阅读说明：本技术 一种预防高血压并发的心血管疾病的联合用药物组合物及其应用 (Combined pharmaceutical composition for preventing cardiovascular diseases complicated by hypertension and application thereof ) 是由 彭浩 李静 陈立楠 卢莹 于 2021-07-01 设计创作，主要内容包括：本发明涉及一种预防高血压并发的心血管疾病的联合用药物组合物,包括降同型半胱氨酸药物和降血小板药物,其中,降同型半胱氨酸药物为叶酸,降血小板药物为阿司匹林或氯吡格雷。本发明提供的联合用药物组合物不仅可用于高血压患者的血压管理,还可用于预防高血压患者的心血管事件。(The invention relates to a combined medicine composition for preventing cardiovascular diseases complicated by hypertension, which comprises a homocysteine-reducing medicine and a platelet-reducing medicine, wherein the homocysteine-reducing medicine is folic acid, and the platelet-reducing medicine is aspirin or clopidogrel. The combined medicine composition provided by the invention not only can be used for managing the blood pressure of a hypertensive patient, but also can be used for preventing cardiovascular events of the hypertensive patient.)

1. A combined pharmaceutical composition for preventing cardiovascular diseases complicated by hypertension is characterized in that: the combined medicine composition comprises a homocysteine-reducing medicine and a platelet-reducing medicine, and the hypertension is H-type hypertension.

2. The combination pharmaceutical composition according to claim 1, characterized in that: the homocysteine-reducing drug is folic acid, vitamin B6 or vitamin B12, and the platelet-reducing drug is aspirin or clopidogrel.

3. The combination pharmaceutical composition according to claim 1, characterized in that: the homocysteine-lowering drug and the platelet-lowering drug are administered simultaneously.

4. The combination pharmaceutical composition according to claim 1, characterized in that: the homocysteine-lowering drug and the platelet-lowering drug are administered sequentially.

5. The combination pharmaceutical composition according to claim 1, characterized in that: in the single-day preparation of the combined pharmaceutical composition, the mass ratio of the active component of the homocysteine-reducing drug to the active component of the platelet-reducing drug is 1: 100-150.

6. The combination pharmaceutical composition according to claim 1, characterized in that: the combined medicine composition also comprises any one or the combination of at least two of pharmaceutically acceptable pharmaceutic adjuvants.

7. Use of a combination pharmaceutical composition according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment of hypertension.

8. Use of a combination pharmaceutical composition according to any one of claims 1 to 6 for the manufacture of a medicament for the prevention of cardiovascular diseases complicated by hypertension.

9. Use according to claim 8, characterized in that: the hypertension is H-type hypertension.

10. Use according to claim 8, characterized in that: the cardiovascular disease comprises myocardial infarction, angina pectoris, heart failure or cerebral apoplexy.

Technical Field

The invention relates to the field of biological medicines, in particular to a combined pharmaceutical composition for preventing cardiovascular diseases complicated by hypertension and application thereof.

Background

Hypertension is an important risk factor for cardiovascular diseases and other cardiovascular and cerebrovascular diseases. Worldwide, 67% of heart diseases, 54% of strokes are caused by hypertension, and 13.5% of deaths are due to hypertension. The phenomena of homocysteine (Hcy) and low folic acid commonly exist in Chinese hypertension patients, the hypertension and the Hcy blood have obvious synergistic effect on the attack risk of the stroke, about 3/4 hypertension is accompanied by the Hcy blood in the Chinese hypertension patients, and in order to emphasize the harmfulness and the universality, the Chinese scholars put forward the concept of H-type hypertension, namely the hypertension accompanied with the Hcy rise (the blood Hcy is more than or equal to 10 mu mol/L). At present, 2.8 hundred million hypertension patients exist in China, and 75-80% of the patients are H-type hypertension. The us data show that hypertension is present with high Hcy, with 11.0-fold increase in men and 16.3-fold increase in women at risk of stroke. Hypertension and Hcy of Chinese people exist simultaneously, and the risk of stroke is increased by 11.7 times. Therefore, managing the blood pressure of a hypertensive is important for stroke prevention.

Hcy is a non-essential sulfur-containing amino acid that has been found to be involved in the pathogenesis of cardiovascular disease and its risk factors, such as hypertension and atherosclerosis, by causing endothelial damage, increasing oxidative stress, stimulating proliferation of vascular smooth muscle cells, and altering the elastic properties of the vessel wall. In addition to these basic studies, the potential causal role of Hcy in CVD development has been proposed by a number of prospective observational studies, including mendelian randomization studies with methyltetrahydrofolate reductase gene (MTHFR) polymorphisms. However, the cardiovascular protective effect of reducing Hcy remains controversial. A number of large randomized clinical trials failed to find a significant effect of different doses of folic acid, vitamin b6 and vitamin b12 on reducing the risk of CVD.

Therefore, in order to better manage the blood pressure of the hypertensive, prevent the occurrence of cardiovascular diseases and reduce the medical burden of the hypertensive, it is very significant to develop a strategy capable of effectively treating hypertension and preventing cardiovascular diseases of the hypertensive.

Disclosure of Invention

In order to solve the technical problems, the invention provides a combined medicine composition which has a treatment effect on hypertension and can reduce the cardiovascular disease occurrence risk of a hypertension patient through the research on the combined medicine of the homocysteine-reducing medicine and the platelet-reducing medicine and the cardiovascular disease occurrence risk of the hypertension patient, wherein the platelet-reducing medicine can improve the Hcy reduction (mainly under the action of folic acid components) on the cardiovascular protection effect by regulating the platelet function and the steady state, slow the atherosclerotic damage and reduce the cardiovascular disease occurrence risk.

The combined medicine composition for preventing the cardiovascular diseases complicated by the hypertension comprises a homocysteine-reducing medicine and a platelet-reducing medicine, and the hypertension is H-type hypertension.

Further, the homocysteine-reducing drug is folic acid, vitamin B6 or vitamin B12, and the platelet-reducing drug is aspirin or clopidogrel.

In the current clinical treatment scheme, the effect obtained by treating by independently reducing Hcy or platelets is not obvious, and the applicant finds that Hcy and platelets have interaction through a large amount of researches, and the treatment effect which cannot be realized by independently using drugs can be achieved by jointly applying folic acid and antiplatelet drugs in hypertension patients.

Further, the homocysteine-lowering drug and the platelet-lowering drug are administered simultaneously.

Further, the homocysteine-lowering drug and the platelet-lowering drug are administered sequentially, such as first administration of the homocysteine-lowering drug and then administration of the platelet-lowering drug, or first administration of the platelet-lowering drug and then administration of the homocysteine-lowering drug, or both of them are administered alternately.

Further, in a single daily preparation of the pharmaceutical composition for combination, the mass ratio of the active ingredients of the homocysteine-reducing drug to the active ingredients of the platelet-reducing drug is 1: 100-150.

Further, the administration is once a day.

Further, the dosage form of the homocysteine-reducing drug or the platelet-reducing drug includes any pharmaceutically acceptable dosage form, such as tablets, powders, granules, capsules, injections, sprays, solutions and the like.

Further, the combined medicine composition also comprises any one or the combination of at least two of pharmaceutically acceptable auxiliary materials.

Further, the pharmaceutical combination is a pharmaceutical combination carried on a pharmaceutically acceptable carrier.

The invention claims the application of the combined pharmaceutical composition in preparing a medicament for treating hypertension or atherosclerosis.

The invention also claims the application of the combined medicine composition in preparing a medicine for preventing cardiovascular diseases complicated by hypertension.

Further, hypertension is type H hypertension.

Further, cardiovascular diseases include myocardial infarction, angina pectoris, heart failure or stroke.

By the scheme, the invention at least has the following advantages:

the compound preparation provided by the invention creatively combines the Hcy-reducing medicament and the antiplatelet medicament for use, and the two medicaments generate a synergistic effect, so that the compound preparation not only has the effects of reducing blood pressure and preventing cardiovascular events, but also can improve the medication compliance of hypertension patients and promote the management effect of the hypertension patients.

The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clearly understood and to implement them in accordance with the contents of the description, the following description is made with reference to the preferred embodiments of the present invention and the accompanying detailed drawings.

Drawings

In order that the present disclosure may be more readily and clearly understood, reference will now be made in detail to the present disclosure, examples of which are illustrated in the accompanying drawings.

FIG. 1 is a graph of the correlation of Hcy to CVD risk factor in low MPV and high MPV subgroups;

FIG. 2 is a graph of the effect of Hcy quartiles on CVD development in different groups of MPVs;

FIG. 3 is the cumulative incidence of CVD for MPV ≧ median and/or HHcy risk category;

FIG. 4 is a graph comparing systolic blood pressure at 6 months of intervention with different treatment regimens;

figure 5 is a graph comparing diastolic blood pressure at 6 months of intervention with different treatment regimens.

Detailed Description

The present invention is further described below in conjunction with the following figures and specific examples so that those skilled in the art may better understand the present invention and practice it, but the examples are not intended to limit the present invention.

Example 1

1. Study object

Based on the chronic disease management registration system in Taicang City of China, prospective cohort research is carried out to investigate the influence of Hcy on the CVD risk of hypertension patients. Of the enrolled hypertensive patients, 30379 patients agreed to participate in our study with written informed consent. All participants in 2017 received clinical examinations including personal interviews and physical examinations. Information on social demographic factors, medical history, drug use, and lifestyle factors was collected via a standard questionnaire. Physical examinations were performed on all participants and fasting blood samples were collected for laboratory testing including fasting blood glucose, lipids and Hcy. The study protocol was approved by the ethical committee of the university of suzhou. After excluding participants with a history of cardiovascular disease and cancer (i.e., ═ 3145) prior to baseline examination, a total of 27234 participants followed the new cardiovascular disease event and were included in the current analysis by the end of 2020.

2. Measurement of homocysteine at baseline

Homocysteine was determined by a commercial enzyme assay (Axis Shield Diagnostics ltd., dunde, UK) on a Cobas c501 analyzer (Roche Diagnostics, Indianapolis, IN) by a laboratory worker at the disease prevention control center IN tai cang city. The laboratory staff had no knowledge of the baseline characteristics of the study participants. The measured intra-and inter-batch coefficient of variation was less than 7.5% and 4.5%, respectively. Hyperhomocysteinemia (HHcy) is defined as Hcy ≧ 15 μmol/L.

3. Measurement of routine risk factors at baseline

Demographic data (age, sex, educational level), drug use and lifestyle (current smoking, drinking) were obtained by trained staff through questionnaires. Weight (kg) and height (cm) were measured by trained staff when the participants were wearing light and thin clothes without shoes. Body Mass Index (BMI) is calculated by dividing body weight (in kg) by height (in m) squared (kg/m). Each participant measured three blood pressures after sitting at rest for at least 5 minutes, with the average of the three measurements being taken as the final level of Systolic (SBP) and Diastolic (DBP). Fasting plasma glucose, creatinine, and blood lipids, including total cholesterol, triglycerides, high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C) are determined using standard methods. The blood cell analysis included platelet count (PLT), thrombocyte Pressue (PCT), Platelet Distribution Width (PDW) and Mean Platelet Volume (MPV) obtained by BC-3200 hematology analyzer (meirui medical, shenzhen, china).

4. Follow-up and assessment of cardiovascular events

All participants are followed each year by local community health service staff through telephone or face-to-face access. When a new cardiovascular event or death is found, the staff reviews the hospital records and fills out the standard event table. Based on the incident table, the endpoint review board makes the final diagnosis. Cardiovascular events include non-fatal coronary heart disease (including acute myocardial infarction and unstable angina), non-fatal stroke, and death from any cardiovascular disease. The date of occurrence of each event was determined from the initial diagnosis or proof of death.

5. Statistical analysis

Baseline characteristics of study participants were presented in terms of quartiles of serum homocysteine. The logarithmic transformation is used for the Hcy-maximized normal distribution (logHcy). To examine the prospective association between Hcy and cardiovascular events at baseline, we constructed a Cox proportional hazards model, where the time (in days) at which the cardiovascular event occurred was the dependent variable, Hcy (continuous Hcy or categorical Hcy is quartile) at baseline was the independent variable, and adjusted age, gender, educational level, current smoking status, current alcohol consumption, body mass index, low density lipoprotein cholesterol, high density lipoprotein cholesterol, fasting plasma glucose, creatinine, systolic blood pressure, and baseline antihypertensive drugs. In this model, subjects who are still free of cardiovascular disease or who die for other reasons are defined as losses, based on the date the first cardiovascular event occurred. The relationship between platelet index and cardiovascular events was also examined, followed by interaction tests by adding a multiplicative term for platelet index × LogHcy. In view of the unique significant interaction of MPV and to facilitate interpretation of the data, participants were divided into four groups: participants with high MPV (. gtoreq.median, i.e.. gtoreq.9.68 fL) or HHcy, both with and without, were then investigated for association between these four groups (both without participants as reference) and cardiovascular disease. The additive interaction of high MPV and HHcy on CVD was evaluated by three statistical indicators: relative Excess Risk (RERI), Attribution Proportion (AP) and synergy index (S). If there is no additive interaction, the 95% CI for RERI and AP will contain 0, and the 95% CI for S will contain 1. Finally, the Kaplan-Meier survival curves were used to estimate the cumulative incidence of CVD for the four groups and compared using the log-rank test. All statistical analyses were performed using R version 4.0.2. Bilateral P values of less than 0.05 were statistically significant.

6. Results

This study included 27234 hypertensive patients (mean age 63 years, 52% women) with no apparent cardiovascular disease at baseline. Of these, 5793 people (21%) were considered to have HHcy. The baseline characteristics are shown in table 1, based on the quartile of serum homocysteine. As expected, subjects with higher serum homocysteine levels are more likely to be older, male, smoking, drinking, and have higher BMI, blood pressure, fasting glucose, blood lipids, and creatinine levels (P < 0.05). In terms of platelet activation index, the hypertensive patients with elevated Hcy had a significant increase in MPV and PCT (P < 0.05).

Table 1 study of baseline characteristics of participants based on serum Hcy quartiles (N ═ 27,234)

All results are exPressed with mean±SD unless otherwise noted.

Hcy:homocysteine；LDL:low-density liPoProtein；HDL:high-density liPoProtein.

(2) Prospective association of baseline homocysteine with cardiovascular events

In an average follow-up visit of 3 years, 1063 people developed new cardiovascular events with a cumulative incidence of 3.9%. The prospective association of baseline serum homocysteine with the risk of cardiovascular events is shown in table 2. The higher serum homocysteine levels at baseline, the higher the risk of cardiovascular disease after correction for age, gender, educational level, smoking, alcohol consumption, body mass index, fasting plasma glucose, low density lipoprotein cholesterol, high density lipoprotein cholesterol, creatinine, systolic blood pressure and antihypertensive drugs (HR ═ 1.85, P < 0.001). Similar correlations were also found in regression analysis using the serum homocysteine quartile as predictor. The second, third and fourth quantiles are at higher risk of cardiovascular disease than subjects with the lowest serum homocysteine levels, 30% (HR 1.30, P0.012), 40%, respectively

(HR ═ 1.40, P <0.001) and 57% (HR ═ 1.57, P < 0.001). As expected, subjects with HHcy were at a 1.29-fold higher risk of CVD than subjects without HHcy (HR ═ 1.29, P < 0.001).

TABLE 2 prospective correlation between baseline serum Hcy and CVD events

^*adjusting for age,sex,education level,smoking,drinking,body mass index,low-and high-density liPoProtein cholesterol,fasting glucose,creatinine,systolic blood Pressure,and antihyPertensive medication at baseline.

Hcy:homocysteine；CVD:cardiovascular disease；HHcy:hyPerhomocysteinemia.

(3) Prospective correlation of subgroup baseline Hcy with CVD incidence by MPV

Regression analysis using each platelet index as a predictor found that MPV (HR 1.07, P <0.001) and PCT (HR 23.63, P <0.001) were significantly associated with risk of cardiovascular disease (table 3), while only MPV and Hcy had an interaction with each other in influencing cardiovascular disease risk after multivariate adjustment (P0.030). In addition, we performed a subgroup analysis to examine whether the platelet index could alter the relationship between homocysteine and cardiovascular disease. The results show a similar phenomenon, i.e. the correlation of serum Hcy with CVD in the high MPV group is significantly higher than in the low MPV group (HR 2.71 vs.1.32, P0.029, fig. 1, where a is the low MPV subgroup and B is the high MPV subgroup). We did not find any inter-group differences in the correlation of other platelet indices between homocysteine and cardiovascular disease (table 4).

TABLE 3 baseline level of platelet index associated with CVD and its interaction with serum Hcy

^*adjusting for age,sex,education level,smoking,drinking,body mass index,low-and high-density liPoProtein cholesterol,fasting glucose,creatinine,systolic blood Pressure,and antihyPertensive medication at baseline.

TABLE 4 correlation of baseline serum Hcy with CVD in high and low subgroup of platelet index

^*adjusting for age,sex,education level,smoking,drinking,body mass index,low-and high-density liPoProtein cholesterol,fasting glucose,creatinine,systolic blood Pressure,and antihyPertensive medication at baseline.

(4) Interaction of high MPV and HHcy on event CVD

When the upper quartile of Hcy coexists with high MPV, the risk of developing CVD increases dramatically (fig. 2) suggesting that homocysteine and MPV have a synergistic effect on the risk of developing cardiovascular disease. In individuals with high MPV or HHcy, the uneven distribution of CVD events, and individuals with and without both, showed similar phenomena (Log-rank test P <0.001, fig. 3). The cumulative incidence of CVD was highest in subjects with higher MPV and HHcy (6.38%), and lowest in subjects with neither condition at baseline (3.39%). The risk of CVD in subjects in both cases was significantly increased (HR 1.50, P <0.001) after adjusting the covariates compared to subjects without HHcy and high MPV at baseline (table 5).

Table 5 shows the relationship between serum Hcy and platelet indices at baseline and the risk of cardiovascular events (myocardial infarction, angina pectoris, heart failure, stroke) within 2 years, which indicates that Hcy and mean platelet volume have a synergistic effect on the risk of cardiovascular events, and that the risk of cardiovascular events in hypertensive patients with both elevated levels is significantly greater than in patients with elevated levels alone, and about 26% of the cardiovascular risk can be attributed to the synergistic effect of Hcy and platelets.

TABLE 5 interaction of high Hcy and high platelet volume for cardiovascular disease

^*adjusting for age,sex,education level,smoking,drinking,body mass index,low-and high-density liPoProtein cholesterol,fasting glucose,creatinine,systolic blood Pressure,and antihyPertensive medication at baseline.

CVD:cardiovascular disease；HHcy:hyPerhomocystainemia；MPV:mean Platelet volume；HR:hazard ratio；CI:confidence intervals.

The multiplicative term for high MPV × HHcy is significantly correlated to CVD events (P ═ 0.037). The three statistics of the test additive interactions were statistically significant prior to multivariate adjustment (Table 6), suggesting that subjects with both HHcy and MPV appeared to have significantly higher HR for CVD than the sum of the HR for both subjects.

TABLE 6 statistical data for testing additive interactions associated with high MPV and HHcy and CVD events

^*adjusting for age,sex,education level,smoking,drinking,body mass index,low-and high-density liPoProtein cholesterol,fasting glucose,creatinine,systolic blood Pressure,and antihyPertensive medication at baseline.

RERI:the relative excess risk because of the interaction；AP:the attributable ProPortion because of the interaction；S:the synergy index.

Example 2

Based on the results of the study in example 1, we found that over-activation of platelets may have a synergistic effect with Hcy on the risk of developing cardiovascular disease. To validate this study hypothesis, we performed an RCT test, in which 1000 hypertensive patients (SBP > 150 mmHg) were recruited in the taicang city, randomly divided into four groups, administered with different interventions of regular management, regular management + 0.8 mg folic acid per day, regular management + 100 mg aspirin per day, regular management + folic acid (0.8 mg daily) + aspirin (100 mg daily), respectively, monitored the blood pressure levels at month 6, evaluated the differences in the blood pressure levels of the groups, followed by follow-up for 2 years, and evaluated whether there was a difference in the incidence of cardiovascular events in the groups.

Results 1: treating blood pressure levels at 6 months

As shown in fig. 4, after 6 months of intervention, SBP levels were slightly lower in the drug-alone group than in the conventional treatment group, with no significant statistical difference, but SBP levels were lowest in the combination group, significantly lower than in the remaining 3 groups (P < 0.001). Similarly, the DBP levels were also significantly lower in the combination group than in the remaining 3 groups (P <0.001, fig. 5).

Results 2: treating cardiovascular events at 2 years

As shown in table 7, after 2 years of intervention, the cardiovascular event incidence rates of the conventional treatment group, the folic acid group alone, the aspirin group alone and the combination group were respectively 6.8%, 6.0%, 5.6% and 3.6%, and compared with the conventional treatment group, the cardiovascular risk of the folic acid group alone and the aspirin group alone was not statistically significantly reduced, but the cardiovascular risk of the combination group was 53% that of the conventional treatment group, namely the cardiovascular risk was reduced by 47%. Our experimental results show that 1 cardiovascular event can be reduced by treating 31 patients with hypertension with folic acid in combination with aspirin.

TABLE 7 comparison of cardiovascular event incidence at 2 years of treatment

It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications of the invention may be made without departing from the spirit or scope of the invention.