Application of calcium dobesilate in preparation of medicine for preventing or treating chemotherapeutic phlebitis

Abstract

The invention discloses application of calcium dobesilate in preparation of a medicine for preventing or treating chemotherapeutic phlebitis. The inventor uses fluorouracil to induce a mouse chemotherapeutic phlebitis model, and finds that intravenous injection calcium dobesilate not only has the advantage of rapid efficacy, but also has a blood vessel protection effect, can significantly improve pathological symptoms of chemotherapeutic phlebitis and callback expression of inflammatory factors, and has a good pre-protection effect on chemotherapeutic phlebitis.

Description

Technical Field

[0001] The invention relates to application of calcium dobesilate in preparing medicine for preventing or treating chemotherapy phlebitis. Background Art

[0002] Calcium dobesilate (trade names include Dobesilate, Dobesilate, and Andomin), chemical name 2,5-dihydroxybenzenesulfonate calcium monohydrate. As an established vascular protective drug, calcium dobesilate protects endothelial cells and improves microcirculation. Currently available dosage forms include capsules and dispersible tablets. Clinically, it is mainly used to treat diabetic retinopathy and achieves good results. In recent years, the application and research of calcium dobesilate has gradually expanded to renal fibrosis. [1] , atherosclerosis [2] wait.

[0003] Chemotherapy phlebitis is a disease caused by the infusion of highly irritating chemotherapy drugs, resulting in varying degrees of tissue necrosis and inflammation. Common drugs that are prone to chemotherapy phlebitis in clinic include fluorouracil, vinorelbine, and mitomycin. With the increasing number of cancer patients, the prevention of chemotherapy phlebitis has become an issue that needs to be explored and resolved urgently. Currently, commonly used preventive measures include intravenous infusion of dexamethasone, topical application of drugs, and microwave therapy, but they are accompanied by hormone side effects, cumbersome operation, and high prices.

[0004] Calcium dobesilate is available in capsules and dispersible tablets clinically. Therefore, developing an injection with simple ingredients, low side effects, rapid efficacy, and the ability to be injected into a peripherally inserted central catheter (PICC) in advance is of great significance for preventing chemotherapy-induced phlebitis. Summary of the invention

[0005] The inventors used fluorouracil to induce a mouse chemotherapy-induced phlebitis model and studied the preventive protective effect of intravenous calcium dobesilate on chemotherapy-induced phlebitis. They found that intravenous calcium dobesilate not only has the advantage of rapid efficacy, but also has a vascular protective effect. It can significantly improve the pathological symptoms of chemotherapy-induced phlebitis and adjust the expression of inflammatory factors, and has a good preventive protective effect on chemotherapy-induced phlebitis.

[0006] The purpose of the present invention is to provide the use of calcium dobesilate in preparing a medicine for preventing or treating chemotherapy phlebitis.

[0007] Preferably, the use is the use of calcium dobesilate in the preparation of a drug for preventing or treating chemotherapy-induced phlebitis by reducing inflammatory cell infiltration.

[0008] Preferably, the use is the use of calcium dobesilate in the preparation of a drug for preventing or treating chemotherapy-induced phlebitis by reducing the expression of IL-β, IL-6, TNF-α and VEGF.

[0009] Preferably, the dosage form of the drug is injection, lyophilized powder, capsule, or dispersible tablet.

[0010] The injection is prepared with calcium dobesilate as an effective ingredient, an antioxidant, and water for injection, or with an antioxidant, an osmotic pressure regulator, and water for injection; each 1000 mL injection contains: 1-10 g of calcium dobesilate, 1-10 g of an antioxidant, 0-50 g of an osmotic pressure regulator, and the remainder is water for injection, wherein the antioxidant is selected from sodium pyrosulfite or sodium sulfite; the osmotic pressure regulator is selected from sorbitol, NaCl or glucose.

[0011] Each 1000mL injection contains: 1-10g calcium dobesilate, 1-10g antioxidant, and the balance is water for injection; or each 1000mL injection contains: 1-10g calcium dobesilate, 1-10g antioxidant, 9-50g osmotic pressure regulator, and the balance is water for injection.

[0012] The calcium dobesilate injection of the present invention has simple ingredients, reliable drug efficacy, and low side effects, and can effectively prevent chemotherapy-induced phlebitis.

[0013] The freeze-dried powder is an injectable pharmaceutical preparation prepared by taking calcium dobesilate as an effective ingredient and adding a proper amount of freeze-dried protective agent; wherein the freeze-dried protective agent is mannitol or dextran.

[0014] The mass ratio of the calcium dobesilate to the lyophilization protective agent is 1:5.

[0015] Another object of the present invention is to provide a method for preparing the lyophilized powder, comprising: dissolving a lyophilization protective agent in water for injection, adding calcium dobesilate, and stirring until completely dissolved; adding water for injection until the final concentration of calcium dobesilate is 0.01 mg / mL, filtering with a 0.22 μm filter membrane, filling in a vial, and freeze drying to obtain the lyophilized powder; wherein the freeze drying curve of the freeze drying is as follows:

[0016] a) Adjust the temperature of the heat transfer oil in the freeze dryer to -5°C and place the vial in the freeze dryer;

[0017] b) Adjust the temperature of the heat transfer oil in the freeze dryer to -40°C and keep it for 2 hours after the sample temperature stabilizes;

[0018] c) Open the vacuum and raise the temperature to -15°C (heating rate 0.5°C / min). After the water line of the freeze-dried product disappears, raise the temperature of the heat transfer oil to 30°C within 2 hours;

[0019] d) When the product temperature reaches 25℃, close the diaphragm valve for 2 minutes. If the vacuum in the front box does not rise by more than 2Pa, it can be taken out of the box.

[0020] Preferably, the use is: administering calcium dobesilate as a pre-protective agent before administering a drug that is likely to cause chemotherapy phlebitis.

[0021] More preferably, the use is: pre-protective administration of calcium dobesilate 30 minutes before administration of drugs that are likely to cause chemotherapy phlebitis.

[0022] The drugs that are likely to cause chemotherapy phlebitis are fluorouracil, cytarabine, vinorelbine, mitomycin, doxorubicin, epirubicin, daunorubicin, mechlorethamine, cyclophosphamide, vincristine, vinblastine, cisplatin, carboplatin, paclitaxel, docetaxel, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The appearance of C57 mice was used to judge the phlebitis situation; A: phlebitis grade of mice; B: changes in the swelling degree of the mouse tail; C: changes in the weight of mice; Control: blank control group; Model: model group; Cim: positive control drug group; CaD-L: low-dose calcium dobesilate group; CaD-M: medium-dose calcium dobesilate group; CaD-H: high-dose calcium dobesilate group; n=8, compared with the Control group: ****P<0.0001.

[0024] Figure 2 Comparison of HE staining of tail vein of C57 mice (200 times); A: blank control group; B: model group; C: positive control drug group; D: low-dose calcium dobesilate group; E: medium-dose calcium dobesilate group; F: high-dose calcium dobesilate group.

[0025] Figure 3 The expression of VEGF-positive cells in the tail vein of C57 mice (200 times); A: blank control group; B: model group; C: positive drug control group; D: low-dose calcium dobesilate group; E: medium-dose calcium dobesilate group; F: high-dose calcium dobesilate group.

[0026] Figure 4The expression of serum inflammatory factors in C57 mice (low, medium and high doses injected intravenously); A: IL-1β level; B: IL-6 level; C: TNF-α level; Control: blank control group; Model: model group; Cim: positive drug control group; CaD-L: calcium dobesilate low-dose group; CaD-M: calcium dobesilate medium-dose group; CaD-H: calcium dobesilate high-dose group; n=8, compared with Control group: *** P < 0.001; **** P<0.0001; compared with the Model group: # P < 0.05; ## P < 0.01; ### P < 0.001; #### P<0.0001; ns, no significant difference.

[0027] Figure 5 The effects of different administration methods (intravenous injection, oral gavage) on the expression of serum inflammatory factors in C57 mice; A: IL-6 level; B: IL-1β level; Control: blank control group; Model: model group; CaD-iv: intravenous injection group; CaD-po: oral gavage group; n=8, compared with Control group: ** P<0.01; compared with the Model group: # P < 0.05; ## P < 0.01; ### P<0.001; ns, no significant difference. DETAILED DESCRIPTION

[0028] The technical solution of the present invention is further described below through specific implementation methods.

[0029] All data during the experiment are expressed as mean ± standard deviation. The statistical results were analyzed using T test and non-parametric test (one-way of ANOWA) in GraphPad Prism8. P < 0.05 indicated statistical significance.

[0030] Example 1

[0031] 1. Experimental Materials

[0032] 1. Experimental Animals

[0033] 80 SPF C57 BL / 6J male mice, 7-8 weeks old, weighing (23±2) g (female mice have thin blood vessels and large individual differences).

[0034] 2. Experimental drugs and reagents

[0035] Fluorouracil injection (Shanghai Xudong Haipu Pharmaceutical Co., Ltd., specification: 10mL: 0.25g); cimetidine injection (Sinopharm Group Rongsheng Pharmaceutical Co., Ltd., specification: 2mL: 0.2g); calcium dobesilate (Aladdin, C189068-25g); normal saline (Anhui Shuanghe Pharmaceutical Co., Ltd., specification: 500mL: 4.5g); universal tissue fixative (Wuhan Sevier Biotechnology Co., Ltd., specification: 500mL); EDTA fixative (Wuhan Sevier Biotechnology Co., Ltd., specification: 500mL).

[0036] 3. Drug preparation

[0037] Fluorouracil injection (25 mg / mL) was diluted to 20 mg / mL with normal saline.

[0038] Cimetidine injection (100 mg / mL) was diluted to 2 mg / mL with normal saline.

[0039] Calcium dobesilate injection: Weigh 8 mg of calcium dobesilate and dissolve it in 4 mL of normal saline to prepare a solution with a concentration of 2 mg / mL. Then dilute it with normal saline to a concentration of 1 mg / mL and 0.5 mg / mL in sequence.

[0040] 4. Experimental equipment

[0041] Disposable sterile insulin syringes (Bio-Dixon Medical, Inc., USA); electronic digital calipers (Harbin Measuring Tools & Cutting Tools Group Co., Ltd.); intravenous visualization mouse tail vein injection fixture (Chuangbo Global Biotechnology Co., Ltd., model: GEGD-Q9G); Powerwave X-type microplate reader (BioTek, USA); Milli-Q Gradient A10 ultrapure water machine (Millipore, USA); Minispin small high-speed centrifuge (Eppendorf, Germany).

[0042] (II) Experimental methods

[0043] 1. Animal grouping

[0044] The animals were randomly divided into 6 groups, namely blank control group, model group, positive drug control group (cimetidine group, Cim group), low-dose, medium-dose and high-dose calcium dobesilate groups, with 8 animals in each group; another 4 groups were set up, namely blank control group, model group, intravenous injection group and gavage group, with 8 animals in each group.

[0045] 2. Dose selection

[0046] With reference to the clinical dosage of calcium dobesilate tablets, cimetidine injection and fluorouracil injection, combined with the dosage used in relevant literature, the low, medium and high doses of calcium dobesilate injection in mice were determined to be 5, 10 and 20 mg / kg (calculated as calcium dobesilate), and the oral dose was 10 mg / kg; the intravenous dose of cimetidine injection in mice was 40 mg / kg (calculated as cimetidine), and the intravenous dose of fluorouracil injection in mice was 200 mg / kg (calculated as fluorouracil). The above three drugs were used as investigation drugs, positive drugs and modeling drugs, respectively, and the administration volume was 10 mL / kg.

[0047] 3. Selection of positive drugs

[0048] In addition to inhibiting gastric acid secretion as an H2 receptor antagonist, cimetidine can also exert anti-inflammatory and immunomodulatory effects by inhibiting the expression of IL-1β and E-selectin, and is widely used in skin diseases and vascular diseases. Wang et al. reported that cimetidine can reduce the occurrence of chemotherapy-induced phlebitis in mice induced by vinorelbine by inhibiting the expression of E-selectin. [3] .

[0049] 4. Modeling method

[0050] The positive drug control group, calcium dobesilate low-, medium-, and high-dose groups, and gavage group were injected with 20 mg / mL fluorouracil injection, 10 mL / kg, i.e. 200 mg / kg, through the tail vein for three days, once a day, to establish a stable chemotherapy-induced phlebitis mouse model; the blank control group was injected with normal saline, 10 mL / kg, through the tail vein for three days, once a day.

[0051] 5. Method of administration

[0052] In the positive drug control group, 4 mg / mL cimetidine injection was injected into the tail vein, 10 mL / kg, i.e. 40 mg / kg; in the low-, medium- and high-dose groups of calcium dobesilate, 0.5 mg / mL, 1 mg / mL and 2 mg / mL were injected respectively, i.e. 5 mg / kg, 10 mg / kg and 20 mg / kg, and the oral gavage dose was 10 mg / kg. The drug was administered for three days, once a day, and the model was established 30 minutes after the last administration.

[0053] 6. Observation indicators

[0054] 6.1 Appearance judgment

[0055] 6.1.1 Phlebitis classification

[0056] After the chemotherapy drug is injected, the blood vessels immediately contract and turn white, accompanied by the animal's restlessness and struggle. The resistance during intravenous injection gradually increases with the extension of the injection time. After the injection, the local vein and surrounding tissue at the injection point become hardened, and there is no obvious change in the control group. According to the standards formulated by the American Intravenous Nurses Association (INS), combined with the characteristics of animal experiments, the relevant pain indicators are removed. Phlebitis is divided into 5 levels:

[0057] Grade 0: no symptoms;

[0058] Grade 1: redness at the infusion site;

[0059] Grade 2: redness and edema at the infusion site;

[0060] Grade 3: redness and edema at the infusion site, with cord-like veins forming;

[0061] Grade 4: The infusion site becomes red and edematous, cord-like veins form, and pus exudates.

[0062] Grade 1 and above is considered as phlebitis.

[0063] 6.1.2 Swelling degree measurement

[0064] The dosage was calculated according to body weight and the drug was injected. After modeling, the diameter of the mouse tail was measured with an electronic digital caliper to observe the degree of swelling. The degree of swelling after modeling was significantly higher than that of the blank control group, and the difference was statistically significant, which was considered a successful modeling.

[0065] The calculation formula for swelling degree is:

[0066] Swelling (%) = (diameter of mouse tail on day n - diameter of mouse tail before first administration) / diameter of mouse tail before first administration × 100%

[0067] 4.1.3 Weight changes

[0068] Before administration every day, body weight was measured as a basis for administration and an auxiliary evaluation indicator of inflammation.

[0069] The results are as follows Figure 1 As shown, the phlebitis grade of the same batch reached grade 3 or above. The phlebitis grade standard stipulates that the model construction is successful if the grade is above grade 1. The results of swelling and weight changes showed that the swelling of the tail of the model group increased significantly, and the weight decreased significantly. The calcium dobesilate pre-protection group had a significant correction trend.

[0070] 6.2 Microscope observation

[0071] In order to more intuitively reflect the effect of calcium dobesilate on chemotherapy-induced phlebitis in mice, the inventors observed venous edema and infiltration of inflammatory factors by HE staining, and selected vascular endothelial growth factor (VEGF) for immunohistochemical analysis.

[0072] After the mice were killed by blood sampling, 1.5 cm of tail tissue was taken and quickly fixed in paraformaldehyde for 24 h, and then decalcified in EDTA decalcification solution for 9 days. Paraffin sections were made for hematoxylin and eosin (HE) staining, and immunohistochemical staining was performed to analyze the expression of vascular endothelial growth factor (VEGF). The tail vein injury, inflammatory cell infiltration, thrombosis and tissue edema of the mice were observed under an optical microscope.

[0073] HE staining can visually observe the degree of edema, inflammatory cell infiltration, and thrombosis of the mouse venous wall. The nuclei of inflammatory cells are larger and usually stained blue, and the dark red particles in the blood vessels are thrombi ( Figure 2 A, B, F), light red flakes are residual blood stasis ( Figure 2 D, E).

[0074] HE staining results Figure 2 As shown, compared with the mice in the blank control group, the mice in the model group had severe edema in the vascular wall and a large amount of infiltration of inflammatory factors. The intervention of calcium dobesilate and positive drugs improved the above symptoms, relieved edema, and had mild inflammatory infiltration.

[0075] Immunohistochemical analysis can judge the severity of the disease by the depth of brown-yellow coloration. VEGF is a diffusible endothelial cell-specific mitogen and vascular permeability factor that acts on endothelial cells to promote mitosis and thus induce angiogenesis. It also has a strong effect of promoting vascular permeability and increasing exudation. VEGF is generally expressed at a low level in normal adults and animals. Its expression level is related to the degree of endothelial cell damage and repair, the severity of inflammation, and thrombosis. [4] .

[0076] Immunohistochemistry results Figure 3 The results showed that compared with the blank control group mice, the expression of VEGF-positive cells in the model group was significantly increased, and the positive expression returned to normal levels after intervention with calcium dobesilate and positive drugs.

[0077] 6.3 Enzyme-linked immunosorbent assay (ELISA) analysis

[0078] Blood was collected from the eye sockets of mice, and 50 μL of blood was placed in a dry test tube. After the serum was separated, the upper serum was taken to test the content of inflammatory factors. Inflammatory response factors include interleukin-1β (IL-1β), tumor necrosis factor (TNF-α), interleukin-6 (IL-6), etc.

[0079] like Figure 4 As shown, the expression of inflammatory factors in mouse serum was detected by ELISA. Compared with the blank control group mice, the levels of IL-1β, IL-6, and TNF-α in the model group mice were significantly increased, and the expression levels of inflammatory factors could be significantly restored after protection by calcium dobesilate.

[0080] like Figure 5 As shown in the data, compared with the model group, the intravenous calcium dobesilate group of mice could significantly reduce the levels of IL-1β and IL-6 (P<0.01). The oral gavage group had no callback trend on the IL-6 of the model group, but had a significant reduction trend on the IL-1β of the model group (P<0.05), indicating that intravenous administration has a more significant effect than oral gavage.

[0081] In summary, calcium dobesilate can improve fluorouracil-induced chemotherapy phlebitis in mice by reducing the characteristic indicators of chemotherapy phlebitis, IL-1β, IL-6, TNF-α, and VEGF. Calcium dobesilate and positive drugs have similar anti-inflammatory effects, among which calcium dobesilate is better than positive drugs in reducing IL-6. This shows that calcium dobesilate has a significant therapeutic effect on chemotherapy phlebitis.

[0082] Example 2

[0083] The small volume injection of calcium dobesilate in this embodiment is composed of:

[0084] Calcium dobesilate 10g

[0085] Sodium metabisulfite 1g

[0086] Add water for injection to 1000mL;

[0087] The preparation method is as follows:

[0088] Step (1), take 800 mL of freshly prepared water for injection, heat to 40° C., add sodium metabisulfite, and stir until completely dissolved;

[0089] Step (2), adding calcium dobesilate and stirring until completely dissolved;

[0090] Step (3), after replenishing the water for injection, filter through a 0.22 μm filter membrane;

[0091] Step (4), each vial is filled with nitrogen and sealed in an ampoule of 5 mL, and sterilized by autoclave at 121° C. for 15 min.

[0092] Example 3

[0093] The small volume injection of calcium dobesilate in this embodiment is composed of:

[0094] Calcium dobesilate 10g

[0095] Sodium sulfite 2g

[0096] Sorbitol 50g

[0097] Add water for injection to 1000mL;

[0098] The preparation method is as follows:

[0099] Step (1) Take 800 mL of freshly prepared water for injection, heat it to 40° C., add sodium sulfite and sorbitol, and stir until completely dissolved;

[0100] Step (2) adding calcium dobesilate and stirring until completely dissolved;

[0101] Step (3) after replenishing the water for injection, filter through a 0.22 μm filter membrane;

[0102] Step (4) Each vial is filled with nitrogen and sealed in an ampoule of 5 mL, and sterilized by autoclave at 121° C. for 15 min.

[0103] Example 4

[0104] The calcium dobesilate large-volume injection of the present embodiment is composed of:

[0105] Calcium dobesilate 10g

[0106] Sodium metabisulfite 10g

[0107] NaCl 90g

[0108] Add water for injection to 10000mL;

[0109] The preparation method is as follows:

[0110] Step (1), take 2000 mL of freshly prepared water for injection, add sodium metabisulfite and NaCl, and stir until completely dissolved;

[0111] Step (2), adding calcium dobesilate and stirring until completely dissolved;

[0112] Step (3), after replenishing the water for injection, filter through a 0.22 μm filter membrane;

[0113] Step (4), fill each bottle with 50 mL of nitrogen and seal it in an infusion bottle, and sterilize it by autoclave at 121° C. for 20 min.

[0114] Example 5

[0115] The composition of the large-volume calcium dobesilate injection of the present embodiment is:

[0116] Calcium dobesilate 10g

[0117] Sodium sulfite 10g

[0118] Glucose 500g

[0119] Add water for injection to 10000mL;

[0120] The preparation method is as follows:

[0121] Step (1), take 2000 mL of freshly prepared water for injection, add sodium sulfite and glucose, and stir until completely dissolved;

[0122] Step (2), adding calcium dobesilate and stirring until completely dissolved;

[0123] Step (3), after replenishing the water for injection, filter through a 0.22 μm filter membrane;

[0124] Step (4), fill each bottle with 50 mL of nitrogen and seal it in an infusion bottle, and sterilize it by autoclave at 121° C. for 20 min.

[0125] Example 6

[0126] The composition of the lyophilized calcium dobesilate powder for injection in this embodiment is:

[0127] Calcium dobesilate 10g

[0128] Mannitol 50g

[0129] The preparation method is as follows:

[0130] Step (1), take 800 mL of freshly prepared water for injection, add mannitol, and stir until completely dissolved;

[0131] Step (2), adding calcium dobesilate and stirring until completely dissolved;

[0132] Step (3), adding water for injection to a total volume of 1000 mL;

[0133] Step (4), after filtering through a 0.22 μm filter membrane, the mixture is filled into vials at a rate of 5 ml per vial;

[0134] Step (5), freeze drying, the freeze drying curve is as follows:

[0135] a) Adjust the temperature of the heat transfer oil in the freeze dryer to -5°C and place the vial in the freeze dryer;

[0136] b) Adjust the temperature of the heat transfer oil in the freeze dryer to -40°C and keep it for 2 hours after the sample temperature stabilizes;

[0137] c) Open the vacuum and raise the temperature to -15°C (heating rate 0.5°C / min). After the water line of the freeze-dried product disappears, raise the temperature of the heat transfer oil to 30°C within 2 hours;

[0138] d) When the product temperature reaches 25℃, close the diaphragm valve for 2 minutes. If the vacuum in the front box does not rise by more than 2Pa, it can be taken out of the box;

[0139] e) Stoppering: After freeze-drying is completed, turn off the vacuum pump, introduce clean nitrogen into the front box, and stopper the product.

[0140] Step (6), unpacking and capping.

[0141] Example 7

[0142] The composition of the lyophilized calcium dobesilate powder for injection in this embodiment is:

[0143] Calcium dobesilate 10g

[0144] Dextran 50g

[0145] The preparation method is as follows:

[0146] Step (1), take 800 mL of freshly prepared water for injection, heat to 40° C., add dextran, and stir until completely dissolved;

[0147] Step (2), adding calcium dobesilate and stirring until completely dissolved;

[0148] Step (3), adding water for injection to a total volume of 1000 mL;

[0149] Step (4), after filtering through a 0.22 μm filter membrane, the mixture is filled into vials at a rate of 5 mL per vial;

[0150] Step (5), freeze drying, the freeze drying curve is as follows:

[0151] a) Adjust the temperature of the heat transfer oil in the freeze dryer to -5°C and place the vial in the freeze dryer;

[0152] b) Adjust the temperature of the heat transfer oil in the freeze dryer to -40°C and keep it for 2 hours after the sample temperature stabilizes;

[0153] c) Open the vacuum and raise the temperature to -15°C (heating rate 0.5°C / min). After the water line of the freeze-dried product disappears, raise the temperature of the heat transfer oil to 30°C within 2 hours;

[0154] d) When the product temperature reaches 25℃, close the diaphragm valve for 2 minutes. If the vacuum in the front box does not rise by more than 2Pa, it can be taken out of the box;

[0155] e) Stoppering: After freeze-drying is completed, turn off the vacuum pump, introduce clean nitrogen into the front box, and stopper the product.

[0156] Step (6), unpacking and capping.

[0157] References

[0158] [1] He Shiyang, Li Jun. Research progress of calcium dobesilate in the treatment of renal fibrosis[J]. Journal of Clinical Nephrology, 2023, 23(09): 774-778.

[0159] [2]NJAU F,HALLER H.Calcium Dobesilate Modulates PKCδ-NADPH Oxidase-MAPK-NF-κB Signaling Pathway to Reduce CD14,TLR4,and MMP9 Expression duringMonocyte-to-Macrophage Differentiation:Potential Therapeutic Implications forAtherosclerosis[J].Antioxidants(Basel,Switzerland),2021,10(11).DOI:10.3390 / antiox10111798.

[0160] [3]WANG Z,MA L,WANG

[0161] [4] Yang Wenqin. Experimental study and clinical observation on the prevention of fluorouracil-induced phlebitis with potato juice plus dexamethasone[D]. Shanxi Medical University, 2010.

Claims

1. Use of calcium dobesilate in the preparation of a medicament for preventing or treating chemotherapy-induced phlebitis.

2. The use according to claim 1, characterized in that: The application is the application of calcium dobesilate in the preparation of a medicine for preventing or treating chemotherapy-induced phlebitis by reducing inflammatory cell infiltration.

3. The use according to claim 1, characterized in that: The use is the use of calcium dobesilate in the preparation of a drug for preventing or treating chemotherapy-induced phlebitis by reducing the expression of IL-β, IL-6, TNF-α and VEGF.

4. The use according to claim 1, characterized in that: The dosage form of the medicine is injection, lyophilized powder, capsule and dispersible tablet.

5. The use according to claim 4, characterized in that: The injection is prepared with calcium dobesilate as an effective ingredient, an antioxidant, and water for injection, or with an antioxidant, an osmotic pressure regulator, and water for injection; each 1000 mL injection contains: 1-10 g of calcium dobesilate, 1-10 g of an antioxidant, 0-50 g of an osmotic pressure regulator, and the remainder is water for injection, wherein the antioxidant is selected from sodium pyrosulfite or sodium sulfite; the osmotic pressure regulator is selected from sorbitol, NaCl or glucose.

6. The use according to claim 5, characterized in that: Each 1000mL injection contains: 1-10g calcium dobesilate, 1-10g antioxidant, and the balance is water for injection; or each 1000mL injection contains: 1-10g calcium dobesilate, 1-10g antioxidant, 9-50g osmotic pressure regulator, and the balance is water for injection.

7. The use according to claim 4, characterized in that: The freeze-dried powder is an injectable pharmaceutical preparation prepared by taking calcium dobesilate as an effective ingredient and adding a proper amount of freeze-dried protective agent; wherein the freeze-dried protective agent is mannitol or dextran.

8. The use according to claim 7, characterized in that: The mass ratio of the calcium dobesilate to the lyophilization protective agent is 1:

5.

9. The use according to claim 1, characterized in that: Calcium dobesilate should be administered as a pre-emptive measure before administering drugs that are likely to cause chemotherapeutic phlebitis.

10. The use according to claim 1 or 9, characterized in that: Drugs that cause chemotherapy phlebitis are fluorouracil, cytarabine, vinorelbine, mitomycin, doxorubicin, epirubicin, daunorubicin, nitrogen mustard, cyclophosphamide, vincristine, vinblastine, cisplatin, carboplatin, paclitaxel, and docetaxel.

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