Application of tannic acid in preparation of medicine for treating toxic and side effects caused by Vandetanib

Abstract

The invention discloses application of tannic acid in preparation of a medicine for treating toxic and side effects caused by Vandetanib, and belongs to the technical field of medicines. The invention provides the medicine capable of effectively treating the toxic and side effects of the Vandetanib, the tannic acid can effectively reverse the injury effect of the Vandetanib on the liver and the heart, and the clinical use of the tannic acid is expanded to a great extent. The effective action dose of tannic acid in the medicine provided by the invention does not influence the survival and physiological status of animals, the physiological functions of livers and hearts and the like, and the medicine is high in safety and clinical feasibility.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to application of tannic acid in preparing medicines for treating toxic and side effects induced by vandetanib. Background Art

[0002] Vandetanib is an oral multi-target tyrosine kinase inhibitor, whose targets mainly include epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), and rearrangement during transfection (RET). Currently, vandetanib is approved for the treatment of unresectable, locally advanced or metastatic symptomatic or progressive medullary thyroid cancer. Its efficacy in treating medullary thyroid cancer is 100%, the objective response rate is 44%, the median sustained response time is 22 months, and the progression-free survival is 30.5 months (Wells SA Jr, et al. J Clin Oncol , 2012, 10;30(2):134-141.), and vandetanib can also effectively prolong the progression-free survival of patients with RET fusion-positive advanced non-small cell lung cancer (Yoh K, et al. Lancet Respir Med , 2017, 5(1): 42-50.).

[0003] Vandetanib has good therapeutic effects and broad application prospects, but severe liver and heart toxicity greatly limits its clinical application. Data show that more than 50% of patients have elevated alanine aminotransferase (ALT) levels, and 2% to 5% of patients have ALT levels that exceed 5 times the upper limit of normal (Weil A, et al. Clin Pharmacokinet , 2010, 49(9): 607-618.). Cardiotoxicity is another potential risk of vandetanib treatment. Reports show that it causes QTc interval prolongation, ventricular tachycardia, and fatal heart failure during medication. These side effects force patients to reduce the dosage or even stop taking the drug, which will undoubtedly promote the progression of the patient's disease and affect the patient's quality of life.

[0004] Currently, there is still a lack of effective means to intervene in the toxic side effects of vandetanib in clinical practice because its toxic mechanism is still unclear. Given that vandetanib plays an irreplaceable role in the treatment of medullary thyroid cancer, it is of great significance to study effective intervention strategies for it.

[0005] Tannic acid, a natural organic compound, can be used as a food additive and is one of the important ingredients in traditional Chinese medicine. Studies have shown that tannic acid can play a protective role in the development of chronic diseases such as cancer, cardiovascular disease, liver disease and neurodegeneration by regulating inflammation and oxidative stress (Yeung YT, et al. Curr Pharm Des , 2018, 24(14): 1449-1484.). So far, there are no reports on the intervention of tannic acid on the toxicity and side effects of vandetanib. Summary of the invention

[0006] The purpose of the present invention is to provide a drug that can be used to alleviate the toxic reaction induced by the anti-tumor drug vandetanib, and to reduce the side effects such as liver toxicity and cardiotoxicity caused by vandetanib alone through combined use.

[0007] To achieve the above object, the present invention adopts the following technical solution: The present invention provides the use of tannic acid in the preparation of a drug for preventing or treating the liver and / or heart toxic side effects caused by vandetanib. The CAS number of the tannic acid is 1401-55-4, and the molecular formula is C 76 H 52 O 46 , molecular weight is 1701.22.

[0008] The present invention has been proved by in vivo animal experiments that tannic acid has a significant alleviating effect on vandetanib-induced liver damage and heart damage, and can be used to prevent or treat vandetanib-induced liver toxicity and heart toxicity, thereby expanding the clinical application of vandetanib.

[0009] Furthermore, the liver toxicity caused by vandetanib includes: an increase in the level of at least one of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) in serum. Studies have shown that the increase in ALT and AST caused by vandetanib can be reversed by co-administration of tannic acid.

[0010] Furthermore, the liver toxicity caused by vandetanib includes: yellowing of the liver and lack of blood color. Studies have shown that the above liver damage phenomenon is effectively alleviated after combined use of tannic acid.

[0011] Furthermore, the liver toxicity caused by vandetanib includes at least one of the following: blurred liver cell boundaries, disordered liver cell arrangement, liver cell vacuolization, and liver cell nuclear shrinkage. Studies have shown that the above liver cell injury pathological manifestations are significantly improved after combined use of tannic acid.

[0012] Furthermore, the cardiac toxic side effects induced by vandetanib include at least one of: decreased heart weight / tibia length ratio, cardiac dysfunction, and myocardial hypertrophy. Studies have shown that the combined use of tannic acid can significantly reverse the decreased heart weight / tibia length ratio, decreased cardiac function, and increased cross-sectional area of ​​myocardial cells induced by vandetanib.

[0013] Furthermore, the cardiac dysfunction includes a decrease in the cardiac function indicators left ventricular ejection fraction and left ventricular fractional shortening.

[0014] Furthermore, the cardiac toxicity caused by vandetanib includes: cytoplasmic diffusion and cell vacuolization in cardiac tissue cells, and decreased density of myocardial cells. Studies have shown that the above pathological manifestations of cardiac tissue damage are significantly improved after combined use of tannic acid.

[0015] In the present invention, tannic acid as a main active ingredient can reverse the occurrence of the above-mentioned liver damage and myocardial damage pathological phenomena induced by vandetanib.

[0016] The drug comprises an effective dose of tannic acid and a pharmaceutically acceptable carrier, and can be prepared into a preparation according to a preparation preparation method recorded in pharmacy. In a mouse animal model, the dosage of tannic acid is 30 mg / kg, which is a safe and effective dosage.

[0017] Another object of the present invention is to provide an anti-tumor combined drug, which comprises: a first preparation formed by vandetanib and a pharmaceutically acceptable carrier, and a second preparation formed by tannic acid or a salt thereof and a pharmaceutically acceptable carrier.

[0018] The present invention provides an effective therapeutic drug for vandetanib-induced liver toxicity and cardiotoxicity. Animal experiments show that compared with the vandetanib monotherapy group, the combined use of tannic acid can significantly inhibit liver damage and myocardial damage. In addition, the dosage of tannic acid is low and has no effect on animal survival, normal liver function, normal heart function and structure, etc., indicating that tannic acid is reasonable and safe as a protective agent and has high feasibility.

[0019] Furthermore, the mass ratio of tannic acid to vandetanib in the drug is 0.1-0.3:1.

[0020] Furthermore, the pharmaceutically acceptable carrier is a filler, a wetting agent, a binder, a disintegrant or a lubricant. The drug dosage form is a liquid preparation or a solid preparation, including an oral solid preparation, an oral liquid preparation, an injection, a lyophilized powder injection, a large infusion dosage form, a patch, an ointment, a gel, a soft capsule or a suppository.

[0021] The present invention also provides the use of the anti-tumor combined drug in preparing a drug for treating medullary thyroid cancer or non-small cell lung cancer.

[0022] The present invention has the following beneficial effects: (1) The present invention provides a drug that can effectively treat the toxic side effects of vandetanib. Tannic acid can effectively reverse the damage of vandetanib to the liver and heart. Animal experiments show that compared with the vandetanib monotherapy group, the liver and heart functions of animals in the tannic acid group were significantly improved. Combination therapy with tannic acid can alleviate the severe liver and heart damage caused by vandetanib in tumor patients, thereby greatly expanding the clinical use of tannic acid.

[0023] (2) The effective dose of tannic acid in the drug provided by the present invention will not affect the survival, physiological state, physiological functions of the liver and heart, etc. of animals, and has high safety and clinical feasibility. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The effects of vandetanib on liver function in mice, where A is the level of alanine aminotransferase (ALT); B is the level of aspartate aminotransferase (AST); and C is the level of lactate dehydrogenase (LDH).

[0025] Figure 2 These are photos of liver tissue and HE staining results of liver sections after Vandetanib treatment.

[0026] Figure 3 The effect of tannic acid on transaminase induced by vandetanib in mice, where A is the level of alanine aminotransferase (ALT); B is the level of aspartate aminotransferase (AST).

[0027] Figure 4 The effect of tannic acid on vandetanib-induced liver damage in mice, where A is a photo of liver tissue; B is the HE staining result of liver section.

[0028] Figure 5 The effect of tannic acid on vandetanib-induced cardiac dysfunction, where the left figure is the left ventricular ejection fraction; the right figure is the left ventricular fractional shortening.

[0029] Figure 6 The effect of tannic acid on vandetanib-induced cardiac pathological damage in mice, where A is a photo of heart tissue; B is the HE staining result of heart section.

[0030] Figure 7 It is the ratio of heart weight / tibia length of mice after co-administration of tannic acid.

[0031] Figure 8 To investigate the effects of tannic acid on vandetanib-induced cardiac hypertrophy in mice. DETAILED DESCRIPTION

[0032] The present invention will be further described below in conjunction with specific embodiments. The following embodiments are only used to illustrate the present invention and are not intended to limit the scope of application of the present invention. Without departing from the spirit and essence of the present invention, modifications or replacements made to the inventive method, steps or conditions all belong to the scope of the present invention.

[0033] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the materials and reagents used are reagents and materials that can be obtained from commercial channels unless otherwise specified.

[0034] Vandetanib (CAS No. 443913-73-3), molecular formula is C 22 H 24 BrFN4O2, molecular weight 475.354, purchased from Taoshu Biotechnology Co., Ltd. Tannic acid (CAS No. 1401-55-4), molecular formula C 76 H 52 O 46 , molecular weight 1701.22, purchased from Taoshu Biotechnology Co., Ltd.

[0035] C57BL / 6J mice were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd.; sodium carboxymethyl cellulose (CMC-Na) was purchased from Shanghai Sinopharm Group.

[0036] Example 1: Vandetanib induces liver toxicity 1. Experimental methods Ten male C57BL / 6J mice were randomly divided into two groups, a control group and a vandetanib group. The control group was given 0.5% CMC-Na, and the vandetanib group was given a dose of 100 mg / kg / day. After 4 weeks of continuous administration, blood samples were collected by orbital blood sampling to detect the values ​​of biochemical markers of liver damage, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) in the serum. The mice were then killed, the livers were dissected, and the liver tissues were photographed, embedded, and sliced ​​under normal light, and the liver tissue sections were stained with HE.

[0037] 2. Experimental results Liver function test results Figure 1As shown in the data, the liver function indicators of the control group and the vandetanib group were alanine aminotransferase (ALT) of 27.36 ± 2.42 U / L and 139.92 ± 18.10 U / L, aspartate aminotransferase (AST) of 129.24 ± 22.81 U / L and 229.74 ± 32.56 U / L, and lactate dehydrogenase (LDH) of 865.20 ± 106.02 U / L and 1458.60 ± 216.91 U / L, respectively. The data showed that vandetanib caused upregulation of ALT, AST, and LDH in mice.

[0038] The liver tissue was photographed under normal light and the liver sections were stained with HE. The results are as follows Figure 2 As shown, the results of normal light photography showed that the liver of mice in the vandetanib group was yellowish, bloodless, and gritty. The results of HE staining showed that vandetanib caused the morphological characteristics of blurred boundaries of mouse liver cells, chaotic and irregular cell arrangement, severe cavitation, and obvious shrinkage of cell nuclei, indicating that vandetanib induced liver damage in mice.

[0039] Example 2: Effect of combined use of tannic acid on the liver toxicity induced by vandetanib 1. Experimental methods Twenty-four male C57BL / 6J mice were randomly divided into four groups, namely the control group, vandetanib group, tannic acid group, and vandetanib + tannic acid group, with 6 mice in each group, and the drugs were administered by gavage. The dose of vandetanib was 100 mg / kg / day, and the dose of tannic acid was 30 mg / kg / day. The control group was replaced with 0.5% CMC-Na. After four weeks of continuous administration, blood samples were collected by orbital bleeding, and the biochemical markers of liver damage, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), were detected in the serum. Then the mice were killed, the livers were dissected, and the liver tissues were photographed, embedded, and sliced ​​under normal light, and the liver tissue sections were stained with HE.

[0040] 2. Experimental results Liver function test results Figure 3 As shown in the data, the liver function index alanine aminotransferase (ALT) in the control group, vandetanib group, tannic acid group, and vandetanib + tannic acid combined group was 32.10 ± 8.48 U / L, 167.72 ± 23.81 U / L, 39.60 ± 7.79 U / L, and 108.3 ± 20.57 U / L, respectively; aspartate aminotransferase (AST) was 174.92 ± 37.78 U / L, 633.91 ± 225.35 U / L, 173.70 ± 34.73 U / L, and 198.94 ± 30.01 U / L, respectively. The data showed that the upregulation of ALT and AST in mice caused by vandetanib was significantly reversed after the combined use of tannic acid.

[0041] Liver tissue sections were photographed under normal light and stained with HE. Figure 4 As shown, the results of normal light photography (A) showed that the obvious brown-yellow and bloodless liver of mice treated with vandetanib alone was effectively alleviated after combined use of tannic acid. HE staining results (B) showed that the morphological characteristics of liver tissue cell fuzziness, disordered and irregular cell arrangement, severe cavitation and obvious shrinkage of cell nuclei caused by vandetanib alone were significantly improved after combined use of tannic acid.

[0042] These results collectively indicate that tannic acid can improve vandetanib-induced liver damage in mice.

[0043] Example 3: Effect of combined use of tannic acid on the cardiac toxicity induced by vandetanib 1. Experimental methods Twenty-four male C57BL / 6J mice were randomly divided into four groups, namely, control group, vandetanib group, tannic acid group, and vandetanib + tannic acid group, with 6 mice in each group, and the drugs were administered by gavage. The dose of vandetanib was 100 mg / kg / day, and the dose of tannic acid was 30 mg / kg / day. The control group was replaced with 0.5% CMC-Na. After continuous administration for 4 weeks, the cardiac function of mice in each group was detected by echocardiography. Then the mice were killed, the hearts were dissected, and the morphological changes of the hearts were observed by normal light photography. The heart weight / tibia length ratio (HW / TL) was observed by weighing. The heart tissues were fixed, embedded and sliced. HE staining was used to detect the pathological changes of mouse heart tissues, and WGA staining was used to analyze the hypertrophy of mouse cardiomyocytes.

[0044] 2. Experimental results Echocardiographic results Figure 5 As shown, the cardiac function index of mice in the control group, vandetanib group, tannic acid group, and vandetanib + tannic acid combination group, the left ventricular ejection fraction (Ejection Fraction) were 74.98 ± 6.29%, 59.47 ± 5.59%, 71.95 ± 5.00% and 68.46 ± 3.32%, respectively; the left ventricular fractional shortening (FractionalShortening) were 43.48 ± 5.43%, 30.76 ± 3.68%, 40.82 ± 4.14% and 37.49 ± 2.36%, respectively, indicating that vandetanib can cause decreased cardiac function in mice, and the decreased cardiac function induced by vandetanib was improved after combined use of tannic acid.

[0045] The results of normal light photography and HE staining are as follows Figure 6As shown. Normal light photography (A) showed that the heart of mice became significantly smaller after the treatment of vandetanib, indicating that vandetanib would cause changes in the heart structure, and the combined use of tannic acid could partially reverse the heart shrinkage caused by vandetanib; HE staining results (B) showed that the heart tissue of mice in the vandetanib group showed cytoplasmic diffusion, cell vacuolation, and decreased myocardial cell density, and the combined use of tannic acid significantly improved these pathological changes, indicating that vandetanib can cause cardiac pathological damage in mice, and the combined use of tannic acid can improve the cardiac pathological damage induced by vandetanib.

[0046] Heart weight / tibia length ratio (HW / TL) results are as follows Figure 7 As shown, the HW / TL of mice in the control group, vandetanib group, tannic acid group, and vandetanib + tannic acid combination group were 7.12 ± 0.35 mg / mm, 4.41 ± 0.10 mg / mm, 7.22 ± 0.31 mg / mm, and 6.16 ± 0.67 mg / mm, respectively. This result was consistent with the result of normal light photography, indicating that the decrease in HW / TL value induced by vandetanib was significantly reversed after the combination with tannic acid.

[0047] WGA staining results Figure 8 As shown in Figure 2, the cross-sectional area of ​​cardiomyocytes in the vandetanib-treated group was 199.21 ± 35.06 μm 2 , compared with 157.69 ± 15.29 μm in the control group 2 , significantly increased; after combined use of tannic acid, the cross-sectional area of ​​myocardial cells was 134.82 ± 24.28 μm 2 , indicating that vandetanib can cause myocardial hypertrophy in mice, and the vandetanib-induced myocardial hypertrophy was improved after combined use of tannic acid.

[0048] These results collectively indicate that tannic acid can improve vandetanib-induced cardiac injury in mice.

[0049] In summary, tannic acid can improve vandetanib-induced liver and heart damage. Vandetanib is an inhibitor of VEGFR, EGFR and RET, and a specific target inhibitor. Tannic acid will not have a direct effect on these targets. Therefore, the combined use of tannic acid will not affect the anti-cancer effect of vandetanib.

Claims

1. Use of tannic acid in the preparation of a drug for preventing or treating liver and / or heart toxic side effects induced by vandetanib.

2. The use according to claim 1, characterized in that The liver toxicity induced by vandetanib includes: an increase in the content of at least one of alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase in serum.

3. The use according to claim 1, characterized in that The liver toxicity caused by vandetanib includes: the liver turns yellow and bloodless.

4. The use according to claim 1, characterized in that The liver toxic side effects induced by vandetanib include at least one of blurred hepatocyte boundaries, disordered hepatocyte arrangement, hepatocyte cavitation, and hepatocyte nuclear shrinkage.

5. The use according to claim 1, characterized in that The cardiac toxic side effects induced by vandetanib include at least one of: decreased heart weight / tibia length ratio, cardiac dysfunction, and myocardial hypertrophy.

6. The use according to claim 5, characterized in that The cardiac dysfunction includes a decrease in left ventricular ejection fraction and left ventricular fractional shortening, which are cardiac function indicators.

7. The use according to claim 1, characterized in that The cardiac toxic side effects induced by vandetanib include: diffuse cytoplasm and vacuolization of cardiac tissue cells, and decreased density of myocardial cells.

8. An anti-tumor combined drug, characterized in that: The drug comprises: a first preparation formed by vandetanib and a pharmaceutically acceptable carrier, and a second preparation formed by tannic acid or a salt thereof and a pharmaceutically acceptable carrier.

9. The anti-tumor combination drug according to claim 8, characterized in that: The mass ratio of tannic acid to vandetanib in the drug is 0.1-0.3:

1.

10. Use of the anti-tumor combination drug according to claim 8 in the preparation of a drug for treating medullary thyroid cancer or non-small cell lung cancer.

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