Use of tannic acid in the preparation of a medicament for treating a vandetanib-induced adverse effect
The combined use of tannic acid and vandetanib has solved the toxicity problem of vandetanib during treatment by alleviating liver and cardiotoxic side effects, thereby improving liver and cardiofunction and expanding its clinical application.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- INNOVATION INST FOR ARTIFICIAL INTELLIGENCE IN MEDICINE OF ZHEJIANG UNIV
- Filing Date
- 2025-01-08
- Publication Date
- 2026-07-03
AI Technical Summary
The existing anti-tumor drug vandetanib causes serious liver and cardiotoxic side effects during treatment, which limits its clinical application, and there is a lack of effective intervention methods.
The combination of tannic acid and vandetanib was used to alleviate the liver and cardiotoxicity side effects caused by vandetanib through the application of tannic acid, and the formulation was prepared into a pharmaceutically acceptable form.
Tannic acid significantly alleviated liver and heart damage caused by vandetanib, improved liver and cardiac function indicators, expanded the clinical application of vandetanib, and has high safety without affecting anti-cancer efficacy.
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Figure CN119925394B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical technology, specifically to the use of tannic acid in the preparation of drugs for treating the toxic side effects caused by vandetanib. Background Technology
[0002] Vandetanib is an oral multi-target tyrosine kinase inhibitor whose main targets include epidermal growth factor receptor (EGFR), angiogenesis factor receptor (VEGFR), and transfection rearrangement (RET). Currently, vandetanib is approved for the treatment of unresectable, locally advanced, or metastatic symptomatic or progressive medullary thyroid carcinoma. It has a 100% response rate, an objective response rate of 44%, a median duration of response of 22 months, and a progression-free survival of 30.5 months (Wells SA Jr, et al.). J Clin Oncol , 2012, 10;30(2):134-141.), while vandetanib can also effectively prolong progression-free survival in 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 shown good therapeutic efficacy and broad application prospects; however, its severe liver and cardiotoxicity greatly limits its clinical application. Data indicate that more than 50% of patients have elevated alanine aminotransferase (ALT) levels, with 2% to 5% of these patients having ALT levels exceeding five 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, with reports showing QTc interval prolongation, ventricular tachycardia, and fatal heart failure during treatment. These side effects force patients to reduce the dosage or even discontinue the drug, which undoubtedly promotes disease progression and affects the patient's quality of life.
[0004] Currently, there are no effective means to intervene in the toxic side effects of vandetanib in clinical practice because its toxic mechanism is not yet clear. Given the irreplaceable role of vandetanib in the treatment of medullary thyroid carcinoma, researching effective intervention strategies is of great significance.
[0005] Tannic acid, a natural organic compound, is used as a food additive and is an important component of traditional Chinese medicine. Studies have reported 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.). There are currently no research reports on the intervention of tannic acid in the toxic side effects of vandetanib. Summary of the Invention
[0006] The purpose of this invention is to provide a drug that can alleviate the toxic reactions induced by the antitumor drug vandetanib, thereby reducing the liver toxicity, cardiotoxicity and other side effects caused by vandetanib alone through combination therapy.
[0007] To achieve the above objectives, the present invention adopts the following technical solution:
[0008] This invention provides the use of tannic acid in the preparation of medicaments for the prevention or treatment of hepatic and / or cardiac toxicity caused by vandetanib. The tannic acid has the CAS number 1401-55-4 and the molecular formula C2. 76 H 52 O 46 Its molecular weight is 1701.22.
[0009] Animal in vivo experiments have demonstrated that tannic acid has a significant alleviating effect on vandetanib-induced liver and heart damage, and can be used to prevent or treat vandetanib-induced liver and heart toxicity, thereby expanding the clinical application of vandetanib.
[0010] Furthermore, the liver toxicity caused by vandetanib includes elevated levels of at least one of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) in serum. Studies have shown that the upregulation of ALT and AST caused by vandetanib can be reversed by co-administration of tannic acid.
[0011] Furthermore, the liver toxicity side effects caused by vandetanib include: yellowing and anemia of the liver. Studies have shown that the above-mentioned liver damage symptoms are effectively alleviated when used in combination with tannic acid.
[0012] Furthermore, the hepatotoxic side effects induced by vandetanib include at least one of the following: blurred hepatocyte boundaries, disordered hepatocyte arrangement, hepatocyte vacuolation, and hepatocyte nuclear shrinkage. Studies have shown that the above-mentioned pathological manifestations of hepatocyte damage were significantly improved after the combined use of tannic acid.
[0013] Furthermore, the cardiotoxic side effects induced by vandetanib include at least one of the following: 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 decrease in heart weight / tibia length ratio, decreased cardiac function, and increased cardiomyocyte cross-sectional area caused by vandetanib.
[0014] Furthermore, the cardiac dysfunction includes a decrease in cardiac function indicators such as left ventricular ejection fraction and left ventricular fractional shortening.
[0015] Furthermore, the cardiotoxic side effects induced by vandetanib include: diffuse cytoplasm and vacuolation of cardiac tissue cells, and decreased density of cardiomyocytes. Studies have shown that the combined use of tannic acid significantly improves the aforementioned pathological manifestations of cardiac tissue damage.
[0016] In this invention, tannic acid, as the main active ingredient, can reverse the pathological phenomena of liver and myocardial damage induced by vandetanib.
[0017] The drug comprises an effective dose of tannic acid and a pharmaceutically acceptable carrier, and can be formulated according to pharmaceutically available methods. In mouse models, the dosage of tannic acid is 30 mg / kg, which is considered a safe and effective dose.
[0018] Another object of the present invention is to provide an antitumor combination drug comprising: a first formulation formed of vandetanib and a pharmaceutically acceptable carrier, and a second formulation formed of tannic acid or a salt thereof and a pharmaceutically acceptable carrier.
[0019] This invention provides an effective therapeutic agent for vandetanib-induced hepatotoxicity and cardiotoxicity. Animal experiments show that, compared with vandetanib monotherapy, the combination with tannic acid significantly inhibits liver and myocardial damage. Furthermore, the low dosage of tannic acid has no effect on animal survival, normal liver function, or normal cardiac function and structure, indicating that tannic acid is a reasonable and safe protective agent with high feasibility.
[0020] Furthermore, the mass ratio of tannic acid to vandetanib in the drug is 0.1 to 0.3:1.
[0021] Furthermore, the pharmaceutically acceptable carrier is a filler, wetting agent, binder, disintegrant, or lubricant. The drug dosage form is a liquid or solid dosage form, including oral solid dosage forms, oral liquid dosage forms, injections, lyophilized powder for injection, large-volume parenteral solutions, patches, ointments, gels, soft capsules, or suppositories.
[0022] The present invention also provides the application of the aforementioned antitumor combination drug in the preparation of a drug for treating medullary thyroid carcinoma or non-small cell lung cancer.
[0023] The beneficial effects of this invention are as follows:
[0024] (1) This invention provides a drug that can effectively treat the toxic side effects of vandetanib. Tannic acid can effectively reverse the liver and heart damage caused by vandetanib. Animal experiments show that, compared with the vandetanib monotherapy group, the liver and heart function of animals in the tannic acid combination group were significantly improved. The combination of tannic acid and vandetanib can alleviate the severe liver and heart damage caused by vandetanib in cancer patients, thereby greatly expanding the clinical use of tannic acid.
[0025] (2) The effective dose of tannic acid in the drug provided by the present invention will not affect the survival, physiological state, liver and heart function of animals, etc., and has high safety and high clinical feasibility. Attached Figure Description
[0026] Figure 1 The effects of vandetanib on liver function in mice are shown in Figure 1, where A represents the level of alanine aminotransferase (ALT), B represents the level of aspartate aminotransferase (AST), and C represents the level of lactate dehydrogenase (LDH).
[0027] Figure 2 Photographs of liver tissue after vandetanib treatment and HE staining results of liver sections.
[0028] Figure 3 The effect of tannic acid on vandetanib-induced transaminase levels in mice was investigated, where A represents the level of alanine aminotransferase (ALT) and B represents the level of aspartate aminotransferase (AST).
[0029] Figure 4 The effect of combined use of tannic acid on vandetanib-induced liver injury in mice is shown in Figure A, which is a photograph of liver tissue; and Figure B is the HE staining result of liver sections.
[0030] Figure 5 The effect of combined use of tannic acid on vandetanib-induced cardiac dysfunction is shown in the figure. The left figure represents the left ventricular ejection fraction, and the right figure represents the left ventricular fractional shortening.
[0031] Figure 6 To illustrate the effect of combined use of tannic acid on vandetanib-induced cardiac pathological damage in mice, A shows a photograph of cardiac tissue; B shows the HE staining results of cardiac sections.
[0032] Figure 7 The ratio of heart weight to tibia length in mice after administration of tannic acid.
[0033] Figure 8 To investigate the effect of combined use of tannic acid on vandetanib-induced myocardial hypertrophy in mice. Detailed Implementation
[0034] The present invention will be further described below with reference to specific embodiments. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Any modifications or substitutions made to the methods, steps, or conditions of the present invention without departing from the spirit and essence of the invention are within the scope of the invention.
[0035] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; the materials and reagents used are commercially available unless otherwise specified.
[0036] Vandetanil (CAS No. 443913-73-3), molecular formula C 22 H 24 BrFN4O2, with a molecular weight of 475.354, was purchased from Taoshu Biotechnology Co., Ltd. Tannic acid (CAS No. 1401-55-4), with the molecular formula C2... 76 H 52 O 46 The molecular weight is 1701.22, and it was purchased from Taoshu Biotechnology Co., Ltd.
[0037] C57BL / 6J mice were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.; sodium carboxymethyl cellulose (CMC-Na) was purchased from Shanghai Sinopharm Group.
[0038] Example 1: Vandetanib causes liver toxicity.
[0039] 1. Experimental Methods
[0040] Ten male C57BL / 6J mice were randomly divided into two groups: a control group and a vandetanib group. The control group received 0.5% CMC-Na, while the vandetanib group received 100 mg / kg / day. After four weeks of continuous administration, blood samples were collected via orbital sampling to detect the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH), biochemical markers of liver injury. The mice were then sacrificed, and the livers were dissected, photographed under normal light, embedded, and sectioned. The liver tissue sections were then stained with hematoxylin and eosin (HE).
[0041] 2. Experimental Results
[0042] Liver function test results as follows Figure 1As shown, the liver function indicators of the control group and the vandetanib group were 27.36 ± 2.42 U / L and 139.92 ± 18.10 U / L, respectively; aspartate aminotransferase (AST) was 129.24 ± 22.81 U / L and 229.74 ± 32.56 U / L, respectively; and lactate dehydrogenase (LDH) was 865.20 ± 106.02 U / L and 1458.60 ± 216.91 U / L, respectively. The data indicate that vandetanib caused upregulation of ALT, AST, and LDH in mice.
[0043] Liver tissue was photographed under normal light and liver sections were stained with hematoxylin and eosin (HE). The results are as follows: Figure 2 As shown in the photographs, the livers of mice in the vandetanib group were yellowish and bloodless, with a gritty appearance. HE staining results showed that vandetanib caused blurred cell boundaries, disordered and irregular cell arrangement, severe vacuolization, and obvious nucleus shrinkage in mouse liver cells, indicating that vandetanib induced liver damage in mice.
[0044] Example 2: Effect of combined use of tannic acid on hepatotoxicity induced by vandetanib
[0045] 1. Experimental Methods
[0046] Twenty-four male C57BL / 6J mice were randomly divided into four groups: a control group, a vandetanib group, a tannic acid group, and a vandetanib + tannic acid combination group, with six mice in each group. The drugs were administered via gavage. Vandetanib was administered at a dose of 100 mg / kg / day, and tannic acid at a dose of 30 mg / kg / day. The control group was treated with 0.5% CMC-Na. After four weeks of continuous administration, blood samples were collected via orbital sampling to detect serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), biochemical markers of liver injury. The mice were then sacrificed, and the livers were dissected. Liver tissue was photographed under normal light, embedded, sectioned, and stained with hematoxylin and eosin (HE).
[0047] 2. Experimental Results
[0048] Liver function test results as follows Figure 3As shown, the liver function indicators of alanine aminotransferase (ALT) in the control group, vandetanib group, tannic acid group, and vandetanib + tannic acid combination group were 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; and aspartate aminotransferase (AST) were 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 indicate that the upregulation of ALT and AST in mice induced by vandetanib was significantly reversed after the administration of tannic acid.
[0049] Liver tissue sections were photographed under normal light and stained with hematoxylin and eosin (HE). The results are as follows: Figure 4 As shown in the photographs (A), the obvious brownish-yellow and bloodless appearance of the liver in mice treated with vandetanib alone was effectively alleviated after the combined administration of tannic acid. HE staining results (B) showed that the morphological characteristics of the liver tissue caused by vandetanib alone—namely, blurred cell boundaries, disordered and irregular cell arrangement, severe vacuolization, and significantly shrunken cell nuclei—were significantly improved after the combined administration of tannic acid.
[0050] The above results collectively indicate that tannic acid can improve vandetanib-induced liver damage in mice.
[0051] Example 3: Effect of combined use of tannic acid on cardiotoxicity induced by vandetanib
[0052] 1. Experimental Methods
[0053] Twenty-four male C57BL / 6J mice were randomly divided into four groups: a control group, a vandetanib group, a tannic acid group, and a vandetanib + tannic acid combination group, with six mice in each group. The drugs were administered via gavage. Vandetanib was administered at a dose of 100 mg / kg / day, and tannic acid at a dose of 30 mg / kg / day. The control group received 0.5% CMC-Na instead of vandetanib. After four weeks of continuous administration, cardiac function was assessed using echocardiography. The mice were then sacrificed, and the hearts were dissected. Morphological changes were observed by radiographic imaging, and the heart weight / tibia length ratio (HW / TL) was measured. The heart tissue was fixed, embedded, and sectioned. HE staining was used to detect pathological changes in the mouse heart tissue, and WGA staining was used to analyze the hypertrophy of mouse cardiomyocytes.
[0054] 2. Experimental Results
[0055] Echocardiogram results as follows Figure 5As shown, the left ventricular ejection fraction (LVEF) of mice in the control group, vandetanib group, tannic acid group, and vandetanib + tannic acid combination group were 74.98 ± 6.29%, 59.47 ± 5.59%, 71.95 ± 5.00%, and 68.46 ± 3.32%, respectively; the left ventricular fractional shortening (FRM) was 43.48 ± 5.43%, 30.76 ± 3.68%, 40.82 ± 4.14%, and 37.49 ± 2.36%, respectively. This indicates that vandetanib can cause a decrease in cardiac function in mice, and the decrease in cardiac function induced by vandetanib was improved after the administration of tannic acid.
[0056] Normal light photography and HE staining results are as follows Figure 6 As shown in the image, normal light photography (A) shows that the hearts of mice treated with vandetanib were significantly smaller, indicating that vandetanib causes changes in cardiac structure. The combined use of tannic acid can partially reverse the vandetanib-induced decrease in heart size in mice. HE staining results (B) show that the cardiac tissue of mice in the vandetanib-treated group exhibited cytoplasmic diffusion, cell vacuolation, and decreased cardiomyocyte density. 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 vandetanib-induced cardiac pathological damage.
[0057] Heart weight / tibia length ratio (HW / TL) results are as follows Figure 7 As shown, the HW / TL values 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 is consistent with the results of normal light photography, indicating that the decrease in HW / TL value induced by vandetanib after the combination with tannic acid was significantly reversed.
[0058] WGA staining results are as follows Figure 8 As shown, the cross-sectional area of cardiomyocytes in the vandetanib-treated group was 199.21 ± 35.06 μm. 2 Compared with the control group, it was 157.69 ± 15.29 μm 2 The number of myocardial cells increased significantly after the combined use of tannic acid; the cross-sectional area of myocardial cells was 134.82 ± 24.28 μm. 2 This indicates that vandetanib can induce myocardial hypertrophy in mice, and that vandetanib-induced myocardial hypertrophy is improved after combined administration of tannic acid.
[0059] These results collectively indicate that tannic acid can improve vandetanib-induced cardiac injury in mice.
[0060] In summary, tannic acid can improve vandetanib-induced liver and heart damage. Vandetanib is an inhibitor of VEGFR, EGFR, and RET, and is a specific target inhibitor. Tannic acid does not have a direct effect on these targets. Therefore, the combined use of tannic acid does not affect the anticancer effect of vandetanib.
Claims
1. The use of tannic acid in the preparation of medicaments for the prevention or treatment of hepatic and / or cardiac toxicity caused by vandetanib, characterized in that, The liver toxicity side effects caused by vandetanib include: yellowing or bloodless liver color; at least one of the following: blurred hepatocyte boundaries, disordered hepatocyte arrangement, hepatocyte vacuolation, and hepatocyte nucleus shrinkage; The cardiotoxic side effects caused by vandetanib include at least one of the following: decreased heart weight / tibia length ratio, cardiac dysfunction, and myocardial hypertrophy. The cardiac dysfunction includes decreased cardiac function indicators such as left ventricular ejection fraction and left ventricular fractional shortening. Cardiac tissue cells exhibit cytoplasmic diffusion, cell vacuolation, and decreased myocardial cell density.
2. The application as described in claim 1, characterized in that, The liver toxicity caused by vandetanib includes elevated levels of at least one of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase in serum.
3. A combination antitumor drug, characterized in that, The drug comprises: a first formulation of vandetanib and a pharmaceutically acceptable carrier, and a second formulation of tannic acid or its salt form and a pharmaceutically acceptable carrier.
4. The antitumor combination drug as described in claim 3, characterized in that, The mass ratio of tannic acid to vandetanib in the drug is 0.1~0.3:
1.
5. The use of the antitumor combination drug as described in claim 3 in the preparation of a drug for treating medullary thyroid carcinoma or non-small cell lung cancer.