WO2024058527A1 - Composition pharmaceutique pour la prévention ou le traitement de la perte auditive comprenant de l'ésoméprazole ou du dexlansoprazole en tant que principe actif - Google Patents

Composition pharmaceutique pour la prévention ou le traitement de la perte auditive comprenant de l'ésoméprazole ou du dexlansoprazole en tant que principe actif Download PDF

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Publication number
WO2024058527A1
WO2024058527A1 PCT/KR2023/013653 KR2023013653W WO2024058527A1 WO 2024058527 A1 WO2024058527 A1 WO 2024058527A1 KR 2023013653 W KR2023013653 W KR 2023013653W WO 2024058527 A1 WO2024058527 A1 WO 2024058527A1
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hearing loss
esomeprazole
dexlansoprazole
pharmaceutical composition
cisplatin
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PCT/KR2023/013653
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English (en)
Korean (ko)
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최준
이인균
허우영
전한울
Original Assignee
고려대학교 산학협력단
한국과학기술연구원
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Priority claimed from KR1020230119511A external-priority patent/KR20240036481A/ko
Application filed by 고려대학교 산학협력단, 한국과학기술연구원 filed Critical 고려대학교 산학협력단
Publication of WO2024058527A1 publication Critical patent/WO2024058527A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating hearing loss containing Esomeprazole or Dexlansoprazole as an active ingredient.
  • cisplatin cis-diamminedichloroplatinum II
  • cisplatin cis-diamminedichloroplatinum II
  • Cisplatin enters cells by diffusion or a transporter and is hydrated, thereby lowering the chloride concentration inside the cell and releasing chloride ions.
  • the hydrated form of cisplatin cross-links with nucleotides in nuclear and mitochondrial DNA to form adducts, inhibiting the unrestricted replication of cancer cells.
  • cisplatin causes nephrotoxicity, neurotoxicity, and ototoxicity as side effects in normal tissues.
  • ototoxicity induced by cisplatin can cause irreversible sensorineural hearing loss, or hearing loss, and is a more serious problem, especially in the pediatric population.
  • Hearing loss can greatly impair a patient's quality of life. In particular, it can have a significant impact on social development such as language acquisition and speech in pediatric patients.
  • cisplatin inhibits the death receptor pathway, endoplasmic reticulum-stress pathway, and mitochondrial reactive oxygen species in normal cells. It has been shown to activate the mitochondrial reactive oxygen species (ROS)-generating pathway, which ultimately leads to cell death.
  • ROS mitochondrial reactive oxygen species
  • Excessive ROS production is believed to be the main cause of cisplatin-induced ototoxic hearing loss, and is also considered to be a direct attack of cisplatin on DNA.
  • the organ of Corti, spiral ganglion and lateral wall within the cochlea have been suggested to be key targets of cisplatin for potent ROS generation.
  • the purpose of the present invention is to provide a pharmaceutical composition for preventing or treating hearing loss containing Esomeprazole or Dexlansoprazole as an active ingredient.
  • Another object of the present invention is to provide a health functional food composition for preventing or improving hearing loss containing Esomeprazole or Dexlansoprazole as an active ingredient.
  • Another object of the present invention is to provide a reagent composition for inhibiting cisplatin uptake of OCT2 (Organ Cation Transporter 2) protein in hair cells containing Esomeprazole or Dexlansoprazole as an active ingredient.
  • OCT2 Organic Transporter 2
  • Another object of the present invention is one or more proton pump inhibitors selected from Esomeprazole or Dexlansoprazole; and a drug selected from anticancer drugs or aminoglucoside antibiotics, wherein the proton pump inhibitor inhibits the drug absorption by OCT2 (Organ Cation Transporter 2) protein in hair cells and improves hair cell survival.
  • OCT2 Organic Cation Transporter 2
  • the present invention provides a pharmaceutical composition for preventing or treating hearing loss containing Esomeprazole or Dexlansoprazole as an active ingredient.
  • the present invention provides a health functional food composition for preventing or improving hearing loss containing Esomeprazole or Dexlansoprazole as an active ingredient.
  • the present invention provides a reagent composition for inhibiting cisplatin uptake of OCT2 (Organ Cation Transporter 2) protein in hair cells containing Esomeprazole or Dexlansoprazole as an active ingredient.
  • OCT2 Organic Transporter 2
  • the present invention relates to one or more proton pump inhibitors selected from Esomeprazole or Dexlansoprazole; and a drug selected from anticancer drugs or aminoglucoside antibiotics, wherein the proton pump inhibitor inhibits the drug absorption by OCT2 (Organ Cation Transporter 2) protein in hair cells and improves hair cell survival.
  • OCT2 Organic Cation Transporter 2
  • a pharmaceutical composition containing Esomeprazole or Dexlansoprazole as an active ingredient is It can be used to prevent and treat hearing loss, a side effect of using the anticancer drug cisplatin.
  • Figure 1 shows the results of analyzing the cytotoxicity of Cisplatin in auditory cells. ns; not significant, ****p ⁇ 0.0001.
  • Figure 2 shows the results of a compound screening analysis to identify substances showing a cytoprotective effect against cytotoxicity caused by cisplatin in auditory cells.
  • Figure 3 shows the results of analyzing the cytoprotective effect against cytotoxicity caused by cisplatin in auditory cells of the eight primary active substances identified through the above compound screening. *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001, ****p ⁇ 0.0001.
  • Figure 4 shows the results of analyzing the cytoprotective effect of Esomeprazole and Dexlansoprazole against cytotoxicity caused by cisplatin in auditory cells. *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001, ****p ⁇ 0.0001.
  • Figures 5 and 6 show the results of analyzing the cytoprotective effect of esomeprazole and dexlansoprazole against apoptosis caused by cisplatin in auditory cells.
  • Figure 7 shows the results of analyzing the effect of esomeprazole and dexlansoprazole on OCT2 (Organ Cation Transporter 2). ***p ⁇ 0.001
  • Figure 8 shows the results of analyzing the cytoprotective effect of esomeprazole against cell death caused by cisplatin in an animal model. ****p ⁇ 0.0001.
  • the present invention provides a pharmaceutical composition for preventing or treating hearing loss containing Esomeprazole or Dexlansoprazole as an active ingredient.
  • the hearing loss may be selected from ototoxic hearing loss, sudden hearing loss, noise-induced hearing loss, or age-related hearing loss, but is not limited thereto.
  • the ototoxic hearing loss may be caused by drugs selected from anticancer drugs or aminoglucoside antibiotics.
  • the anticancer agent may be cisplatin or carboplatin, but is not limited thereto.
  • the aminoglucoside antibiotics include amikacin, arbekacin, kanamycin, gentamicin, neomycin, netilmicin, and dibekacin. , sisomycin, streptomycin, tobramycin, ribodomycin, and paromomycin, but is not limited thereto.
  • Esomeprazole or Dexlansoprazole can inhibit the uptake of cisplatin by OCT2 (Organ Cation Transporter 2) protein in hair cells.
  • OCT2 Organic Transporter 2
  • the pharmaceutical composition may contain suitable carriers, excipients, disintegrants, sweeteners, coating agents, bulking agents, lubricants, lubricants, flavoring agents, antioxidants, buffers, bacteriostatic agents, etc. commonly used in the preparation of pharmaceutical compositions. It may further include one or more additives selected from the group consisting of diluents, dispersants, surfactants, binders, and lubricants.
  • carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, and microcrystalline.
  • Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil can be used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, and capsules.
  • Such solid preparations can be prepared by mixing the composition with at least one or more excipients, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc.
  • excipients such as starch, calcium carbonate, sucrose or lactose, gelatin, etc.
  • lubricants such as magnesium styrate and talc can also be used.
  • Liquid preparations for oral use include suspensions, oral solutions, emulsions, and syrups.
  • various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included.
  • Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, etc.
  • Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate.
  • injectable ester such as ethyl oleate.
  • As a base for suppositories witepsol, macrogol, tween 61, cacao, laurin, glycerogeratin, etc. can be used.
  • the pharmaceutical composition is intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, intrasternal, transdermal, intranasal, inhalational, topical, rectal, oral, intraocular or It can be administered to a subject in a conventional manner via the intradermal route.
  • the dosage of the active ingredient according to the present invention may vary depending on the subject's condition and weight, type and degree of disease, drug form, administration route and period, and may be appropriately selected by a person skilled in the art, and the daily dosage is 0.01 mg.
  • Administration may be administered once a day or divided into several administrations, and the scope of the present invention is not limited thereby.
  • the present invention provides a health functional food composition for preventing or improving hearing loss containing Esomeprazole or Dexlansoprazole as an active ingredient.
  • the health functional food includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavors, colorants and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, It may contain organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. In addition, it may contain pulp for the production of natural fruit juice, synthetic fruit juice, and vegetable drinks. These ingredients can be used independently or in combination.
  • the health functional food composition may be in the form of any one of meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, gum, ice cream, soup, beverages, tea, functional water, drink, alcohol, and vitamin complex. It can be.
  • the above-mentioned health functional food may additionally contain food additives, and its suitability as a “food additive” is determined according to the general provisions and general test methods of the Food Additives Code approved by the Food and Drug Administration, unless otherwise specified. Determination is made according to relevant standards and standards.
  • Items listed in the "Food Additives Code” include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as subchromic pigment, licorice extract, crystalline cellulose, cold pigment, and guar gum, L -Mixed preparations such as sodium glutamate preparations, noodle-added alkaline preparations, preservative preparations, and tar color preparations are included.
  • the content of the active ingredients added to the food can be appropriately adjusted as needed, and is preferably added in an amount of 1 to 90 parts by weight per 100 parts by weight of the food. .
  • the present invention provides a reagent composition for inhibiting cisplatin uptake of OCT2 (Organ Cation Transporter 2) protein in hair cells containing Esomeprazole or Dexlansoprazole as an active ingredient.
  • OCT2 Organic Transporter 2
  • the present invention relates to one or more proton pump inhibitors selected from Esomeprazole or Dexlansoprazole; and a drug selected from anticancer drugs or aminoglucoside antibiotics, wherein the proton pump inhibitor inhibits the drug absorption by OCT2 (Organ Cation Transporter 2) protein in hair cells and improves hair cell survival.
  • OCT2 Organic Cation Transporter 2
  • HEI-OC1 cells House Ear Institute, Los Angeles, CA, USA
  • DMEM Dulbecco modified eagle medium, Welgene, Korea
  • IFN- ⁇ interferon gamma, Peprotech, USA
  • HEK293T cells CL-1573; American Type Culture Collection, Rockville, MD
  • a cell line derived from human embryonic kidney were grown in DMEM medium supplemented with 1% penicillin-streptomycin solution (Welgene) and 8% FBS. , cultured at 37°C and 5% CO 2 conditions.
  • CIS a protective effect against cytotoxicity by cisplatin
  • 923 FDA-approved drugs purchased from Prestwick Chemical. 923 drugs were evenly distributed in 100 ⁇ L culture medium of a 96-well plate, and cells cultured for 18 hours were treated with 0.5 ⁇ L of each drug so that the final drug concentration was 50 ⁇ M. After 2 hours, 20 ⁇ M CIS was added.
  • a well containing only DMSO (Dimethyl sulfoxide) was set as a negative control, and a well containing only 2mM erdosteine (erdosteine, Sigma-Aldrich, St.
  • HEI-OC1 cells were evenly distributed at 100 ⁇ L each at 1,000 cells/well using medium without IFN- ⁇ in a 96-well plate.
  • the distributed HEI-OC1 cells were cultured at 33°C and 10% CO 2 for 16 hours before being treated with the effective substance of Experimental Example 2.
  • the cultured HEI-CO1 cells were first treated with the active substance at different concentrations and cultured for 2 hours. Then, to induce cytotoxicity, the medium was replaced with 20 ⁇ M CIS and cultured for 48 hours. The control group was treated with DMSO without treatment with the active substance and then cultured under the same conditions.
  • Cell viability was measured by measuring ATP levels using the CellTiter-Glo assay (Promega Corp., Madison, WI, USA). 50 ⁇ L of ATP detection solution was added to each well of the plate containing cells in 100 ⁇ L of culture medium, reacted in the dark at room temperature for 10 minutes, and then luminescence was measured using an automated EnVision plate reader (Perkin-Elmer, Waltham, MA, USA). did. The experiment was repeated three times independently, and the results were calculated from six independent wells.
  • V-FITC fluorescein isothiocyanate
  • PI propidium iodide
  • HEK293T cells were transiently transfected with a plasmid expressing human organic cation transporter (hOCT2).
  • hOCT2 human organic cation transporter
  • One day before transfection HEK293T cells were subcultured at a density of 1 ⁇ 10 6 for 24 hours to reach 70-80% cell confluency. It was transfected with polyethylenimine (PEI) and hOCT2-expressing plasmid.
  • PEI polyethylenimine
  • HEK293T cells transfected using an empty vector that does not express hOCT were set as a control group.
  • the transfected HEK293T cells were evenly distributed at 100,000 cells/well in black poly L-lysine-coated 96-well plates (Greiner Bio-One, Frickenhausen, Germany) and cultured for 18 hours. Afterwards, the cells were washed twice with assay buffer (Hanks' Balanced Salt SolutionL; HBSS) (containing 5.6mM D-glucose, pH 7.4) stored at room temperature, and the active substance (esomeprazole or dexlansoprazole) was added by concentration ( 0.0001 ⁇ 1000 ⁇ M) and reacted for 5 minutes.
  • assay buffer Horte' Balanced Salt SolutionL; HBSS
  • active substance esomeprazole or dexlansoprazole
  • Fluorescence uptake assay was started by adding uptake buffer containing 10 ⁇ M fluorescent substrate organic cation 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP+). After reacting at room temperature for 3 minutes, the reaction mixture was aspirated and washed twice with assay buffer containing 500 ⁇ M cimetidine to terminate the reaction. Afterwards, 100 ⁇ L RIPA buffer was added and the cells were lysed at room temperature for 5 minutes. ASP+fluorescence was measured at 485 nm and 500 nm for excitation and emission, respectively, using an EnVision plate reader (Perkin-Elmer).
  • ASP+fluorescence was measured at 485 nm and 500 nm for excitation and emission, respectively, using an EnVision plate reader (Perkin-Elmer).
  • Transgenic zebrafish (Brn3C:EGFP) embryos were obtained through mating of adult zebrafish maintained at 28.5°C at the zebrafish facility at Korea University Ansan Hospital.
  • Naturally occurring green neuromasts from transgenic zebrafish (Brn3C:EGFP) which can be viewed without staining using a fluorescence microscope, were used to monitor ototoxicity.
  • Five days after fertilization, transgenic zebrafish embryos were fed live paramecia and plant-based food.
  • Embryos were maintained in embryo medium (1mM MgSO 4 , 120 ⁇ M KH 2 PO 4 , 74 ⁇ M Na 2 HPO 4 , 1mM CaCl 2 , 500 ⁇ M KCl, 15 ⁇ M NaCl, and 500 ⁇ M NaHCO 3 ) at a density of approximately 50 embryos per 100mm 2 Petri dish.
  • This animal experiment was conducted with approval from Korea University's Animal Experiment Practice Committee (approval number: KOREA-2022-0097). All protocols were performed in accordance with the guidelines of the Korea University Medical Center Animal Care and Ethics Committee and the National Institutes of Health.
  • CIS solution was prepared by adding pure CIS to embryo medium. At 5 days after zebrafish fertilization, 27 zebrafish embryos were incubated in solvent control (EtOH 1.36%), 1000 ⁇ M CIS (Sigma-Aldrich) and esomeprazole (Aldrich, Milwaukee, WI, USA) (2, 20 and 200 ⁇ M) for 4 days. exposed for a period of time. Afterwards, the embryos were washed three times with embryonic medium and anesthetized with tricaine (MS-222, Sigma-Aldrich, Darmstadt, Germany, A5040) for 5 minutes.
  • solvent control EtOH 1.36%
  • 1000 ⁇ M CIS Sigma-Aldrich
  • esomeprazole Aldrich, Milwaukee, WI, USA
  • Cells within the neurosphere of zebrafish were identified using an in-situ cell detection kit (Roche Molecular Biochemicals, Mannheim, Germany) and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL) method (according to the manufacturer's instructions). Death was analyzed. Embryos were exposed to medium containing 1000 ⁇ M CIS and 200 ⁇ M esomeprazole for 4 h. Afterwards, the embryos were washed with PBS and fixed with 4% paraformaldehyde.
  • embryos were incubated in 50 mL of TUNEL reaction mixture (TdT and fluorescein-dUTP) at 37°C for 60 min. Zebrafish were analyzed using an AxioCam MRc5 fluorescence microscope (Nikon, Spinning Disc Confocal Microscope).
  • the primary effective substance was administered to HEI-OC1 cells at different concentrations (8, 20, and 100 ⁇ M).
  • all eight active substances showed significant cell protection effects at all treatment concentrations, of which five active substances (esomeprazole, dexlansoprazole, emtricitabine, metoprolol, and cimetidine) ) showed a dose-dependent cytoprotective effect.
  • the cell protection effect according to the dose was analyzed by increasing the treatment concentration for the most effective esomeprazole and dexlansoprazole.
  • TUNEL was positive in the group treated only with CIS (1000 ⁇ M) compared to the control group. While the number of cells (red) significantly increased, the number of TUNEL-positive cells (red) significantly decreased in the esomeprazole (200 ⁇ M) treated group compared to the CIS only treated group. From the above results, it was confirmed that esomeprazole inhibits apoptosis caused by CIS in zebrafish hair cells.

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Abstract

La présente invention concerne une composition pharmaceutique pour prévenir ou traiter une perte auditive comprenant de l'ésoméprazole ou du dexlansoprazole en tant que principe actif. Les effets de l'ésoméprazole ou du dexlansoprazole sur la protection des cellules capillaires contre l'apoptose provoquée par le cisplatine et l'inhibition de l'absorption du cisplatine par la protéine de transport de cations organiques 2 (OCT2) des cellules capillaires ont été confirmés, ainsi, une composition pharmaceutique les comprenant en tant que principe actif peut être utilisée pour prévenir et traiter une perte auditive qui est un effet secondaire de l'utilisation du cisplatine, un médicament anticancéreux.
PCT/KR2023/013653 2022-09-13 2023-09-12 Composition pharmaceutique pour la prévention ou le traitement de la perte auditive comprenant de l'ésoméprazole ou du dexlansoprazole en tant que principe actif WO2024058527A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2022-0115202 2022-09-13
KR20220115202 2022-09-13
KR1020230119511A KR20240036481A (ko) 2022-09-13 2023-09-08 에스오메프라졸 또는 덱스란소프라졸을 유효성분으로 포함하는 난청 예방 또는 치료용 약학 조성물
KR10-2023-0119511 2023-09-08

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080242703A1 (en) * 2007-04-02 2008-10-02 National Taiwan University Pharmaceutical compositions for the treatment of hearing loss
KR20110033295A (ko) * 2008-07-21 2011-03-30 오토노미, 인코포레이티드 귀 질병 치료를 위한 제어 방출형 항미생물성 조성물 및 방법
US20150150793A1 (en) * 2008-07-21 2015-06-04 Otonomy, Inc. Controlled Release Antimicrobial Compositions and Methods for the Treatment of Otic Disorders
US20180161340A1 (en) * 2015-06-18 2018-06-14 St. Jude Children's Research Hospital Methods and compositions for the prevention and treatment of hearing loss

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080242703A1 (en) * 2007-04-02 2008-10-02 National Taiwan University Pharmaceutical compositions for the treatment of hearing loss
KR20110033295A (ko) * 2008-07-21 2011-03-30 오토노미, 인코포레이티드 귀 질병 치료를 위한 제어 방출형 항미생물성 조성물 및 방법
US20150150793A1 (en) * 2008-07-21 2015-06-04 Otonomy, Inc. Controlled Release Antimicrobial Compositions and Methods for the Treatment of Otic Disorders
US20180161340A1 (en) * 2015-06-18 2018-06-14 St. Jude Children's Research Hospital Methods and compositions for the prevention and treatment of hearing loss

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WAKAI ERI, IKEMURA KENJI, MIZUNO TOSHIRO, TAKEUCHI KAZUHIKO, TAMARU SATOSHI, OKUDA MASAHIRO, NISHIMURA YUHEI: "Repositioning of Lansoprazole as a Protective Agent Against Cisplatin-Induced Ototoxicity", FRONTIERS IN PHARMACOLOGY, FRONTIERS RESEARCH FOUNDATION, CH, vol. 13, 15 July 2022 (2022-07-15), CH , pages 896760, XP093146218, ISSN: 1663-9812, DOI: 10.3389/fphar.2022.896760 *

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