CN116059209A - Application of armetinib mesylate in preparation of medicines for treating radiation lung injury - Google Patents
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Abstract
The invention discloses an application of armetinib mesylate in preparing a medicament for treating radiation lung injury, and belongs to the technical field of medicines. The invention provides an effective therapeutic drug for radiation lung injury. According to the invention, animal in-vivo experimental researches prove that the armetinib mesylate has a remarkable treatment effect on the radioactive lung injury, and the lung injury inflammation and the lung fibrosis caused by radiation can be effectively reduced by combining with the armetinib mesylate treatment, so that the armetinib mesylate can be used for preparing the medicines for treating the radioactive lung injury and has a good development prospect.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a novel application of ametinib mesylate in preparing a medicine for treating radiation lung injury.
Background
Chest radiation therapy (radiotherapy) is a conventional treatment for malignant tumors of the chest, such as lung cancer, breast cancer, and mediastinal lymphoma. However, the radioactive lung injury (radio-pulmonic version) caused by chest radiotherapy severely threatens the health and quality of life of patients with radiotherapy cancer, greatly limiting the application of radiotherapy. Radiation lung injury is a complication caused by radiotherapy, and is mostly seen in radiotherapy of lung cancer, breast cancer, esophageal cancer and mediastinal malignant tumor. The lung injury varies in magnitude depending on the radiation dose, the radiation site and the radiation range. Large-area, high-dose radiotherapy has a high incidence and severity of lung injury. The main clinical manifestations are pulmonary congestion, increased alveolar fibrin exudation or hyaline membrane formation, eventually forming pulmonary interstitial fibrosis. The occurrence of radiation lung injury greatly reduces the therapeutic effect and prognosis survival rate of patients receiving chest irradiation. Therefore, the method has extremely important medical significance for protecting and treating the radioactive lung injury caused by the chest tumor radiotherapy.
The occurrence mechanism of the radioactive lung injury has not been uniformly concluded in academia. Most of them are thought to be due to immune imbalance of various inflammatory cells, fibroblasts and their related cytokines induced by ionizing radiation, resulting in hyperproliferative migration of fibroblasts and deposition of extracellular matrix, thereby causing damage to the body. At present, effective prevention and treatment measures for the radioactive lung injury caused by chest radiotherapy are not available, and most of treatments are symptomatic treatment, long-term large-dose corticosteroid treatment and the like. The effects of conventional treatments are extremely limited and steroid drugs and the like can also increase the risk of secondary infection and femoral head necrosis in patients (The Impact of Corticosteroids on Secondary Infection and Mortality in Critically Ill COVID-19Patients.J Intensive Care Med.2021Oct;36 (10): 1201-1208;Aseptic necrosis of the femoral head associated with steroid therapy.JAMA.1963Apr 27;184:262-5.).
At present, the experimental research of the medicine for preventing and treating the radioactive lung injury is mainly focused on antioxidant, gene therapy, stem cell therapy and the like, for example, patent document CN109453201A discloses the use of mesenchymal stem cells for preventing radiation pneumonitis and advanced fibrosis and improving the survival rate of the radioactive lung injury. However, these methods have drawbacks such as insignificant effects and large side effects (Mesenchymal Stem Cells for Mitigating Radiotherapy Side effects. Cells.2021Feb 1;10 (2): 294.). Thus, there is a need to find other effective pharmaceutical interventions.
Ametinib mesylate (HS-10296), commercially available as Aminox, is a third generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor, and is used for the treatment of local advanced or metastatic non-small cell lung cancer adult patients with EGFR T790M mutation positive, which are confirmed by detection to have disease progression when treated by or after the EGFR tyrosine kinase inhibitor, has no side effects of inducing interstitial pneumonia and has higher Safety compared with other EGFR inhibitors (Safety, efficiency, and Pharmacokinetics of Almonertinib (HS-10296) in Pretreated Patients With EGFR-Mutated Advanced NSCLC: A Multicenter, open-label, phase 1Trial.J Thorac Oncol,2020,15 (12): 1907-1918.). There has been no report on the use of armetinib mesylate as a therapeutic drug for lung injury caused by radiotherapy.
Disclosure of Invention
The present invention aims to provide a compound which can effectively improve the radiation lung injury caused by chest radiotherapy and develop the compound into a medicament which can be used for preventing and treating the radiation lung injury.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the invention provides an application of armetinib mesylate in preparing a medicament for treating radiation lung injury, the structural formula of the armetinib mesylate is shown as a formula (I),
further, the radiation lung injury comprises one or more of radiation pneumonitis and pulmonary fibrosis caused by ionizing radiation.
The ionizing radiation is of a radiation type commonly used for radiotherapy, such as X-rays, gamma rays, charged particles (e.g. electrons, protons and heavy ions). Specifically, the ionizing radiation is X-ray radiation, and the irradiation dose is 22.5Gy/10min.
The animal in vivo experimental study proves that the armetinib mesylate has remarkable treatment effect on lung injury caused by radiation, and can be used for treating radiation-induced radiation pneumonitis and relieving lung fibrosis caused by radiation.
Specifically, the radiation pneumonitis is manifested by an increase in inflammatory factors, an increase in inflammatory cell numbers, and an increase in protein content. By combining with the treatment of the armetinib mesylate, the early-stage pneumonia caused by ionizing radiation can be obviously improved, inflammatory cell infiltration in lung tissues is inhibited, inflammatory factor release is inhibited, and the late-stage pulmonary fibrosis caused by the ionizing radiation is improved.
The invention utilizes the armetinib mesylate as an effective active ingredient to prepare the medicament for treating the radioactive lung injury, and the medicament contains the armetinib mesylate with pharmaceutically effective dose. The pharmaceutical preparation is in the form of oral preparation.
The study of the invention shows that the effective dosage of the amitriptinib mesylate in the drug is 1-40mg/kg (converted to human 0.1-4 mg/kg) and the preferable dosage is 20mg/kg aiming at the mouse model and being administered within 24 hours after ionizing radiation. When the medicine is applied to human body, the administration time can be properly delayed.
The invention also provides a pharmaceutical composition for preventing or treating radiation lung injury, which comprises effective dose of the ametinib mesylate and pharmaceutically acceptable auxiliary materials.
The pharmaceutical composition is prepared by taking the armetinib mesylate as a main active ingredient and adding pharmaceutically acceptable auxiliary materials, and can be prepared into a preparation according to a preparation method recorded in pharmaceutics.
The medicine preparation is liquid preparation or solid preparation, including oral solid preparation, oral liquid preparation, injection, freeze-dried powder injection, infusion preparation, patch, ointment, gel, soft capsule or suppository.
The invention also provides a method for applying the ametinib mesylate and the radiotherapy to the treatment of tumors such as EGFR mutant lung cancer, wherein the ametinib mesylate is used as an EGFR inhibitor antitumor drug and is combined with the radiotherapy, so that on one hand, the tumor treatment effect can be synergistically exerted, and on the other hand, the lung injury caused by the radiotherapy can be alleviated.
The invention has the beneficial effects that:
the invention provides an effective therapeutic drug for radiation lung injury. According to the invention, the in-vivo experimental study proves that the amitriptinib mesylate has a remarkable treatment effect on the radioactive lung injury, and the combination of the treatment of the amitriptinib mesylate can effectively relieve lung injury inflammation and lung fibrosis caused by radiation, and the amitriptinib mesylate has higher medication safety and no side effect of inducing the lung injury, so that the amitriptinib mesylate can be used for preparing the medicament for treating the radioactive lung injury and has good development prospect.
Drawings
FIG. 1 is a schematic diagram of the operation flow of the animal experiment in example 1, in which Vehicle is a solvent control group, radiation is a Radiation model group, HS-10220 mg/kg+radiation is an amitriptinib mesylate drug intervention Radiation group, and the following is the same.
Fig. 2 shows the measurement of lung fibrosis injury by Ashcroft score, wherein a is hematoxylin-eosin staining picture of lung tissue and B is Ashcroft score.
FIG. 3 shows the measurement of inflammatory cell number and protein content in mouse serum inflammatory factor, alveolar lavage fluid, wherein A is the number of White Blood Cells (WBC) and protein content in the alveolar lavage fluid (BALF) at week 2 after irradiation, B is the number of white blood cells and protein content in the alveolar lavage fluid at week 8 after irradiation, and C is the IL-6 content in the serum inflammatory factor at week 2 after irradiation.
FIG. 4 shows Giemsa staining of cells after BALF precipitation.
Detailed Description
The invention will be further illustrated with reference to specific examples. The following examples are only for illustrating the present invention and are not intended to limit the scope of the present invention. Modifications and substitutions to methods, procedures, or conditions of the present invention without departing from the spirit and nature of the invention are intended to be within the scope of the present invention.
The test methods used in the following examples are conventional methods unless otherwise specified; the materials, reagents and the like used, unless otherwise specified, are those commercially available.
Armetinib mesylate, molecular weight 621.75, molecular formula C 30 H 35 N 7 O 2 ·CH 4 SO 3 The structural formula is as follows:
example 1
1. Animal experiment: 36 male C57BL/6 mice are randomly divided into 3 groups, namely a solvent control group, a radiation model group and an armitinib mesylate (HS-10296) drug intervention radiation group, wherein 12 mice in each group are administrated in a gastric lavage mode, and the solvent control group is an equivalent amount of physiological saline.
C57BL/6 mice were anesthetized with sodium pentobarbital and were intraperitoneally injected at 45 mg/kg; loading anesthetized C57BL/6 mice into a mouse irradiator for irradiation, and fixing four limbs of the mice; after PET-CT scanning is carried out on the whole body of the mouse, a 10X 10mm visual field is arranged for positioning the lung, and the laser beam records the projection position of the body surface of the mouse; after 24 hours of local precise irradiation of the lungs of the mice (X-rays, irradiation dose 22.5Gy/10 min), the respective groups were given the corresponding solvent controls or drug interventions.
Mice were sacrificed at week 2 and week 8, respectively, and serum was collected from each group, and the left lung was ligated and fixed in 10% formalin, stained with hematoxylin & eosin, and assayed for pulmonary fibrosis injury using Ashcroft score.
The right lung was lavaged with 500 μl PBS, bronchoalveolar lavage fluid (Bronchoalveolar lavage fluid, BALF) was recovered, and repeated 3 times to give a recovery of greater than 90%. Centrifuging BALF, and quantitatively detecting the protein content of supernatant by using BCA; the pelleted cells after centrifugation were resuspended in 200 μl PBS, mixed well, stained with 50 μl Giemsa and photographed for recording, and the remaining were assayed for total leukocyte by hemocytometer. The flow is shown in fig. 1.
2. As shown in figure 2, the Ashcroft scoring results are shown in a solvent control group, a radiation model group and an HS-10296 drug intervention radiation group, and the pathological scores of the lung tissues after 8 weeks of administration are respectively 0.33+/-0.52, 3.83+/-0.75 and 1.67+/-0.52, which indicate that the lung fibrosis condition of the radioactive lung injury mice after the administration of the amitinib mesylate is obviously improved.
3. The detection results of the serum and bronchoalveolar lavage fluid are shown in figure 3, and the solvent control group, the radiation model group and the HS-10296 medicine intervention radiation group show that the IL-6 level in serum after 2 weeks of the Elisa detection irradiation is respectively 10.74+/-9.01, 143.00 +/-7.57 and 107.40 +/-4.69 pg/ml, which indicates that the IL-6 inflammatory factor level of the serum of a radiation lung injury mouse is obviously reduced after the administration of the amitinib mesylate.
The total white blood cell amount in BALF is detected by a full-automatic blood analyzer, and each group after irradiation for 2 weeks is respectively: 0.28.+ -. 0.04, 0.56.+ -. 0.29 and 0.27.+ -. 0.14X10 9 L; each group was: 0.65.+ -. 0.14, 1.18.+ -. 0.41 and 0.78.+ -. 0.33X 10 9 and/L, showing that the white blood cell level in BALF of radiation lung injury mice is obviously reduced after the administration of the amitriptinib mesylate.
BCA quantitatively detects the total protein content in BALF, and each group after irradiation for 2 weeks is respectively: 204.24 + -24.34, 511.31 + -211.26 and 336.01 + -51.01 μg/ml; each group was: 245.40 + -25.71, 405.30 + -25.69 and 342.50 + -65.37 μg/ml, showed a significant decrease in total protein content in BALF of radiation lung injured mice after administration of axitinib mesylate.
4. The results of the Giemsa staining of the cells after BALF precipitation are shown in FIG. 4, and the results of the Giemsa staining of the cells after BALF precipitation, the solvent control group, the radiation model group and the HS-10296 medicine intervention radiation group show that the content of neutrophils in the BALF of the radiation lung injury mice after the administration of the amitinib mesylate is obviously reduced.
The above-described embodiments are only preferred embodiments of the present invention and are not intended to limit the present invention. Various changes and modifications may be made by one of ordinary skill in the pertinent art without departing from the spirit and scope of the present invention. Therefore, all the technical schemes obtained by adopting the equivalent substitution or equivalent transformation are within the protection scope of the invention.
Claims (8)
1. The application of the armetinib mesylate in preparing the medicines for treating the radiation lung injury is characterized in that the structural formula of the armetinib mesylate is shown as the formula (I),
2. the use of claim 1, wherein the radiation lung injury comprises one or more of radiation pneumonitis, pulmonary fibrosis caused by ionizing radiation.
3. The use according to claim 2, wherein the ionizing radiation comprises X-ray radiation.
4. Use according to claim 2, wherein ametinib mesylate inhibits inflammatory cell infiltration in lung tissue caused by ionizing radiation.
5. Use according to claim 2, wherein ametinib mesylate inhibits the release of inflammatory factors by ionizing radiation.
6. The use according to claim 1, wherein the medicament is an oral formulation.
7. A pharmaceutical composition for preventing or treating radiation lung injury, comprising an effective dose of ametinib mesylate and a pharmaceutically acceptable adjuvant.
8. The pharmaceutical composition of claim 7, wherein the pharmaceutical dosage form is a liquid formulation or a solid formulation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310090335.6A CN116059209A (en) | 2023-02-09 | 2023-02-09 | Application of armetinib mesylate in preparation of medicines for treating radiation lung injury |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111971046A (en) * | 2017-12-20 | 2020-11-20 | 韩国原子力医学院 | Use for protecting or reducing radiation damage and for preventing or treating pulmonary fibrosis |
| CN113509469A (en) * | 2021-04-16 | 2021-10-19 | 浙江大学智能创新药物研究院 | Application of amitinib mesylate in preparing medicine for treating acute respiratory distress syndrome |
| CN115403564A (en) * | 2021-05-28 | 2022-11-29 | 江苏豪森药业集团有限公司 | Armenitinib mesylate crystal form and preparation method and medical application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111971046A (en) * | 2017-12-20 | 2020-11-20 | 韩国原子力医学院 | Use for protecting or reducing radiation damage and for preventing or treating pulmonary fibrosis |
| CN113509469A (en) * | 2021-04-16 | 2021-10-19 | 浙江大学智能创新药物研究院 | Application of amitinib mesylate in preparing medicine for treating acute respiratory distress syndrome |
| CN115403564A (en) * | 2021-05-28 | 2022-11-29 | 江苏豪森药业集团有限公司 | Armenitinib mesylate crystal form and preparation method and medical application thereof |
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| LUCHENG ZHU等: "Thoracic radiotherapy and concurrent almonertinib for unresectable stage III EGFR-mutated non-small-cell lung cancer: a phase 2 study", 《BMC CANCER》, vol. 21, pages 1 - 5 * |
| YAOSHUAI ZHANG等: "Experimental study of EGFR-TKI aumolertinib combined with ionizing radiation in EGFR mutated NSCLC brain metastases tumor", 《EUR J PHARMACOL.》, vol. 15, pages 1 - 13 * |
| 陈家祯等: "放射性肺损伤发病机制及分子靶向治疗研究进展", 《中国辐射卫生》, vol. 30, no. 3, pages 377 - 380 * |
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