Application of a Traditional Chinese Medicine Composition in the Preparation of a Drug for Treating Myocardial Infarction Complicated with Acute Kidney Injury

Abstract

This invention discloses the application of a traditional Chinese medicine composition in the preparation of a drug for treating myocardial infarction complicated with acute kidney injury, specifically relating to the field of biomedical technology. The traditional Chinese medicine composition is a preparation made from Danshen (Salvia miltiorrhiza), Baishao (Paeonia lactiflora), Yujin (Curcuma longa), Ciwujia (Acanthopanax senticosus), and Shanzha (Crataegus pinnatifida) as raw materials, plus pharmaceutically acceptable excipients. Xinshubao tablets have a good therapeutic effect on myocardial infarction complicated with acute kidney injury, and can alleviate the acute kidney injury caused by renal tubular thinning, severe dilation, epithelial cell shedding, and inflammatory cell infiltration. The preparation of Xinshubao tablets as a drug for treating myocardial infarction complicated with acute kidney injury offers broad application prospects.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, specifically to the application of Xinshubao tablets in the preparation of a drug for treating myocardial infarction complicated with acute kidney injury. Background Technology

[0002] Patients with myocardial infarction complicated by acute kidney injury not only exhibit the primary manifestations of acute myocardial infarction and renal insufficiency, but also often have advanced age, long-term metabolic diseases (such as hypertension and diabetes), and electrolyte disturbances and vascular endothelial damage caused by long-term renal insufficiency, making their clinical characteristics more complex. Patients with both myocardial infarction and renal failure often respond poorly to medications and are prone to functional damage to other organs; therefore, advanced life support technology is extremely important for the treatment of these patients.

[0003] Xinshubao tablets are composed of Danshen (Salvia miltiorrhiza), Baishao (Paeonia lactiflora), Yujin (Curcuma longa), Ciwujia (Acanthopanax senticosus), and Shanzha (Crataegus pinnatifida). Danshen invigorates blood circulation, removes blood stasis, clears the heart, and relieves irritability; Yujin invigorates blood circulation, relieves pain, regulates qi, and alleviates depression; Baishao nourishes blood, astringes yin, softens the liver, and relieves pain; Ciwujia invigorates qi, strengthens the spleen, tonifies the kidneys, and calms the mind; Shanzha regulates qi, disperses blood stasis, and lowers lipids. The combined effects of these herbs are to invigorate blood circulation, remove blood stasis, invigorate qi, and relieve pain. Clinically, it is mainly used to treat coronary heart disease, chest tightness and angina pectoris caused by qi deficiency and blood stasis, as well as hypertension, hyperlipidemia, and arteriosclerosis.

[0004] It is rare for medications used to treat myocardial infarction to be combined with treatment for acute kidney injury. Currently, in clinical practice, Western medicines such as trimetazidine and captopril are often used for myocardial infarction complicated with acute kidney injury. Captopril itself has a nephroprotective effect, while trimetazidine may indirectly protect kidney function only in the preventive use of certain cardiac surgeries. However, the use of Western medicine to treat myocardial infarction complicated with acute kidney injury often carries the risk of hyperkalemia. Chinese Patent CN116726124A discloses a traditional Chinese medicine composition for treating myocardial infarction, its preparation method, and its application. The composition, by weight, comprises: 10-20 parts Coptis chinensis, 9-15 parts Pinellia ternata, 15-30 parts Trichosanthes kirilowii, 5-15 parts Cinnamomum cassia, 9-30 parts Allium macrostemon, 5-15 parts Citrus aurantium, 5-30 parts Astragalus membranaceus, 6-15 parts Curcuma zedoaria, and 15-30 parts Salvia miltiorrhiza. Although this traditional Chinese medicine composition shows good efficacy against myocardial infarction, subsequent experiments have verified that it is ineffective in treating myocardial infarction complicated with acute kidney injury.

[0005] There are currently no research studies on the application of Xinshubao tablets in myocardial infarction complicated with acute kidney injury. Summary of the Invention

[0006] Therefore, this invention provides the application of Xinshubao tablets in the preparation of a drug for treating myocardial infarction complicated with acute kidney injury, in order to solve the problems in the prior art.

[0007] To achieve the above objectives, the present invention provides the following technical solution:

[0008] According to a first aspect of the present invention, a traditional Chinese medicine composition is used in the preparation of a medicament for treating myocardial infarction complicated with acute kidney injury. The traditional Chinese medicine composition is a preparation made from raw materials of Salvia miltiorrhiza, Paeonia lactiflora, Curcuma longa, Acanthopanax senticosus and Crataegus pinnatifida, plus pharmaceutically acceptable excipients.

[0009] Furthermore, the traditional Chinese medicine composition includes 100-300 parts of Salvia miltiorrhiza, 1000-3000 parts of Paeonia lactiflora, 150-450 parts of Curcuma longa, 500-1500 parts of Acanthopanax senticosus, and 1000-3000 parts of Crataegus pinnatifida.

[0010] As an example, preferably, the composition contains 150-250 parts of Salvia miltiorrhiza, 1500-2500 parts of Paeonia lactiflora, 200-400 parts of Curcuma longa, 700-1300 parts of Acanthopanax senticosus, and 1500-2500 parts of Crataegus pinnatifida. More preferably, the composition contains 200 parts of Salvia miltiorrhiza, 2000 parts of Paeonia lactiflora, 300 parts of Curcuma longa, 1000 parts of Acanthopanax senticosus, and 2000 parts of Crataegus pinnatifida.

[0011] Furthermore, the drug is used to simultaneously improve cardiac function damage following myocardial infarction and renal dysfunction caused by acute kidney injury.

[0012] Furthermore, the drug is a traditional Chinese medicine composition that improves renal blood flow.

[0013] Furthermore, the drug is a traditional Chinese medicine composition that inhibits myocardial cell apoptosis and renal tubular epithelial cell shedding.

[0014] Furthermore, the drug reduces serum creatinine (CREA) and blood urea nitrogen (BUN) levels.

[0015] Furthermore, the drug regulates the expression of inflammatory factors such as TNF-α, IL-6, and IL-1β.

[0016] Furthermore, the myocardial infarction complicated with acute kidney injury is classified as cardiorenal syndrome (CRS) Type 1.

[0017] Furthermore, the formulation is an oral formulation; as an example, tablets are preferably Xinshubao tablets.

[0018] Furthermore, the pharmaceutically acceptable excipients include at least one of the following: fillers, disintegrants, binders, lubricants, flavoring agents, pH adjusters, antioxidants, or sterile solvents.

[0019] As an example, the clinically equivalent dose is preferred as the dosage in Xinshubao tablets.

[0020] The present invention has the following advantages:

[0021] Animal experiments conducted according to this invention demonstrate that Xinshubao tablets have a good therapeutic effect on myocardial infarction complicated with acute kidney injury, and can alleviate the acute kidney injury caused by renal tubular thinning, severe dilation, epithelial cell shedding, and inflammatory cell infiltration. This provides a broad application prospect for the preparation of Xinshubao tablets as a drug for treating myocardial infarction complicated with acute kidney injury. Attached Figure Description

[0022] To more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are merely exemplary, and those skilled in the art can derive other embodiments based on the provided drawings without creative effort.

[0023] The structures, proportions, sizes, etc. illustrated in this specification are only for the purpose of assisting those skilled in the art in understanding and reading the content disclosed herein, and are not intended to limit the conditions under which the present invention can be implemented. Therefore, they have no substantial technical significance. Any modifications to the structure, changes in the proportions, or adjustments to the size, without affecting the effects and objectives that the present invention can produce, should still fall within the scope of the technical content disclosed in the present invention.

[0024] Figure 1 The kidney tissue pathological staining (20x) provided for the experimental examples of this invention is shown in the figure. A is the sham-operated group, B is the model group, C is the low-dose Xinshubao tablet group, D is the medium-dose Xinshubao tablet group, E is the high-dose Xinshubao tablet group, and F is the trimetazidine group. The length unit in the lower right corner of the figure is 50 μm.

[0025] Figure 2 The expression level of serum CREA provided in the experimental examples of this invention, wherein *P<0.05 vs sham, **P<0.01 vs model;

[0026] Figure 3 The expression levels of serum BUN provided in the experimental examples of this invention are shown in the figures, where *P<0.05 vs sham, **P<0.01 vs model, and ***P<0.001 vs model.

[0027] Figure 4 The expression levels of serum TNF-α provided in the experimental examples of this invention are shown in the figures. *P<0.05 vs sham, *P<0.05 vs model, **P<0.01 vs model, ***P<0.001 vs model.

[0028] Figure 5 The expression levels of serum IL-6 provided in the experimental examples of this invention are shown in the figures, where *P<0.05 vs sham, **P<0.01 vs model, and ***P<0.001 vs model.

[0029] Figure 6 The expression level of serum IL-1β provided in the experimental examples of this invention, wherein, **P<0.01 vs sham, **P<0.01 vs model;

[0030] Figure 7 The ejection fraction of the rat heart provided in the experimental examples of this invention;

[0031] Figure 8 The expression level of NT-proBNP in rat serum provided for experimental examples of this invention. Detailed Implementation

[0032] The following specific embodiments illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0033] Example 1

[0034] This embodiment provides a Xinshubao tablet:

[0035] Salvia miltiorrhiza 200 parts, Paeonia lactiflora 2000 parts, Curcuma longa 300 parts, Acanthopanax senticosus 1000 parts, Crataegus pinnatifida 2000 parts.

[0036] Xinshubao tablets were prepared by adding pharmaceutical fillers, disintegrants, binders, lubricants, flavoring agents, pH adjusters, and antioxidants using conventional tableting methods.

[0037] Example 2

[0038] This embodiment provides a Xinshubao tablet:

[0039] Salvia miltiorrhiza 100 parts, Paeonia lactiflora 1000 parts, Curcuma longa 150 parts, Acanthopanax senticosus 500 parts, Crataegus pinnatifida 3000 parts.

[0040] Everything else is the same as in Example 1.

[0041] Example 3

[0042] This embodiment provides a Xinshubao tablet:

[0043] Salvia miltiorrhiza 300 parts, Paeonia lactiflora 3000 parts, Curcuma longa 450 parts, Acanthopanax senticosus 1500 parts, Crataegus pinnatifida 1000 parts.

[0044] Everything else is the same as in Example 1.

[0045] Comparative Example

[0046] This comparative example does not add the drug of Example 1, but uses equal amounts of pharmaceutical fillers, disintegrants, binders, lubricants, flavoring agents, pH adjusters, and antioxidants to prepare a placebo group using conventional tableting methods.

[0047] Experimental Example 1

[0048] This experimental example demonstrates the application of the Xinshubao tablets prepared in Example 1 in the preparation of a drug for treating myocardial infarction complicated with acute kidney injury:

[0049] (a) Methods

[0050] 1. Laboratory animals

[0051] One hundred and forty-four male SD rats, SPF grade, weighing 200±10g, were purchased from Peking University School of Medicine. They were housed in the SPF-grade animal laboratory of the Medical Experimental Center of the China Academy of Chinese Medical Sciences. The entire experiment was conducted under constant temperature (23±1℃) and constant humidity (50-85%) conditions. All experiments were approved by the Animal Ethics Committee of the Medical Experimental Center of the China Academy of Chinese Medical Sciences (No. ERCC-ACMS21-2201-01). The rats were fed standard diets with free access to water and food, and underwent acclimatization for 3-5 days.

[0052] 2. Establishment of a model of myocardial infarction complicated with acute kidney injury

[0053] Rats were randomly divided into a sham group and a model group using a random number table. A rat model of myocardial infarction complicated with acute kidney injury was established using a combination of laboratory and literature methods (method reference: Chinese Patent CN114469427A). Rats were anesthetized with intraperitoneal injection of 1% sodium pentobarbital (50 mg / kg), intubated, and connected to a ventilator. The rats were placed in a right lateral decubitus position. The thoracic cavity was opened between the third and fourth ribs using microscissors to fully expose the heart and the area containing the left anterior descending coronary artery (LAD). A needle was inserted 2 mm below the lower edge of the left atrial appendage to ligate the LAD. The thoracic cavity and skin were sutured. In the sham group, only the heart was exposed, without ligation. Sixty rats with successful model establishment underwent subsequent experiments.

[0054] The model group consisted of 60 animals; the sham surgery group consisted of 10 animals.

[0055] In the sham-operated group, the renal interstitium, renal tubules, and glomeruli showed basically normal tissue structures with neatly arranged cells and no pathological changes such as tubular dilation, degeneration, or necrosis. In the model group, the glomeruli in the kidney tissue were basically normal in morphology, but pathological changes such as thinning of the renal tubular walls, severe dilation, epithelial cell shedding, and inflammatory cell infiltration were observed.

[0056] 3. Grouping

[0057] The rats in the model group were randomly divided into a model control group (Model), a low-dose Xinshubao tablet group (XSB_L), a medium-dose Xinshubao tablet group (XSB_M), a high-dose Xinshubao tablet group (XSB_H), a trimetazidine group (TMZ), and a captopril group (Cap), with 10 rats in each group.

[0058] 4. Administration

[0059] The dosage for rats was calculated based on the conversion of human and rat body surface areas. The clinically equivalent dose (using Xinshubao tablets from Example 1 as the experimental formulation) was used as the median dose of Xinshubao tablets (0.18 g·kg). -1 ·d -1 The effective dose was increased by two times as the high dose of Xinshubao tablets (0.36 g·kg). -1 ·d -1 The effective dose was reduced by two times as the low dose of Xinshubao tablets (0.09 g·kg). -1 ·d -1 Trimetazidine group (6.3 mg·kg) -1 ·d -1 ), captopril group (4.875 mg·kg) -1 ·d -1 Prepare suspensions of appropriate concentrations. Rats in each group were administered the corresponding drugs by gavage, while the sham-operated group and the model control group were administered an equal volume of placebo by gavage, once daily. The gavage was continued for 4 weeks (w) from the start of myocardial infarction (MI) modeling.

[0060] 5. HE staining

[0061] Four weeks later, the frozen kidney tissue was embedded and sectioned, and dewaxed to water. The sections were then stained sequentially with hematoxylin, differentiation solution, blue solution, 85% ethanol, and 95% ethanol, and finally stained with eosin. The sections were mounted with neutral resin. Observation and photography were performed using a panoramic scanner with a digital slide system.

[0062] 6. ELISA detection of CREA and BUN expression

[0063] Four weeks after modeling, using the CREA and BUN ELISA kits, the wells were incubated with standards and test samples at 37°C for 60 min, followed by 50 μL of biotin antibody working solution and incubation at 37°C for 45 min. The wells were then washed three times with 350 μL of washing buffer for 2 min each time. Next, 100 μL of enzyme conjugate working solution was added, and the plates were covered and incubated at 37°C for 30 min. The plates were then washed five times with washing buffer for 2 min each time, followed by 90 μL of substrate solution and incubation at 37°C in the dark for 15 min. Finally, 50 μL of stop solution was added, and the absorbance of each well was measured at 450 nm using a microplate reader within 5 min.

[0064] 7. ELISA was used to detect the expression of serum NT-proBNP, IL-1β, IL-6, and TNF-α.

[0065] Using an ELISA kit for NT-proBNP, IL-1β, IL-6, and TNF-α, the wells were incubated with standards and test samples at 37°C for 60 min. Then, 50 μL of biotin antibody working solution was added, and the plate was incubated at 37°C for 45 min. The plate was then washed three times with 350 μL of washing buffer for 2 min each time. Next, 100 μL of enzyme conjugate working solution was added, and the plate was covered and incubated at 37°C for 30 min. The plate was then washed five times with washing buffer for 2 min each time, and then 90 μL of substrate solution was added. The plate was incubated at 37°C in the dark for 15 min. Finally, 50 μL of stop solution was added, and the absorbance of each well was measured at 450 nm using a microplate reader within 5 min.

[0066] 8. Echocardiography to assess cardiac function

[0067] Rats were fixed in a supine position on the operating table and anesthetized with 1% isoflurane. Echocardiographic parameters were recorded using M-mode ultrasound in the parasternal short-axis view, with the level of the left ventricular papillary muscles as a landmark. Ventricular wall motion images were recorded using B-mode echocardiography in the parasternal long-axis view, with the level of the left ventricular outflow tract as a landmark. Cardiac function was observed in the rats for 4 weeks.

[0068] 9. Statistical methods

[0069] Statistical analysis was performed using GraphPad Prism 8.0, and data are expressed as mean ± standard deviation (x±s). One-way ANOVA was used if the data were normally distributed and homogeneous in variance; otherwise, the rank-sum test was used. A p-value < 0.05 was considered statistically significant.

[0070] (II) Results

[0071] 1. Effects of Xinshubao tablets on the histopathology of rat kidney tissue

[0072] Depend on Figure 1Histopathological staining of kidney tissue revealed that in the low-dose group of Xinshubao tablets, the glomerular morphology was basically normal, but pathological changes such as severe tubular dilation, epithelial cell shedding, and inflammatory cell infiltration were still observed. In the medium-dose group of Xinshubao tablets, the glomerular morphology was basically normal, and the tubular dilation was reduced compared with the model group, but a small number of tubular dilations were still observed, and localized tubular epithelial cell shedding was also observed. In the high-dose group of Xinshubao tablets, the glomerular morphology was basically normal, and the tubular dilation was significantly reduced, with only occasional tubular epithelial cell shedding. In the trimetazidine group, the glomerular morphology was basically normal, but pathological changes such as tubular dilation, thinning of the tubular wall, and inflammatory cell infiltration were still observed.

[0073] 2. Serum creatinine (CREA) and blood urea nitrogen (BUN) expression levels

[0074] Depend on Figure 2 and Figure 3 The results showed that ELISA detection of serum CREA and BUN expression levels in each group of rats significantly increased creatinine and urea nitrogen expression in the model group compared with the sham-operated group (P<0.05). Compared with the model group, the high- and medium-dose groups of Xinshubao tablets and the captopril group significantly decreased creatinine and urea nitrogen expression (P<0.01, P<0.001). Trimetazidine had little effect on serum creatinine CREA and urea nitrogen (BUN) expression levels and had little therapeutic effect on acute renal failure. However, it is mainly used for myocardial infarction. Indicators related to myocardial infarction need to be compared with those of trimetazidine, and indicators related to acute renal failure need to be compared with those of captopril.

[0075] 3. Changes in serum IL-6, IL-1β, and TNF-α expression

[0076] Depend on Figure 4-6 It was found that, compared with the sham-operated group, the expression of IL-6, IL-1β, and TNF-α in the serum of rats in the model group was significantly increased (P < 0.05, P < 0.01). Compared with the model group, both the low-dose and medium-dose groups of Xinshubao tablets could reduce the expression of IL-6 and TNF-α (P < 0.05, P < 0.01, P < 0.001), with the medium-dose group of Xinshubao tablets also reducing the expression of IL-1β (P < 0.01). Trimetazidine only reduced the expression of IL-6 and TNF-α (P < 0.01, P < 0.001). This indicates that both the medium-dose group of Xinshubao tablets and trimetazidine can reduce the expression of inflammatory factors to some extent, with the medium-dose group of Xinshubao tablets showing better results.

[0077] This invention demonstrates that both medium and high doses of Xinshubao tablets can reduce serum creatinine and blood urea nitrogen in mice with myocardial infarction complicated by acute kidney injury, and can significantly reduce the expression of IL-6, IL-1β, and TNF-α, thus reducing kidney damage. The medium-dose group significantly reduced the expression of IL-6, IL-1β, and TNF-α in mice with myocardial infarction complicated by acute kidney injury, reducing kidney damage. However, the low-dose group had no significant effect on reducing IL-1β. Combined with HE staining, the low-dose group showed a significantly lower therapeutic effect on kidney tissue than the medium and high doses. Other experiments in this invention, such as serum creatinine and blood urea nitrogen, were conducted using medium and high doses of Xinshubao tablets.

[0078] 4. Results of cardiac function in rats

[0079] Cardiac function in rats was analyzed using echocardiography (e.g., Figure 7 As shown in the figure, compared with the sham-operated group, the ejection fraction (EF) in the model group was significantly reduced (P < 0.001). However, compared with the model group, the medium- and high-dose groups of Xinshubao tablets and the trimetazidine group significantly increased the EF level (P < 0.01, P < 0.001). These results further demonstrate that the myocardial infarction model was successfully established, and that both Xinshubao tablets and trimetazidine effectively improved cardiac function and related indicators in rats with decreased cardiac function.

[0080] 5. Serum NT-proBNP expression level

[0081] ELISA was used to detect the expression level of NT-proBNP in rat serum. Compared with the sham-operated group, the expression of NT-proBNP in the serum of rats in the model group was significantly higher (P<0.001). The low-dose, medium-dose, and high-dose groups of Xinshubao tablets and the trimetazidine group all significantly reduced the expression of NT-proBNP (P<0.001), indicating that both Xinshubao tablets and trimetazidine can improve the levels of myocardial injury markers (such as...). Figure 8 (As shown).

[0082] In conclusion, the medium dose of Xinshubao tablets has a good therapeutic effect on myocardial infarction complicated with acute kidney injury.

[0083] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. The application of a traditional Chinese medicine composition in the preparation of a medicament for treating myocardial infarction complicated with acute kidney injury, characterized in that, The drug is a preparation made from a traditional Chinese medicine composition using Danshen, Baishao, Yujin, Ciwujia and Hawthorn as raw materials, plus pharmaceutically acceptable excipients; The raw materials of the traditional Chinese medicine composition are: 100-300 parts of Salvia miltiorrhiza, 1000-3000 parts of Paeonia lactiflora, 150-450 parts of Curcuma longa, 500-1500 parts of Acanthopanax senticosus, and 1000-3000 parts of Crataegus pinnatifida.

2. The application according to claim 1, characterized in that, The traditional Chinese medicine composition is used to simultaneously improve cardiac function damage after myocardial infarction and renal dysfunction caused by acute kidney injury.

3. The application according to claim 1, characterized in that, The aforementioned traditional Chinese medicine composition is a traditional Chinese medicine composition that inhibits the shedding of renal tubular epithelial cells.

4. The application according to claim 1, characterized in that, The traditional Chinese medicine composition is a composition that reduces serum creatinine (CREA) and blood urea nitrogen (BUN) levels.

5. The application according to claim 1, characterized in that, The traditional Chinese medicine composition is a traditional Chinese medicine composition that regulates the expression of inflammatory factors such as TNF-α, IL-6, and IL-1β.

6. The application according to claim 1, characterized in that, The preparation is an oral preparation.

7. The application according to claim 6, characterized in that, The preparation is Xinshubao tablets.

8. The application according to claim 1, characterized in that, The pharmaceutically acceptable excipients include at least one of the following: fillers, disintegrants, binders, lubricants, flavoring agents, pH adjusters, antioxidants, or sterile solvents.

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