing. Y-27632 has shown good application prospects in anticancer and neuroprotection: studies have shown that the Rho signaling pathway plays a key role in anticancer drug-induced neurotoxicity, and inhibition of this pathway can effectively reduce drug neurotoxicity. Y-27632 inhibits tumor growth by inhibiting the RhoA-NF-kB signaling pathway, reducing cell proliferation and enhancing apoptosis; at the same time, it can also alleviate cisplatin-induced peripheral nerve damage and protect nerve function. In addition, Y-27632 protects neurons from drug damage during chemotherapy and shows potential in the treatment of cardiovascular diseases, providing a theoretical basis for the treatment of heart disease.

[0029] Blebbistatin is used in neuroscience to study the development and regeneration of neurons. It reduces neuron apoptosis caused by oxidative stress by inhibiting myosin-actin interaction. For example, in inner ear hair cells, Blebbistatin effectively inhibits neomycin-induced hair cell apoptosis by maintaining mitochondrial function and reducing reactive oxygen species (ROS) levels, indicating that Blebbistatin may have potential clinical application value in preventing aminoglycoside antibiotic-induced hair cell damage and hearing loss. In addition, Blebbistatin also has therapeutic potential for reducing intraocular pressure and relieving symptoms of glaucoma.

[0030] Latrunculin A also shows potential application prospects in anticancer research. As an F-actin inhibitor, Latrunculin A inhibits phagocytosis between CAR-NK cells and tumor cells by blocking actin polymerization. This inhibitory effect prevents the functional exhaustion of CAR-NK cells, thereby enhancing their anti-tumor activity and prolonging their anti-cancer efficacy in vivo.

[0031] The present application proposes a method for improving embryo implantation in scarred uterus using a cell blebbing inhibitor. The effectiveness of the cell blebbing inhibitor in reducing the incidence of scar pregnancy is verified through experiments. The specific design idea is as follows:

[0032] (1) Select model mice with uterine scars as experimental subjects.

[0033] (2) Use a cell blebbing inhibitor with a concentration of 10 μM for the experiment.

[0034] (3) Administer the drug through uterine perfusion.

[0035] (4) By comparing the embryo implantation site and number of the experimental group and the control group, evaluate the effectiveness of the cell blebbing inhibitor as a drug for preventing or treating scar pregnancy.

[0036] Example 1

[0037] Experimental subjects: model mice with uterine scars.

[0038] Drug use: AACOCF3 (concentration of 10 μM), physiological saline, 1% blue dye solution, anesthetic.

[0039] Consumables: 1 ml syringe, disposable side-opening dental irrigation needle.

[0040] Specific experimental steps:

[0041] (1) Preparation: After the experimental mice are plugged, they are divided into two groups, the experimental group and the control group.

[0042] Experimental group (AA group): AACOCF3, concentration of 10 μM, administered 4 times, 0.02 ml / time.

[0043] Control group (NS group): physiological saline, concentration of 0.9%, administered 4 times, 0.02 ml / time.

[0044] (2) Drug perfusion: At E3.5 (3.5 days of embryo development), after the mice are anesthetized, a disposable side-opening dental irrigation needle is used to perfuse AACOCF3 solution into the uterus of the experimental group mice through uterine perfusion, and the control group is perfused with an equal volume of physiological saline.

[0045] (3) Staining and dissection: At E5.5 (5.5 days of embryo development), after the mice are anesthetized, all mice are injected with 1% blue dye solution through the tail vein. After 5 minutes of dye injection, the mice are dissected, the uterus is isolated, and the embryo implantation site and number are observed and recorded.

[0046] (4) Data recording and analysis: The distribution of the implantation sites of the experimental and control groups of mice was counted and compared, and the effect of AACOCF3 on the hardening migration of embryos was analyzed.

[0047] Results analysis:

[0048] 1. Healthy side lower 1 / 2:

[0049] There was no significant difference in the implantation rate between the NS group and the AA group (p=0.4), indicating that AA treatment did not affect the normal implantation of embryos in the healthy side lower 1 / 2.

[0050] 2. Scar site on the modeling side:

[0051] The implantation rate of the scar site in the NS group was higher, while the implantation rate of the AA group was lower. The implantation rate of the NS group was significantly higher than that of the AA group (p=0.0089), indicating that AA treatment may help reduce the implantation rate in the scar tissue on the modeling side. This result suggests that AA treatment may have an inhibitory effect on embryo implantation in scar tissue.

[0052] 3. Total number of implantations on the healthy side:

[0053] The difference in the total number of implantations in the uterus on the healthy side between the NS group and the AA group was not significant (p=0.688), indicating that the use of AA treatment did not affect the normal implantation of embryos in the overall uterus. Moreover, the average number of implantations in the NS group and the AA group was 4.73 and 5.12, respectively, and there was no significant difference between them, further supporting the fact that AA treatment had no negative impact on the overall implantation rate.

[0054] Conclusion:

[0055] AA treatment did not affect the normal implantation of embryos in the uterus.

[0056] AA treatment had a significant effect on reducing the implantation rate in the scar tissue on the modeling side, which may help reduce the risk of abnormal implantation in the scar tissue area.

[0057] Overall, the application of AA treatment in embryo implantation is safe and effective, and has high clinical application value.

[0058] The above is only a preferred embodiment of the present application and is not intended to limit the present application. Those skilled in the art can make various modifications and changes to the present application. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. Use of arachidonic acid trifluoromethyl ketone in the preparation of a medicament for preventing or treating scar pregnancy.

2. The use according to claim 1, characterized in that The drug is administered non-invasively.

3. The use according to claim 2, characterized in that The drug is infused into the uterus or uterine cavity.

4. The use according to any one of claims 1 to 3, characterized in that The drug is administered during the first trimester.

5. The use according to claim 4, characterized in that The drug is administered within a week of embryonic development.

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