Nattokinase product for preventing and / or treating atherosclerosis and application thereof

Abstract

The invention discloses a nattokinase product for preventing and / or treating atherosclerosis and application of the nattokinase product. Cardiovascular diseases become the primary reason of human death, and the vascular plaque problem caused by atherosclerosis is always a difficult problem to be solved urgently. Blood vessel stenosis caused by plaques is a main cause of cerebral arterial thrombosis, and traditional medicines and operations face the problems of low compliance, side effect risk, indication limitation and the like. The invention provides nattokinase or a product thereof for high-risk groups with cardiovascular diseases, and the nattokinase or the product thereof is preferably in a non-drug form. As a precise nutrition intervention means, nattokinase is effective in plaque progress inhibition, unique in effect, safe to eat, convenient, easy to implement and wide in applicable crowd. The invention provides a new thought and method for management of vascular plaques and prevention and treatment of cardiovascular diseases.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of atherosclerosis treatment products, and relates to a nattokinase product for preventing and / or treating atherosclerosis and application thereof, in particular to a product having an improvement effect on atherosclerosis for high-risk cardiovascular and cerebrovascular groups. BACKGROUND

[0002] At present, cardiovascular diseases (CVD) have become the leading cause of human death, and have the characteristics of high incidence, high disability rate and high mortality. Even if the most advanced treatment method is adopted, most patients still have adverse consequences due to the gradual development of atherosclerosis. With the accumulation of experience in the treatment of cardiovascular diseases and the improvement of public awareness of nutrition and health, people have gradually realized that precise nutritional intervention is an effective way to prevent and treat cardiovascular diseases.

[0003] Consumption of fermented soy products is significantly negatively correlated with the risk of cardiovascular diseases. Natto is a traditional soybean food fermented by Bacillus natto, and is rich in nattokinase (NK), which is a basic serine protease with strong thrombolytic activity and substrate specificity. Nattokinase has multiple thrombolytic mechanisms. It not only can directly degrade fibrin and dissolve thrombus, but also can indirectly enhance the activity of the endogenous fibrinolysis system by increasing the level of tissue-type plasminogen activator (t-PA) and reducing the level of plasminogen activator inhibitor-1 (PAI-1), thereby promoting the conversion of plasminogen to plasmin and more effectively dissolving fibrin / thrombus.

[0004] Although there are reports that nattokinase can reduce plaque area, there is no evidence that nattokinase can directly reduce plaque thickness, and plaque thickness significantly affects blood supply. An increase in plaque thickness can lead to the following problems: 1) Increased direct stenosis risk: Significant thickness increase (especially >3.5mm) leads to a residual lumen diameter ≤0.285cm (stenosis ≥70%), causing ipsilateral cerebral perfusion pressure to decrease, ipsilateral cerebral blood flow (CBF) to decrease by >50%, and the risk of watershed infarction to increase by 5 times.

[0005] 2) Increased indirect embolization risk: Thickness increases rapidly (>0.3mm / year) with intraplaque hemorrhage (IPH) or thinning of the fibrous cap (<65μm), and the plaque surface is prone to rupture, leading to a complete infarction risk of 28.7% due to embolization.

[0006] Therefore, reducing plaque thickness is of great significance for atherosclerosis patients.

[0007] Although NK is considered as a promising microbe-derived enzyme to reduce the risk of thrombosis, data on the application of NK in human body are still limited. In particular, the mechanism and effect of the treatment of atherosclerotic plaques are not clear. SUMMARY

[0008] The present application aims at solving the problems in the prior art and provides a nattokinase product for preventing and / or treating atherosclerosis and an application thereof, in particular, a product having an improving effect on atherosclerosis for high-risk cardiovascular and cerebrovascular groups. The main effect of the present application is that the thickness of atherosclerotic plaques can be effectively reduced, and a better diet therapy, treatment, improvement and prevention effect can be achieved.

[0009] The present application is mainly realized by the following technical solutions: In one aspect, the present application provides a use of nattokinase or a product composition thereof in the preparation of a product for preventing and / or treating, improving or delaying the progression of cardiovascular and cerebrovascular diseases in a patient.

[0010] In some preferred embodiments, the cardiovascular and cerebrovascular disease is specifically atherosclerosis, In some preferred embodiments, the cardiovascular and cerebrovascular disease is more preferably carotid atherosclerosis.

[0011] In some preferred embodiments, the product is a product for reducing the thickness of atherosclerotic plaques.

[0012] In some preferred embodiments, the product is a product for reducing the thickness of carotid atherosclerotic plaques.

[0013] In some preferred embodiments, the patient is a high-risk cardiovascular and cerebrovascular patient.

[0014] In some preferred embodiments, the patient is a patient meeting two or more of the following conditions: hypertension; hyperlipidemia; diabetes history ≥ 10 years; abnormal increase in blood viscosity; abnormal blood flow detected by TCD; carotid plaque; coronary artery stenosis; ever had a stroke / TIA; ever had coronary heart disease; ever had venous thrombosis; ever had peripheral vascular disease; body mass index ≥ 26 kg / m 2 or waist circumference > 85 cm for men and > 80 cm for women; numbness or pricking sensation of limbs caused by poor blood circulation; smoking habit > 10 years; abnormal increase in D-dimer level; abnormal increase in C-reactive protein level; abnormal increase in homocysteine level.

[0015] In some preferred embodiments, the patient is 30-75 years old, and has not used NK for 1 month before enrollment.

[0016] In some preferred embodiments, the patient is not one of the following groups: ① those with severe Alzheimer's disease; ② pregnant or lactating women; ③ those with mental illness; ④ those who have undergone ordinary trauma surgery within the past 3 months; ⑤ those who have undergone cerebral hemorrhage or major surgery within the past 3 months; ⑥ those with hemangiomas; ⑦ those with advanced cancer; ⑧ those with severe liver or kidney dysfunction; ⑨ those with coagulation disorders; ⑩ those with protein allergies.

[0017] In some preferred embodiments, the patient is a patient with carotid atherosclerosis.

[0018] In some preferred embodiments, the patient is a patient with carotid atherosclerotic plaques.

[0019] In some preferred embodiments, the nattokinase or its product composition is taken daily at a dose of not less than 8000 FU, based on nattokinase activity, for at least 90 days.

[0020] In some preferred embodiments, the dosage is 8000 FU / day, divided into two doses: 4000 FU after breakfast and 4000 FU after dinner.

[0021] In some preferred embodiments, the product is a capsule, tablet, or powder.

[0022] In some preferred embodiments, the product is preferably in capsule form.

[0023] In some preferred embodiments, the product can be a hard capsule or a soft capsule, more preferably a soft capsule.

[0024] In some preferred embodiments, each serving of the product contains, but is not limited to, 1000 FU, 2000 FU, 3000 FU, or 4000 FU of nattokinase, based on nattokinase activity.

[0025] In some preferred embodiments, when the product is a soft capsule, each serving of the product refers to each capsule.

[0026] In some preferred embodiments, the soft capsule dosage form contains nattokinase per capsule, which may contain, but is not limited to, 1000 FU, 2000 FU, 3000 FU or 4000 FU, based on nattokinase activity.

[0027] In another aspect, the present invention provides a product for preventing and / or treating, improving, or delaying the progression of cardiovascular and cerebrovascular diseases in patients, wherein the active ingredient of the product includes nattokinase.

[0028] In the field of chronic disease health management, vascular plaque has always been a pressing problem that needs to be solved. Plaque-induced vascular stenosis is a major cause of ischemic stroke, while traditional drugs and surgery face problems such as low compliance, risk of side effects, and limited indications.

[0029] Increased plaque thickness has a significant negative impact on blood flow, particularly in the carotid artery, where it significantly reduces blood supply to the brain. Furthermore, increased plaque thickness thins the fibrous cap; when plaque thickness is >3.5 mm, 62% of patients have a fibrous cap <65 μm. This is due to the expansion and stretching of the fibrous cap by the lipid core, resulting in decreased mechanical strength. Additionally, it further increases blood flow stress injury, with the thickened area experiencing high wall shear stress (WSS >40 Pa), promoting inflammatory infiltration and collagen degradation.

[0030] The nattokinase product used in this invention can effectively reduce plaque thickness. Reduced plaque thickness can significantly reduce the risk of stroke, and reduced plaque thickness is conducive to the thickening of the local fibrous cap. When the fibrous cap thickening is >50μm, the risk of rupture can be reduced by 80% (OR=0.15) (Hattori K, JACC Imaging 2020).

[0031] Against this backdrop, non-pharmacological nattokinase and its products offer a new option for precision nutritional intervention. As a precise nutritional intervention method, nattokinase is effective in inhibiting plaque progression, exhibiting unique effects, and is safe, convenient, and suitable for a wide range of people. This provides a new approach and methodology for the management of vascular plaques and the prevention and treatment of cardiovascular diseases. Detailed Implementation

[0032] The technical solution of the present invention will be further described in detail below through specific embodiments.

[0033] Unless otherwise specified, the raw materials and equipment used in this invention can be purchased from the market or are commonly used in the field.

[0034] Nattokinase (NK), also known as Bacillus subtilis protein kinase, is a serine protease produced during natto fermentation that can dissolve fibrin in blood clots. In 1980, Professor Hiroyuki Sumi discovered a substance in natto that could rapidly dissolve artificial blood clots and named it nattokinase. Nattokinase is a single-chain polypeptide composed of 275 amino acid residues with a molecular weight of approximately 27.7 kDa; it mainly consists of three parts: a signal peptide, a leader peptide, and a mature peptide.

[0035] In this embodiment of the invention, NSKSD Natto Product V Soft Capsules provided by NSK Life Science (Zhejiang) Co., Ltd. are used. Each capsule contains more than 4000 FU of nattokinase activity. The method of administration is to take 2 capsules per day, that is, 8000 FU / day, divided into two doses: 4000 FU after breakfast in the morning and 4000 FU after dinner in the evening.

[0036] To verify the efficacy of nattokinase, the following examples were set up.

[0037] Example 1.1 General Information Based on the order of their visits and according to whether their consultation numbers were odd or even, 97 high-risk cardiovascular and cerebrovascular patients admitted to the First Affiliated Hospital of Westlake University School of Medicine in Hangzhou from January 2021 to December 2024 were randomly selected as the study subjects. All patients were informed about the contents of this study and signed informed consent forms. This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Westlake University School of Medicine in Hangzhou and strictly adhered to all ethical regulations (Hangzhou First Affiliated Hospital Medical Ethics Review No. 2020042).

[0038] 1.2 Inclusion and Exclusion Criteria Inclusion criteria: ① Age 30–75 years. ② No NK cell use in the month prior to enrollment. ③ Two or more of the following criteria were considered "yes": hypertension; hyperlipidemia; history of diabetes for ≥10 years; abnormally high blood viscosity; abnormal blood flow as detected by TCD; carotid artery plaque; coronary artery stenosis; history of stroke / TIA; history of coronary heart disease; history of venous thrombosis; history of peripheral vascular disease; body mass index ≥26 kg / m². 2 Or, a waist circumference >85cm for men and >80cm for women; numbness or tingling in the limbs due to poor blood circulation; a smoking habit of >10 years; abnormally high D-dimer levels; abnormally high C-reactive protein levels; abnormally high homocysteine ​​levels.

[0039] Exclusion criteria: ① Severe Alzheimer's disease; ② Pregnant or breastfeeding women; ③ Mental illness; ④ Those who have undergone ordinary trauma surgery within the past 3 months; ⑤ Those who have undergone cerebral hemorrhage or major surgery within the past 3 months; ⑥ Hemangioma patients; ⑦ Late-stage cancer patients; ⑧ Those with severe liver or kidney dysfunction; ⑨ Those with coagulation disorders; ⑩ Those with protein allergies.

[0040] 1.3 Methods Basic information was collected for each subject (including basic information, physical examination, and current medical conditions and medications). NSKSD Natto Product V soft capsules, provided by NSK Life Sciences (Zhejiang) Co., Ltd., were used. Each capsule contains over 4000 FU of nattokinase activity. The dosage was 2 capsules daily, totaling 8000 FU / day, divided into two doses: 4000 FU after breakfast and 4000 FU after dinner. Before treatment, vital signs, clinical symptoms and signs, laboratory tests, and imaging results were recorded for each subject. Laboratory tests included total cholesterol (TC) (mmol / L), low-density lipoprotein cholesterol (LDL-C) (mmol / L), coagulation parameters, international normalized ratio (INR), platelet aggregation rate (PAgT) (%), D-dimer (mg / L), whole blood low-shear viscosity, and plasma viscosity. Imaging studies included transcranial Doppler (TCD) measurements [MCA (cm / s), ACA (cm / s), PCA (cm / s), VA (cm / s), BA (cm / s), and OA (cm / s)] and carotid ultrasound (L-CCA, R-CCA, intima-media thickness (IMT), plaque area, and plaque thickness). Laboratory and imaging studies were performed 90 days after the start of NSKSD (nattokinase) treatment.

[0041] Ultrasound diagnostic criteria: A localized structural abnormality in the carotid artery wall (rather than simple increased intima-media thickness), manifested as localized thickening and bulging of the vessel wall protruding into the lumen, with the thickness of this bulge ≥1.5 mm, or 0.5 mm thicker than the adjacent IMT, or ≥1.5 times the IMT of the adjacent site, is sufficient to diagnose carotid artery plaque. Note: IMT is the sum of the thickness of the intima and media of the carotid artery wall; normally it should be <1.0 mm; 1.0~1.4 mm is considered intimal thickening, and ≥1.5 mm is defined as plaque.

[0042] 1.4 Statistical Analysis SPSS 26.0 statistical software was used for analysis. Rank-sum tests were used for ordinal data. Quantitative data conforming to a normal distribution were expressed as (x±s) and analyzed using t-tests; those not conforming to a normal distribution were analyzed using the Wilcoxon & Hodges-Lehmann method. P<0.05 was considered statistically significant, and multiple comparisons were performed using the Bonferroni method as needed.

[0043] 2. Results of a study on the thickness of carotid artery plaques 2.1 Basic information about the research subjects: There were no cases of loss to follow-up or discontinuation of treatment during the trial. Baseline clinical characteristics of the subjects: A total of 45 patients (cases) met the diagnostic criteria for carotid artery plaques. No adverse events occurred during the clinical trial.

[0044] 2.2 Imaging Results The efficacy of NSKSD nattokinase for 90 days showed a significant change in the thickness of carotid artery plaques, as shown in the table below.

[0045] 2.2.1 Analysis results based on plaque thickness changes before and after treatment (unit: cm): Table 1. Comparison of key indicators of plaque thickness before and after NSKSD nattokinase treatment 2.2.2. Thickness variation distribution 2.2.3. Paired Samples t-Test Results 2.2.4. Evaluation of therapeutic effects 2.2.5. Examples of typical case changes 2.3 Conclusion After 90 days of use, NSKSD nattokinase showed statistical significance: paired t-test showed that nattokinase significantly reduced carotid plaque thickness (p < 0.001), with a mean reduction of 0.032 mm (95% CI: -0.048 to -0.016). Clinical efficacy showed that plaque thickness decreased in 68.9% of patients (mean reduction of 0.05 cm); plaque thickness did not increase in 84.4% of patients (decreased or remained unchanged); the mean reduction from baseline was 15.2%; effect strength: Cohen's d = 0.615, reaching an intermediate effect level; 5. Individual differences: a small number of patients (15.6%) experienced a slight increase (maximum +0.04 cm), indicating the existence of individual differences.

[0046] Finally, it should be noted that the above examples are merely some specific embodiments of the present invention. The present invention is not limited to the above embodiments and many variations are possible. All variations that can be directly derived or conceived by those skilled in the art from the content disclosed in this invention should be considered within the scope of protection of this invention.

Claims

1. The use of a nattokinase or a product composition thereof in the preparation of a product, characterized in that, The product is for the prevention and / or treatment of cardiovascular and cerebrovascular diseases in patients or for slowing their progression.

2. The use according to claim 1, characterized in that, The cardiovascular and cerebrovascular diseases mentioned are specifically atherosclerosis, more preferably carotid atherosclerosis.

3. The use according to claim 1 or 2, characterized in that, The product is a product that reduces the thickness of atherosclerotic plaques, and more preferably a product that reduces the thickness of carotid atherosclerotic plaques.

4. The use according to claim 1 or 2, characterized in that, The product described is designed to reduce the thickness of atherosclerotic plaques in the carotid arteries.

5. The use according to any one of claims 1-4, characterized in that, The patient in question is at high risk for cardiovascular and cerebrovascular diseases.

6. The use according to claim 5, characterized in that, The patients described are those who meet two or more of the following criteria: hypertension; hyperlipidemia; history of diabetes for ≥10 years; abnormally high blood viscosity; abnormal blood flow as detected by TCD; carotid artery plaque; coronary artery stenosis; history of stroke / TIA; history of coronary heart disease; history of venous thrombosis; history of peripheral vascular disease; body mass index ≥26 kg / m². 2 Or, a waist circumference >85cm for men and >80cm for women; numbness or tingling in the limbs due to poor blood circulation; a smoking habit of >10 years; abnormally high D-dimer levels; abnormally high C-reactive protein levels; abnormally high homocysteine ​​levels.

7. The use according to any one of claims 1-6, characterized in that, The nattokinase or its product composition shall be administered at a rate of not less than 8000 FU daily for at least 90 days, based on nattokinase activity.

8. The use according to any one of claims 1-7, characterized in that, The product is in the form of capsules, tablets, or powder, with capsules being preferred.

9. The use according to claim 8, characterized in that, Each serving of the product contains, but is not limited to, 1000 FU, 2000 FU, 3000 FU, or 4000 FU of nattokinase, based on nattokinase activity.

10. A product for preventing and / or treating, improving, or delaying the progression of cardiovascular and cerebrovascular diseases in patients, as described in any one of claims 1-9, characterized in that, The active ingredient in the product includes nattokinase.

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