Use of a preparation of panax notoginseng saponins in the preparation of a medicament for the prevention and treatment of stroke

Abstract

This invention belongs to the field of biomedicine, specifically disclosing the use of Panax notoginseng total saponins as an effective component for the prevention and treatment of stroke, and its application in the preparation of drugs for the prevention and treatment of stroke. Data demonstrate that Panax notoginseng total saponins can effectively improve neurological deficits, with a significantly lower incidence of combined cardiovascular and cerebrovascular events at 1 year compared to the chemical drug group, and the incidence of combined cardiovascular and cerebrovascular events at 2-year and 3-year long-term follow-up was also significantly lower than that of the chemical drug group. Therefore, Xuesaitong soft capsules alone, compared to chemical drugs, demonstrate better efficacy and safety in the prevention of combined cardiovascular and cerebrovascular events in patients with ischemic stroke.

Description

Technical Field

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

[0002] Stroke is one of the major diseases threatening the health of the Chinese population, characterized by high incidence, high disability rate, high mortality rate, and high recurrence rate. Over the past 30 years, the prevalence of stroke in my country has increased significantly, and the number of people currently suffering from stroke in my country ranks first in the world. Stroke is the third leading cause of death in my country. Stroke is mainly divided into ischemic stroke and hemorrhagic stroke. A nationwide multicenter prospective study of chronic disease 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 occlusion of intracranial blood vessels, leading to impaired local blood flow to the brain and causing ischemic and hypoxic necrosis of brain tissue. Effective secondary prevention is an important means to reduce stroke recurrence and mortality. According to guidelines, for cardiogenic ischemic stroke, secondary prevention includes risk factor control and oral anticoagulation and / or antiplatelet therapy, depending on the different etiologies; for non-cardiogenic ischemic stroke, secondary prevention includes risk factor control and oral antiplatelet drugs. Among these, 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, the antiplatelet drugs with sufficient evidence-based medicine and widely used in clinical practice in my country include aspirin and clopidogrel.

[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 for the prevention of stroke currently lacks theoretical basis and specific mechanism of action. In view of this, this invention is proposed. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to overcome the shortcomings of the prior art and provide an application of Panax notoginseng total saponin preparation in the preparation of drugs for the prevention and / or treatment of stroke, thereby expanding the application scope of Panax notoginseng total saponin preparation 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 to provide a total saponin preparation of Panax notoginseng as an effective ingredient for the prevention and / or treatment of stroke, and its use in the preparation of a medicament for the prevention and / or treatment of stroke.

[0009] A further embodiment, 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] A further embodiment of this technical solution is that the total saponins of Panax notoginseng are the only effective component acting on stroke.

[0012] The second objective of this invention is to provide a Panax notoginseng total saponin preparation as an effective ingredient 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 ingredient of the medicament includes a total saponin preparation of Panax notoginseng.

[0014] A further embodiment of the technical solution is that the drug described uses Panax notoginseng total saponins as the sole effective ingredient for the prevention and / or treatment of stroke.

[0015] In a further embodiment, the drug for preventing and / or treating stroke described in this technical solution also contains a pharmaceutically acceptable carrier.

[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 this invention is Xuesaitong soft capsules or related Panax notoginseng total saponin preparations produced by Kunming Pharmaceutical Group Co., Ltd., and such products can be purchased from the market.

[0023] By adopting the above technical solution, the present invention has the following beneficial effects compared with the prior art: The analytical data described in this invention demonstrate that, in secondary prevention of ischemic stroke, the incidence of combined cardiovascular and cerebrovascular events treated with XueSaiTong soft capsules alone was significantly lower in the 1-year group than in the group treated with chemical drugs, and the incidence of combined cardiovascular and cerebrovascular events was also significantly lower in the 2-year and 3-year follow-up groups. Therefore, XueSaiTong soft capsules alone, compared with chemical drugs, has better efficacy and safety in the prevention of combined cardiovascular and cerebrovascular events in patients with ischemic stroke. 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 I and control group I.

[0025] Example Example

[0026] 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] The pre-designed groupings for this study were as follows, adjusted based on database conditions: Patients in observation group I received monotherapy with XueSaiTong soft capsules; patients in control group I received chemotherapy. By comparing observation group I and control group I, the efficacy and safety of XueSaiTong soft capsules in secondary prevention of ischemic stroke were analyzed and evaluated. Observation group I and control group I were the primary populations analyzed in this study. Index date: The date of stroke occurrence meeting the inclusion and exclusion criteria.

[0028] To be eligible for this study, candidates 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, candidates 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: conventional oral antiplatelet therapy (aspirin and / or clopidogrel, hereinafter referred to as chemotherapy, control group I), or monotherapy with XueSaiTong soft capsules (observation group I). Clopidogrel and aspirin can be obtained by prescription or commercially available, and XueSaiTong soft capsules are manufactured by Kunming Pharmaceutical Group Co., Ltd.

[0029] Primary research endpoint: 1-year incidence of combined cardiovascular and cerebrovascular events: defined as the proportion of 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, undergoing cardiovascular or cerebrovascular stent surgery, or undergoing revascularization treatment (thrombectomy, thrombectomy, etc.)] within one year. Criteria for determining combined cardiovascular and cerebrovascular events: After the initial diagnosis of stroke, any one of the following diseases [ischemic stroke, hemorrhagic stroke, transient ischemic attack (TIA), myocardial infarction, angina pectoris, acute coronary syndrome] newly appears in the main diagnosis of the emergency department or inpatient medical record, or corresponding treatment [thrombolytic drugs, cardiovascular or cerebrovascular stent surgery, etc.] is administered.

[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 methods: SAS 9.4 was used for statistical analysis. For continuous data, the following statistical descriptions were used: number of cases, mean, standard deviation, minimum, upper quartile (Q1), median, lower quartile (Q3), and maximum. For categorical or ordinal data, the following statistical descriptions were used: frequency, percentage, or proportion. A 95% confidence interval may be added if necessary. Unless otherwise specified, missing values ​​will not be included in the percentage calculations.

[0032] Unless otherwise specified, all statistical tests in this study were two-tailed, with P-value as the criterion for statistical significance between groups. Missing data will not be imputed unless otherwise specified.

[0033] Statistical population: 39,029 cases met all inclusion criteria, of which 780 cases were included in observation group I and 37,249 cases were included in control group I.

[0034] Statistical analysis results Table 1. Occurrence of complex cardiovascular and cerebrovascular events in patients over 1 year - matched analysis set (observation group I and control group I) Observation indicators Observation group I (N=778) Control group I (N=17894) Cardiovascular and cerebrovascular complex events occurred within 1 year Number of cases / Total number of people 25 / 778 2380 / 17894 Percentage (95% CI) (%) 3.21(2.09, 4.71) 13.30(12.81, 13.81) The statistical analysis results are shown in Table 1: The incidence of cardiovascular and cerebrovascular events (including death, the same below) in the observation group I was 3.21% in 1 year, while the incidence of cardiovascular and cerebrovascular events in the control group I (matched with the observation group I) was 13.30% in 1 year, showing a significant decrease.

[0035] Table 2. All-cause mortality in patients at 1 year - matched analysis set (observation group I and control group I) Observation group I (N=778) Control group I (N=17894) One year of all-cause mortality Number of cases / Total number of people 0 / 778 45 / 17894 Percentage (95% CI) (%) 0.00(0.00, 0.47) 0.25(0.18, 0.34) Statistical results showed that the 1-year all-cause mortality rates in observation group I and control group I (after matching with observation group I) were 0.00% and 0.25%, respectively, indicating a decrease in the all-cause mortality rate.

[0036] Table 3. Patients' visits to rehabilitation departments or hospitals over 1 year - matched analysis set (Observation Group I and Control Group I) Observation group I (N=778) Control group I (N=17894) The patient visited a rehabilitation department or rehabilitation hospital for one year. Number of cases / Total number of people 12 / 778 411 / 17894 Percentage (95% CI) (%) 1.54(0.80, 2.68) 2.30(2.08, 2.53) The 1-year visit rates to rehabilitation departments or rehabilitation hospitals for patients in observation group I and control group I (after matching with observation group I) were 1.54% and 2.30%, respectively, which is a decrease.

[0037] Table 4. Incidence of combined cardiovascular and cerebrovascular events in patients over 2 years (Observation Group I vs. Control Group I) Observation group I (N=778) Control group I (N=17894) p-value Two years of combined cardiovascular and cerebrovascular events <0.001# Number of cases / Total number of people 32 / 778 3148 / 17894 Percentage (95% CI) (%) 4.11(2.83, 5.76) 17.59(17.04, 18.16) Table 5. Incidence of combined cardiovascular and cerebrovascular events in patients over 3 years (Observation Group I vs. Control Group I) Observation group I (N=778) Control group I (N=17894) p-value Three years of combined cardiovascular and cerebrovascular events <0.001# Number of cases / Total number of people 38 / 778 3574 / 17894 Percentage (95% CI) (%) 4.88(3.48, 6.64) 19.97(19.39, 20.57) Exploratory indicators: The incidence of combined cardiovascular and cerebrovascular events at 2 and 3 years in observation group I was 4.11% and 4.88%, respectively, while the incidence of combined cardiovascular and cerebrovascular events at 2 and 3 years in control group I (matched with observation group I) was 17.59% and 19.97%, respectively. The incidence of combined cardiovascular and cerebrovascular events at 2 and 3 years in observation group I was significantly lower than that in control group, and the differences between the groups were statistically significant. Figure 1The results showed that, compared with the control group I, the cumulative incidence of cardiovascular and cerebrovascular complex events in the observation group I was significantly lower.

[0038] Safety data: The total incidence of AESI and the incidence of each AE included in the observation group I were lower than those in the control group I (after matching with the observation group I). Among them, the incidence of AESI (18.25% vs. 21.29%) and nausea (1.03% vs. 3.82%) showed statistically significant differences between the groups, while the incidence of gastrointestinal bleeding (1.80% vs. 2.43%) and other gastrointestinal discomfort excluding nausea (17.22% vs. 19.57%) showed no statistically significant differences between the groups. A detailed analysis of other gastrointestinal discomfort excluding nausea showed statistically significant differences in the incidence of vomiting (1.41% vs. 4.32%) and diarrhea (0.90% vs. 2.15%) between the groups. The results are shown in Table 6.

[0039] Table 6. Safety statistics (Observation Group I vs. Control Group I)

[0040] Therefore, compared with chemical drugs, XueSaiTong soft capsules alone have better safety and a lower overall incidence of AESI in patients with ischemic stroke.

[0041] In secondary prevention of ischemic stroke, the incidence of combined cardiovascular and cerebrovascular events treated with XueSaiTong soft capsules alone was significantly lower in the 1-year group than in the group treated with chemical drugs, and the incidence of combined cardiovascular and cerebrovascular events was also significantly lower in the 2-year and 3-year follow-up groups. Therefore, XueSaiTong soft capsules alone, compared with chemical drugs, demonstrates better efficacy and safety in the prevention of combined cardiovascular and cerebrovascular events in patients with ischemic stroke.

[0042] 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 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. The use as described in claim 1, characterized in that, The stroke mentioned therein includes ischemic stroke or hemorrhagic stroke, and the prevention mentioned therein is secondary prevention of stroke.

3. The use as described in 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. The use as described in 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 of the Panax notoginseng total saponin preparation as described in claim 1, characterized in that, In the aforementioned drug, the total saponins of Panax notoginseng are the only effective component acting on stroke.

6. The use of a total saponin preparation of Panax notoginseng as an effective ingredient 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.

8. The pharmaceutical composition according to claim 7, characterized in that, The pharmaceutical composition uses total saponins of Panax notoginseng as the sole effective ingredient for the prevention and treatment of stroke, wherein 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.

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