Application of traditional Chinese medicine composition in preparation of medicine for treating myocardial infarction complicated with acute kidney injury

Abstract

The invention discloses application of a traditional Chinese medicine composition in preparation of a medicine for treating myocardial infarction complicated with acute kidney injury, and particularly relates to the technical field of biological medicine. The traditional Chinese medicine composition is a preparation prepared by taking salvia miltiorrhiza, radix paeoniae alba, radix curcumae, acanthopanax and hawthorn as raw material medicines and adding pharmaceutically acceptable auxiliary materials. The Xinshubao tablet has a good treatment effect on myocardial infarction and acute kidney injury, and can relieve the combined acute kidney injury caused by the pathologies such as tube wall thinning, serious expansion, epithelial cell exfoliation and inflammatory cell infiltration of renal tubules. The Xinshubao tablet is used for preparing the medicine for treating myocardial infarction complicated with acute kidney injury, and a wide application prospect is provided.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to the use of Xinshubao tablets in preparing a medicine for treating myocardial infarction combined with acute kidney injury. Background Art

[0002] Patients with myocardial infarction and acute kidney injury not only present with the primary manifestations of acute myocardial infarction and renal insufficiency, but also often have advanced age, chronic metabolic diseases (such as hypertension and diabetes), and electrolyte imbalances and endothelial damage caused by long-term renal insufficiency, further complicating their clinical features. Patients with combined myocardial infarction and renal failure often respond poorly to medications and are prone to developing functional impairment in other organs. Advanced life support technologies are crucial for the treatment of these patients.

[0003] Xinshubao tablets are composed of salvia miltiorrhiza, white peony root, curcuma, acanthopanax senticosus, and hawthorn fruit. Salvia miltiorrhiza promotes blood circulation, dispels blood stasis, and clears the heart, alleviating restlessness. Curcuma promotes blood circulation, relieves pain, and promotes qi circulation to relieve depression. White peony root nourishes blood, consolidates yin, softens the liver, and relieves pain. Acanthopanax senticosus invigorates qi, strengthens the spleen, nourishes the kidneys, and calms the mind. Hawthorn fruit promotes qi circulation, disperses blood stasis, and clears turbidity and reduces lipids. The combined effects of these herbs promote blood circulation, dissipate blood stasis, and invigorate qi and relieve pain. Currently, this tablet is primarily used clinically to treat coronary heart disease, chest tightness and angina pectoris caused by qi deficiency and blood stasis, as well as hypertension, arteriosclerosis, and hyperlipidemia.

[0004] It is rare to find drugs that can treat myocardial infarction and acute kidney injury. Currently, Western medicines such as trimetazidine and captopril are often used in clinical treatment of myocardial infarction combined with acute kidney injury. Captopril itself has a renal protective effect, while trimetazidine may only indirectly protect renal function in preventive medication during specific cardiac surgery. However, Western medicine treatment of myocardial infarction combined with acute kidney injury is often accompanied by the risk of hyperkalemia. Chinese patent CN116726124A, a traditional Chinese medicine composition for treating myocardial infarction, its preparation method and application, the traditional Chinese medicine composition for treating myocardial infarction, the raw materials of which are calculated by mass: 10-20 parts of coptis chinensis, 9-15 parts of pinellia ternata, 15-30 parts of whole trichosanthes kirilowii, 5-15 parts of cinnamon twig, 9-30 parts of allium macrostemon, 5-15 parts of immature bitter orange, 5-30 parts of raw astragalus, 6-15 parts of zedoaria, and 15-30 parts of salvia miltiorrhiza; although the traditional Chinese medicine composition has a good effect on myocardial infarction, subsequent experiments have verified that the traditional Chinese medicine composition is not effective in treating myocardial infarction combined with acute kidney injury.

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

[0006] To this end, the present invention provides the use of Xinshubao tablets in the preparation of a medicament for treating myocardial infarction combined with acute kidney injury, so as to solve the problems in the prior art.

[0007] In order to achieve the above object, the present invention provides the following technical solutions: According to the first aspect of the present invention, a traditional Chinese medicine composition is provided for use in preparing a drug for treating myocardial infarction combined with acute kidney injury. The traditional Chinese medicine composition is a preparation prepared with salvia miltiorrhiza, white peony root, turmeric, acanthopanax senticosus and hawthorn as raw materials, and pharmaceutically acceptable excipients.

[0008] Furthermore, the Chinese medicine composition includes 100-300 parts of salvia miltiorrhiza, 1000-3000 parts of white peony root, 150-450 parts of turmeric, 500-1500 parts of acanthopanax senticosus, and 1000-3000 parts of hawthorn.

[0009] As an example, preferably, the composition contains 150-250 parts of Danshen, 1500-2500 parts of Baishao, 200-400 parts of Curcuma, 700-1300 parts of Acanthopanax, and 1500-2500 parts of Crataegus pinnatifida, respectively. More preferably, the composition contains 200 parts of Danshen, 2000 parts of Baishao, 300 parts of Curcuma, 1000 parts of Acanthopanax, and 2000 parts of Crataegus pinnatifida, respectively.

[0010] Furthermore, the drug is used to simultaneously improve cardiac function damage after myocardial infarction and renal dysfunction caused by acute kidney injury.

[0011] Furthermore, the medicine is a traditional Chinese medicine composition for improving renal blood flow.

[0012] Furthermore, the drug is a traditional Chinese medicine composition that inhibits myocardial cell apoptosis and renal tubular epithelial cell shedding.

[0013] Furthermore, the drug reduces serum creatinine CREA and urea nitrogen BUN levels.

[0014] Furthermore, the drug regulates the expression of inflammatory factors such as TNF-α, IL-6, and IL-1β.

[0015] Furthermore, the myocardial infarction combined with acute kidney injury is cardiorenal syndrome (CRS) Type 1.

[0016] Furthermore, the preparation is an oral preparation. As an example, the preferred tablet is Xinshubao tablet.

[0017] Furthermore, the pharmaceutically acceptable excipients include at least one of a filler, a disintegrant, a binder, a lubricant, a flavoring agent, a pH regulator, an antioxidant, or a sterile solvent.

[0018] As an example, a clinically equivalent dose is preferred as the dose in Xinshubao tablets.

[0019] The present invention has the following advantages: Animal experiments conducted in the present invention demonstrate that Xinshubao tablets have a beneficial therapeutic effect on myocardial infarction complicated by acute kidney injury, alleviating acute kidney injury caused by pathological changes in the renal tubules, such as thinning of the tubular wall, severe dilation, epithelial cell shedding, and inflammatory cell infiltration. This provides broad application prospects for the preparation of Xinshubao tablets as a drug for treating myocardial infarction complicated by acute kidney injury. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] To more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for the embodiments or the description of the prior art. Obviously, the drawings described below are merely exemplary, and those skilled in the art can derive other implementation drawings based on the provided drawings without inventive effort.

[0021] The structures, proportions, sizes, etc. illustrated in this specification are intended only to complement the contents disclosed herein and to facilitate understanding and reading by persons familiar with the art. They are not intended to limit the conditions under which the present invention may be implemented and therefore have no substantive technical significance. Any structural modifications, changes in proportions, or adjustments in sizes, without affecting the efficacy and objectives of the present invention, shall still fall within the scope of the technical contents disclosed herein.

[0022] Figure 1 Pathological tissue staining of kidney tissue provided in the experimental examples of the present invention (20x), wherein A is the sham operation 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; Figure 2 The expression levels of serum CREA provided in the experimental examples of the present invention, where *P<0.05 vs sham, **P<0.01 vs model; Figure 3 The expression levels of serum BUN provided in the experimental examples of the present invention, where *P<0.05 vs sham, **P<0.01 vs model, ***P<0.001 vs model; Figure 4 The expression levels of serum TNF-α provided in the experimental examples of the present invention, where *P<0.05 vs sham, *P<0.05 vs model, **P<0.01 vs model, ***P<0.001 vs model; Figure 5The expression levels of serum IL-6 provided in the experimental examples of the present invention, where *P<0.05 vs sham, **P<0.01 vs model, ***P<0.001 vs model; Figure 6 The expression levels of serum IL-1β provided in the experimental examples of the present invention, where **P<0.01 vs sham, **P<0.01 vs model; Figure 7 The ejection fraction of the rat heart provided in the experimental examples of the present invention; Figure 8 The expression level of NT-proBNP in rat serum provided in the experimental examples of the present invention. DETAILED DESCRIPTION

[0023] The following describes the implementation of the present invention using specific embodiments. Those skilled in the art will readily understand the other advantages and benefits of the present invention from the disclosure herein. Obviously, the embodiments described are only a portion of the present invention, not all of it. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without inventive effort are intended to fall within the scope of protection of the present invention.

[0024] Example 1 This embodiment provides a Xinshubao tablet: 200 parts of Salvia miltiorrhiza, 2000 parts of white peony root, 300 parts of Curcuma aromatica, 1000 parts of Acanthopanax senticosus, and 2000 parts of Crataegus.

[0025] Pharmaceutical fillers, disintegrants, adhesives, lubricants, flavoring agents, pH regulators, and antioxidants are added to prepare Xinshubao tablets by a conventional tableting method.

[0026] Example 2 This embodiment provides a Xinshubao tablet: 100 parts of Salvia miltiorrhiza, 1000 parts of white peony roots, 150 parts of Curcuma aromatica, 500 parts of Acanthopanax senticosus, and 3000 parts of Crataegus.

[0027] Other details are the same as those in Example 1.

[0028] Example 3 This embodiment provides a Xinshubao tablet: 300 parts of Salvia miltiorrhiza, 3000 parts of white peony root, 450 parts of Curcuma aromatica, 1500 parts of Acanthopanax senticosus, and 1000 parts of Crataegus.

[0029] Other details are the same as those in Example 1.

[0030] Comparative Example In this comparative example, the drug of Example 1 was not added, and only equal amounts of pharmaceutical fillers, disintegrants, binders, lubricants, flavoring agents, pH regulators, and antioxidants were used to prepare a placebo group by conventional tableting method.

[0031] Experimental Example 1 This experimental example provides the use of Xinshubao tablets prepared in Example 1 in the preparation of a drug for treating myocardial infarction combined with acute kidney injury: 1. Methods 1. Experimental Animals 144 male Sprague-Dawley rats, SPF grade, weighing 200 ± 10 g, were purchased from Peking University Health Science Center. They were housed in the SPF animal laboratory of the Experimental Medical Center of the China Academy of Chinese Medical Sciences. The experiments were conducted under constant temperature (23 ± 1°C) and humidity (50–85%). All experiments were approved by the Animal Ethics Committee of the Experimental Medical Center of the China Academy of Chinese Medical Sciences (No. ERCC-ACMS21-2201-01). Rats were fed a standard diet with free access to food and water and were acclimated for 3–5 days.

[0032] 2. Establishment of Myocardial Infarction Combined with Acute Kidney Injury Model A randomized control group (RCT) was used to randomly divide the rats into a sham group (Sham) and a model group (Model). A rat model of myocardial infarction combined with acute kidney injury was established using laboratory methods combined with literature (referring to Chinese Patent CN114469427A). Rats were anesthetized with 1% sodium pentobarbital (50 mg / kg) intraperitoneally, intubated, and connected to a ventilator. The rats were placed in the right lateral decubitus position. The chest cavity was opened between the third and fourth intercostal spaces using microscissors to fully expose the heart and the left anterior descending coronary artery (LAD). A needle was inserted 2 mm below the inferior edge of the left atrial appendage and the LAD was ligated. The chest cavity and skin were sutured. In the sham group, only the heart was exposed without ligation. Sixty rats with successfully established RCTs were used for subsequent experiments.

[0033] There were 60 rats in the model group and 10 rats in the sham operation group.

[0034] In the sham-operated group, the renal interstitial tissue, renal tubules, and glomeruli were essentially normal, with neatly arranged cells and no pathological changes such as tubular dilatation, degeneration, or necrosis. In the model group, the glomerular morphology was essentially normal, but pathological changes such as thinning and severe dilatation of the tubular wall, epithelial cell desquamation, and inflammatory cell infiltration were observed.

[0035] 3. Grouping The rats in the model group were randomly divided into model control group (Model), Xinshubao tablets low-dose group (XSB_L), Xinshubao tablets medium-dose group (XSB_M), Xinshubao tablets high-dose group (XSB_H), trimetazidine group (TMZ), and captopril group (Cap), with 10 rats in each group.

[0036] 4. Medication The rat dosage was calculated based on the body surface area of ​​humans and rats, and the clinical equivalent dose (using Xinshubao tablets in Example 1 as the experimental preparation) was used as the medium dose of Xinshubao tablets (0.18 g·kg -1 ·d -1 ), increase the equivalent dose by two times as the high dose of Xinshubao tablets (0.36 g·kg -1 ·d -1 ), reducing the equivalent dose 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 corresponding concentrations. Rats in each group were gavaged with the corresponding drugs, while the sham-operated group and the model control group were gavaged with an equal volume of placebo once daily for 4 weeks (w) starting from the establishment of myocardial infarction (MI) model.

[0037] 5. HE staining After four weeks, the frozen kidney tissue was embedded and sectioned, dewaxed, and then hydrated. The sections were then stained sequentially with hematoxylin solution, differentiation solution, bluing solution, 85% ethanol, 95% ethanol, and finally eosin solution. The sections were mounted with neutral gum and observed and photographed using a panoramic scanner on a digital slide system.

[0038] 6. Elisa detection of CREA and BUN expression Four weeks after modeling, using the CREA and BUN Elisa kit, the plate was incubated in a 37°C oven for 60 min with the standard and test samples. Then, 50 μL of biotin antibody working solution was added and incubated in a 37°C oven for 45 min. The plate was then soaked in 350 μL of wash buffer three times for 2 min. Then, 100 μL of enzyme conjugate working solution was added, the plate was covered, and the plate was incubated in a 37°C oven for 30 min. The plate was soaked in wash buffer five times for 2 min, and 90 μL of substrate solution was added. The plate was incubated in the dark at 37°C 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.

[0039] 7. Elisa detection of serum NT-proBNP, IL-1β, IL-6, and TNF-α expression Elisa kits for NT-proBNP, IL-1β, IL-6, and TNF-α were used. Standards and test samples were added to the plate and incubated at 37°C for 60 minutes. Then, 50 μL of biotin antibody working solution was added and incubated at 37°C for 45 minutes. The plate was then soaked three times for 2 minutes with 350 μL of wash buffer. Then, 100 μL of enzyme conjugate working solution was added, the plate was covered, and the plate was incubated at 37°C for 30 minutes. The plate was soaked five times for 2 minutes with wash buffer, and 90 μL of substrate solution was added. The plate was incubated at 37°C in the dark for 15 minutes. 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 minutes.

[0040] 8. Echocardiography to detect heart function Rats were placed in the supine position on an operating table and anesthetized with 1% isoflurane. Echocardiographic parameters were recorded using M-mode echocardiography in the parasternal short-axis view, with the left ventricular papillary muscle as a landmark. Wall motion images were recorded using B-mode echocardiography in the parasternal long-axis view, with the left ventricular outflow tract as a landmark. Cardiac function was observed in the rats for 4 weeks.

[0041] 9. Statistical Methods Statistical analysis was performed using GraphPad Prism 8.0, and data are presented as x ± s. If the data were normally distributed and had homogeneous variances, one-way analysis of variance was used; if not normally distributed or had heterogeneous variances, the rank sum test was used. P < 0.05 was considered statistically significant.

[0042] (2) Results 1. Effects of Xinshubao Tablets on Rat Kidney Histopathology Depend on Figure 1 Pathological staining of renal tissue showed that the glomerular morphology in the low-dose Xinshubao tablet group was basically normal, but pathological changes such as severe tubular dilatation, epithelial cell desquamation, and inflammatory cell infiltration were still observed. The glomerular morphology in the renal tissue of the medium-dose Xinshubao tablet group was basically normal, and compared with the model group, tubular dilatation was alleviated, but a small amount of tubular dilatation was still observed, and pathological changes such as localized tubular epithelial cell desquamation were observed. The glomerular morphology in the renal tissue of the high-dose Xinshubao tablet group was basically normal, with significantly alleviated tubular dilatation, and only occasional tubular epithelial cell desquamation was observed. The glomerular morphology in the renal tissue of the trimetazidine group was basically normal, but pathological changes such as tubular dilatation, tubular wall thinning, and inflammatory cell infiltration were still observed.

[0043] 2. Expression levels of serum creatinine (CREA) and urea nitrogen (BUN) Depend on Figure 2 and Figure 3It can be seen that ELISA detected the expression levels of CREA and BUN in the serum of rats in each group. Compared with the sham operation group, the model group could significantly increase the expression of creatinine and urea nitrogen (P<0.05). Compared with the model group, the high-dose and medium-dose groups of Xinshubao tablets and the captopril group could significantly reduce the expression of creatinine and urea nitrogen (P<0.01, P<0.001). Trimetazidine had no significant effect on the expression levels of serum creatinine CREA and urea nitrogen BUN, and had no significant therapeutic effect on acute renal failure. However, the treatment of myocardial infarction mainly relied on trimetazidine. The indicators related to myocardial infarction needed to be compared with trimetazidine, and the indicators related to acute renal failure needed to be compared with captopril.

[0044] 3. Changes in serum IL-6, IL-1β, and TNF-α expression Depend on Figure 4-6 Compared with the sham-operated group, the model group showed significantly increased serum IL-6, IL-1β, and TNF-α expressions (P < 0.05, P < 0.01). Compared with the model group, both the low- and medium-dose Xinshubao tablets groups reduced IL-6 and TNF-α expressions (P < 0.05, P < 0.01, P < 0.001), with the medium-dose Xinshubao tablets group also reducing IL-1β expression (P < 0.01). Trimetazidine administration only reduced IL-6 and TNF-α expressions (P < 0.01, P < 0.001). This suggests that both the medium-dose Xinshubao tablets group and trimetazidine can reduce the expression of inflammatory factors to a certain extent, with the medium-dose Xinshubao tablets group showing a more pronounced effect.

[0045] The present invention shows that both medium and high doses of Xinshubao tablets can reduce blood creatinine and blood urea nitrogen in mice with myocardial infarction and acute kidney injury, and can significantly reduce the expression of IL-6, IL-1β, and TNF-α, reducing kidney damage. The medium dose group can significantly reduce the expression of IL-6, IL-1β, and TNF-α in mice with myocardial infarction and acute kidney injury, reducing kidney damage, but the low dose has no significant effect on reducing IL-1β. Combined with HE staining, the therapeutic effect of the low dose on kidney tissue is significantly lower than that of the medium and high doses. Other experiments in the present invention, such as blood creatinine and blood urea nitrogen, are all conducted using medium and high doses of Xinshubao tablets.

[0046] 4. Results of Rat Cardiac Function Cardiac function analysis in rats using cardiac ultrasound (e.g. Figure 7As shown in the table, compared with the sham-operated group, the ejection fraction (EF) in the model group was significantly decreased (P < 0.001). However, compared with the model group, the medium- and high-dose Xinshubao tablets groups, as well as the trimetazidine group, significantly increased EF (P < 0.01, P < 0.001). These results further demonstrate that the myocardial infarction model was successfully established, with decreased cardiac function in rats. Both Xinshubao tablets and trimetazidine effectively improved cardiac function and related parameters in rats.

[0047] 5. Serum NT-proBNP expression level Elisa was used to detect the expression level of NT-proBNP in the serum of rats. Compared with the sham operation group, the expression of NT-proBNP in the serum of 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 shown).

[0048] In summary, medium dose of Xinshubao tablets has a good therapeutic effect on myocardial infarction combined with acute kidney injury.

[0049] Although the present invention has been described in detail above using general descriptions and specific embodiments, it will be apparent to those skilled in the art that modifications and improvements may be made thereto. Therefore, such modifications and improvements, without departing from the spirit of the present invention, are intended to be within the scope of protection claimed herein.

Claims

1. Use of a Chinese medicine composition in the preparation of a medicament for treating myocardial infarction combined with acute kidney injury, characterized in that: The traditional Chinese medicine composition is a preparation prepared by taking salvia miltiorrhiza, white peony root, turmeric, acanthopanax senticosus and hawthorn as raw materials and adding pharmaceutically acceptable auxiliary materials.

2. The use according to claim 1, characterized in that The traditional Chinese medicine composition comprises 100-300 parts of salvia miltiorrhiza, 1000-3000 parts of white peony root, 150-450 parts of turmeric, 500-1500 parts of acanthopanax senticosus and 1000-3000 parts of hawthorn.

3. The use according to claim 1, characterized in that The drug is used to simultaneously improve cardiac function damage after myocardial infarction and renal dysfunction caused by acute kidney injury.

4. The use according to claim 1, characterized in that The medicine is a traditional Chinese medicine composition for improving renal blood flow.

5. The use according to claim 1, characterized in that The medicine is a traditional Chinese medicine composition that inhibits myocardial cell apoptosis and epithelial cell shedding.

6. The use according to claim 1, characterized in that The drug reduces serum creatinine (CREA) and blood urea nitrogen (BUN) levels.

7. The use according to claim 1, characterized in that The drug regulates the expression of inflammatory factors such as TNF-α, IL-6 and IL-1β.

8. The use according to claim 1, characterized in that The preparation is an oral preparation.

9. The use according to claim 8, characterized in that The preparation is Xinshubao tablets.

10. The use according to claim 1, characterized in that The pharmaceutically acceptable excipients include at least one of a filler, a disintegrant, a binder, a lubricant, a flavoring agent, a pH regulator, an antioxidant or a sterile solvent.

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