Use of a cefradine monohydrate in the manufacture of a medicament for the prevention of cisplatin ototoxicity

Abstract

The application discloses application of cefradine monohydrate in preparation of a drug for resisting cisplatin ototoxicity, and belongs to the field of drug use. The cefradine monohydrate is a first-generation semi-synthetic broad-spectrum cephalosporin and has a bactericidal effect. The application first finds that the cefradine monohydrate has a protective effect on HEI-OC1 cell damage, cochlea explant hair cells and mouse ototoxicity induced by cisplatin, is an antibiotic which can be developed into a drug for preventing and treating drug-induced deafness, and provides a new idea and a new scheme for preventing and treating cisplatin-induced ototoxicity in clinic, and has important social benefits and economic values.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical use research, specifically to the application of cefadroxil monohydrate in the preparation of anti-cisplatin ototoxic drugs. Background Technology

[0002] Hearing impairment is a global health problem. According to statistics from the World Health Organization (WHO), approximately 20.3% of the world's population, or 1.5 billion people, suffer from hearing loss. There are many causes of hearing loss, among which ototoxic drugs are a significant contributing factor.

[0003] Cisplatin is an effective chemotherapy drug widely used in cancer treatment, but its ototoxicity also seriously affects the quality of life of patients treated with cisplatin.

[0004] Cefadroxil monohydrate, also known as cephalosporin VI, is an organic compound and a first-generation semi-synthetic cephalosporin. It exhibits rapid and reliable bactericidal activity against methicillin-resistant Staphylococcus aureus and various other bacilli resistant to broad-spectrum antibiotics. Clinically, it is mainly used for infections of the respiratory tract, urinary tract, skin, and soft tissues, such as bronchitis, pneumonia, pyelonephritis, cystitis, ear, nose, and throat infections, enteritis, and dysentery. However, its application in treating hearing loss caused by cisplatin toxicity has not yet been studied.

[0005] Chinese patent CN114848836B discloses a conjugate and its application in treating inner ear diseases. The conjugate combines an inner ear-targeting peptide with a main drug for diagnosing, preventing, or treating inner ear diseases. The inner ear-targeting peptide assists the main drug in targeting the inner ear or specific structures and cells within the inner ear, achieving drug enrichment. This conjugate is precise, efficient, and improves the bioavailability of the drug in the inner ear.

[0006] Currently, research indicates that platinum-based drugs can cross the blood-endolymphatic barrier to enter the inner ear, causing hair cell death. Clinically, some drugs have been explored to prevent or treat cisplatin-induced hearing loss, but there are currently no clinically approved drugs for the treatment and prevention of cisplatin-induced hearing loss. Summary of the Invention

[0007] To overcome the above shortcomings, the present invention aims to provide the application of cefadroxil monohydrate in the preparation of anti-cisplatin ototoxic drugs, so as to solve the ototoxicity problem caused by cisplatin chemotherapy.

[0008] To achieve the above objectives, the technical solution provided in this application is as follows:

[0009] The application of cefadroxil monohydrate in the preparation of an anti-cisplatin ototoxicity drug, the anti-cisplatin ototoxicity drug comprising cefadroxil monohydrate.

[0010] Furthermore, the adult injection dose of the drug is 1-10 mg / kg, preferably 2-8 mg / kg.

[0011] Furthermore, the drug administration method includes oral administration, local administration, or injection administration.

[0012] Furthermore, the drug is made from a pharmaceutically acceptable carrier or excipient.

[0013] Furthermore, the oral drug preparations include oral liquids, tablets, powders, pellets, capsules, and granules; the injectable preparations are aqueous injections or sterile powders for injection; and the external preparations are drops, sprays, or gels.

[0014] The beneficial effects of this application, based on the above technical solutions, are as follows:

[0015] 1. This invention is the first to discover that cefadroxil monohydrate has the potential to inhibit cisplatin ototoxicity, and confirms at the cellular level, in cochlear explants and mouse models that the application of cisplatin after treatment with cefadroxil monohydrate can effectively reduce cisplatin-induced ototoxicity.

[0016] 2. The cefadroxil monohydrate-cisplatin combination therapy in this invention is simple and effective;

[0017] 3. The cefadroxil monohydrate in this invention is an FDA-approved drug, which can greatly shorten the time for drug development and approval and accelerate clinical translation. Attached Figure Description

[0018] Figure 1 This is a bar chart showing the inhibitory effect of different concentrations of cefadroxil monohydrate on cisplatin ototoxicity in HEI-OC1 cells according to the present invention.

[0019] Figure 2 This is a line graph showing the ABR audiometry values ​​of mice injected intraperitoneally with cefadroxil monohydrate injection at 5-6 weeks of age according to the present invention, after three cycles.

[0020] Figure 3 This is a structural diagram of the cochlear basilar membrane after three cycles of intraperitoneal injection of the drug in 5-6 week old mice according to the present invention, stained with immunofluorescence. Detailed Implementation

[0021] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments and the accompanying drawings. It should be understood that these descriptions are merely exemplary and not intended to limit the scope of the invention. Furthermore, descriptions of well-known structures and techniques are omitted in the following description to avoid unnecessarily obscuring the concept of the invention.

[0022] This invention is the first to discover that cefadroxil monohydrate can prevent or treat drug-induced hearing loss. Specific implementation methods are as follows:

[0023] Example 1: Protective effect of cefadroxil monohydrate against cisplatin-induced HEI-OC1 cell damage

[0024] 1.1 Experimental Methods

[0025] HEI-OC1 mouse cochlear hair cell line was grown to a confluence state in culture dishes, digested with 0.25% EDTA trypsin solution, and repeatedly and slowly pipetted to form a cell suspension. The suspension was then diluted to 5 x 10⁻⁶ cells / mL with DEME high-glucose medium (10% FBS). 4 Cells were seeded at a concentration of 100 μL / L in 96-well plates using diluted cell suspension and incubated statically at 37°C and 5% CO2 for 24 hours. Different drug concentrations (40 μM, 20 μM, 10 μM, 5 μM, 2.5 μM) were used to treat cells for 24 hours. The drug was then aspirated from the 96-well plates, and 50 μM cisplatin was added for further treatment for 24 hours. A control group was also included. Cell viability was then assessed by adding 10 μL of CCK-8 to each well and measuring the absorbance at 450 nm after 45 minutes. The absorbance was calculated using the following formula: As: Experimental group (treated with drug and cisplatin simultaneously).

[0026] Ac: Control group (cisplatin-only treatment)

[0027] Ab: Contains only culture medium, no cells present.

[0028] Cell viability = [(As-Ab) / (Ac-Ab)] x 100%

[0029] Statistical analysis methods: One-way ANOVA and significance analysis were performed using DPS software. P < 0.05 was considered significant.

[0030] like Figure 1 Twenty-four hours after cisplatin-induced modeling, the survival rate of the mouse cochlear hair cell line HEI-OC1 was significantly reduced. Cefadroxil monohydrate at concentrations of 2.5 μM, 5 μM, 10 μM, 20 μM and 40 μM could improve cisplatin-induced cell damage, with the 10 μM concentration showing the most significant improvement.

[0031] Example 2: Protective effect of cefadroxil monohydrate against cisplatin-induced hearing loss in mice

[0032] 2.1 Animal grouping and experimental methods

[0033] Five- to six-week-old C57 / BL6 wild-type mice were used for in vivo validation experiments. The numbered mice were randomly divided into five groups:

[0034] Group 1 (n=6): 25 mg / kg cefadroxil was injected first, followed by 3 mg / kg cisplatin half an hour later. Cisplatin was then injected for 4 consecutive days, followed by a 3-day break. One cycle was completed, and a total of three cycles were performed.

[0035] Group 2 (n=6): 50 mg / kg cefadroxil was injected first, followed by 3 mg / kg cisplatin half an hour later. Cisplatin was then injected for 4 consecutive days, followed by a 3-day break. One cycle was completed, and a total of three cycles were performed.

[0036] Group 3 (n=6): 75 mg / kg cefadroxil was injected first, followed by 3 mg / kg cisplatin half an hour later. Cisplatin was then injected for 4 consecutive days, followed by a 3-day break. This completed one cycle, and there were a total of three cycles.

[0037] Control group: Follow the procedure of the drug administration group, but replace all injected drugs with an equal volume of normal saline;

[0038] Control group: Cefadroxil injection was omitted from the treatment protocol. Mice were provided with the same sterile diet and water daily. After three cycles, the auditory brainstem response (ABR) test was performed, followed by cochlear tissue collection for examination.

[0039] 2.2 Auditory Brainstem Response (ABR) Test

[0040] Mice were anesthetized by intraperitoneal injection of sodium pentobarbital and placed on a 37°C constant-temperature mat in a shielded chamber. A detection electrode was inserted subcutaneously at the center of the mouse's head, a reference electrode was inserted subcutaneously below the left ear, and a grounding electrode was inserted subcutaneously on the lower back. A sound wave device was placed at the mouse's left ear, and stimulation was then performed at frequencies of 4kHz, 8kHz, 12kHz, 16kHz, 24kHz, and 32kHz, with the sound wave intensity gradually decreasing from 90dB to 10dB until it could not be recorded and was reproducible.

[0041] 2.3 Immunofluorescence staining of cochlear hair cells

[0042] Mice were euthanized and decapitated. Cochlear tissue was removed and fixed overnight in 4% paraformaldehyde (PFA). After decalcification with 10% EDTA solution, the cochlear basilar membrane was dissected under a dissecting microscope. Immunofluorescence staining was performed using hair cell marker antibody (Myosin 7a), and the tissue was observed under a laser confocal microscope.

[0043] like Figure 2 As shown, a hearing loss model was established in 5-6 week old mice by intraperitoneal injection of cisplatin and cephalexin. Audiometry was performed after three cycles. Injection of 75 mg / kg cephalexin monohydrate significantly improved hearing in the mice. Figure 3 As shown, different concentrations of cefadroxil monohydrate all have a protective effect against cisplatin toxicity, with the 75 mg / kg dose group showing the most significant improvement in mice.

[0044] It should be understood that the specific embodiments described above are merely illustrative or explanatory of the principles of the invention and do not constitute a limitation thereof. Therefore, any modifications, equivalent substitutions, improvements, etc., made without departing from the spirit and scope of the invention should be included within the protection scope of the invention. Furthermore, the appended claims are intended to cover all variations and modifications falling within the scope and boundaries of the appended claims, or equivalent forms of such scope and boundaries.

Claims

1. The application of cefadroxil monohydrate in the preparation of anti-cisplatin ototoxic drugs, characterized in that, Anti-cisplatin-induced ototoxicity drugs include cefadroxil monohydrate.

2. The application of cefadroxil monohydrate according to claim 1 in the preparation of anti-cisplatin ototoxic drugs, characterized in that, The drug administration methods include oral administration, local administration, or injection administration.

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