CN113384568A - Combined medicine for preventing and/or repairing heart damage caused by atmospheric pollution - Google Patents
Combined medicine for preventing and/or repairing heart damage caused by atmospheric pollution Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
Abstract
The invention belongs to the technical field of medicines, and discloses a combined medicine for preventing and/or repairing heart damage caused by atmospheric pollution. The combined medicine comprises a component A and a component B, wherein the component A comprises the following components: taurine and coenzyme Q10; the component B comprises the following components: alpha-linolenic acid, linoleic acid, eicosapentaenoic acid and docosahexaenoic acid. The composition can effectively improve PM2.5Exposure to heart rate effects; in PM2.5Can inhibit the increase of active oxygen and inflammatory factors during the exposure process; for PM2.5The resulting heart rate failure has a certain inhibiting effect; effectively improve the cause PM2.5Resulting in abnormal morphology of myocardial cells, inhibiting collagen deposition, reducing fibrosis, and reducing PM2.5Risk of heart failure disease from exposure.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a combined medicine for preventing and/or repairing heart damage caused by atmospheric pollution.
Background
PM in the atmosphere2.5Is a fine particulate with a diameter of 0.1 to 2.5 μm (based on aerodynamic diameter). PM compared to other atmospheric particulates2.5The PM has complex composition, large amount, small average particle diameter and large surface area, and the characteristics of the PM enable the PM to have good stability2.5The surface of (A) can carry a large number of harmful and toxic substances (heavy metals, persistent organic pollutants, pathogenic microorganisms), so that the PM2.5Is one of the important indicators for evaluating air pollution. In addition to the concentration of PM2.5The chemical components of (a) are also critical factors causing environmental pollution, and the main components of the chemical components comprise organic pollutants, soluble salts, metals, carbonaceous components, biological components and the like. PM, a complex mixture of solid and liquid airborne particles2.5Has the property of atmosphere accumulation, and is a typical complex pollutant form. Evidence suggests that atmospheric pollution can induce damage and dysfunction of the cardiac system, and that there is a strong dose-effect relationship between atmospheric pollution and cardiac disease. Meanwhile, the elderly belong to typical cardiovascular disease susceptible population, and the PM is treated2.5More sensitive to exposure and more susceptible to PM2.5Toxic stress of (2). At present, PM2.5The overall treatment situation is generally gradually clear, but the pollution treatment in a short period is not obvious, so that residents are subjected to PM in local areas with serious atmospheric pollution2.5The potential risk of stress remains severe. Therefore, the research and development of the medicine which has low cost and strong pertinence and can prevent and/or repair the heart damage caused by the atmospheric pollution has important social and economic benefits.
Disclosure of Invention
It is an object of the first aspect of the invention to provide a combination.
The object of the second aspect of the present invention is to provide the use of the combination according to the first aspect for the manufacture of a medicament for the prevention and/or treatment of cardiovascular diseases.
The object of the third aspect of the invention is to provide the use of a combination of component a and component B for the preparation of a medicament for the prevention and/or treatment of cardiovascular diseases.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
in a first aspect of the invention, there is provided a combination comprising an a-component and a B-component, the a-component comprising the following ingredients: taurine and coenzyme Q10; the component B comprises the following components: alpha-linolenic acid, linoleic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA).
Preferably, the component A comprises the following components in parts by weight: 194.4 to 712.8 parts of taurine and 0.54 to 1.98 parts of coenzyme Q10.
Preferably, the component B comprises the following components in parts by weight: 29.7-108.9 parts of alpha-linolenic acid, 7.776-28.512 parts of linoleic acid, 9.882-36.234 parts of eicosapentaenoic acid (EPA) and 6.48-23.76 parts of docosahexaenoic acid (DHA).
Further preferably, the component A comprises the following components in parts by weight: 216-648 parts of taurine and 0.6-1.8 parts of coenzyme Q10.
Further preferably, the component B comprises the following components in parts by weight: 33-99 parts of alpha-linolenic acid, 8.64-25.92 parts of linoleic acid, 10.98-32.94 parts of eicosapentaenoic acid (EPA) and 7.2-21.6 parts of docosahexaenoic acid (DHA).
Preferably, the weight ratio of the component A to the component B is (1-13): 1; further preferably, the weight ratio of the component A to the component B is (1.21-10.86): 1.
preferably, the component A and the component B also comprise pharmaceutically acceptable auxiliary materials.
Preferably, the component A comprises the following components in parts by weight: 194.4-712.8 parts of taurine, 0.54-1.98 parts of coenzyme Q10 and 1359.18-2137.74 parts of pharmaceutically acceptable auxiliary materials.
Preferably, the component B comprises the following components in parts by weight: 29.7-108.9 parts of alpha-linolenic acid, 7.776-28.512 parts of linoleic acid, 9.882-36.234 parts of eicosapentaenoic acid (EPA), 6.48-23.76 parts of docosahexaenoic acid (DHA) and 16038.49-19734.20 parts of pharmaceutically acceptable auxiliary materials.
Further preferably, the component A comprises the following components in parts by weight: 216-648 parts of taurine, 0.6-1.8 parts of coenzyme Q10 and 1510.2-1943.4 parts of pharmaceutically acceptable auxiliary materials.
Further preferably, the component B comprises the following components in parts by weight: 33-99 parts of alpha-linolenic acid, 8.64-25.92 parts of linoleic acid, 10.98-32.94 parts of eicosapentaenoic acid (EPA), 7.2-21.6 parts of docosahexaenoic acid (DHA) and 17820.54-17940.18 parts of pharmaceutically acceptable auxiliary materials.
Preferably, the pharmaceutically acceptable auxiliary material is at least one of microcrystalline cellulose, lactose, croscarmellose sodium, povidone K30, magnesium stearate and vegetable oil.
Preferably, the pharmaceutically acceptable auxiliary materials in the component A are at least one of microcrystalline cellulose, lactose, croscarmellose sodium, povidone K30 and magnesium stearate.
Preferably, the pharmaceutically acceptable auxiliary material in the component B is vegetable oil.
Preferably, the combination is a combination for the prevention and/or treatment of cardiovascular diseases.
Further, the cardiovascular disease is PM2.5Cardiovascular diseases caused by pollution.
Preferably, the combination is administered in such a way that component a and component B are administered simultaneously, separately or sequentially; further preferably, the combination is administered in such a way that the a-component and the B-component are administered simultaneously.
In a second aspect of the invention there is provided the use of a combination according to the first aspect of the invention in the manufacture of a medicament for the prevention and/or treatment of cardiovascular disease.
Preferably, the cardiovascular disease is PM2.5Pollution guideAnd cardiovascular diseases.
In a third aspect of the invention, there is provided the use of a combination of component a and component B for the manufacture of a medicament for the prevention and/or treatment of cardiovascular disease; the component A comprises the following components: taurine and coenzyme Q10; the component B comprises the following components: alpha-linolenic acid, linoleic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA).
Preferably, the component A comprises the following components in parts by weight: 194.4-712.8 parts of taurine and 0.54-1.98 parts of coenzyme Q10; the component B comprises the following components in parts by weight: 29.7-108.9 parts of alpha-linolenic acid, 7.776-28.512 parts of linoleic acid, 9.882-36.234 parts of eicosapentaenoic acid (EPA) and 6.48-23.76 parts of docosahexaenoic acid (DHA).
Further preferably, the component A comprises the following components in parts by weight: 216-648 parts of taurine and 0.6-1.8 parts of coenzyme Q10; the component B comprises the following components in parts by weight: 33-99 parts of alpha-linolenic acid, 8.64-25.92 parts of linoleic acid, 10.98-32.94 parts of eicosapentaenoic acid (EPA) and 7.2-21.6 parts of docosahexaenoic acid (DHA).
Preferably, the weight ratio of the component A to the component B is (1-13): 1; further preferably, the weight ratio of the component A to the component B is (1.21-10.86): 1.
preferably, the cardiovascular disease is PM2.5Cardiovascular diseases caused by pollution.
The invention has the beneficial effects that:
the invention provides a combination drug which can effectively improve PM2.5Exposure to heart rate effects; in PM2.5Can inhibit the increase of active oxygen and inflammatory factors during the exposure process; for PM2.5The resulting heart rate failure has a certain inhibiting effect; effectively improve the cause PM2.5Resulting in abnormal morphology of myocardial cells, inhibiting collagen deposition, reducing fibrosis, and reducing PM2.5Risk of heart failure disease from exposure; that is, the compositions provided by the present invention can prevent and/or treat PM2.5Cardiovascular disease caused by contamination; combinations provided by the inventionThe medicine is used for inhibiting PM by combining the component A and the component B2.5The effects of heart rate reduction, abnormal increase of active oxygen and inflammatory factors caused by pollution are better than the effects of the component A and the component B on inhibiting PM respectively2.5The sum of the effects of heart rate reduction, abnormal increase of active oxygen and inflammatory factors caused by pollution, namely the combination of the component A and the component B produces a synergistic effect, and the PM is obviously reduced2.5Exposure leading to cardiovascular disease risk.
Drawings
FIG. 1 is mouse PM2.5Real-time exposure flow chart.
Fig. 2 is a graph of heart rate of differently treated mice: wherein, represents p < 0.05, and represents p < 0.01.
Figure 3 is a graph of the in vivo active oxygen content of differently treated mice: wherein, represents p < 0.05, and represents p < 0.01.
Figure 4 is a statistical map of the echographic data measurements for differently treated mice: wherein A is a statistical plot of the end-systolic ventricular Intervals (IVSs) of the mice treated differently; b is a statistical plot of end-diastolic chamber spacing (IVSd) for differently treated mice; c is a statistical plot of the terminal systolic diameters (LVIDs) of the differently treated mice; d is a statistical plot of the end-diastolic diameter (LVIDd) of the differently treated mice; e is a statistical plot of post-systolic wall thickness (LVPWs) for differently treated mice; f is a statistical plot of the post-diastolic wall thickness (LVPWd) of differently treated mice; denotes p < 0.05.
Figure 5 is a statistical plot of Ejection Fraction (EF) and ventricular short axis shortening rate (FS) for differently treated mice: wherein, A is an Ejection Fraction (EF) statistical chart of mice treated differently; b is a short-axis shortening rate (FS) statistical graph of ventricles of different treatments; p < 0.001; p < 0.001.
Fig. 6 is a staining pattern of hearts of different treated mice: wherein A is PM2.5HE staining pattern of the exposure drug group; b is PM2.5HE staining profile of the exposed placebo group; c is PM2.5Masson staining pattern of exposed drug group; d is PM2.5Masson staining pattern of the exposed placebo group.
Figure 7 is a statistical plot of inflammatory factors and Reactive Oxygen Species (ROS) in differently treated mice: wherein A is a statistical chart of IL-1 beta in mice treated differently; b is a statistical plot of IL-6 in differently treated mice; c is a statistical plot of TNF- α in differently treated mice; d is a Reactive Oxygen Species (ROS) histogram in differently treated mice; p < 0.05, p < 0.01.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. The materials, reagents and the like used in the present examples are commercially available reagents and materials unless otherwise specified.
Example 1A combination
The combination of example 1 comprises a component A and a component B, wherein the components of the component A and the component B (in parts by weight) are respectively as follows:
the component A comprises: 4.32 parts of taurine and 100.012 parts of coenzyme Q;
and B component: 0.66 portion of alpha-linolenic acid, 0.1728 portions of linoleic acid, 0.2196 portions of eicosapentaenoic acid (EPA) and 0.144 portion of docosahexaenoic acid (DHA).
The weight ratio of the A component to the B component is about 3.62: 1.
the preparation method of the component A comprises the following steps: mixing taurine and coenzyme Q10 to obtain component A.
The preparation method of the component B comprises the following steps: mixing alpha-linolenic acid, linoleic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to obtain component B.
Example 2A combination
The combination of example 2 comprises a component A and a component B, wherein the components of the component A and the component B (in parts by weight) are respectively as follows:
the component A comprises: 2.16 parts of taurine and 100.006 parts of coenzyme Q;
and B component: 0.99 part of alpha-linolenic acid, 0.2592 parts of linoleic acid, 0.3294 parts of eicosapentaenoic acid (EPA) and 0.216 part of docosahexaenoic acid (DHA).
The weight ratio of the A component to the B component is about 1.21: 1.
the preparation method of the component A comprises the following steps: mixing taurine and coenzyme Q10 to obtain component A.
The preparation method of the component B comprises the following steps: mixing alpha-linolenic acid, linoleic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to obtain component B.
Example 3A combination
The combination of example 3 comprises a component A and a component B, wherein the components of the component A and the component B (in parts by weight) are respectively as follows:
the component A comprises: 6.48 parts of taurine and 100.018 parts of coenzyme Q;
and B component: 0.33 part of alpha-linolenic acid, 0.0864 parts of linoleic acid, 0.1098 parts of eicosapentaenoic acid (EPA) and 0.072 part of docosahexaenoic acid (DHA).
The weight ratio of the A component to the B component is about 10.86: 1.
the preparation method of the component A comprises the following steps: mixing taurine and coenzyme Q10 to obtain component A.
The preparation method of the component B comprises the following steps: mixing alpha-linolenic acid, linoleic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to obtain component B.
Example 4A combination
The combination of example 4 comprises a component a and a component B, the components of the component a and the component B (in parts by weight) are respectively as follows:
the component A comprises: 4.32 parts of taurine, 100.012 parts of coenzyme Q, 3.561 parts of microcrystalline cellulose, 10.683 parts of lactose, 1.62 parts of croscarmellose sodium, 301.08 parts of povidone and 0.324 part of magnesium stearate;
and B component: 0.66 part of alpha-linolenic acid, 0.1728 parts of linoleic acid, 0.2196 parts of eicosapentaenoic acid (EPA), 0.144 part of docosahexaenoic acid (DHA) and 178.8036 parts of soybean oil.
The weight ratio of the A component to the B component is about 1: 8.33.
the preparation method of the component A comprises the following steps: preparing taurine, coenzyme Q10, microcrystalline cellulose, lactose, croscarmellose sodium and povidone K30 into granules by a granulation process, adding magnesium stearate, mixing uniformly, and tabletting to obtain the component A.
The preparation method of the component B comprises the following steps: dissolving alpha-linolenic acid, linoleic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in soybean oil, and mixing to obtain mixed oily solution, i.e. component B.
Example 5A combination
The combination of example 5 comprises a component A and a component B, wherein the components of the component A and the component B (in parts by weight) are respectively as follows:
the component A comprises: 2.16 parts of taurine, 100.006 parts of coenzyme Q, 4.1025 parts of microcrystalline cellulose, 12.3075 parts of lactose, 1.62 parts of croscarmellose sodium, 301.08 parts of povidone K and 0.324 part of magnesium stearate;
and B component: 0.99 part of alpha-linolenic acid, 0.2592 parts of linoleic acid, 0.3294 parts of eicosapentaenoic acid (EPA), 0.216 part of docosahexaenoic acid (DHA) and 178.2054 parts of soybean oil.
The weight ratio of the A component to the B component is about 1: 8.33.
the preparation method of the component A comprises the following steps: preparing taurine, coenzyme Q10, microcrystalline cellulose, lactose, croscarmellose sodium and povidone K30 into granules by a granulation process, adding magnesium stearate, and uniformly mixing to obtain mixed granules to obtain the component A.
The preparation method of the component B comprises the following steps: dissolving alpha-linolenic acid, linoleic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in olive oil, and mixing to obtain mixed oily solution, i.e. component B.
Example 6A combination
The combination of example 6 comprises a component a and a component B, the components of the component a and the component B (in parts by weight) are respectively as follows:
the component A comprises: 6.48 parts of taurine, 100.018 parts of coenzyme Q, 3.0195 parts of microcrystalline cellulose, 9.0585 parts of lactose, 1.62 parts of croscarmellose sodium, 301.08 parts of povidone K and 0.324 part of magnesium stearate;
and B component: 0.33 part of alpha-linolenic acid, 0.0864 parts of linoleic acid, 0.1098 parts of eicosapentaenoic acid (EPA), 0.072 part of docosahexaenoic acid (DHA) and 179.4018 parts of soybean oil.
The weight ratio of the A component to the B component is about 1: 8.33.
the preparation method of the component A comprises the following steps: preparing taurine, coenzyme Q10, microcrystalline cellulose, lactose, croscarmellose sodium and povidone K30 into granules by a granulation process, adding magnesium stearate, and uniformly mixing to obtain mixed granules, namely the component A.
The preparation method of the component B comprises the following steps: dissolving alpha-linolenic acid, linoleic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in soybean oil, and mixing to obtain mixed oily solution, i.e. component B.
Example 7 combination drug pair PM2.5Effect of Exposure model mice
1. 50 mice (aged mice, 17 months old, purchased from Guangdong university of traditional Chinese medicine and having a weight of 18-22 g) in the same age group of C57BJ/6 are selected and placed in a standard breeding room for breeding (breeding temperature is 18-22 ℃, humidity is 45-55%, and breeding time is 12h day and night alternately). The mice were acclimated for 10 days before exposure and their physiological data such as heart rate were recorded in a natural state as a reference value. The PM2.5 exposure experiment was then performed, with the following experimental procedure:
(1) mice were domesticated and divided into four groups (14 mice per group): PM (particulate matter)2.5Exposure placebo group (PM)2.5-Placebo group)、PM2.5Drug exposure group (PM)2.5Compound group), clean air Placebo group (Control-pacifo group), clean air drug group (Control-Compound group).
(2) Firstly, mice are raised in an SPF laboratory animal raising room for one week and then transferred into an exposure box for raising: four groups of mice were placed in a real-time exposure system (as shown in figure 1), PM2.5Two groups of mice of the exposed group are introduced into the atmosphere of the Hongkong county on the same day; to reduce the effect of other variables, the atmosphere is passed through a small filter to filter out large particulate pollutants such as PM10And screening out the PM of the flood tunnel county on the same day2.5(ii) a Group mice in clean air groupAir was introduced into the filter-filtered clean air for control experiments, the next day of dosing was followed by a single dose every other day as follows: the drug combination of example 1 was injected with PM at regular time daily into 0.17328g A (0.1728g taurine; 0.00048g coenzyme Q10)/Kg mice, 0.047856g B (0.0264g alpha-linolenic acid; 0.006912g linoleic acid; 0.008784g eicosapentaenoic acid; 0.00576g docosahexaenoic acid)/Kg mice by gavage2.5Exposing the bodies of the two groups of mice of the drug group and the clean air drug group; for placebo group (PM) at the same time2.5Exposed placebo, clean air placebo) mice were injected daily at regular intervals with an equivalent dose of placebo (0.17328g water lactose, 0.047856g peanut oil) by gavage as a control.
(3) After 12 weeks of exposure, the detection of multiple indexes such as heart rate, ROS, cardiac ultrasound and the like is carried out.
2. Heart rate index detection: the heart rate data of the mouse is obtained by measuring the pulse frequency according to the measuring working principle by adopting a Medlab mouse noninvasive blood pressure testing system and measuring the heart rate and blood pressure of the mouse at the same time. After 12 weeks exposure, based on physical characteristics and morphological evaluation of the mice, the heart rate of the mice was as shown in figure 2, ensuring that the mice did not die and aberrated: after 12 weeks exposure, the heart rate of mice in the clean air placebo (Control-placebo group) and the clean air drug (Control-compound group) was about the same as the heart rate before exposure with no significant change, indicating that: the combined medicament has no negative effect on the heart rate of the mouse; PM (particulate matter)2.5Exposure placebo group (PM)2.5Placebo group) mice have a heart rate trend downward compared to pre-exposure, whereas PM is present2.5Drug exposure group (PM)2.5Compound group) no significant change in mouse heart rate compared to pre-exposure; by the Control-compound group (PM) and the clean air2.5Exposure placebo group (PM)2.5Placebo group) were analyzed statistically (t-test) and found to be very significantly different (P-0.009151 < 0.01), i.e., PM2.5Exposure of (a) negatively affected the heart rate impact of the mice; at the same time, by the pair of PM2.5Exposure placebo group (P)M2.5Placebo group) with PM, respectively2.5Drug exposure group (PM)2.5Compound group), clean air drug group (Control-Compound group) were statistically analyzed (t-test) and found: PM (particulate matter)2.5Exposure placebo group (PM)2.5Placebo group) was significantly different from the clean air-Compound group (P-0.014723 < 0.05), suggesting that PM2.5 exposure may lead to abnormal heart rate in mice, PM2.5Exposure placebo group (PM)2.5-Placebo group) with PM2.5Drug exposure group (PM)2.5Compound group) is significantly different (P0.018827 < 0.05), indicating that the composition is effective in improving PM2.5Exposure had an effect on heart rate in mice.
3. Detecting cardiac ultrasound indexes: pair PM of high-resolution small animal ultrasonic imaging system2.5Exposure placebo group (PM)2.5-Placebo group)、PM2.5Drug exposure group (PM)2.5Compound group) mouse to scan the long and short axes of the B-mode and generate the curve of the heart motion law and time of the mouse, analyze the curve data by a recorder to obtain the echocardiogram, manually and accurately measure the scanned heart echogram, and automatically recognize by software to obtain: the results of six sets of data, end diastole inner diameter (LVIDd), end diastole chamber interval (IVSd), end diastole rear wall thickness (LVPWd) and end systole inner diameter (LVIDs), end systole chamber Interval (IVSs), end systole rear wall thickness (LVPWs), are shown in fig. 4: PM (particulate matter)2.5Mice exposed to placebo had left ventricular end-systolic internal diameter (LVIDs) significantly greater than PM2.5The exposed drug group (P is less than 0.05) shows that the combined drug can effectively control PM2.5Abnormal contractile function of the myocardium resulting from exposure; PM2.5 after 12 weeks of PM exposure2.5Exposure to drug groups and PM2.5The EF and FS of the mice (shown in figure 5) are closer to the normal level of the mice compared with the exposed placebo group, and meanwhile, the EF and FS of the placebo group and the drug group are tested t, and have significant difference (P < 0.05), namely the PM is treated by the drug combination2.5The resulting heart failure has some inhibitory effect.
4. Detecting respiratory burst indexes: PM (particulate matter)2.5After 12 weeks of exposure, the hearts of 8 mice were randomly selected, immediately placed in liquid nitrogen for quick freezing, and then stored at-80 ℃; to measure the concentration level of Reactive Oxygen Species (ROS), hearts were ground in liquid nitrogen and then homogenized in pre-cooled PBS (tissue weight (g): PBS volume (mL): 1: 9) with the addition of protease inhibitors. The suspension was then sonicated on ice to further disrupt the cells. The homogenate was then centrifuged at 5000 Xg for 10min to obtain a heart supernatant. With reference to the ROS detection kit (chinese Beyotime biotech institute), the mouse heart supernatants were mixed with 2, 7-Dichlorofluorescein (DCFH) diacetate reagent and incubated at 37 ℃ in the dark, and finally the samples were analyzed three times at 450nm using a microplate reader (variaoskan LUX, Thermo Fisher Scientific, usa) with the results shown in fig. 3: control-placebo group (Control-placebo group) and PM2.5Exposure placebo group (PM)2.5Placebo group) with a very significant difference (P)10.0014 < 0.05), Control-compound group (PM) and PM2.5Drug exposure group (PM)2.5Compound group) there is a significant difference (P)20.0185 < 0.05), indicating PM2.5After exposure, the active oxygen content in the mouse body is obviously increased; at the same time, P2Much greater than P1It was found that the drug group had less variability than the placebo group, and it was concluded that the composition was in PM2.5Can inhibit the increase of active oxygen in mice during the exposure process.
Evaluation of HE staining and MASSON staining pathomorphology: the remaining 6 mouse hearts were used for tissue immunohistochemical analysis: embedding whole heart paraffin fixed in 4% paraformaldehyde, preparing section with thickness of 5 μm by longitudinal cutting, and respectively adding hematoxylin according to standard procedure&Eosin (H)&E) And Masson kit (ServiceBio) staining. Images of inflammatory cells and myocardial fibrosis were obtained under a microscope (DM6B, Leica Micro Systems inc., USA) with 20 × and 40 × as observation targets, respectively, and the results are shown in fig. 6: the cells in the drug group are arranged regularly and have no necrotic foci and the collagen fiber deposition among the cells is not obvious, while the myocardial cells in the placebo group are disordered and have necrotic foci, and large cells among cardiac cells appearCollagen fibril deposition, indicated by PM2.5After exposure, the left ventricle of the mouse shows a large amount of fibrosis, and the combined medicament can effectively improve the PM2.5Resulting in abnormal morphology of myocardial cells, inhibiting collagen deposition, reducing fibrosis, and reducing PM in mice2.5Risk of heart failure disease from exposure.
Example 8 synergistic Effect of A-and B-Components in combination
1. 40 mice (aged mice, 17 months old, purchased from Guangdong university of traditional Chinese medicine and having a weight of 18-22 g) of the same age group C57BJ/6 are selected and are placed in a standard breeding room for breeding (breeding temperature is 18-22 ℃, humidity is 45-55%, and breeding time is 12h day and night alternately). The mice were acclimated for 10 days before exposure and their physiological data such as heart rate were recorded in a natural state as a reference value. Followed by PM2.5Exposure experiments, the experimental procedure was as follows:
(1) mice were domesticated and divided into five groups (8 mice per group): PM (particulate matter)2.5Exposure placebo group (PM)2.5-Placebo group)、PM2.5Drug exposure group (PM)2.5Compound group), clean air Placebo group (Control-Placebo group), PM2.5Group of exposed drug A groups (PM)2.5-Compound-A group)、PM2.5Group of exposed drug B groups (PM)2.5-Compound-B group)。
(2) Firstly, mice are raised in an SPF laboratory animal raising room for one week and then transferred into an exposure box for raising: five groups of mice were placed in a real-time exposure system (as shown in figure 1), PM2.5Three groups of mice in the exposed group are introduced into the atmosphere of the Hongkong county on the same day; to reduce the effect of other variables, the atmosphere is passed through a small filter to filter out large particulate pollutants such as PM10And screening out the PM of the flood tunnel county on the same day2.5(ii) a The control experiment was carried out by introducing clean air filtered by a filter into the air of the mice in the clean air group, and the drugs were administered the next day, and then the drugs were administered every other day, as follows: the combined medicine of the embodiment 1 is prepared from 0.17328g A components (0.1728g taurine; 0.00048g coenzyme Q10)/Kg mice, 0.047856g B components (0.0264g alpha-linolenic acid; 0.006912g linoleic acid; 0.008784g eicosapentaenoic acid; 0.005 g76g docosahexaenoic acid)/Kg mice are respectively injected with PM at regular time every day by means of gastric lavage2.5Drug exposure group (PM)2.5Compound group), the a fraction of example 1 was taken as 0.17328g A fractions (0.1728g taurine; 0.00048g coenzyme Q10)/Kg mice are respectively injected with PM at regular time every day by means of stomach irrigation2.5Group of exposed drug A groups (PM)2.5Compound-a group), 0.047856g B component of example 1 (0.0264g α -linolenic acid; 0.006912g of linoleic acid; 0.008784g eicosapentaenoic acid; 0.00576g docosahexaenoic acid)/Kg mice are respectively injected with PM at regular time every day by means of gastric lavage2.5Group of exposed drug B groups (PM)2.5Compound-B group), for placebo group (PM)2.5Exposed placebo, clean air placebo) mice were injected daily at regular intervals with an equivalent dose of placebo (0.17328g water lactose, 0.047856g peanut oil) by gavage as a control.
(3) Assays for inflammatory factor (IL-1. beta., IL-6, TNF) and ROS indices were performed 12 weeks after exposure.
2. Detecting respiratory burst indexes: the concentration levels of Reactive Oxygen Species (ROS) and inflammatory cytokines in the heart were measured with reference to ROS detection kit (Beyotime Biotech institute, china) and ELISA kit (Sangon Biotech, shanghai, china), respectively: mixing the heart supernatant (preparation method refer to example 4) with 2, 7-Dichlorofluorescein (DCFH) diacetate reagent and incubation in the dark at 37 deg.C; the protein concentration in the supernatant was determined by the classical Bradford method using BSA as standard, 100ug of protein was used for assay to study the concentration of TNF-. alpha.MCP-1, intercellular adhesion molecule 1(ICAM-1, CD54), IL-6 and IL-1. beta. in the heart, and finally, the samples were analyzed three times at 450nm using a microplate reader (Varioskan LUX, Thermo Fisher Scientific, USA) to obtain the active oxygen content in the mice, as shown in FIG. 7 and Table 1: the component A, the component B and the composition can reduce PM2.5Concentration levels of Reactive Oxygen Species (ROS) and inflammatory cytokines in the hearts of mice after exposure, but combination of drugs on PM2.5The reduction degree (32.19 +/-7.171) of the inflammatory factor IL-1 beta in hearts of mice after exposure is larger than that of the A component and the B component for PM respectively2.5Sum of the reduction of the inflammatory factor IL-1 β in the heart of mice after exposure (20.5 + -7.171, 2 + -1.987); similarly, combination drug pairs for PM2.5After exposure, the reduction degree of inflammatory factors IL-6 and TNF-alpha in the heart of the mouse is larger than that of the component A and the component B to PM respectively2.5Sum of the reduction of inflammatory factors IL-6 and TNF- α in the heart of mice after exposure; as can be seen, the A component and the B component can achieve the synergistic effect by combined administration, and can effectively inhibit the mouse from causing PM2.5Abnormal increase of inflammatory factors and ROS caused by exposure, and effective reduction of PM2.5Exposure leading to cardiovascular disease risk.
TABLE 1 Effect of different treatments on reactive oxygen species and inflammatory factors in mouse hearts
Note: p < 0.001, P < 0.05 compared to the clean air placebo group.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A combination comprising: the combination drug comprises a component A and a component B, wherein the component A comprises the following components: taurine and coenzyme Q10; the component B comprises the following components: alpha-linolenic acid, linoleic acid, eicosapentaenoic acid and docosahexaenoic acid.
2. The combination of claim 1, wherein:
the component A comprises the following components in parts by weight: 194.4-712.8 parts of taurine and 0.54-1.98 parts of coenzyme Q10;
the component B comprises the following components in parts by weight: 29.7-108.9 parts of alpha-linolenic acid, 7.776-28.512 parts of linoleic acid, 9.882-36.234 parts of eicosapentaenoic acid and 6.48-23.76 parts of docosahexaenoic acid.
3. The combination as claimed in claim 2, wherein:
the component A comprises the following components in parts by weight: 216-648 parts of taurine and 0.6-1.8 parts of coenzyme Q10;
the component B comprises the following components in parts by weight: 33-99 parts of alpha-linolenic acid, 8.64-25.92 parts of linoleic acid, 10.98-32.94 parts of eicosapentaenoic acid and 7.2-21.6 parts of docosahexaenoic acid.
4. The combination according to claim 2 or 3, wherein:
the weight ratio of the component A to the component B is (1-13): 1.
5. the combination according to claim 4, wherein:
the component A and the component B also comprise pharmaceutically acceptable auxiliary materials.
6. The combination according to claim 4, wherein:
the administration mode of the combination drug is that the component A and the component B are administered simultaneously, separately or sequentially.
7. Use of a combination according to any one of claims 1 to 5 for the preparation of a medicament for the prevention and/or treatment of cardiovascular diseases.
8. Use according to claim 7, characterized in that: the cardiovascular disease is PM2.5Cardiovascular diseases caused by pollution.
The use of a combination of component a and component B for the manufacture of a medicament for the prevention and/or treatment of cardiovascular disease; the method is characterized in that: the component A comprises the following components: taurine and coenzyme Q10; the component B comprises the following components: alpha-linolenic acid, linoleic acid, eicosapentaenoic acid and docosahexaenoic acid.
10. Use according to claim 9, characterized in that: the component A comprises the following components in parts by weight: 194.4-712.8 parts of taurine and 0.54-1.98 parts of coenzyme Q10; the component B comprises the following components in parts by weight: 29.7-108.9 parts of alpha-linolenic acid, 7.776-28.512 parts of linoleic acid, 9.882-36.234 parts of eicosapentaenoic acid and 6.48-23.76 parts of docosahexaenoic acid;
preferably, the weight ratio of the component A to the component B is (1-13): 1.
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