Use of Wenxin granules in the preparation of drugs for treating heart failure caused by canine myxomatous mitral valve disease

Abstract

The application discloses application of Wenxin granules in preparation of a medicine for treating heart failure caused by canine myxomatous mitral valve disease, and belongs to the technical field of veterinary medicines. The Wenxin granules are combined with pimobendan for use in combination with ACVIM B2 period canine; the Wenxin granules are combined with furosemide, benazepril hydrochloride and spironolactone for use in combination with C period canine. The application further provides corresponding pharmaceutical compositions, wherein the mass ratio of the Wenxin granules to pimobendan is (800-1200):(0.2-0.3); and the mass ratio of the five drugs in combination is (800-1200):(0.2-0.3):(1.5-2.5):(0.4-0.6):(1.5-2.5). The application realizes synergistic effect of Chinese medicine and western medicine, and has outstanding advantages in delaying MMVD progression, improving clinical symptoms and ensuring safety of drug use.

Description

[0001] Application in medicine Technical Field

[0002] This invention belongs to the field of veterinary drug technology, specifically relating to the application of Wenxin Granules in the preparation of a drug for treating heart failure caused by canine myxomatous mitral valve disease. Background Technology

[0003] In the veterinary clinical field, canine myxomatous mitral valve disease (MMVD) is a cardiovascular disease with a high incidence rate in older dogs. Currently, the management of this disease stage mainly follows the consensus guidelines framework of the American College of Veterinary Medicine (ACVIM): for stage B2, pimoxemandib is used as the basic intervention drug; as the disease progresses to stage C, furosemide, benazepril hydrochloride, and spironolactone are introduced for combined intervention.

[0004] However, existing technical solutions still have many limitations in practical applications. (1) The process of cardiac remodeling is difficult to effectively curb. Even under standardized drug intervention, the tendency of cardiac chamber expansion and the degree of valvular regurgitation in affected dogs are still difficult to control effectively. Related echocardiographic parameters such as LA / Ao (the ratio of the diameter of the left atrium to the diameter of the aortic root) and LVIDdN (the standardized value of the diastolic diameter of the left ventricle) still show a continuous increase. (2) Poor control of clinical symptoms: After long-term use of drugs, symptoms such as cough and decreased exercise tolerance in stage C dogs are still difficult to control stably, and the quality of life is reduced. (3) Adverse drug reactions: Long-term use of high-dose diuretics can easily induce cardiorenal syndrome, leading to electrolyte disturbance and renal perfusion injury, resulting in diuretic resistance. (4) Existing RAAS inhibitors (such as benazepril hydrochloride) can inhibit the renin-angiotensin-aldosterone system to a certain extent, but it is difficult to completely prevent the "aldosterone escape" phenomenon and cannot fundamentally reverse myocardial fibrosis and ventricular remodeling.

[0005] Wenxin Granules, as a traditional Chinese medicine preparation for human use, have multiple effects in the cardiovascular field, including improving arrhythmia, resisting myocardial fibrosis, and regulating neuroendocrine function. However, there are very few reports in the existing technical field regarding the application of Wenxin Granules to canine cardiovascular diseases, especially in the preparation of pharmaceutical compositions for treating heart failure caused by canine myxomatous mitral valve disease. Summary of the Invention

[0006] In view of the shortcomings of the prior art, the present invention provides the application of Wenxin Granules in the preparation of a drug for treating heart failure caused by canine myxomatous mitral valve disease. The present invention, by combining Wenxin Granules with existing Western medicines, effectively improves the therapeutic effect of heart failure caused by canine myxomatous mitral valve disease, significantly improves cardiac function indicators of affected dogs, delays disease progression, and has good safety.

[0007] To achieve the above objectives, the present invention provides the following technical solution: This invention provides the application of Wenxin Granules in the preparation of a drug for treating heart failure caused by canine myxomatous mitral valve disease.

[0008] Furthermore, the drug comprises pimoxim and Wenxin granules, and the drug is suitable for dogs with ACVIM stage B2 MMVD.

[0009] Furthermore, the single dose of the pimoxendan is 0.2~0.3 mg / kg body weight.

[0010] Furthermore, the drug comprises pimoxendan, furosemide, benazepril hydrochloride, spironolactone, and Wenxin granules, and is indicated for dogs with ACVIM stage C MMVD.

[0011] Furthermore, the single dose of pimoxim is 0.2-0.3 mg / kg body weight, the single dose of furosemide is 1.5-2.5 mg / kg body weight, the single dose of benazepril hydrochloride is 0.4-0.6 mg / kg body weight, and the single dose of spironolactone is 1.5-2.5 mg / kg body weight.

[0012] Furthermore, the single dose of the said stabilizing granules is 0.8~1.2 g / kg body weight.

[0013] The present invention also discloses a pharmaceutical composition for treating heart failure caused by canine myxomatous mitral valve disease, comprising Wenxin granules and pimoxendan.

[0014] Furthermore, the mass ratio of the stabilized particles to pimoxendan is (800~1200):(0.2~0.3).

[0015] Furthermore, the above-mentioned pharmaceutical composition also contains furosemide, benazepril hydrochloride, and spironolactone.

[0016] Furthermore, the mass ratio of the stabilized granules, pimoxendan, furosemide, benazepril hydrochloride and spironolactone is (800~1200):(0.2~0.3):(1.5~2.5):(0.4~0.6):(1.5~2.5).

[0017] Compared with the prior art, the present invention has the following beneficial effects: The application of the Wenxin granules provided by this invention in the treatment of heart failure caused by canine myxomatous mitral valve disease has the following significant beneficial effects: (1) Significantly improved clinical symptoms and enhanced the quality of life of affected dogs. In dogs with ACVIM stage C MMVD, after 12 months of treatment, the total clinical symptom score in the experimental group (using Wenxin granules in combination with other medications) was significantly lower than that in the control group (3.0 vs 4.5, P=0.040), and the difference in quality of life score was highly significant (P<0.0001). This was manifested in: a significant decrease and maintenance of the cough score in the experimental group; and a clear trend of reduced heart murmur severity, with a significant decrease in the proportion of extremely severe murmurs. These results confirm that Wenxin granules can effectively alleviate the clinical symptoms of affected dogs and significantly improve their quality of life.

[0018] (2) Effectively delays the process of cardiac remodeling. For dogs in stage C, Wenxin Granules significantly slowed the growth rate of peak mitral regurgitation velocity (MR Vel) (monthly average change: 0.00 m / s / month in the experimental group vs. 0.04 m / s / month in the control group, P=0.038); for dogs in stage B2, the cone fraction (VHS) in the experimental group decreased significantly from the baseline after 3 months of administration (P<0.05); the standardized values ​​of left atrial volume (LA Vol) and diastolic diameter (LVIDdN) in the experimental group remained relatively stable throughout the observation period, effectively inhibiting the progressive expansion of the cardiac chambers, indicating that Wenxin Granules have a significant inhibitory effect on cardiac remodeling.

[0019] (3) Maintaining stable cardiac systolic and diastolic function. Regarding cardiac function protection, the mitral annular plane systolic displacement (MAPSE) in the phase B2 trial group showed a marginally significant upward trend at 12 months (P=0.059), suggesting that Wenxin granules have a protective effect on left ventricular longitudinal systolic function. The increase in the ratio of mitral valve blood flow spectrum to tissue Doppler spectrum (E / e') in the phase C trial group was relatively gradual, indicating that Wenxin granules help delay the deterioration of left ventricular diastolic function. This demonstrates that Wenxin granules can maintain relative stability of cardiac systolic and diastolic function during disease progression.

[0020] (4) Good safety profile. The 12-month follow-up showed that the liver function indicators (AST, ALT) and kidney function indicators (CREA, BUN) of the experimental group dogs were stable within the normal reference range, with no significant difference compared with the control group (P>0.05); in addition, the fluctuation range of blood urea nitrogen (BUN) in the experimental group was significantly smaller than that in the control group; suggesting that Wenxin Granules not only have good safety profile, but may also have potential protective effects on important organs such as the liver and kidneys, providing a safety guarantee for long-term use. Attached Figure Description

[0021] Figure 1 The overall trend of clinical symptoms and quality of life changes in dogs with MMVD before and after treatment; where A: total clinical symptom score; B: cough score; C: comprehensive quality of life score (the lower the score, the better the quality of life). P<0.05, P<0.0001.

[0022] Figure 2 The trends of changes in core cardiac function indicators before and after medication in dogs with MMVD; where A: ejection fraction (EF%); B: fractional shortening (FS%); C: mitral annular plane systolic displacement (MAPSE, mm); D: mitral valve orifice E-peak velocity (E-Vel, m / s); E: E / e' ratio.

[0023] Figure 3 The trends of liver and kidney safety indicators after long-term medication in dogs with MMVD are shown. Among them, A: serum aspartate aminotransferase (AST, U / L); B: serum alanine aminotransferase (ALT, U / L); C: serum creatinine (CREA, μmol / L); D: blood urea nitrogen (BUN, mmol / L). Detailed Implementation

[0024] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. 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.

[0025] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0026] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0027] The technical solution of the present invention will be further described below with reference to the accompanying drawings and specific embodiments: Example 1 (1) Case screening and grouping: A total of 28 dogs with MMVD meeting the diagnostic criteria of the ACVIM 2019 guidelines were selected, including 14 dogs with stage B2 and 14 dogs with stage C, as shown in Table 1. The dogs with stage B2 and stage C were randomly divided into experimental group and control group, with 7 dogs in each group, for a total of four groups: stage B2-experimental group, stage B2-control group, stage C-experimental group, and stage C-control group.

[0028] Table 1

[0029] (2) Dosing regimen: All affected dogs received standardized Western medicine treatment according to their ACVIM stage, and the experimental group also received Wenxin Granules in addition to this treatment.

[0030] Phase B2 control group: Pimobendan (0.25 mg / kg, twice daily, orally); Phase C control group: pimoxendan (0.25 mg / kg, twice daily, orally), furosemide (2.0 mg / kg, twice daily, orally), benazepril hydrochloride (0.5 mg / kg, twice daily, orally), spironolactone (2.0 mg / kg, twice daily, orally). Phase B2 experimental group: In addition to the treatment regimen of the Phase B2 control group, Wenxin granules (1.0 g / kg, twice daily, orally) were added. Phase C experimental group: In addition to the Phase C control group regimen, Wenxin granules (1.0 g / kg, twice daily, orally) were added. All affected dogs received the medication continuously for 12 months.

[0031] (3) Collection of observation indicators: The following indicators were collected by the system at four time points: before administration (0 months) and at 3 months, 6 months, and 12 months after administration: ① Clinical assessment: clinical symptom score, heart murmur grade, and overall quality of life score; ② Imaging examinations: Core echocardiographic parameters, including LA / Ao, left atrial volume (LA Vol), standardized left ventricular diastolic diameter (LVIDdN), ejection fraction (EF%), fractional shortening (FS%), mitral annular plane systolic displacement (MAPSE), peak mitral valve velocity (E Vel), E / e' ratio, and peak mitral regurgitation velocity (MR Vel). ③ X-ray assessment: Vertebral body fraction (VHS); ④ Biochemical indicators: N-terminal pro-brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP), liver function (AST, ALT), and kidney function (CREA, BUN).

[0032] (4) Data statistical analysis Statistical analysis was performed using SPSS 26.0 software. Quantitative data were expressed as median M (1st quartile Q1, 3rd quartile Q3). The Mann-Whitney U rank-sum test was used for intergroup comparisons, and P < 0.05 was considered statistically significant.

[0033] (5) Experimental Results and Analysis ①Comprehensive score of clinical symptoms and quality of life: such as Figure 1As shown, after 12 months of treatment, the total clinical symptom score of dogs in the C-stage experimental group was significantly lower than that in the C-stage control group (3.0 vs 4.5, P=0.040), and the difference in quality of life score reached a highly significant level (P<0.0001). The cough score of dogs in the experimental group significantly decreased and remained at a low level, and the severity of heart murmurs showed a clear decreasing trend, with a significant decrease in the proportion of extremely severe murmurs. The results indicate that the combination of Wenxin granules and Western medicine can effectively alleviate clinical symptoms related to heart failure and improve the quality of life of dogs.

[0034] ② Changes in cardiac structural indicators are shown in Table 2.

[0035] Table 2

[0036] Table 2 shows that the baseline levels in the B2 stage experimental group were higher than those in the control group, indicating a more severe underlying condition. During the 12-month follow-up, the left atrial and left ventricular related indicators in the experimental group showed gradual fluctuations without statistically significant differences within the group, and no uncontrolled dilation occurred, consistent with the natural progression of MMVD in stage B2. Only at 3 months did the VHS show a slight decrease from baseline (P<0.05), suggesting that the drug could have a positive impact on the overall cardiac structure early on. In the stage C control group, a significant increase in LA Vol was observed after 3 months of follow-up (P<0.05), indicating that under conventional treatment, dogs with MMVD experienced increased left atrial volume load and rapid remodeling progression early on. However, during the 12-month follow-up in the experimental group, core structural indicators such as LA / Ao, LA Vol, and LVIDdN did not show significant fluctuations within the group, and the left atrial and left ventricular structure remained stable throughout. The results indicate that Wenxin Granules can effectively delay the cardiac remodeling process in dogs with MMVD at different stages.

[0037] ③ Regarding changes in cardiac function indicators, such as Figure 2 As shown.

[0038] Depend on Figure 2 It was found that during the follow-up period, systolic function indicators such as EF, FS, and MAPSE in the B2 phase experimental group showed a continuous upward trend, with both the magnitude of improvement and long-term maintenance effect being superior to those in the control group. Regarding diastolic function, the experimental group's E Vel remained stable throughout the follow-up, while E / e' decreased early, indicating stable left ventricular diastolic filling. In contrast, the control group showed a declining trend in diastolic function. In the C phase experimental group, MAPSE progressively increased during follow-up, left ventricular long-axis systolic function continued to improve, and overall systolic indicators such as EF remained stable without decline throughout the follow-up, with diastolic filling function also remaining stable. The control group showed no significant improvement in systolic function, and the overall improvement in cardiac function was limited. The results indicate that Wenxin Granules can effectively improve and maintain cardiac systolic and diastolic function in dogs with MMVD at different stages, delaying the progression of cardiac function decline.

[0039] ④ The average monthly changes in cardiac function indicators are shown in Table 3.

[0040] Table 3

[0041] Note: Compared with the control group, P <0.05. The indicator value represents the average monthly change; a positive value indicates an increase, and a negative value indicates a decrease.

[0042] Table 3 shows that in the B2 stage experimental group, systolic and diastolic related indicators remained stable without progressive decline, indicating that Wenxin Granules can effectively maintain cardiac function stability in dogs with B2 stage disease. In the C stage experimental group, the monthly average change in mitral regurgitation velocity (MR-Vel) was significantly lower than that in the control group (P<0.05), and the degree of regurgitation did not progressively worsen. Other systolic and diastolic function indicators showed no significant differences between the two groups, but the experimental group exhibited smaller overall fluctuations and a more stable cardiac function. The results indicate that Wenxin Granules can effectively inhibit the progression of mitral regurgitation in dogs with MMVD, stabilize cardiac function in dogs at different stages, and delay the decline of cardiac function.

[0043] ⑤ Regarding the safety of long-term medication, such as Figure 3 As shown.

[0044] During the 12-month follow-up period, liver function (AST, ALT) and kidney function (CREA, BUN) indicators in all experimental groups remained stable within the normal reference range, with no significant differences compared to their respective control groups (P>0.05). Furthermore, the fluctuation range of BUN in the experimental group was significantly smaller than that in the control group. Combined with the improvement in cardiac function, this suggests that Wenxin Granules not only have good safety during long-term use but may also have a potential protective effect on vital organs such as the liver and kidneys by improving cardiac output and systemic perfusion.

[0045] In summary, this invention provides a novel application of Wenxin granules in the treatment of canine myxomatous mitral valve disease (MMVD), specifically for heart failure caused by MMVD. Adding Wenxin granules to conventional Western medicine treatment not only significantly improves the clinical manifestations of dogs in ACVIM stages B2 and C, effectively slows down pathological changes in cardiac structure, and maintains stable cardiac function, but also has minimal long-term impact on liver and kidney function, demonstrating good safety. This invention provides a novel drug option for the integrated traditional Chinese and Western medicine treatment of canine MMVD.

[0046] Example 2 Based on the above clinical validation, this embodiment also provides a pharmaceutical composition.

[0047] Composition A (suitable for Phase B2): Wenxin Granules (1000 mg / kg) + Pimobendan (0.25 mg / kg), in a mass ratio of 1000:0.25; Composition B (suitable for Phase C): Wenxin Granules (1000 mg / kg) + Pimobendan (0.25 mg / kg) + Furosemide (2.0 mg / kg) + Benazepril Hydrochloride (0.5 mg / kg) + Spironolactone (2.0 mg / kg), in a mass ratio of 1000:0.25:2.0:0.5:2.0; Formulation: It can be made into granules, tablets or capsules. Among them, Wenxin granules are a commercially available Chinese patent medicine for human use (National Drug Approval Number Z10950026). After being crushed and sieved, it is mixed evenly with the Western medicine ingredients. The single dose is calculated according to body weight and is administered twice a day.

[0048] In actual clinical practice, the dosage can be slightly adjusted according to the individual response of the dog, but the dosage of Wenxin Granules should be controlled within the range of 0.8~1.2g / kg / time to ensure a balance between efficacy and safety.

[0049] The application of the Wenxin granules disclosed in this invention in the preparation of a drug for treating heart failure caused by canine myxomatous mitral valve disease has been described in detail above. Specific examples have been used to illustrate the principles and implementation methods of this invention. The descriptions of the above embodiments are only for the purpose of helping to understand the method and core ideas of this invention. It should be noted that those skilled in the art can make several improvements and modifications to this invention without departing from the principles of this invention, and these improvements and modifications also fall within the protection scope of the claims of this invention.

Claims

1. Application of Wenxin Granules in the preparation of drugs for treating heart failure caused by canine myxomatous mitral valve disease.

2. The application according to claim 1, characterized in that, The drug contains pimoxandan and Wenxin granules.

3. The application according to claim 2, characterized in that, The single dose of pimoxendan is 0.2~0.3 mg / kg body weight.

4. The application according to claim 1, characterized in that, The drug comprises pimoxendan, furosemide, benazepril hydrochloride, spironolactone, and Wenxin granules.

5. The application according to claim 4, characterized in that, The single dose of pimoxim is 0.2-0.3 mg / kg body weight, the single dose of furosemide is 1.5-2.5 mg / kg body weight, the single dose of benazepril hydrochloride is 0.4-0.6 mg / kg body weight, and the single dose of spironolactone is 1.5-2.5 mg / kg body weight.

6. The application according to any one of claims 2-5, characterized in that: The single dose of the Wenxin Granules is 0.8~1.2 g / kg body weight.

7. A pharmaceutical composition for treating heart failure caused by canine myxomatous mitral valve disease, characterized in that, It contains sedative granules and pimoxendan.

8. The pharmaceutical composition according to claim 7, characterized in that, The mass ratio of the stabilized granules to pimoxendan is (800~1200):(0.2~0.3).

9. The pharmaceutical composition according to claim 7, characterized in that, It also contains furosemide, benazepril hydrochloride, and spironolactone.

10. The pharmaceutical composition according to claim 9, characterized in that, The mass ratio of the stabilized granules, pimoxendan, furosemide, benazepril hydrochloride and spironolactone is (800~1200):(0.2~0.3):(1.5~2.5):(0.4~0.6):(1.5~2.5).

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