Use of calcium dobesilate in the preparation of a medicament for the prevention or treatment of chemotherapy-induced phlebitis

Abstract

The application discloses use of calcium dobesilate in preparation of a medicine for preventing or treating chemotherapy phlebitis. The inventor induces a mouse chemotherapy phlebitis model by using fluorouracil, and finds that intravenous injection of calcium dobesilate not only has the advantage of rapid drug effect, but also has a vascular protection effect, can significantly improve the pathological symptoms of chemotherapy phlebitis and adjust the expression of inflammatory factors, and has a good prophylactic effect on chemotherapy phlebitis.

Description

Technical Field

[0001] This invention relates to the use of calcium dobesilate in the preparation of medicaments for the prevention or treatment of chemotherapy-induced phlebitis. Background Technology

[0002] Calcium dobesilate (trade names include Dobesilate, Calcium Dobesilate, and Calcium Dobesilate), chemically known as calcium 2,5-dihydroxybenzenesulfonate monohydrate, is a proven vascular protectant with effects such as protecting endothelial cells and improving microcirculation. Currently available dosage forms include capsules and dispersible tablets. Clinically, it is primarily used to treat diabetic retinopathy with good efficacy. In recent years, the application and research of calcium dobesilate have gradually expanded to renal fibrosis. [1] Atherosclerosis [2] wait.

[0003] Chemotherapy-induced phlebitis is a condition characterized by varying degrees of tissue necrosis and inflammation caused by the infusion of highly irritating chemotherapy drugs. Common drugs that easily induce chemotherapy-induced phlebitis include fluorouracil, vinorelbine, and mitomycin. With the increasing number of cancer patients each year, the prevention of chemotherapy-induced phlebitis has become an urgent issue that needs to be explored and resolved. Currently used preventive measures include intravenous dexamethasone infusion, topical medication, and microwave therapy; however, these methods are often accompanied by side effects from hormones, are cumbersome to perform, and are expensive.

[0004] Calcium dobesilate is only available in capsules and dispersible tablets in clinical practice. Therefore, developing an injectable formulation with simple ingredients, low side effects, rapid efficacy, and the ability to be pre-injected into a PICC (peripherally inserted central catheter) is of great significance for the prevention of chemotherapy-induced phlebitis. Summary of the Invention

[0005] The inventors used fluorouracil to induce a mouse model of chemotherapy-induced phlebitis and studied the pre-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 restore the expression of inflammatory factors, thus having a good pre-protective effect on chemotherapy-induced phlebitis.

[0006] The purpose of this invention is to provide the use of calcium dobesilate in the preparation of medicaments for the prevention or treatment of chemotherapy-induced phlebitis.

[0007] Preferably, the use is that of calcium dobesilate in the preparation of a medicament for the prevention or treatment of chemotherapy-induced phlebitis by reducing inflammatory cell infiltration.

[0008] Preferably, the use is that of calcium dobesilate in the preparation of a medicament for the prevention or treatment of 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 an injection, lyophilized powder, capsule, or dispersible tablet.

[0010] The injection is made with calcium dobesilate as the active ingredient, along with 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 calcium dobesilate, 1–10 g antioxidant, 0–50 g osmotic pressure regulator, and the remainder is water for injection. The antioxidant is selected from sodium metabisulfite 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 remainder is water for injection; or each 1000mL injection contains: 1-10g calcium dobesilate, 1-10g antioxidant, 9-50g osmotic pressure regulator, and the remainder is water for injection.

[0012] The calcium dobesilate injection of this invention has a simple composition, reliable efficacy, and low side effects, and can effectively prevent chemotherapy-induced phlebitis.

[0013] The lyophilized powder is an injectable pharmaceutical preparation prepared by adding an appropriate amount of lyophilization protectant to calcium dobesilate as the active ingredient; wherein the lyophilization protectant is mannitol or dextran.

[0014] The mass ratio of calcium dobesilate to the freeze-drying protectant is 1:5.

[0015] Another object of the present invention is a method for preparing the aforementioned lyophilized powder, comprising: dissolving a lyophilization protectant in water for injection, then 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 through a 0.22 μm filter membrane; filling into vials; and lyophilizing to obtain the lyophilized powder; wherein the lyophilization curve of the aforementioned lyophilization is as follows:

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

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

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

[0019] d) After the product temperature reaches 25℃, close the middle diaphragm valve for 2 minutes. If the vacuum rise of the front chamber does not exceed 2pa, the product can be removed from the chamber.

[0020] Preferably, the intended use is to provide pre-protective administration of calcium dobesilate before administering drugs that are prone to causing chemotherapy-induced phlebitis.

[0021] More preferably, the intended use is to pre-protectively administer calcium dobesilate 30 minutes before administering a drug that is likely to cause chemotherapy-induced phlebitis.

[0022] The drugs that are prone to causing chemotherapy-induced phlebitis include fluorouracil, cytarabine, vinorelbine, mitomycin, doxorubicin, epirubicin, daunorubicin, mechlorethamine, cyclophosphamide, vincristine, vinblastine, cisplatin, carboplatin, paclitaxel, and docetaxel. Attached Figure Description

[0023] Figure 1 To assess phlebitis status in C57 mice based on their appearance; where A: phlebitis grading; B: tail swelling; C: body weight; Control: blank control group; Model: model group; Cim: positive control 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 veins in C57 mice (200x magnification); where 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 in the tail vein of C57 mice was 200-fold; where 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 4Serum inflammatory factor expression in C57 mice (low, medium, and high doses administered intravenously); where A: IL-1β level; B: IL-6 level; C: TNF-α level; Control: blank control group; Model: model group; Cim: positive control 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<0.001; **** P < 0.0001; Compared with the Model group: # P<0.05; ## P<0.01; ### P<0.001; #### P<0.0001; no significant difference in ns.

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

[0028] The technical solution of the present invention will be further described below through specific embodiments.

[0029] All data in the experiment are expressed as mean ± standard deviation. The statistical results were analyzed using the T-test and one-way ANOWA test in GraphPad Prism8, and P < 0.05 was considered statistically significant.

[0030] Example 1

[0031] (I) Experimental Materials

[0032] 1. Laboratory animals

[0033] Eighty male SPF grade C57 BL / 6J mice, 7-8 weeks old, weighing (23±2)g (female mice have finer blood vessels, and there is a large individual variation).

[0034] 2. Experimental drugs and reagents

[0035] Fluorouracil injection (Shanghai Xudong Haipu Pharmaceutical Co., Ltd., specification: 10mL: 0.25g); Cimetidine injection (Sinopharm Rongsheng Pharmaceutical Co., Ltd., specification: 2mL: 0.2g); Calcium dobesilate (Aladdin, C189068-25g); Normal saline (Anhui Shuanghe Pharmaceutical Co., Ltd., specification: 500mL: 4.5g); General-purpose tissue fixative (Wuhan Sewell Biotechnology Co., Ltd., specification: 500mL); EDTA fixative (Wuhan Sewell Biotechnology Co., Ltd., specification: 500mL).

[0036] 3. Drug preparation

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

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

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

[0040] 4. Experimental equipment

[0041] Disposable sterile insulin syringe (BD Medical Devices Co., Ltd., USA); Electronic digital caliper (Harbin Measuring & Cutting Tool Group Co., Ltd.); Vein-visible mouse tail vein injection fixation device (Chuangbo Global Biotechnology Co., Ltd., model: GEGD-Q9G); Powerwave X-type ELISA reader (BioTek, USA); Milli-Q Gradient A10 ultrapure water system (Millipore, USA); Minispin mini high-speed centrifuge (Eppendorf, Germany).

[0042] (II) Experimental Methods

[0043] 1. Animal grouping

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

[0045] 2. Dosage selection

[0046] Referring to the clinical dosages of calcium dobesilate tablets, cimetidine injection, and fluorouracil injection, and combining the dosages used in relevant literature, the low, medium, and high doses of calcium dobesilate injection for intravenous injection in mice were determined to be 5, 10, and 20 mg / kg (calculated as calcium dobesilate), respectively, with an oral gavage dose of 10 mg / kg; the intravenous injection dose of cimetidine injection in mice was 40 mg / kg (calculated as cimetidine), and the intravenous injection dose of fluorouracil injection in mice was 200 mg / kg (calculated as fluorouracil). These three drugs were used as experimental drugs, positive control drugs, and modeling drugs, respectively, with an administration volume of 10 mL / kg for each drug.

[0047] 3. Selection of positive control drugs

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

[0049] 4. Modeling methods

[0050] In the positive control group, the low-, medium-, and high-dose calcium dobesilate groups, and the gavage group, 20 mg / mL fluorouracil injection was injected via the tail vein (10 mL / kg, i.e., 200 mg / kg) once a day for three days to establish a stable mouse model of chemotherapy-induced phlebitis. In the blank control group, physiological saline was injected via the tail vein (10 mL / kg) once a day for three days.

[0051] 5. Administration method

[0052] In the positive control group, cimetidine injection at a dose of 4 mg / mL was administered via the tail vein, or 10 mL / kg, which is equivalent to 40 mg / kg. In the low, medium, and high dose groups of calcium dobesilate, injections of 0.5 mg / mL, 1 mg / mL, and 2 mg / mL, respectively, were administered, or 5 mg / kg, 10 mg / kg, and 20 mg / kg, respectively. The gavage dose was 10 mg / kg. The administration was carried out once a day for three days, with modeling occurring 30 minutes after the last administration.

[0053] 6. Observation Indicators

[0054] 6.1 Appearance Judgment

[0055] 6.1.1 Classification of phlebitis

[0056] Immediately after the injection of chemotherapy drugs, the blood vessels constricted and turned white, accompanied by restlessness and struggling in the animals. Resistance during intravenous injection gradually increased with the duration of the injection. The injection site and surrounding tissues hardened after injection, while the control group showed no significant changes. Following the standards established by the Infusion Nurses Association (INS) of America, and considering the characteristics of animal experiments, relevant pain indicators were removed. Phlebitis was classified into five grades:

[0057] Level 0: No symptoms;

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

[0059] Grade 2: Redness and swelling at the infusion site;

[0060] Grade 3: Redness and edema at the infusion site, with the formation of cord-like veins;

[0061] Grade 4: Redness and edema at the infusion site, formation of cord-like veins, and purulent exudate.

[0062] Grade 1 and above are considered phlebitis.

[0063] 6.1.2 Measurement of Swelling Degree

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

[0065] Formula for calculating the degree of swelling:

[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] Weigh yourself before administering medication each day, as this serves as the basis for medication administration and as an auxiliary indicator for evaluating inflammation.

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

[0070] 6.2 Microscopic observation

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

[0072] After euthanizing mice by blood collection, a 1.5 cm section of tail tissue was harvested and rapidly fixed in paraformaldehyde for 24 hours, followed by decalcification in EDTA decalcification solution for 9 days. Paraffin sections were prepared and stained with hematoxylin and eosin (HE). Immunohistochemical staining was performed to analyze the expression level of vascular endothelial growth factor (VEGF). Tail vein injury, inflammatory cell infiltration, thrombosis, and tissue edema were observed under a light microscope.

[0073] HE staining allows for direct observation of the degree of edema in the venous walls of mice, the extent of inflammatory cell infiltration, and thrombus formation. The larger nuclei of inflammatory cells are typically stained blue, while the dark red granular structures in the blood vessels represent thrombi. Figure 2 A, B, F), the light red flakes are residual blood clots ( Figure 2 D, E).

[0074] HE staining results are as follows Figure 2 As shown, compared with the blank control group mice, the model group mice had severe edema of the blood vessel wall and a large amount of inflammatory factors infiltration. The above symptoms were improved after intervention with calcium dobesilate and positive drug, the edema was relieved and the inflammation was mild.

[0075] Immunohistochemical analysis can assess disease severity by the intensity of brown-yellow staining. VEGF is a diffusible endothelial cell-specific mitogen and vascular permeability factor. It acts on endothelial cells to promote mitosis and thus angiogenesis, while also strongly increasing vascular permeability and exudation. VEGF expression levels are generally low in normal adults and animals. Its expression level is related to the degree of endothelial cell damage repair, the severity of inflammation, and thrombosis. [4] .

[0076] Immunohistochemical results as follows 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 control drugs.

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

[0078] Blood was collected from the orbital region of mice, and 50 μL of blood was placed in a dried test tube. After serum separation, the supernatant serum was used to test the levels of inflammatory factors. Inflammatory factors include interleukin-1β (IL-1β), tumor necrosis factor (TNF-α), and interleukin-6 (IL-6).

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

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

[0081] In summary, calcium dobesilate can improve fluorouracil-induced chemotherapy-induced phlebitis in mice by reducing characteristic markers of chemotherapy-induced phlebitis, including IL-1β, IL-6, TNF-α, and VEGF. Calcium dobesilate and the positive control drug have similar anti-inflammatory effects, with calcium dobesilate showing a superior effect in reducing IL-6 compared to the positive control drug. This indicates that calcium dobesilate has a significant therapeutic effect on chemotherapy-induced phlebitis.

[0082] Example 2

[0083] The composition of the small-volume calcium dobesilate injection solution in this embodiment is as follows:

[0084] Calcium dobesilate 10g

[0085] 1g of sodium metabisulfite

[0086] Add water for injection to a final volume of 1000 mL;

[0087] The preparation method is as follows:

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

[0089] Step (2): Add calcium dobesilate and stir until completely dissolved;

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

[0091] Step (4): Fill each ampoule with nitrogen at a rate of 5 mL and autoclave at 121°C for 15 min.

[0092] Example 3

[0093] The composition of the small-volume calcium dobesilate injection solution in this embodiment is as follows:

[0094] Calcium dobesilate 10g

[0095] 2g of sodium sulfite

[0096] Sorbitol 50g

[0097] Add water for injection to a final volume of 1000 mL;

[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) Add calcium dobesilate and stir until completely dissolved;

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

[0102] Step (4) Fill each ampoule with nitrogen at 5 mL and autoclave at 121°C for 15 min.

[0103] Example 4

[0104] The composition of the calcium dobesilate injection solution in this embodiment is as follows:

[0105] Calcium dobesilate 10g

[0106] 10g sodium metabisulfite

[0107] NaCl 90g

[0108] Add water for injection to a final volume of 10,000 mL;

[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): Add calcium dobesilate and stir until completely dissolved;

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

[0113] Step (4): Fill each bottle with nitrogen at 50 mL and seal it in an infusion bottle. Sterilize by autoclaving at 121°C for 20 min.

[0114] Example 5

[0115] The composition of the large-volume calcium dobesilate injection solution in this embodiment is as follows:

[0116] Calcium dobesilate 10g

[0117] 10g of sodium sulfite

[0118] 500g of glucose

[0119] Add water for injection to a final volume of 10,000 mL;

[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): Add calcium dobesilate and stir until completely dissolved;

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

[0124] Step (4): Fill each bottle with nitrogen at 50 mL and seal it in an infusion bottle. Sterilize by autoclaving at 121°C for 20 min.

[0125] Example 6

[0126] The composition of the injectable calcium dobesilate lyophilized powder in this embodiment is as follows:

[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): Add calcium dobesilate and stir until completely dissolved;

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

[0133] Step (4): After filtration through a 0.22μm filter membrane, fill each vial with 5ml.

[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℃, and place the vial in the freeze dryer;

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

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

[0138] d) After the product temperature reaches 25℃, close the middle diaphragm valve for 2 minutes. If the vacuum rise of the front chamber does not exceed 2pa, the product can be removed from the chamber.

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

[0140] Step (6): Remove from box and roll up the lid.

[0141] Example 7

[0142] The composition of the injectable calcium dobesilate lyophilized powder in this embodiment is as follows:

[0143] Calcium dobesilate 10g

[0144] 50g dextran

[0145] The preparation method is as follows:

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

[0147] Step (2): Add calcium dobesilate and stir until completely dissolved;

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

[0149] Step (4): After filtration through a 0.22μm filter membrane, fill each vial with 5mL.

[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℃, and place the vial in the freeze dryer;

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

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

[0154] d) After the product temperature reaches 25℃, close the middle diaphragm valve for 2 minutes. If the vacuum rise of the front chamber does not exceed 2pa, the product can be removed from the chamber.

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

[0156] Step (6): Remove from box and roll up the lid.

[0157] References

[0158] [1] He Shiyang, Li Jun. Research progress on 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 by adding potato juice and dexamethasone [D]. Shanxi Medical University, 2010.

Claims

1. Use of calcium dobesilate for the preparation of a medicament for the prevention of chemotherapy-induced phlebitis, characterized in that, The drugs causing chemotherapy phlebitis are fluorouracil, cytarabine, vinorelbine, mitomycin, doxorubicin, epirubicin, daunorubicin, nitrogen mustard, cyclophosphamide, vincristine, vinblastine, cisplatin, carboplatin, paclitaxel, docetaxel; The dosage form of the drug is injection or lyophilized powder.

2. Use according to claim 1, characterized in that: The injection takes calcium dobesilate as effective component, is prepared with antioxidant and injection water, or is prepared with antioxidant, osmotic pressure regulator and injection water; 1000 mL injection contains 1-10 g calcium dobesilate, 1-10 g antioxidant, 0-50 g osmotic pressure regulator, and the rest is injection water; the antioxidant is selected from sodium metabisulfite or sodium sulfite; the osmotic pressure regulator is selected from sorbitol, NaCl or glucose.

3. Use according to claim 2, characterized in that: 1000 mL injection contains 1-10 g calcium dobesilate, 1-10 g antioxidant, and the rest is injection water; or 1000 mL injection contains 1-10 g calcium dobesilate, 1-10 g antioxidant, 9-50 g osmotic pressure regulator, and the rest is injection water.

4. Use according to claim 1, characterized in that: The lyophilized powder takes calcium dobesilate as effective component, and is prepared by adding appropriate amount of lyophilization protective agent to obtain injectable pharmaceutical preparation; the lyophilization protective agent is mannitol or dextran.

5. Use according to claim 4, characterized in that: The mass ratio of calcium dobesilate to lyophilization protective agent is 1:5.

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