Use of a panax notoginseng saponins combined preparation in the prevention and treatment of stroke drugs

Abstract

This invention belongs to the field of biomedicine, specifically disclosing the use of a combination of Panax notoginseng total saponins and chemical drugs as effective components in the preparation of drugs for the prevention and treatment of stroke. Experiments have shown that the combination of Panax notoginseng total saponins and chemical drugs can effectively improve neurological deficits, significantly reduce the incidence of combined cardiovascular and cerebrovascular events within one year, and further significantly reduce the incidence of combined cardiovascular and cerebrovascular events in long-term follow-ups of 2 and 3 years. Therefore, the combination of Panax notoginseng total saponins and chemical drugs can be used for the prevention of combined cardiovascular and cerebrovascular events in stroke patients, with good efficacy and safety.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically, it relates to the use of a combined preparation of total saponins of Panax notoginseng in the preparation of drugs for the prevention and treatment of stroke. Background Technology

[0002] Stroke is mainly divided into ischemic stroke and hemorrhagic stroke. A nationwide multicenter prospective study of chronic diseases in China (China Kadoorie Biobank, CKB) with 489,586 samples showed that among newly diagnosed stroke patients during the study's follow-up period, 80% were ischemic stroke, 16% were hemorrhagic stroke, 2% were subarachnoid hemorrhage, and 2% were other types of stroke.

[0003] Modern medicine believes that the pathogenesis of ischemic stroke is due to cerebral vascular occlusion leading to impaired local blood flow to the brain, resulting in cerebral ischemia and hypoxic necrosis. Effective secondary prevention is a crucial means of reducing stroke recurrence and mortality. According to guidelines, for cardiogenic ischemic stroke, secondary prevention, based on different etiologies, includes risk factor control and oral anticoagulation and / or antiplatelet therapy; for non-cardiogenic ischemic stroke, secondary prevention includes risk factor control and oral antiplatelet drugs. Antiplatelet therapy can significantly reduce the occurrence of serious vascular events (non-fatal myocardial infarction, non-fatal stroke, and vascular death) in patients with a history of ischemic stroke. Currently, aspirin and clopidogrel are among the antiplatelet drugs with strong evidence-based medicine and are widely used in clinical practice in my country.

[0004] However, some stroke patients exhibit aspirin resistance. A systematic review of 42 studies showed an average incidence of 25% for aspirin resistance. A prospective study of 634 Chinese stroke patients revealed that approximately 24.8% had some degree of aspirin resistance. Compared to aspirin-sensitive patients, those with varying degrees of aspirin resistance had significantly increased rates of stroke recurrence, all-cause mortality, myocardial infarction, and ischemic vascular events. Common adverse reactions to aspirin include gastrointestinal bleeding and dyspepsia; other adverse reactions include intracranial hemorrhage.

[0005] Clopidogrel has a different antiplatelet mechanism than aspirin and can be used alone or in combination with aspirin for secondary prevention of ischemic stroke. Its most common complication is systemic bleeding; other complications include headache, joint pain, epistaxis, and skin irritation. Liver disease, lactation, or the presence of pathological bleeding are contraindications for clopidogrel use.

[0006] The clinical application of Panax notoginseng total saponins preparations in combination with chemical drugs, especially in combination with oral anticoagulants and / or antiplatelet agents to prevent stroke, currently lacks theoretical basis and specific mechanisms of action. In view of this, this invention is proposed. Summary of the Invention

[0007] The technical problem to be solved by the invention is to overcome the shortcomings of the existing technology and provide an application of a combined preparation of Panax notoginseng total saponins in the preparation of drugs for the prevention and / or treatment of stroke, thereby expanding the application scope of Panax notoginseng total saponins preparations and providing experimental and theoretical basis for the clinical prevention and / or treatment of stroke-related diseases.

[0008] To solve the above-mentioned technical problems, the basic concept of the technical solution adopted by the present invention is as follows: The first objective of this invention is the use of Panax notoginseng total saponin preparations combined with anticoagulants and / or antiplatelet agents as effective components for the prevention and / or treatment of stroke in the preparation of medicaments for the prevention and / or treatment of stroke.

[0009] In a further embodiment, the anticoagulant and / or antiplatelet agent is a conventional drug in the art, preferably aspirin or clopidogrel, wherein the stroke includes ischemic stroke or hemorrhagic stroke, and wherein the prevention is secondary prevention of stroke.

[0010] A further embodiment of this technical solution includes the high expression of the following biomarkers in stroke patients: IL-1, IL-6, NLRP3, TNF-α, or IL-8; inflammatory factors: A1AC (A1-antitrypsin), BPI (bactericidal / permeability-promoting protein), C5a (complement component 5a), and interleukin-1β (IL-1β). Preferably, the biomarkers include: tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β).

[0011] In a further embodiment, the total saponin preparation of Panax notoginseng described in this technical solution is Xuesaitong soft capsules.

[0012] The second objective of this invention is to provide a Panax notoginseng total saponin preparation combined with an anticoagulant and / or antiplatelet therapeutic agent as an effective component for the prevention and / or treatment of stroke, and its use in the preparation of a medicament for treating patients with stroke, wherein the patients also suffer from: coronary heart disease, angina pectoris, myocardial infarction, acute coronary syndrome, atrial fibrillation, hypertension, diabetes, obesity, chronic kidney disease, etc.

[0013] A third objective of this invention is to provide a medicament for the prevention and / or treatment of stroke, wherein the active ingredients of the medicament include a total saponin preparation of Panax notoginseng and an anticoagulant and / or antiplatelet therapeutic agent.

[0014] In a further embodiment, the anticoagulant and / or antiplatelet therapeutic agent in the pharmaceutical composition of the technical solution is aspirin or clopidogrel. In a further embodiment, the medicament for the prevention and / or treatment of stroke of the technical solution also contains a pharmaceutically acceptable carrier.

[0015] A further embodiment of the present invention, a total saponin preparation for the prevention and / or treatment of stroke, may contain commonly used excipients, such as binders, fillers, diluents, tableting agents, lubricants, disintegrants, colorants, flavoring agents, and humectants, and the tablets may be coated if necessary. The drug in the preparation may be an injectable or oral drug.

[0016] The total saponins of Panax notoginseng of the present invention, when administered orally, may contain commonly used excipients such as binders, fillers, diluents, tableting agents, lubricants, disintegrants, colorants, flavoring agents and humectants, and the tablets may be coated if necessary.

[0017] Suitable fillers include cellulose, mannitol, lactose, and other similar fillers. Suitable disintegrants include starch, polyvinylpyrrolidone, and starch derivatives, such as sodium glycolate starch. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.

[0018] Solid oral compositions can be prepared using common methods such as mixing, filling, and tableting. Repeated mixing allows the active ingredient to be distributed throughout compositions that use a large amount of filler.

[0019] A further embodiment of the embodiment is that the form of the medicine for the prevention and / or treatment of stroke is selected from tablets, capsules, granules, suspensions, emulsions, solutions, syrups or injections.

[0020] The oral liquid formulation is in a form conventional in the art, such as an aqueous or oily suspension, solution, emulsion, syrup, or elixir, or a dried product that can be reconstituted with water or other suitable carriers before use. This liquid formulation may contain conventional additives, such as suspending agents like sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, or hydrogenated edible fats; emulsifiers like lecithin, dehydrated sorbitan monooleate, or gum arabic; non-aqueous carriers (which may include edible oils such as almond oil, fractionated coconut oil, oily esters such as glycerol, propylene glycol, or ethanol); preservatives such as methylparaben or propylparaben or sorbic acid; and, if desired, conventional flavorings or colorings.

[0021] The injectable formulation is a conventional injectable form in the art, and the prepared liquid unit dosage form contains the active substance of the present invention and a sterile carrier. Depending on the carrier and concentration, the compound can be suspended or dissolved. Solution preparation typically involves dissolving the active substance in a carrier, filtering and sterilizing it before filling it into a suitable vial or ampoule, and then sealing it. Excipients such as a local anesthetic, preservative, and buffer can also be dissolved in this carrier. To improve its stability, the composition can be frozen after filling into the vial, and water can be removed under vacuum.

[0022] Preferably, the Panax notoginseng total saponin preparation used in the experiment of the present invention is Xuesaitong soft capsules or related Panax notoginseng total saponin preparations produced by Kunming Pharmaceutical Group Co., Ltd., and the aspirin and clopidogrel are products that can be purchased from the market or obtained by prescription.

[0023] After adopting the above technical solution, the present invention has the following beneficial effects compared with the prior art: 1. Primary indicator - the incidence of cardiovascular and cerebrovascular events in 1 year is significantly reduced; secondary indicator - the incidence of all-cause mortality in 1 year is significantly reduced. Exploratory indicator - the rate of visits to rehabilitation departments or rehabilitation hospitals in 1 year has decreased. Safety refers to the fact that the total incidence of AESI and the incidence of its three included AES are both lower than those in the chemical drug group, and the incidence of AESI is significantly reduced, indicating good safety. In observation group II (Xuesaitong soft capsules combined with chemical drug group), the incidence of cardiovascular and cerebrovascular events in 2-year and 3-year patients was 19.41% and 21.27%, respectively, while the incidence of cardiovascular and cerebrovascular events in the chemical drug group in 2-year and 3-year patients was 23.85% and 26.57%, respectively. Both groups showed a decrease, and the differences were statistically significant. Attached Figure Description

[0024] The accompanying drawings, as part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments and descriptions of the invention are used to explain the invention, but do not constitute an undue limitation of the invention. Obviously, the drawings described below are merely some embodiments, and those skilled in the art can obtain other drawings based on these drawings without creative effort. In the drawings: Figure 1 The cumulative incidence curves of combined cardiovascular and cerebrovascular events in observation group II and control group II. Detailed Implementation

[0025] The specific embodiments of the present invention will be described in further detail below with reference to examples.

[0026] Example 1 This study is a multicenter, controlled, retrospective real-world study based on the Tianjin Health and Medical Big Data Super Platform database. It collected desensitized clinical diagnosis and treatment data of patients diagnosed with ischemic stroke from January 1, 2017 to December 31, 2021. All patients' medical records must meet the following requirements: no target drug was used before the first diagnosis (outpatient, emergency, or inpatient) of stroke, and the target drug was used for a cumulative period of at least 2 months within 1 year after diagnosis or for a cumulative period of at least 1 month within 6 months after diagnosis.

[0027] To be eligible for this study, patients must meet all of the following criteria: 1. Age ≥ 18 years, gender not limited; 2. Diagnosed with ischemic stroke between January 1, 2017 and December 31, 2021; 3. Within one year of diagnosis, patients must have used any of the following treatment regimens for at least 2 months cumulatively or for at least 1 month cumulatively within 6 months: Patients in Observation Group II received antiplatelet therapy with Xuesaitong soft capsules combined with chemotherapy drugs (oral formulations, aspirin and / or clopidogrel, hereinafter referred to as chemotherapy treatment); Patients in Control Group II received Naoxintong capsules combined with chemotherapy drugs. Clopidogrel, aspirin, Xuesaitong soft capsules, and Naoxintong capsules are all available by prescription or commercially available. Xuesaitong soft capsules are manufactured by Kunming Pharmaceutical Group Co., Ltd.

[0028] Primary study endpoint: 1-year incidence of combined cardiovascular and cerebrovascular events: defined as the proportion of all patients who experience a combined cardiovascular and cerebrovascular event [ischemic stroke, hemorrhagic stroke, transient ischemic attack (TIA), myocardial infarction, angina pectoris, acute coronary syndrome, use of thrombolytic drugs, cardiovascular and cerebrovascular stent surgery, or revascularization treatment (thrombectomy, thrombectomy, etc.)] within 1 year.

[0029] Rules for judging complex cardiovascular and cerebrovascular events: After the initial diagnosis of stroke, any of the following diseases appear in the main diagnosis of the emergency or inpatient medical record [ischemic stroke, hemorrhagic stroke, transient ischemic attack (TIA), myocardial infarction, angina pectoris, acute coronary syndrome] or corresponding treatments [thrombolytic drugs, cardiovascular and cerebrovascular stent surgery, etc.].

[0030] Regarding safety, the incidence of adverse events of special concern (AESI) is defined as the proportion of patients who experience an AESI out of all patients; AESI includes nausea, other gastrointestinal discomfort excluding nausea, and gastrointestinal bleeding.

[0031] Statistical analysis method: SAS 9.4 was used for statistical analysis.

[0032] For continuous data, statistical descriptions will be provided using the number of cases, mean, standard deviation, minimum, upper quartile (Q1), median, lower quartile (Q3), and maximum. For categorical or ordinal data, statistical descriptions will be provided using frequency, percentage, or composition ratio, with 95% confidence intervals added if necessary. Unless otherwise specified, missing values ​​will not be included in percentage calculations.

[0033] Unless otherwise specified, all statistical tests in this study are two-tailed tests, with P being the criterion for determining statistical significance of differences between groups. Missing data will not be imputed unless otherwise specified.

[0034] A total of 3,605 cases were selected based on all inclusion criteria, of which 1,403 were admitted to observation group II and 1,983 were admitted to control group II.

[0035] Statistical results: The incidence of cardiovascular and cerebrovascular events in the observation group II patients was 15.03% at 1 year, while that in the control group II patients was 19.18% at 1 year. The incidence was significantly lower, and the difference between the groups was statistically significant.

[0036] The 1-year all-cause mortality rate in observation group II and control group II was 0.21% and 0.25%, respectively, showing a certain decrease. The rate of patients visiting rehabilitation departments or rehabilitation hospitals in observation group II and control group II was 3.07% and 3.97%, respectively, also showing a certain decrease.

[0037] The incidence rates of combined cardiovascular and cerebrovascular events at 2 and 3 years were 19.41% and 21.27% in observation group II, respectively, while those in control group II were 23.85% and 26.57% at 2 and 3 years, respectively. The incidence rates showed a significant decrease, and the differences between the groups were statistically significant. Figure 1 As shown, the cumulative incidence of cardiovascular and cerebrovascular events in observation group II was significantly lower than that in control group II.

[0038] Safety data: The total incidence of AESI and the incidence of the three AES included in the observation group II were lower than those in the control group II. The differences between the groups in the incidence of AESI (18.56% vs. 21.82%), nausea (3.71% vs. 5.38%), gastrointestinal bleeding (1.64% vs. 2.73%), and other gastrointestinal discomfort excluding nausea (17.20% vs. 19.71%) were all statistically significant. A detailed analysis of other gastrointestinal discomfort excluding nausea showed that the difference in the incidence of vomiting (4.21% vs. 6.05%) was statistically significant.

[0039] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-described technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. The use of Panax notoginseng total saponins preparations combined with anticoagulants and / or antiplatelet agents as effective components for the prevention and / or treatment of stroke in the preparation of drugs for the prevention and / or treatment of stroke.

2. Use according to claim 1, characterized in that, The anticoagulant and / or antiplatelet agent is aspirin or clopidogrel, the stroke includes ischemic stroke or hemorrhagic stroke, and the prevention is secondary prevention of stroke.

3. Use according to claim 2, characterized in that, The stroke is characterized by high expression of the following biomarkers: IL-1, IL-6, NLRP3, TNF-α or IL-8, and inflammatory factors: A1AC (A1-antitrypsin), BPI (bactericidal / permeability-promoting protein), C5a (complement component 5a) and IL-1β.

4. Use according to claim 3, characterized in that, The stroke patients expressed high levels of the following biomarkers: TNF-α, IL-6, and IL-1β.

5. The use according to claim 1, characterized in that, The total saponins of Panax notoginseng are Xue Sai Tong soft capsules.

6. The use of a total saponin preparation of Panax notoginseng combined with an anticoagulant and / or antiplatelet therapeutic agent as an effective component for the prevention and / or treatment of stroke, in the preparation of a medicament for treating stroke patients, characterized in that, The patients mentioned also suffer from: coronary heart disease, angina pectoris, myocardial infarction, acute coronary syndrome, atrial fibrillation, hypertension, diabetes, obesity, chronic kidney disease, and other diseases.

7. A pharmaceutical composition for the prevention and / or treatment of stroke, characterized in that, The effective components for preventing and treating stroke in the pharmaceutical composition include total saponins of Panax notoginseng and anticoagulants and / or antiplatelet agents.

8. The pharmaceutical composition according to claim 7, characterized in that, The anticoagulant and / or antiplatelet agent in the pharmaceutical composition is aspirin or clopidogrel, the stroke includes ischemic stroke or hemorrhagic stroke, and the prevention is secondary prevention of stroke.

9. The pharmaceutical composition according to claim 8, characterized in that, The pharmaceutical composition also contains a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, characterized in that, The pharmaceutical composition is an injectable or oral medication, and the form of the pharmaceutical composition may be selected from tablets, capsules, granules, suspensions, emulsions, solutions, syrups, or injections.

Images