Use of radix astragali-ramulus cinnamomi five-ingredient decoction optimized formula in the preparation of drug for preventing and / or treating cardiotoxicity caused by oxaliplatin

Abstract

The use of a radix astragali-ramulus cinnamomi five-ingredient decoction optimized formula in the preparation of a drug for preventing and / or treating cardiotoxicity caused by oxaliplatin. Said optimized formula is derived from a traditional Chinese medicine composition consisting of radix astragali, ramulus cinnamomi, radix paeoniae, fructus jujubae, fresh ginger and radix glycyrrhizae, or from extracts of radix astragali, ramulus cinnamomi, radix paeoniae, fructus jujubae, fresh ginger and radix glycyrrhizae. The use of said optimized formula is provided, which can be used for preparing a drug for preventing and / or treating cardiotoxicity caused by oxaliplatin.

Description

Application of the optimized Huangqi Guizhi Wuwu Decoction in the preparation of drugs for preventing and / or treating oxaliplatin-induced cardiotoxicity Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to the use of an optimized Huangqi Guizhi Wuwu Decoction in the preparation of a drug for preventing and / or treating oxaliplatin-induced cardiotoxicity. Background Art

[0002] In Traditional Chinese Medicine (TCM), chemotherapy-induced cardiotoxicity falls under the rubric of arthralgia and palpitations. The "Golden Chamber" states in its "Pulse Symptoms and Treatments for Chest Bi, Heart Pain, Shortness of Breath, and Symptoms of Chest Bi" that "Yang is weak and Yin is stringy, indicating chest bi and pain." The optimized Huangqi Guizhi Wuwu Decoction (Huangqi Guizhi Wuwu Tang) comprises six herbs: Huangqi (Huangqi), Guizhi (Cinnamon Twig), Shaoyao (Peony Root), Jujube (Daizi), Ginger (Rhizoma Zangji), and Licorice (Licorice). Huangqi is the main ingredient in this formula, known for its sweet and warming properties that invigorate Qi and strengthen the exterior's Wei Qi. Guizhi dispels wind-cold, warms the meridians, and relieves arthralgia. Combined with Huangqi, it invigorates Qi and warms Yang, harmonizing blood and activating menstruation. Combined with Huangqi, Huangqi strengthens the exterior, preventing pathogenic factors from lingering. Peony nourishes blood and harmonizes the Ying and Wei, relieving blood stasis. Combined with Guizhi, it regulates the Ying and Wei, harmonizing the exterior and interior, with the two herbs acting as assistants. Ginger is pungent and warm, dispersing wind pathogens, complementing the effects of Huangqi. Jujube is sweet and warm, nourishing blood and invigorating Qi, complementing the effects of Huangqi and Guizhi. Combined with ginger, it harmonizes the Ying and Wei, regulating the other herbs and acting as an adjuvant. Licorice is added to balance the biases of the other herbs, taking advantage of its sweet and soothing properties. "It is used heavily to achieve the desired effect, yet can also be adjusted to achieve the desired effect. It is an indispensable ingredient in medicine, not something that can be ignored." Licorice is paired with peony, echoing the principle of Peony and Licorice Decoction, which uses sweet and soothing properties to relieve pain, and also serves as a guiding herb. The entire formula works to invigorate Qi, warm Yang, harmonize blood circulation, and relieve numbness, relaxing the meridians and activating the collaterals.

[0003] Oxaliplatin is currently the first-line chemotherapy drug for colorectal cancer, but its reported adverse reactions include peripheral neurotoxicity, thrombocytopenia, neutropenia, anemia, diarrhea, vomiting, bradycardia, and QT interval prolongation. Clinically, treatments for oxaliplatin-induced peripheral neurotoxicity primarily include calcium-magnesium compounds, methylcobalamin, analgesics, and glucocorticoids. None of these drugs have independent cardioprotective effects, and no drugs have been reported to treat oxaliplatin-induced cardiotoxicity.

[0004] Summary of the Invention

[0005] Purpose of the invention: The technical problem to be solved by the present invention is to address the deficiencies of the existing technology and provide the use of an optimized formula of Huangqi Guizhi Wuwu Decoction in the preparation of a drug for preventing and / or treating cardiotoxicity caused by oxaliplatin, as well as a pharmaceutical composition for preventing and / or treating cardiotoxicity caused by oxaliplatin.

[0006] In order to solve the above technical problems, the present invention discloses the following technical solutions:

[0007] In a first aspect, the present invention discloses a use of a traditional Chinese medicine composition in the preparation of a drug for preventing and / or treating cardiotoxicity caused by oxaliplatin, wherein the traditional Chinese medicine composition is a traditional Chinese medicine composition derived from astragalus, cinnamon twig, peony root, jujube, ginger and licorice.

[0008] In a second aspect, the present invention discloses an extract for preparing a drug for preventing and / or treating cardiotoxicity caused by oxaliplatin, wherein the extract is an extract of astragalus, cinnamon twig, peony, jujube, ginger and licorice.

[0009] In a third aspect, the present invention discloses a pharmaceutical composition for preventing and / or treating cardiotoxicity, comprising: (i) a Chinese herbal composition derived from astragalus, cinnamon twig, peony root, jujube, ginger and licorice, or an extract of the aforementioned mixed herbs; and (ii) oxaliplatin.

[0010] In the present invention, the prevention and / or treatment of oxaliplatin-induced cardiotoxicity is any one or a combination of the following:

[0011] (i) improving oxaliplatin-induced cardiac function impairment; wherein the cardiac function impairment is cardiac diastolic and / or systolic dysfunction.

[0012] (ii) Alleviate oxaliplatin-induced cardiac ischemia.

[0013] (iii) Improve myocardial fibrosis induced by oxaliplatin.

[0014] (iv) Improve mental state.

[0015] (vi) Improve hair volume and / or shine.

[0016] The improvement of cardiac function damage caused by oxaliplatin in the present invention is to reduce cardiac function damage, such as reducing cardiac diastolic and / or systolic dysfunction. The improvement of myocardial fibrosis caused by oxaliplatin in the present invention is to inhibit myocardial fibrosis caused by oxaliplatin.

[0017] In the present invention, the optimized formula of Huangqi Guizhi Wuwu Decoction consists of six herbs: Huangqi, Guizhi, Paeonia lactiflora, jujube, ginger and licorice, including a Chinese medicine composition derived from Huangqi, Guizhi, Paeonia lactiflora, jujube, ginger and licorice, or an extract of Huangqi, Guizhi, Paeonia lactiflora, jujube, ginger and licorice, and the mass ratio of Huangqi, Guizhi, Paeonia lactiflora, jujube, ginger and licorice is 2:0.4-2.5:0.4-2.5:0.4- 2.5:0.4~2.5:0.358~0.978, preferably 2:0.6~2:0.6~2:0.6~2:0.6~2:0.458~0.878, more preferably 2:0.8~1.5:0.8~1.5:0.8~1.5:0.8~1.5:0.558~0.778, further preferably 2:1:1:1:1:0.668.

[0018] In the present invention, the traditional Chinese medicine composition derived from astragalus, cinnamon twig, peony, jujube, ginger and licorice, or the preparation method of the extract of astragalus, cinnamon twig, peony, jujube, ginger and licorice comprises the following steps: taking cinnamon twig and ginger according to the formula ratio, extracting with water to obtain a first water decoction; extracting other components according to the formula ratio to obtain a second water decoction; combining the first water decoction and the second water decoction, and concentrating.

[0019] Among them, during the preparation of the first water decoction, the water extraction is performed 1 to 3 times, preferably 2 times. Preferably, 6 to 10 times the amount of water is added first, and 1 to 4 times the amount of distillate of the slices is distilled and extracted. The water decoction is filtered, and 6 to 10 times the amount of water is added to the residue, and reflux extraction is performed for 0.5 to 3 hours.

[0020] Wherein, during the preparation of the second water decoction, the water extraction is performed 1 to 3 times, preferably 2 times. Preferably, 7 to 9 times the amount of water is first added, reflux extraction is performed for 1.5 to 3 hours, the water decoction is filtered, and 5 to 6.8 times the amount of water is added to the medicinal residue, and reflux extraction is performed for 0.5 to 1.4 hours.

[0021] The concentration is to concentrate to a density of 1.15 to 1.25, preferably 1.18 to 1.22. Beneficial effects:

[0022] The present invention provides a pharmaceutical composition comprising an optimized Huangqi Guizhi Wuwu Decoction, which can be used to prepare a drug for preventing and / or treating oxaliplatin-induced cardiotoxicity. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more apparent.

[0024] Figure 1 shows the animal groups and drug administration.

[0025] Figure 2 shows the effect of the optimized Huangqi Guizhi Wuwu Decoction on the general condition of rats treated with oxaliplatin.

[0026] Figure 3 shows the effect of the optimized Huangqi Guizhi Wuwu Decoction on cardiac function in oxaliplatin-treated rats. (A) Legend of peak E and peak A in each group. (BC) Numerical statistics of EF, FS, and E / A in each group. * indicates comparison with the blank group. * P < 0.05; ** P < 0.01; *** P < 0.001; **** P<0.0001. # indicates that compared with the oxaliplatin group, # P < 0.05; ## P < 0.01; ### P < 0.001; #### P<0.0001.

[0027] Figure 4 shows the TTC staining of the optimized Huangqi Guizhi Wuwu Decoction on the hearts of rats treated with oxaliplatin.

[0028] Figure 5 shows the histopathological staining of rat heart sections after administration of the optimized Huangqi Guizhi Wuwu Decoction. DETAILED DESCRIPTION

[0029] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.

[0030] The optimized Huangqi Guizhi Wuwu Decoction (mHGWD) described in the present invention comprises: 500g of Huangqi, 250g of Paeonia lactiflora, 250g of Guizhi, 250g of ginger, 250g of jujube, and 167g of Licorice. The relative density is 1.195, and the crude drug content is 2.27g / g.

[0031] Example 1

[0032] 1. Experimental Materials:

[0033] (1) Animals: 60 female Wistar rats weighing 200 ± 20 g, clean grade.

[0034] (2) Main reagents and equipment: oxaliplatin (OXA), mHGWD thick paste, dextromethorphan (DEX), PowerLab15T data acquisition and analysis system, and VINNO portable small animal high-resolution ultrasound system.

[0035] 2. Experimental steps:

[0036] 2.1 Reagent preparation:

[0037] Preparation of mHGWD thick paste: Take cinnamon twig and ginger, add 8 times the amount of water, distill and extract 3 times the amount of distillate of the slices, filter the decoction, add 8 times the amount of water to the residue, reflux extract for 2 hours, filter, and combine the two filtrates for later use; the remaining four ingredients, astragalus, peony, jujube, and licorice, are decocted twice with water, the first time with 8 times the amount of water, reflux extract for 2 hours, filter, and the second time with 6 times the amount of water, reflux extract for 1 hour, filter, and combine the filtrate with the decoction of cinnamon twig and ginger, and concentrate under reduced pressure to a thick paste with a relative density of 1.18-1.22 (60°C).

[0038] Preparation of mHGWD solution: For the low-dose group (mHGWD-L), 8.1 g of mHGWD thick paste was dissolved in 30 ml of double-distilled water; for the medium-dose group (mHGWD-M), 16.2 g of mHGWD thick paste was dissolved in 30 ml of double-distilled water; for the high-dose group (mHGWD-H), 32.4 g of mHGWD thick paste was dissolved in 30 ml of double-distilled water. Prepare the solution immediately and preheat it in a 37°C water bath before use.

[0039] Preparation of oxaliplatin (OXA) solution: Dissolve 50 mg of oxaliplatin in 25 ml of 5% glucose solution to a final concentration of 2 mg / mL and store at 4°C until use. Dilute with 5% glucose solution to a working solution of 0.4 mg / ml before use.

[0040] Preparation of dexrazoxane (DEX) solution: Before use, 67.5 mg of dexrazoxane was dissolved in 10 ml of 0.167 mol / L sodium lactate injection by ultrasonication.

[0041] 2.2 Animal grouping and drug administration:

[0042] Sixty Wistar rats were adaptively fed for one week and then weighed and randomly divided into 6 groups, with 10 rats in each group, namely blank control group (Vehicle), model group (OXA 4 mg / kg), positive control group (DEX 67.5 mg / kg), mHGWD-L group (mHGWD 2.7 g crude drug / kg), mHGWD-M group (mHGWD 5.4 g crude drug / kg), and mHGWD-H group (mHGWD 10.8 g crude drug / kg).

[0043] A rat cardiac injury model was established in all groups except the blank control group, which received an intraperitoneal injection of 4 mg / kg oxaliplatin at a dose volume of 10 ml / kg on days 1, 2, 8, 9, 15, 16, 22, and 23. The blank control group received an equal volume of 5% glucose solution. Starting on day 1, each animal in each mHGwD dose group received a corresponding dose of 10 ml / kg via gavage once daily for 32 consecutive days. The positive control group received an intraperitoneal injection of dexrazoxane (DEX) solution (67.5 mg / kg) on ​​days 15, 16, 22, and 23, and a blank control solution (double-distilled water) was administered on the remaining days. When co-administered with OXA, DEX and mHGWD were administered 0.5 hours prior to OXA administration. Two hours after dosing on day 32, cardiac ultrasound was performed on the rats. Blood samples were collected via the abdominal aorta at 9:00 AM the following day. After blood collection, rats were sacrificed by cervical dislocation. The hearts were then dissected and quickly frozen on dry ice before being stored at -80°C for TTC staining. Alternatively, the hearts were fixed in 4% paraformaldehyde for histopathological observation. Grouping and dosing are detailed in Figure 1.

[0044] 3. Results:

[0045] 3.1 Effect of the optimized Huangqi Guizhi Wuwu Decoction on the general condition of rats after oxaliplatin treatment

[0046] At the end of drug administration, the rats' mental state and skin and hair condition were observed. Animal hair condition, such as hair sparseness and glossiness, can, to a certain extent, reflect the animal's health status. As shown in Figure 2, the rats in the Vehicle group were in good mental state, with smooth, shiny hair. The rats in the OXA group were in poor mental state, with sparse, dull hair, and large areas of hair loss on the neck and abdomen. Compared with the OXA group, the rats in the OXA+mHGWD group had significantly less hair loss, which was no different from the Vehicle group. Compared with the OXA group, the hair loss in the OXA+DEX group improved, but the animals' mental state and hair loss were still more severe than those in the OXA+mHGWD group. This suggests that mHGWD can significantly improve the effects of OXA on the general condition of rats.

[0047] 3.2 Effect of the optimized Huangqi Guizhi Wuwu Decoction on cardiac function in rats treated with oxaliplatin

[0048] To evaluate the effects of the optimized Huangqi Guizhi Wuwu Tang formula on cardiac function in rats treated with oxaliplatin, we performed M-mode echocardiographic analysis at the end of the fourth chemotherapy cycle (Figure 3A). EF (%) refers to the left ventricular ejection fraction, which is the ratio of the volume of blood pumped by the left ventricle during each cardiac cycle to the left ventricular end-diastolic volume. FS (%) refers to the left ventricular fractional shortening, which estimates left ventricular systolic function. As shown in Figure 3B, compared with the Vehicle group, the OXA group showed a significant decrease in cardiac systolic function, as demonstrated by a significant decrease in EF (%) and FS (%) (P < 0.0001). However, compared with the OXA group, rats in the OXA+mHGWD-L and OXA+mHGWD-M groups had significantly improved EF and FS (P < 0.001).

[0049] Peak E represents the maximum velocity during early mitral diastole, and peak A represents the maximum velocity during atrial systole. The E / A ratio reflects the diastolic function of the heart. As shown in Figure 3B, OXA affected the diastolic function of the rat heart. Compared with the Vehicle group, the peak E to peak A ratio of the OXA group showed a downward trend, but there was no statistical difference (P>0.05). Compared with the OXA group, the OXA+mHGWD group and the OXA+DEX group showed similar results, effectively preventing these changes, indicating that mHGWD can improve the diastolic function damage caused by OXA in rat hearts.

[0050] The results showed that mHGWD could improve the decreased cardiac function in rats caused by OXA.

[0051] 3.3 Effect of the optimized Huangqi Guizhi Wuwu Decoction on oxaliplatin-induced myocardial ischemia in rats

[0052] To investigate whether the optimized Huangqi Guizhi Wuwu Decoction formula could improve oxaliplatin-induced myocardial ischemia, rat hearts were harvested after ultrasound. Fresh hearts were longitudinally sectioned and stained with TTC. As shown in Figure 4, the heart tissue in the OXA group appeared pale, indicating myocardial ischemia, with the white areas in the atrial tissue being more pronounced. The OXA + mHGWD group showed similar results to the OXA + DEX group, significantly alleviating OXA-induced cardiac ischemia.

[0053] 3.4 Effect of the optimized Huangqi Guizhi Wuwu Decoction on the pathological changes of myocardial injury induced by oxaliplatin in rats

[0054] In order to observe whether Huangqi Guizhi Wuwu Decoction has an organic effect on the hearts of rats treated with oxaliplatin, the rat heart tissue sections were stained with HE, Masson and picrosirius red.

[0055] As shown in Figure 5, the cardiomyocyte nuclei of rats in the Vehicle group were normal in size, regular in morphology, and neatly arranged between cells. Compared with the Vehicle group, the cardiomyocyte nuclei of rats in the OXA group became darker in color and larger in size, with irregular morphology and disordered arrangement, enlarged interstitial spaces, and inflammatory infiltration. Compared with the OXA group, the cardiomyocyte morphology of rats in the OXA+mHGWD group was relatively regular and the structure was clearer. The cardiomyocyte nuclei of the OXA+DEX group were significantly larger in size, irregular in morphology and disordered arrangement, and the interstitial spaces of the myocardium were significantly enlarged, showing inflammatory infiltration. This suggests that compared with the OXA+DEX group, mHGWD can improve the inflammatory infiltration of the rat myocardium caused by OXA.

[0056] In Masson staining, cardiomyocytes are red, while fibrotic connective tissue is blue. As shown in Figure 5, the cardiomyocytes of rats in the Vehicle group were normal, bright red overall, with cells arranged in an orderly manner and little blue fibrous tissue visible. In the OXA group, cells were arranged in a disordered manner, with a large amount of fibrous tissue accumulated. In the OXA+mHGWD group, cardiomyocytes in the OXA+mHGWD-L group showed fibrosis, while cardiomyocytes in the OXA+mHGWD-M and OXA+mHGWD-H groups were normal, with no significant difference from the normal group. Cardiomyocytes in the OXA+DEX group were arranged in a disordered manner, with obvious fibrosis. The OXA+mHGWD group was more effective in improving the myocardial fibrosis of rats induced by oxaliplatin than the OXA+DEX group.

[0057] In picrosirius red staining, normal cardiomyocytes appear orange and fibrous tissue appears red. Cardiomyocytes in the Vehicle group were neatly arranged, while red fibrous tissue was significantly increased in the OXA group. Among the OXA+mHGWD groups, cardiomyocytes in the OXA+mHGWD-L group showed fibrosis, while cardiomyocytes in the OXA+mHGWD-M and OXA+mHGWD-H groups were normal, with no significant difference from the normal group. Cardiomyocytes in the OXA+DEX group were disorderly arranged, with significant fibrosis. The OXA+mHGWD group was more effective in improving OXA-induced myocardial fibrosis in rats than the OXA+DEX group.

[0058] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be determined by the appended claims.

Claims

1. Use of a Chinese medicine composition in the preparation of a drug for preventing and / or treating cardiotoxicity caused by oxaliplatin, characterized in that: The traditional Chinese medicine composition is a traditional Chinese medicine composition derived from astragalus, cinnamon twig, peony root, jujube, ginger and liquorice.

2. Use of an extract in the preparation of a drug for preventing and / or treating cardiotoxicity caused by oxaliplatin, characterized in that: The extract is an extract of astragalus, cassia twig, peony root, jujube, ginger and liquorice.

3. A pharmaceutical composition for preventing and / or treating cardiotoxicity, characterized in that: include: (i) a Chinese medicinal composition derived from astragalus, cinnamon twig, peony root, jujube, ginger and liquorice, or an extract of the aforementioned mixed herbs; (ii) Oxaliplatin.

4. The use according to claim 1 or 2 or the pharmaceutical composition according to claim 3, characterized in that: The prevention and / or treatment of oxaliplatin-induced cardiotoxicity is to improve the cardiac function damage caused by oxaliplatin.

5. The use or pharmaceutical composition according to claim 4, characterized in that: The cardiac function damage is cardiac diastolic and / or systolic dysfunction.

6. The use according to claim 1 or 2 or the pharmaceutical composition according to claim 3, characterized in that: The prevention and / or treatment of oxaliplatin-induced cardiotoxicity is to alleviate the cardiac ischemia caused by oxaliplatin.

7. The use according to claim 1 or 2 or the pharmaceutical composition according to claim 3, characterized in that: The prevention and / or treatment of oxaliplatin-induced cardiotoxicity is to improve myocardial fibrosis caused by oxaliplatin.

8. The use according to claim 1 or 2 or the pharmaceutical composition according to claim 3, characterized in that: The prevention and / or treatment of oxaliplatin-induced cardiotoxicity is to improve mental status.

9. The use according to claim 1 or 2 or the pharmaceutical composition according to claim 3, characterized in that: The method for preventing and / or treating oxaliplatin-induced cardiotoxicity is to increase the volume and / or gloss of hair.

10. The use according to claim 1 or 2 or the pharmaceutical composition according to claim 3, characterized in that: The mass ratio of astragalus, cinnamon twig, peony, jujube, ginger and licorice is 2:0.4-2.5:0.4-2.5:0.4-2.5:0.4-2.5:0.358-0.978, preferably 2:0.6-2:0.6-2:0.6-2:0.6-2:0.458-0.878, further preferably 2:0.8-1.5:0.8-1.5:0.8-1.5:0.8-1.5:0.558-0.778, and further preferably 2:1:1:1:1:0.668.

Images