Application of adrenochromic hydrazone in preparation of medicine for treating subdural hematoma

Abstract

The invention provides application of adrenochromic hydrazone in preparation of a medicine for treating subdural hematoma, and belongs to the technical field of medicines. The invention finds that the adrenochrome can improve the expression level of endothelial connexin of epidural blood vessels, enhance the resistance of blood capillaries to injury, reduce the permeability of the blood capillaries, reduce the bleeding amount of subdural hematoma, relieve inflammatory response caused by hematoma stimulation and accelerate the recovery of subdural hematoma for the first time. Therefore, the compound can be used for preparing medicines for treating subdural hematoma. The medicine can be administrated through oral administration, the risk existing in a traditional drilling drainage operation is avoided, and an alternative or auxiliary treatment scheme is provided for patients who are intolerant to statins or hormones and patients who are ineffective in treatment through combination of statins and hormones.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and in particular relates to application of adrenaline in preparing medicine for treating subdural hematoma. Background Art

[0002] Chronic subdural hematoma (CSDH) is one of the common diseases in neurosurgery, with an incidence of 1-13.1 per 100,000 people per year, and its incidence tends to increase with age. With the increase in elderly patients and those who receive stent treatment, heart bypass surgery, and cerebrovascular bypass surgery due to heart or cerebrovascular diseases, the use of anticoagulants is very common, and refractory CSDH or recurrent CSDH is gradually increasing, becoming another difficult problem faced by neurosurgeons.

[0003] Currently, surgical treatment is still the main treatment option for this type of hematoma, but it cannot achieve zero recurrence and prevent complications, resulting in poor prognosis for up to 30% of patients. In addition, many elderly patients often refuse surgical treatment or cannot undergo surgery immediately due to coagulation disorders or cardiopulmonary diseases, making treatment difficult, which has attracted great attention in the neurosurgery community.

[0004] The applicant's patent ZL201710037311.9 discloses the combined treatment of chronic subdural hematoma with statins and adrenal cortical hormones, which has been repeatedly proven to be effective and safe in clinical observational studies and has become the preferred adjuvant treatment for chronic subdural hematoma by most neurosurgeons. Although the combination of statins and dexamethasone can effectively promote the absorption of subdural hematoma, clinical studies have found that some elderly patients are intolerant to statins and hormones. Among them, some patients who are intolerant to statins cannot take them orally because statins cause rhabdomyolysis, and some cannot take them orally because statins cause liver dysfunction; there are fewer patients who are allergic to hormones, but some patients have to interrupt the use of hormones because hormones cause accelerated heart rate, increased blood pressure and / or abnormally increased blood sugar. When these patients have to choose non-surgical methods due to surgical contraindications such as coagulation mechanism disorders or severe heart, lung, liver and kidney dysfunction, but cannot use statins or statins combined with hormones, their treatment becomes very difficult and may lead to poor prognosis for patients. Therefore, it is urgent to find alternative treatment options for chronic subdural hematoma. Summary of the invention

[0005] In view of the shortcomings of the prior art, the present invention aims to provide an application of adrenaline in the preparation of a drug for treating subdural hematoma.

[0006] To achieve this object, the present invention adopts the following technical solutions:

[0007] In a first aspect, the present invention provides a use of adrenaline in preparing a medicine for treating subdural hematoma.

[0008] In some embodiments of the present invention, the subdural hematoma is a chronic subdural hematoma.

[0009] In a second aspect, the present invention provides a use of adrenaline in preparing a drug for alleviating inflammatory response of the dura mater around a hematoma.

[0010] In a third aspect, the present invention provides a use of adrenaline in the preparation of a drug for increasing the expression level of dura mater vascular endothelial junction protein.

[0011] The pathogenesis of chronic subdural hematoma is still unclear, and there is no unified opinion in academia. In the early days, it was believed that trauma was the cause of chronic subdural hematoma, but this theory has long been controversial. Chronic subdural hematoma usually occurs 4-7 weeks after trauma, and the degree of trauma does not match the formation of CSDH. Even very minor trauma may cause a large amount of hematoma accumulation. The formation of chronic subdural hematoma is a complex process, and multiple factors are involved. One possible factor is the presence of a large number of inflammatory factors in the hematoma cavity, which stimulates the formation of "fragile" capillaries and causes continuous bleeding.

[0012] The applicant has conducted long-term research on chronic subdural hematoma and found that controlling the bleeding of new capillaries under the dura mater is the key to treating chronic subdural hematoma. Experiments using a rat subdural hematoma model found that adrenal hydrazone can increase the expression level of dural vascular endothelial junction proteins, enhance the resistance of capillaries to damage, reduce the permeability of capillaries, reduce the amount of bleeding in subdural hematoma, and reduce the inflammatory response caused by hematoma stimulation, accelerating its recovery; clinical experiments have confirmed that adrenal hydrazone can effectively treat subdural hematoma.

[0013] Adrenochromazone is the sodium salt of semicarbazide salicylate of adrenochrome, the oxidation product of adrenaline. It is also known as sodium adrenochromazone salicylate, and is also known as Andronoxine, Antenoxine, adrenochrome semicarbazine, adrenochrome peptide, Anlox, salicylic Anlox, sulfonic Anlox, Carbac, AC-17, AdrenobazonSylicylate, Adrenochromazone, etc. Up to now, the indications of adrenochromazone are epistaxis, retinal hemorrhage, hemoptysis, gastrointestinal bleeding, hematuria, hemorrhoids and uterine bleeding, etc. There are no reports on the use of adrenochromazone to treat subdural hematoma and explore its mechanism of treating subdural hematoma.

[0014] In a fourth aspect, the present invention provides a drug for treating subdural hematoma, wherein the drug comprises adrenaline.

[0015] In some embodiments of the present invention, the subdural hematoma is a chronic subdural hematoma.

[0016] In some embodiments of the present invention, the drug further comprises a pharmaceutically acceptable excipient.

[0017] In some embodiments of the present invention, the dosage form of the drug is oral tablets or intramuscular injection.

[0018] In some embodiments of the present invention, the drug is administered orally;

[0019] And / or, the dosage is: based on the mass of adrenaline, 1.25-5 mg / time (for example, 1.25 mg / time, 1.5 mg / time, 1.8 mg / time, 2 mg / time, 2.5 mg / time, 3 mg / time, 3.5 mg / time, 4 mg / time, 4.5 mg / time or 5 mg / time, etc.), 1-3 times a day (for example, 1 time, 2 times, or 3 times);

[0020] And / or, the administration period is: continuous administration for more than 2 weeks or continuous administration permanently.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] The present invention first studies and finds that adrenaline can increase the expression level of dural vascular endothelial junction proteins, enhance the resistance of capillaries to damage, reduce the permeability of capillaries, reduce the amount of bleeding in subdural hematoma, and alleviate the inflammatory response caused by hematoma stimulation, accelerate the recovery of subdural hematoma, and therefore can be used to prepare drugs for treating subdural hematoma.

[0023] The drug containing adrenochrome provided by the present invention can be orally administered, avoiding the disadvantages of the traditional drilling and drainage for treating chronic subdural hematoma, such as the risk of anesthesia, the risk of pain, the risk of surgical bleeding, the disruption of brain physiological circulation, the damage of brain function, the postoperative infection and the postoperative recurrence. At the same time, it provides a good alternative or auxiliary treatment scheme for the treatment of chronic subdural hematoma with drugs for patients who are intolerant to statins or hormones, and for a very small number of patients for whom the combined treatment of statins and hormones is ineffective. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is a diagram showing the therapeutic effect of adrenal chromohydrazone (AC-17) on subdural hematoma model rats in Example 1 of the present invention;

[0025] Among them, Figure A is the coronal section of the brain of rats in the sham operation group (Sham), Figure B is the coronal section of the brain of rats in the subdural hematoma group (SDH), Figure C is the coronal section of the brain of rats in the AC-17 treatment group with different dosages, and Figure D is a statistical chart of the remaining amount of subdural hematoma in each group of rats.

[0026] Figure 2 These are confocal fluorescence images of dura mater blood vessels and endothelial junction proteins of rats in each group in Example 2 of the present invention.

[0027] Figure 3A This is the gel electrophoresis diagram of the inflammatory proteins IL-6, TNF-α and IL-1β expressed in the dura mater of each group of rats in Example 3 of the present invention.

[0028] Figure 3B This is a statistical diagram of the relative expression of IL-6 protein in the dura mater of each group of rats in Example 3 of the present invention.

[0029] Figure 3C This is a statistical diagram of the relative expression of TNF-α protein in the dura mater of each group of rats in Example 3 of the present invention.

[0030] Figure 3D This is a statistical diagram of the relative expression of IL-1β protein in the dura mater of each group of rats in Example 3 of the present invention.

[0031] Figure 4A Head CT images of clinical case 1 at different treatment stages.

[0032] Figure 4B Head CT images of clinical case 1 at different treatment stages.

[0033] Figure 5 Head CT images of clinical case 2 at different treatment stages.

[0034] Figure 6 Head CT images of clinical case 3 at different treatment stages. DETAILED DESCRIPTION

[0035] The technical solution of the present invention is further described below with reference to the accompanying drawings and through specific implementations. It should be understood by those skilled in the art that the specific implementations are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0036] Example 1 Adrenochrome (AC-17) promotes the absorption of subdural hematoma

[0037] The rats were randomly divided into sham operation group (Sham), subdural hematoma group (SDH), and AC-17 treatment group. The AC-17 treatment group was further divided into three groups with different dosages. After anesthesia, a bone window of about 1 mm was opened at 3 mm on the right side of the sagittal suture of the skull in the subdural hematoma group and the AC-17 treatment group, the dura mater was punctured, and 350 μL of autologous blood was injected into the subdural space at a rate of 60 μL / min to establish a subdural hematoma model; after anesthesia, a bone window of about 1 mm was opened at 3 mm on the right side of the sagittal suture of the skull in the sham operation group, the dura mater was punctured, and then disinfected and sutured. After the modeling was completed, the rats in the AC-17 treatment group were gavaged with AC-17 at doses of 0.5 mg / kg, 0.75 mg / kg, and 1 mg / kg daily (AC-17 was dissolved in PBS (pH about 7.4) at different concentrations, and the AC-17 concentrations were 1.552 mM, 2.328 mM, and 3.104 mM, respectively). The sham operation group and subdural hematoma group were given an equal amount of PBS (pH about 7.4). After continuous administration and the establishment of the rat subdural hematoma model, the rats were euthanized 3 days later, and the rat brain tissues were harvested and fixed with paraformaldehyde. After dehydration and embedding, the rat coronal frozen sections were made with a thickness of 10 μm. The sections were stained with HE, and the thickness of the subdural hematoma was observed and evaluated under a microscope. The results are as follows Figure 1 As shown in the figure, Figure A is the coronal section of the brain of rats in the sham operation group (Sham), Figure B is the coronal section of the brain of rats in the subdural hematoma group (SDH), Figure C is the coronal section of the brain of rats in the AC-17 treatment groups with different dosages, and Figure D is a statistical diagram of the residual amount of subdural hematoma in rats in each group, ns means no significant difference, *p<0.05, ****p<0.0001.

[0038] from Figure 1 It can be seen that compared with the subdural hematoma group, the residual amount of subdural hematoma in rats treated with AC-17 at a dose of 0.5 mg / kg was reduced, but the difference was small. Compared with the subdural hematoma group, the residual amount of subdural hematoma in rats treated with AC-17 at doses of 0.75 mg / kg and 1 mg / kg was significantly reduced. There was no significant difference in the effect between the AC-17 treatment groups at doses of 0.75 mg / kg and 1 mg / kg. This shows that 0.75 mg / kg of AC-17 can effectively promote hematoma absorption.

[0039] Example 2AC-17 protects dural vascular endothelial junctions

[0040] Rats were randomly divided into sham group (Sham), subdural hematoma group (SDH), and AC-17 treatment group. After anesthesia, rats in the subdural hematoma group and AC-17 treatment group were opened with a bone window of about 1 mm at 3 mm to the right of the sagittal suture of the skull, the dura mater was punctured, and 350 μL of autologous blood was injected into the subdural cavity at a rate of 60 μL / min to establish a subdural hematoma model; after anesthesia, rats in the sham group were opened with a bone window of about 1 mm at 3 mm to the right of the sagittal suture of the skull, the dura mater was punctured, and then disinfected and sutured. After the modeling was completed, rats in the AC-17 treatment group were given AC-17 (AC-17 dissolved in PBS (pH about 7.4), AC-17 concentration 2.328 mM) by oral gavage at a dose of 0.75 mg / kg daily, and the sham group and subdural hematoma group were given an equal amount of PBS (pH about 7.4). After continuous administration of the drug, rats were euthanized 3 days after the establishment of a subdural hematoma model. The dura mater was harvested and fixed with paraformaldehyde. Endothelial junction proteins were labeled with VE-cadherin (vascular endothelial cadherin) and blood vessels were labeled with CD31 (platelet-endothelial cell adhesion molecule). Changes in vascular structure were observed under a confocal microscope (20×). Figure 2 shown.

[0041] from Figure 2 It can be seen that compared with Sham, the dura mater vascular endothelial junction protein in the SDH group was severely broken. After AC-17 treatment, the expression level of dura mater vascular endothelial junction protein in rats was significantly upregulated, indicating that AC-17 can protect the dura mater vascular structure.

[0042] Example 3 AC-17 relieves the inflammatory microenvironment of the dura mater around the hematoma

[0043] Rats were randomly divided into sham group (Sham), subdural hematoma group (SDH), and AC-17 treatment group. Among them, after anesthesia, the rats in the subdural hematoma group and AC-17 treatment group were opened with a bone window of about 1 mm at 3 mm on the right side of the sagittal suture of the skull, the dura mater was punctured, and 350 μL of autologous blood was injected into the subdural cavity at a rate of 60 μL / min to establish the subdural hematoma model; after anesthesia, the rats in the sham group were opened with a bone window of about 1 mm at 3 mm on the right side of the sagittal suture of the skull, the dura mater was punctured, and then disinfected and sutured. After the modeling was completed, the rats in the AC-17 treatment group were given AC-17 (AC-17 was dissolved in PBS (pH about 7.4), AC-17 concentration 2.328mM) by oral gavage at a dose of 0.75 mg / kg daily, and the sham group and subdural hematoma group were given the same amount of PBS (pH about 7.4). After continuous administration, the rats were euthanized 3 days after the establishment of the rat subdural hematoma model, and the rat dura mater was harvested. All proteins in rat dura mater were extracted, and changes in inflammatory proteins (IL-6, TNF-α, and IL-1β) were detected by western blotting. Figure 3A to Figure 3DAs shown. Among them, Figure 3A The gel electrophoresis diagrams of inflammatory proteins IL-6, TNF-α, and IL-1β expressed in the dura mater of rats in each group (β-actin was used as an internal reference); Figure 3B The statistical diagram of the relative expression of IL-6 protein in the dura mater of rats in each group; Figure 3C The statistical diagram of the relative expression of TNF-α protein in the dura mater of rats in each group; Figure 3D The relative expression of IL-1β protein in the dura mater of rats in each group is statistically shown in Figure 2. ns means no significant difference, *p<0.05, **p<0.01, ****p<0.0001.

[0044] from Figure 3A to Figure 3D It can be seen that compared with the Sham group, the expression of inflammatory proteins in the dura mater around the hematoma in the SDH group was significantly increased, and the inflammation was aggravated. After AC-17 treatment, the expression of inflammatory proteins in the dura mater of rats was significantly downregulated, indicating that AC-17 can alleviate the inflammatory microenvironment of the dura mater around the hematoma.

[0045] Example 4 Clinical Cases

[0046] Case 1

[0047] Zhou, male, 80 years old, had a left subdural hematoma without any cause, limited speech function, and unstable walking. The patient's head CT examination results at each stage of treatment are as follows: Figure 4A and Figure 4B shown.

[0048] On May 12, 2023, he developed a left-sided subdural hematoma and was treated with combined treatment of atorvastatin calcium and dexamethasone for more than a month without good effect; on June 27, 2023, he underwent burr hole drainage, but the disease recurred after the operation; on September 9, 2023, he underwent middle meningeal artery embolization the next day, but it was ineffective; on October 26, 2023, he started taking oral adrenal chromohydrazone tablets, 5 mg / time (measured by the mass of adrenal chromohydrazone), once a day, and took it continuously until February 1, 2024, when the hematoma basically disappeared and he was cured.

[0049] Case 2

[0050] Chen, male, 71 years old, had a huge right subdural hematoma after trauma. The patient's head CT examination results at each stage of treatment are as follows Figure 5 shown.

[0051] After drilling and drainage, the mental symptoms were relieved. After the operation, atorvastatin calcium and dexamethasone were given for 1 week. On August 17, 2024, the transaminase was found to be about 20 times the normal value. Atorvastatin calcium was replaced with adrenaline chromohydrazone tablets, 5 mg / time (based on the mass of adrenaline chromohydrazone) orally, once a day; at the same time, dexamethasone was still given for the first three weeks of oral adrenaline chromohydrazone tablets (first week, 3 tablets / time, once a day; second week, 2 tablets / time, once a day; third week, 1 tablet / time, once a day; each tablet contains 0.75 mg dexamethasone), and dexamethasone was stopped from the fourth week. The amount of hematoma decreased on August 23, 2024; the amount of hematoma further decreased on September 01, 2024, and the treatment effect was obvious. Until September 28, 2024, the hematoma basically disappeared and was cured.

[0052] Case 3

[0053] Lei, male, 42 years old. Left subdural hematoma after trauma. The patient's head CT examination results at each stage of treatment are as follows: Figure 6 shown.

[0054] After one week of treatment with statins and hormones, the patient's transaminase level was found to be about 8 times higher than the normal value. The statin was changed to epinephrine tablets, which was effective after taking them.

[0055] On August 13, 2024, a patient developed a left subdural hematoma after trauma. After one week of treatment with atorvastatin calcium and dexamethasone, on August 20, 2024, because the transaminase level was 8 times higher than the normal value, atorvastatin calcium was replaced with adrenaline chromohydrazone tablets, 5 mg / time (based on the mass of adrenaline chromohydrazone) orally, once a day; at the same time, dexamethasone was still given for the first three weeks of oral adrenaline chromohydrazone tablets (first week, 3 tablets / time, once a day; second week, 2 tablets / time, once a day; third week, 1 tablet / time, once a day; each tablet contains 0.75 mg dexamethasone), and dexamethasone was stopped from the fourth week. The test on September 03, 2024 showed that the amount of hematoma decreased; on September 17, 2024, the amount of hematoma further decreased, and the treatment effect was obvious. On October 19, 2024, the hematoma basically disappeared and was cured.

[0056] The above animal experiments and clinical cases all show that adrenaline can effectively treat subdural hematoma.

[0057] The above description is only a specific embodiment of the present disclosure, so that those skilled in the art can understand or implement the present disclosure. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present disclosure. Therefore, the present disclosure will not be limited to the embodiments described herein, but will conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. Application of adrenaline in the preparation of drugs for treating subdural hematoma.

2. The use according to claim 1, characterized in that: The subdural hematoma is a chronic subdural hematoma.

3. The use of adrenaline in the preparation of drugs for reducing the inflammatory response of the dura mater around hematoma.

4. Application of adrenaline in the preparation of drugs for increasing the expression level of dural vascular endothelial junction proteins.

5. A drug for treating subdural hematoma, characterized in that: The drug includes adrenaline.

6. The drug according to claim 5, characterized in that The subdural hematoma is a chronic subdural hematoma.

7. The drug according to claim 5 or 6, characterized in that The drug also includes pharmaceutically acceptable excipients.

8. The drug according to any one of claims 5 to 7, characterized in that The dosage form of the drug is oral tablets or intramuscular injection.

9. The drug according to any one of claims 5 to 8, characterized in that The drug is administered orally; and / or, the dosage is: based on the mass of adrenochrome, 1.25-5 mg / time, 1-3 times a day; And / or, the administration period is: continuous administration for more than 2 weeks or continuous administration permanently.

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