WO2019201195A1 - 预防或治疗肿瘤疗法副作用的方法 - Google Patents
预防或治疗肿瘤疗法副作用的方法 Download PDFInfo
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- WO2019201195A1 WO2019201195A1 PCT/CN2019/082623 CN2019082623W WO2019201195A1 WO 2019201195 A1 WO2019201195 A1 WO 2019201195A1 CN 2019082623 W CN2019082623 W CN 2019082623W WO 2019201195 A1 WO2019201195 A1 WO 2019201195A1
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Definitions
- VEGFR Vascular Endothelial Growth Factor Receptor
- nitric oxide releasing agents eg, nitroglycerin
- the effective dose of the nitrogen oxide releasing agent may be as low as 0.5% or less, for example, 0.45% or less, 0.4% or less, 0.3% or less, 0.25% or less, or 0.2%.
- it may be 0.15% or less, or may be 0.1% or less, and functions to prevent or treat side effects of tumor therapy, for example, to prevent or treat diseases or conditions associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor.
- the application provides the use of a nitric oxide releasing agent in the manufacture of a medicament.
- the medicaments are useful for preventing or treating a disease or condition associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor in a subject.
- the disease or condition can be caused by the administration of a VEGFR inhibitor and/or a VEGF inhibitor.
- the VEGFR inhibitor and/or the VEGF inhibitor is for use in treating a tumor.
- the affected area of the disease or condition is different from the affected area of the tumor.
- the medicament is prepared for topical administration.
- the application provides a method of preventing or treating a disease or condition associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor in a subject, the method comprising administering to the subject a prophylaxis or A therapeutically effective amount of a nitric oxide releasing agent.
- the subject comprises a human or a non-human animal.
- the non-human animal can include an animal selected from the group consisting of a monkey, a chicken, a goose, a cat, a dog, a mouse, and a rat.
- the subject comprises a cancer patient.
- the subject has been, is being, and/or will be administered the VEGFR inhibitor and/or the VEGF inhibitor.
- the nitric oxide releasing agent can be administered prior to, concurrently with, or subsequent to administration of the VEGFR inhibitor and/or VEGF inhibitor to the subject.
- the VEGFR inhibitor and/or the VEGF inhibitor is for use in treating a tumor.
- the affected area of the disease or condition is different from the affected area of the tumor.
- the administration of the nitric oxide release agent is topical.
- the site of administration of the topical administration is not a site of cancer or a potential site of metastasis of cancer.
- the concentration of the nitric oxide releasing agent applied is from about 0.0001% (w/w) to about 50% (w/w).
- the administration of the nitric oxide releasing agent is for external administration. In certain embodiments, the nitric oxide release agent is administered in an ointment. In certain embodiments, the nitric oxide releasing agent is co-administered with one or more other active ingredients. In certain embodiments, administration of the nitric oxide releasing agent does not substantially affect the therapeutic effect of the VEGFR inhibitor and/or VEGF inhibitor.
- the concentration of the nitric oxide releasing agent is from about 0.0001% (w/w) to about 50% (w/w).
- the nitric oxide releasing agent of 2) is capable of preventing or treating a disease or condition caused by the VEGFR inhibitor and/or VEGF inhibitor in 1).
- the nitric oxide releasing agent of 2) does not substantially affect the therapeutic effect of the VEGFR inhibitor and/or VEGF inhibitor in 1).
- the nitric oxide releasing agent of 2) is administered prior to, simultaneously with, or after administration of the VEGFR inhibitor and/or VEGF inhibitor of 1).
- the application provides a method comprising administering to a subject a nitric oxide releasing agent, wherein the subject has been, is being, and/or will be administered a VEGFR inhibitor and/or a VEGF inhibitor and Having or susceptible to a disease or condition associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor.
- the application provides a method of preventing or treating a disease or condition comprising administering a nitric oxide releasing agent to a subject susceptible to or having the disease or condition, wherein the disease or condition is Hand and foot syndrome.
- the subject has been, is being, and/or will be administered a VEGFR inhibitor and/or a VEGF inhibitor.
- the subject does not have the disease or condition prior to administration of the VEGFR inhibitor and/or VEGF inhibitor.
- the VEGFR inhibitor and/or VEGF inhibitor does not comprise the nitric oxide releasing agent. In certain embodiments, the VEGFR inhibitor and/or VEGF inhibitor does not comprise nitroglycerin.
- the disease or condition is an epithelial tissue disease or condition.
- the VEGFR inhibitor and/or VEGF inhibitor is administered to treat cancer.
- the affected area of the disease or condition is different from the affected area of the cancer.
- the nitric oxide releasing agent is administered topically to the subject.
- the nitric oxide releasing agent is administered topically to a site of the subject that is substantially free of cancer cells. In certain embodiments, the nitric oxide releasing agent is administered to a non-cancer site in the subject.
- At least one VEGFR inhibitor described herein acts directly on a VEGFR protein and/or a nucleic acid encoding a VEGFR protein.
- At least one VEGF inhibitor described herein acts directly on a VEGF protein and/or a nucleic acid encoding a VEGF protein.
- a VEGFR inhibitor as described herein and/or a VEGF inhibitor described herein is used to treat a tumor.
- a VEGFR inhibitor as described herein includes a small molecule VEGFR inhibitor, a protein macromolecule that specifically binds to VEGFR, an RNAi that inhibits VEGFR protein expression, and/or an antisense oligonucleoside that inhibits VEGFR protein expression. acid.
- a VEGF inhibitor described herein includes a VEGF capture agent and/or an agent that reduces the amount of VEGF expression.
- the VEGFR inhibitors and/or VEGF inhibitors described herein include remollozumab, bevacizumab, regorafenib, punatinib, cabozantini, le Vatitinib, sorafenib, pazopanib, apatinib, axitinib, nidanib, vandetanib, sunitinib, militalin, tivozani, fur Quinidine, cediranib, brinicib, donerefenib, sovanidinib, erlotinib, famitinib, Tesevatinib, Vorolanib, Motsenyi, Linifanib, Semaxanib, dovetinib, orantinib , vastatin, tilatinib, Glesatinib, eritinib, Ilorasertib, Rebastinib, Golvati
- a VEGFR inhibitor and/or VEGF inhibitor described herein is administered in combination with one or more other therapies.
- the one or more other therapies can include one or more other anti-tumor therapies.
- a skin tissue disease or disorder, a facial disease or disorder, and/or a gastrointestinal disease or disorder associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor includes the skin tissue, An epithelial tissue disease or condition associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor in the facial and/or gastrointestinal tract.
- a related epithelial tissue disease or disorder associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor includes the disease or condition associated with endothelial cell lesions, and/or with epithelial cells
- the endothelial cells can include vascular endothelial cells.
- the epithelial cells may include cutaneous epithelial cells, oral epithelial cells, nasal epithelial cells, gastric epithelial cells, and/or intestinal epithelial cells.
- the disease or condition associated with administration of a VEGFR inhibitor and/or VEGF inhibitor comprises a disease or condition selected from the group consisting of a rash associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor, Hand-foot syndrome associated with administration of VEGFR inhibitors and/or VEGF inhibitors, itch associated with administration of VEGFR inhibitors and/or VEGF inhibitors, erythema associated with administration of VEGFR inhibitors and/or VEGF inhibitors, and administration of VEGFR Inhibitor and/or VEGF inhibitor-associated skin dryness, hair loss associated with administration of VEGFR inhibitors and/or VEGF inhibitors, paronychia associated with administration of VEGFR inhibitors and/or VEGF inhibitors, and administration of VEGFR inhibitors And/or VEGF inhibitor-related pigmentation disorders, oral ulcers associated with administration of VEGFR inhibitors and/or VEGF inhibitors, dry mouth associated with administration of VEGFR inhibitors and/or VEGF inhibitors
- the disease or condition associated with administration of a VEGFR inhibitor and/or VEGF inhibitor comprises a hand-foot syndrome associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor.
- the severity of the disease or condition associated with administration of a VEGFR inhibitor and/or VEGF inhibitor is based on level 1 or above, level 2 or above, in NCI-CTCAE V5.0, Level 3 or above, Level 4 or above, and/or Level 5.
- the nitric oxide releasing agent is capable of producing a substance selected from the group consisting of NO + , NO - , N 2 O, NO, N 2 O 3 , NO 2 , NO 3 -, and NO 2 - .
- the nitric oxide releasing agent is capable of producing NO directly or indirectly.
- the nitric oxide release agent comprises NO.
- the nitric oxide releasing agent comprises an organic molecule, an inorganic molecule, a polymeric material, a nanomaterial, and/or an ammonia oxidizing microorganism (AOM).
- AOM ammonia oxidizing microorganism
- the nitric oxide releasing agent comprises an organic molecule
- the organic molecule comprises nitroglycerin, isosorbide mononitrate, pentaerythritol tetranitrate, isosorbide dinitrate, trinitroethanolamine, nicotine , nitrate dihydroxybutanol, morpholamine, 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazole, isoamyl nitrite, 3,3-di(ammonia Ethyl)-1-hydroxy-2-carbonyl-1-triazene (NOC-18), sulfonucleophilic complex disodium salt, S-nitrosoglutathione, S-nitroso-N - acetylpenicillamine, 4-phenyl-3-furanonitrile, ( ⁇ )-(E)-4-ethyl-2-(E)-mercapto-5-nitro-3-hexanamide, streptolactam ⁇ -
- the nitric oxide releasing agent comprises an inorganic molecule, and the inorganic molecule comprises a nitroxyl complex, a nitrosyl complex, a metal nitrosylamino complex, a nitrate, and/or a nitrous acid. salt.
- the nitric oxide release agent comprises an inorganic molecule and the inorganic molecule comprises sodium nitroprusside.
- the nitric oxide releasing agent comprises an ammoxidation microorganism (AOM), and the ammonia oxidizing microorganism (AOM) comprises an ammonia oxidizing bacterium (AOB).
- the nitric oxide releasing agent comprises an ammoxidation microorganism (AOM), and the ammonia oxidizing microorganism (AOM) comprises Nitrosomonas, Nitrosococcus, nitrosation Nitrosospira, Nitrosocystis, Nitrosolobus, and/or Nitrosovibrio.
- the nitric oxide releasing agent has less than or equal to 2000 Daltons, less than or equal to 1500 Daltons, less than or equal to 1200 Daltons, less than or equal to 1000 Daltons, less than or equal to 900 Daltons, less than or equal to 800 Daltons, less than or equal to 700 Daltons, less than or equal to 600 Daltons, less than or equal to 500 Daltons, less than or equal to 400 Daltons, less than or equal to 300 lanes A molecular weight of less than or equal to 200 Daltons or less than or equal to 100 Daltons.
- the nitric oxide releasing agent comprises a polymer or a nano material
- the polymer or nano material comprises S-nitrosothiol nano silicon spheres, S-nitrosoethylene dithiol Chitin and/or oligopropylene diamine grafted chitosan NONOate.
- the nitric oxide releasing agent has one or more of the following groups: azo nonanediol, hydroxydiazenenesulfonic acid, S-nitrosothiol, furazan nitrogen Oxygen, hydrazine, N-nitrosamine, N-hydroxy hydrazine, azo diol salt, nitrate, nitrite, nitrate, nitrite, stilkonimide, sedone, oxatriazole 5-imine, oxatriazole-5-one, hydroxylamine, dioxadiazepine, N-hydroxynitrosamine, N-nitrosenimine, hydroxyurea and metal nitrosylamino complex.
- Figure 1 shows an exemplary synthetic route for S-nitrosothiol nanosilica spheres.
- Figure 2 shows an exemplary synthetic route for S-nitrosoethanedithiol chitin.
- Figure 3 shows an exemplary synthetic route for oligo-propylene diamine grafted chitosan NONOate.
- FIGS. 4A-4C show exemplary results of cell proliferation toxicity measured after administration of a nitric oxide releasing agent (or sildenafil) to HUVEC cells.
- a nitric oxide releasing agent or sildenafil
- Figures 5A-5C show exemplary results of cell proliferation toxicity measured after administration of a nitric oxide releasing agent (or sildenafil) to HaCaT cells.
- Figures 6A-6C show exemplary results of cell proliferation toxicity measured after administration of a nitric oxide releasing agent (or sildenafil) to HOK cells.
- a nitric oxide releasing agent or sildenafil
- Figures 7A-7C show exemplary results of cell proliferation toxicity measured after administration of a nitric oxide releasing agent (or sildenafil) to GES-1 cells.
- a nitric oxide releasing agent or sildenafil
- Figures 8A-8C show exemplary results of cell proliferation toxicity measured after administration of a nitric oxide releasing agent (or sildenafil) to FHs 74 Int cells.
- a nitric oxide releasing agent or sildenafil
- Figures 9A-9D show the relative amounts of nitric oxide in the HUVEC and GES-1 cells.
- Figures 10A-10D show the relative amounts of extracellular nitric oxide after 24 hours of treatment with a nitric oxide releasing agent.
- Figures 11A-11D show the relative levels of nitric oxide in cells after treatment with a nitric oxide releasing agent for 24 hours.
- Figures 12A-12B show the relative levels of extracellular and intracellular nitric oxide at various time points after treatment of HUVEC cells with sildenafil.
- Figures 12C-12D show the relative levels of extracellular and intracellular nitric oxide after 24 hours of treatment of HUVEC cells with different concentrations of sildenafil.
- Figures 13A-13B show the relative levels of extracellular and internal nitric oxide after 24 hours of treatment of GES-1 cells with 100 ⁇ M sildenafil.
- Figures 13C-13D show the relative levels of relative NO monoxide in the extracellular and intracellular, 24 hours after treatment of HaCaT cells with 100 ⁇ M sildenafil.
- Figure 14 shows a left paw enlargement, a left and right paw front view, and a right paw enlargement of a rat model in which VEGFR and/or VEGF are inhibited resulting in hand-foot syndrome.
- Fig. 15 is a magnified view of the left paw of a typical rat (left paw applicator) in the administration group of Examples 55-100 and 111-112 of the present application, a front view of the right and left claws, and an enlarged view of the right paw.
- Fig. 16 is a magnified view of the left paw of a typical rat (right paw applicator) in the administration group of Examples 101 to 108 of the present application, a front view of the right and left claws, and an enlarged view of the right paw.
- Fig. 17 is a magnified view of the left paw of a typical rat (left paw applicator) in the administration group of Examples 113 to 123 of the present application, a front view of the right and left claws, and an enlarged view of the right paw.
- Fig. 18 is a magnified view of the left paw of a typical rat (right paw applicator) in the administration group of Example 124 of the present application, a front view of the right and left claws, and an enlarged view of the right paw.
- Figure 19 is a graph showing the effect of topical application of the nitric oxide releasing agent of Example 143 of the present application on the change in tumor volume in tumor-bearing mice treated with a VEGFR/VEGF inhibitor.
- Figure 20 shows exemplary results of cell proliferation toxicity measured after administration of a nitric oxide releasing agent (or diltiazem) to HUVEC cells.
- Figure 21 shows exemplary results of cell proliferation toxicity measured after administration of a nitric oxide releasing agent (or a calcium channel blocker) to HaCaT cells.
- Figure 22 shows the relative content of nitric oxide after administration of a nitric oxide releasing agent (or calcium channel blocker) to HaCaT cells.
- Figure 23 shows the expression level of calmodulin (CaM) after administration of a nitric oxide releasing agent (or a calcium channel blocker) to HaCaT cells.
- CaM calmodulin
- Figure 24 shows the results of gray value analysis of the relative expression of calmodulin after administration of a nitric oxide releasing agent (or a calcium channel blocker) to HaCaT cells.
- Figure 25 shows the expression level of calreticulin after administration of a nitric oxide releasing agent (or a calcium channel blocker) to HaCaT cells.
- Figure 26 shows the results of gray value analysis of calreticulin relative expression levels after administration of a nitric oxide releasing agent (or a calcium channel blocker) to HaCaT cells.
- Figure 28 is a magnified view of the left paw, a front view of the left and right paws, and an enlarged view of the right paw of a typical rat in the administration group of Example 154 of the present application after application of the left paw and right paw.
- VEGFR inhibitor VEGFR inhibitor, VEGF inhibitor
- VEGFR generally refers to the Vascular Endothelial Grow Factor Receptor, which belongs to the family of tyrosine kinase receptor Receptor tyrosine kinases (RTKs). It is reported to include three major subtypes, VEGFR1, VEGFR2 and VEGFR3. Among them, VEGFR1 and VEGFR2 are mainly distributed on the surface of tumor vascular endothelium, which mediates the formation of tumor blood vessels. VEGFR3 is mainly distributed on the surface of lymphatic endothelium, which mediates the formation of tumor lymphatic vessels. VEGFR2 is reported to be a major VEGF signal transduction receptor for angiogenesis and mitosis.
- RTKs tyrosine kinase receptor Receptor tyrosine kinases
- the VEGF family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and placental growth factor (PGF). It has been reported that VEGF-A binds to VEGFR-1 and VEGFR-2 and regulates almost all cellular responses to VEGF. Activation of VEGFR-2 on endothelial cells results in cell proliferation, migration, increased survival, and increased vascular permeability (see Waldner, Maximilian J. et al, The Journal of Experimental Medicine 207. 13, 2010). The expression of VEGFR or its increased kinase activity is associated with a range of human cancers.
- VEGF generally refers to Vascular Endothelial Grow Factor, which is reported to be a key endothelial cell-specific growth factor, VEGF receptor, required for pathological angiogenic signaling pathways. Inhibition of the tyrosine kinase signaling pathway blocks the formation of new blood vessels in tumor growth, leading to stagnation or regression of angiogenic tumors (see Gerald McMahon, The Oncologist 2000, 5: 3-10).
- VEGFR inhibitor generally refers to any substance or agent known in the art or discovered in the future that is capable of causing a decrease in the expression, amount or activity of VEGFR, including any when it is administered to a subject. Any substance that results in inhibition of biological activity associated with VEGFR activity in a subject, including inhibition of downstream biological effects produced by binding of any VEGFR to its natural ligand.
- a VEGFR inhibitor can include any agent capable of blocking VEGFR activity or any of its downstream biological effects during the treatment of cancer.
- the VEGFR inhibitor can be used to treat a tumor.
- the VEGFR inhibitor can directly inhibit one or more functions of VEGFR.
- the VEGFR inhibitor can bind to a nucleic acid sequence encoding a VEGFR.
- the VEGFR inhibitor can reduce the level of transcription of a VEGFR protein.
- VEGF inhibitor generally refers to any substance or agent known in the art or discovered in the future that is capable of causing a decrease in the expression, amount or activity of VEGF, including any when it is administered to a subject. Any substance that causes inhibition of the biological activity associated with VEGF activity in a subject.
- a VEGF inhibitor can include any agent capable of blocking VEGF activity or any of its downstream biological effects.
- a VEGF inhibitor can include any agent capable of blocking VEGF activity or any of its downstream biological effects during the treatment of cancer.
- the VEGF inhibitor can be used to treat a tumor.
- the VEGF inhibitor can directly inhibit one or more functions of VEGF.
- the VEGF inhibitor can bind to a nucleic acid sequence encoding VEGF.
- the VEGF inhibitor can reduce the level of transcription of the VEGF protein.
- VEGF and/or VEGFR inhibitors are common in the art, and the methods can also be used for identification, standards, screening, and/or Or evaluate a VEGF inhibitor and/or a VEGFR inhibitor as described herein.
- the term "disease or condition associated with administration of a VEGFR inhibitor and/or VEGF inhibitor” generally refers to a disease or condition in which a VEGFR inhibitor and/or a VEGF inhibitor is administered to a subject.
- the disease or condition can be a disease or condition caused by administration of the VEGFR inhibitor and/or the VEGF inhibitor to a subject.
- the disease or condition can include a skin tissue disease or condition associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor, a facial disease or condition associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor, and/or administration A gastrointestinal disease or condition associated with a VEGFR inhibitor and/or a VEGF inhibitor.
- the disease or condition can include a rash associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor, a hand-foot syndrome associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor, and administration of a VEGFR inhibitor and/or VEGF inhibitor-associated pruritus, erythema associated with administration of VEGFR inhibitors and/or VEGF inhibitors, skin dryness associated with administration of VEGFR inhibitors and/or VEGF inhibitors, association with administration of VEGFR inhibitors and/or VEGF inhibitors Alopecia, paronychia associated with administration of VEGFR inhibitors and/or VEGF inhibitors, pigmentation disorders associated with administration of VEGFR inhibitors and/or VEGF inhibitors, association with administration of VEGFR inhibitors and/or VEGF inhibitors Oral ulcers, dry mouth associated with administration of VEGFR inhibitors and/or VEGF inhibitors, nasal discharge associated with administration of VEGFR inhibitors and/or VEGF inhibitors,
- tumor generally refers to a new organism formed by the proliferation of local tissue cells under the action of various tumorigenic factors. Since this new organism is mostly a occupying block-like bulge, it is also called ⁇ . biological. According to the cell characteristics of the new organism and the degree of harm to the body, the tumor is divided into benign tumors and malignant tumors. Cancer is a general term for malignant tumors.
- the tumor may be selected from the group consisting of a malignant tumor of the epithelium (epithelial-derived cancer), lung cancer (for example, non-small cell lung cancer), breast cancer, skin cancer, bladder cancer, colon cancer, intestinal cancer, prostate cancer, Pancreatic cancer, uterine cancer, cervical cancer, ovarian cancer, esophageal cancer, head and neck cancer, stomach cancer and laryngeal cancer.
- the tumor may be liver cancer, kidney cancer, colorectal cancer, stomach cancer, esophageal cancer or thyroid cancer.
- VEGFR inhibitors and/or VEGF inhibitors can be used to determine or screen for VEGFR inhibitors and/or VEGF inhibitors, for example by detecting changes in VEGFR and/or VEGF expression levels or activity following administration of a candidate substance/agent. Detection of the expression level of VEGFR and/or VEGF can also be by methods known in the art, for example, immunohistochemistry, PCR, RT-PCR, in situ hybridization, Southern blot, Western blot, Northern blot, spectrophotometry, and ELISA. Wait.
- At least one may act directly on the VEGFR protein and/or the nucleic acid encoding the VEGFR protein.
- At least one (for example, at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 or more) the VEGF inhibitor may act directly on the VEGF protein and/or the nucleic acid encoding the VEGF protein.
- the VEGFR inhibitor can include a small molecule VEGFR inhibitor, a protein macromolecule that specifically binds to VEGFR, an RNAi that inhibits VEGFR protein expression, and/or an antisense oligonucleotide that inhibits VEGFR protein expression.
- small molecule VEGFR inhibitor may include a small molecule VEGFR inhibitor that binds reversibly or irreversibly to VEGFR or a small molecule VEGFR inhibitor that specifically binds to a mutated VEGFR.
- the small molecule VEGFR inhibitor may include regorafenib, punatinib, cabozantinib, levabinib, sorafenib, apatinib, axitinib, nidanib , vandetanib, sunitinib, militalin, tiwani, furazolinib, cedibutib, brinicib, donerefinib, sovanidinib, erlotinib , Famitinib, Tesevatinib, Vorolanib, Motseni, Linifanib, Semaxanib, Dwetinib, orantinib, Valnitidine, Tilatinib, Glesatinib, Deritinib, Ilorasertib, Rebastinib, Golvatinib, Foretinib, ningetinib, Tafetinib , Altiratinib, T
- the term "specifically binds" generally means that in a complex mixture, the VEGFR inhibitor can specifically recognize and bind to VEGFR without substantially recognizing or binding other components of the complex mixture.
- the inhibitor may have an affinity for VEGFR that is at least 2 times its affinity for other non-specific binding components (eg, at least 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold) , 9 times, 10 times or more).
- the VSR inhibitor binds to VEGFR with an equilibrium dissociation constant having a value less than or equal to 10 -6 (eg, may be less than or equal to 10 -7 M, less than or equal to 10 -8 M, less than or Equal to 10 -9 M, less than or equal to 10 -10 M or less).
- the protein macromolecule that specifically binds to VEGFR may be an antibody, antibody variant, fusion protein, derivative or fragment thereof directed against VEGFR.
- it may be an antibody or antigen-binding fragment thereof that specifically binds to VEGFR.
- the antibody generally refers to a polypeptide molecule capable of specifically recognizing and/or neutralizing a specific antigen.
- an antibody may comprise an immunoglobulin consisting of at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, and includes any molecule comprising an antigen-binding portion thereof.
- the term "antibody” can include monoclonal antibodies, antibody fragments or antibody derivatives including, but not limited to, human antibodies (full human antibodies), humanized antibodies, chimeric antibodies, single chain antibodies (eg, scFv), and Antigen-binding antibody fragments (eg, Fab, Fab', and (Fab) 2 fragments).
- the chimeric antibody may be part of a heavy or light chain amino acid sequence homologous to a corresponding amino acid sequence in an antibody from a species, or belong to a particular class, and the remaining segments of the chain are associated with another species An antibody in which the corresponding sequence is homologous.
- the humanized antibody may refer to a chimeric antibody which contains less sequence derived from a non-human immunoglobulin, thereby reducing the immunogenicity of the heterologous antibody when introduced into humans, while maintaining the complete antigen of the antibody. Binding affinity and specificity.
- the fully human antibody may be an amino acid sequence comprising an antibody corresponding to a non-human source produced by a human or human immune cell, or derived from a non-human source such as a transgenic non-human animal using a human antibody library, or other coding human An antibody to the sequence of the source antibody.
- the antigen-binding fragment antibody may be one or more fragments that function to specifically bind antigen.
- the antigen binding function of an antibody can be achieved by a full length fragment of the antibody.
- the antigen binding function of an antibody can also be achieved by a heavy chain comprising a fragment of Fv, ScFv, dsFv, Fab, Fab' or F(ab') 2 , or comprising Fv, ScFv, dsFv, Fab, Fab' or Light chain of a fragment of F(ab') 2 .
- a Fab fragment a monovalent fragment consisting of VL, VH, CL and CH domains
- a F(ab') 2 fragment comprising two Fab fragments joined by a disulfide bond at the hinge region a bivalent fragment
- an Fd fragment consisting of the VH and CH domains
- an Fv fragment consisting of the VL and VH domains of the one-armed antibody
- a dAb fragment consisting of the VH domain
- the "antigen-binding portion” may further comprise an immunoglobulin fusion protein comprising a binding domain selected from the group consisting of: (1) a binding domain polypeptide fused to an immunoglobulin hinge region polypeptide; (2) An immunoglobulin heavy chain CH2 constant region fused to the hinge region; and (3) an immunoglobulin heavy chain CH3 constant region fused to the CH2 constant region.
- the protein macromolecule that specifically binds to VEGFR can be remollozumab, an antigen binding fragment thereof, or a functional variant thereof.
- VEGF capture agent generally refers to an agent that is capable of capturing it by binding to VEGF.
- the VEGF capture agent can be selected from the group consisting of bevacizumab and aboxicept.
- the term "agent for reducing the amount of VEGF expression” generally refers to a substance capable of directly or indirectly reducing the amount of VEGF expression in a subject.
- the agent that reduces the amount of VEGF expression may be selected from the group consisting of: Temsirolimus and Thalidomide.
- RNAi generally refers to RNA interference, which is usually a foreign or endogenous double-stranded RNA molecule or small RNA, which is generally inhibited by targeting mRNA and specifically degrading it. Expression or translation of the target gene.
- RNAi includes two small RNAs: microRNAs (miRNAs) and small interfering RNAs (siRNAs) that bind to other mRNA molecules to increase or decrease their activity, such as preventing mRNA from being translated into proteins.
- miRNAs microRNAs
- siRNAs small interfering RNAs
- RNAi pathway cleaves long double-stranded RNA (dsRNA) into siRNA double-stranded fragments of about 20-23 nucleotides in length by an RNaseIII enzyme (eg, Dicer, DCL, or Drosha).
- dsRNA double-stranded RNA
- RNaseIII enzyme eg, Dicer, DCL, or Drosha
- Each siRNA is split into two single-stranded RNAs (ssRNAs), a passenger chain and a guide strand.
- the passenger chain is degraded and the guide strand is integrated into the RNA-induced silencing complex (RISC).
- RISC RNA-induced silencing complex
- RNAi that inhibits VEGFR protein expression can inhibit the expression or translation of VEGFR by targeting mRNA encoding VEGFR, thereby specifically degrading the mRNA.
- RNAi that inhibits VEGF protein expression can inhibit VEGF expression or translation by targeting mRNA encoding VEGF, thereby specifically degrading the mRNA.
- oligonucleotide generally refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or any of its mimic or structurally modified nucleic acids.
- the oligonucleotide may comprise an oligonucleotide consisting of a naturally occurring nucleobase, a sugar and a covalent nucleoside (backbone) linkage, and a non-naturally occurring oligonucleotide having a similar function.
- a modified or substituted oligonucleotide is generally preferred over the native form because it has, for example, enhanced cellular uptake, enhanced affinity for the target nucleic acid, and increased stability in the presence of nucleases.
- the term "antisense oligonucleotide” generally refers to a single-stranded oligonucleotide having a nucleobase sequence that allows at least partial hybridization to a corresponding region or fragment of a target nucleic acid.
- the antisense oligonucleotide may comprise from about 8 to about 50 nucleobases.
- the VEGFR inhibitor inhibits VEGFR1, VEGFR2 and/or VEGFR3.
- the VEGFR inhibitor can inhibit one, two or three of VEGFR1, VEGFR2 and VEGFR3.
- the VEGFR inhibitor and/or VEGF inhibitor may comprise remollozumab, bevacizumab, regorafenib, punatinib, cabozantinib, levalzil Nie, sorafenib, pazopanib, apatinib, axitinib, nidanib, vandetanib, sunitinib, militalin, tivozani, furazo Nitro, Medinib, Brinibu, Donafinib, Sovantinib, Erlotinib, Famitinib, Tesevatinib, Vorolanib, Motsenyi, Linifanib, Semaxanib, Dovetinib, Orantinib, Tile Itidine, tilapinib, Glesatinib, Deritinib, Ilorasertib, Rebastinib, Golvatinib, Foretini
- the "pharmaceutically acceptable salt” may mean a pharmaceutically acceptable salt of the compound.
- the pharmaceutically acceptable salt can be selected from the group consisting of sorafenib tosylate, sunitinib malate, pazopanib hydrochloride, and Dovitinib (TKI258) lactic acid salt.
- the VEGFR inhibitor and/or VEGF inhibitor can be administered in combination with one or more other therapies.
- the one or more additional therapies can include one or more other anti-tumor therapies.
- the additional anti-tumor therapy can include a cytotoxic anticancer agent, an immunotherapeutic anticancer agent, and/or a hormonal therapeutic anticancer agent.
- the other anti-tumor therapies may also include radiation therapy or surgery.
- a VEGFR inhibitor and/or a VEGF inhibitor can be administered to the subject simultaneously or separately at intervals.
- the additional anti-tumor therapy can be part of a single agent that is combined with the VEGFR inhibitor and/or VEGF inhibitor to form a single composition.
- the additional anti-tumor therapy can be a separate agent that is administered separately from the VEGFR inhibitor and/or VEGF inhibitor.
- the VEGFR inhibitor and/or VEGF inhibitor may be about 1-99 relative to the total dose.
- % (eg, about 5-95%, about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about A dosage level of 90%, about 95% or about 99%) is present and/or administered.
- the cytotoxic anticancer agent used in the treatment of cancer may include an alkylating agent such as nitrogen mustard, nitrogen mustard N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, Isothiocyanate, busulfan, nimustine hydrochloride, mitoxonium bromide, melphalan, dacarbazine, ramustine, sodium citrate, ethylene triamine, carmustine , lomustine, streptozotocin, pipobroman, ethoglucid, carboplatin, cisplatin, milplatin, nedaplatin, tenetamine, omustine, Dichloropyridine, flupidine, prinidine, pumitepa, Ribomustin, temozolomide, diclofenac, trovafloxacin, zinarostat, simvastatin, Penicillin, cysteustine and
- Hormone therapeutic anticancer agents for use in the treatment of cancer may include statastatin, diethylstilbestrol, chlorhexidine, medroxyprogesterone acetate, megestrol acetate, cyproterone acetate, cyproterone acetate, Danazol, allylestrol, progesterone, mepartricin, raloxifene or meloxifene, levofloxacin, antiestrogens (eg, tamoxifen citrate, torr Remifen citrate, etc., contraceptives, prostacyclane, testosterone lactone, aminosuccinimide, LH-RH agonist (eg, goserelin acetate, buserelin, leuprolide) Lin et al), droloxifene, epiandrostanol, ethinyl estradiol sulfonate, furazolium hydrochloride, anastrozole, letrozole,
- a disease or condition associated with inhibition of VEGFR and/or VEGF A disease or condition associated with inhibition of VEGFR and/or VEGF
- the disease or condition associated with administration of a VEGFR inhibitor and/or VEGF inhibitor may have a statistically significant correlation with inhibition of VEGFR and/or VEGF.
- the disease or condition associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor can be caused by inhibition of VEGFR and/or VEGF.
- the disease or condition associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor can include a skin tissue disease or condition, a facial disease or condition, and/or a gastrointestinal disorder associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor. A disease or condition.
- the skin tissue disease or condition, facial disease or condition, and/or gastrointestinal disease or condition associated with administration of a VEGFR inhibitor and/or VEGF inhibitor can include the skin tissue, facial features, and/or gastrointestinal tract.
- the disease or condition associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor can include a side effect or an adverse reaction caused by administration of a VEGFR inhibitor and/or a VEGF inhibitor.
- the disease or condition associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor can be a novel indication that can be different from any of the other diseases or conditions of the past.
- the manner of diagnosis, treatment, and/or symptom of the disease or condition associated with administration of a VEGFR inhibitor and/or VEGF inhibitor is unique.
- an erythromycin ointment can treat a rash, but has no therapeutic effect on a rash associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor.
- the term "skin tissue disease or condition” generally refers to a pathological change in the morphology, structure and/or function of the skin, including hair and nails.
- the skin tissue disease or condition can include, but is not limited to, rash, hand and foot syndrome, itching, erythema, dry skin, hair loss, paronychia, pigmentation disorders, and the like.
- rash generally refers to a change in the skin that affects the color, appearance or texture of the skin.
- a rash can only be confined to a part of the body or affect the entire skin.
- the rash also includes urticaria.
- HFS Hand Foot Syndrome
- PPE Palmar Plantar Erythrodysesthesia
- HFSR Hand-foot skin reaction
- the typical clinical manifestations are progressive.
- the main clinical manifestations are heat, pain, and erythema swelling. In severe cases, it develops into desquamation, ulcers, and severe pain.
- the pathological manifestations of HFS mainly include, for example, basal keratinocyte vacuolar degeneration, lymphocytes infiltration around the skin, keratinocyte apoptosis, and skin edema.
- HFS may include palmar, blushing of the soles of the feet, or erythema of the extremities caused by chemotherapy.
- Tumor patients may experience symptoms during chemotherapy or molecular targeted therapy such as VEGFR inhibitors and/or VEGF inhibitors.
- Hand-foot syndrome currently has a variety of grading methods, among which the National Cancer Institute (NCI) grading standards are more commonly used.
- NCI National Cancer Institute
- This grading classifies hand-foot syndrome into three grades: grade 1 is mild skin changes or dermatitis with sensation Abnormalities (such as fingerprint disappearance, hyperpigmentation, erythema, peeling, paresthesia, sensation, skin numbness, etc.), but do not affect daily activities; level 2 is the same level of skin changes, accompanied by pain, mildly affecting daily activities, skin The surface is intact; grade 3 is ulcerative dermatitis or skin changes with severe pain, which seriously affects daily life and has obvious tissue damage (such as desquamation, blisters, hemorrhage, edema, etc.).
- Level 4 Level 1 is a feeling of dullness, paresthesia or tingling in the hands and feet; Level 2 is an uncomfortable, painless swelling or erythema in holding and walking. Grade 3 is painful erythema and edema of the palms and soles of the feet, erythema and swelling of the nails; grade 4 is peeling, ulceration, creping and severe pain.
- the term "erythema” generally refers to a localized or systemic red rash that is localized or systemicly dilated by the dermal papillary capillary network.
- retinitis generally refers to an infectious disease of the soft tissue surrounding the nail, usually caused by microscopic damage of the skin of the nail to the skin and reproduction. The clinical manifestation is redness of the affected area. Pain, with inflammatory exudation and granulation tissue proliferation.
- pigmentation disorder generally refers to a condition in which the skin is lighter or deeper in color than normal, causing spots or discoloration.
- Hypigmentation is due to the inability of the body to produce enough pigments.
- Hyperpigmentation is due to excessive pigmentation in the body.
- the term "five-mind disease or condition” generally refers to a pathological change in the morphology, structure and/or function of organs such as the ear, eyebrow, eye, nose, mouth, and the like.
- the facial disease or condition can include, but is not limited to, oral mucositis, dry mouth, epistaxis, nasopharyngitis, and/or cheilitis.
- nasopharynx generally refers to an inflammatory reaction of the nasopharynx mucosa, submucosa and lymphoid tissues, which can be classified into acute nasopharyngitis and chronic nasopharyngitis.
- Symptoms include, but are not limited to, nasopharyngeal dry discomfort, sticky secretions are not easy to cough, often accompanied by nausea, severe cases of hoarse, sore throat, headache, dizziness, fatigue, indigestion, hypothermia and other local or systemic symptoms.
- Nasopharyngeal examination showed chronic mucosal congestion, hyperplasia, hypertrophy, and secretion or dryness.
- cheekitis generally refers to an inflammatory disease or condition that occurs in the lips.
- it may include perioral skin, vermilion borders, and/or inflammation of the lip mucosa, and the like.
- acute cheilitis and chronic cheilitis according to the characteristics of clinical symptoms can be divided into erosive cheilitis, eczema cheilitis, desquamate cheilitis, according to the pathology can be divided into chronic non-specific cheilitis, glandular Cheilitis, benign lymphoproliferative cheilitis, granulomatous cheilitis, Mei-Ro syndrome, actinic cheilitis and allergic cheilitis.
- gastrointestinal disease or condition generally refers to a pathological change in the morphology, structure and/or function of the stomach or gut tissue (eg, the digestive tract tissue from the pylorus of the stomach to the anus).
- the gastrointestinal disease or condition can include, but is not limited to, diarrhea, vomitting, nausea, anorexia, constipation, and/or abdominal pain.
- the VEGFR inhibitor and/or the VEGF inhibitor can be used to treat a tumor.
- the affected area of the disease or condition is different from the affected area of the tumor.
- the skin tissue disease or condition, facial disease or condition and/or gastrointestinal disease or condition associated with administration of a VEGFR inhibitor and/or VEGF inhibitor may comprise the skin tissue, facial features and/or An epithelial tissue disease or condition associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor in the gastrointestinal tract.
- epithelial tissue includes one or more layers of cells covering the free and closed surface of the entire body, including skin, mucus, cavities, serum and glandular spaces. All epithelial layers contain two specific domains: the apical domain facing the mucosal (or lumen) space and the basolateral membrane facing the serosal (or deep) space. Therefore, an important function of epithelial tissue is to provide appropriate barrier work to separate and control many of the physiological processes between the two spaces. Epithelial tissues include epithelial cells and endothelial cells.
- epithelial tissue disease or condition generally refers to a disease or condition caused by epithelial cells and/or endothelial cell lesions.
- the epithelial tissue disease or condition can include rash, acne, itchy skin, hair loss, hair changes, erythema, skin exfoliation, blister pimples, hirsutism, hyper-pigmentation, nail disease ( Nail disorders), paronychia and nail splitting, dry skin, hypersensitivity, mucositis, nasopharyngitis, nosebleeds, dry mouth, cheilitis, mouth ulcers and/or mucosal damage of the gastrointestinal tract.
- the epithelial tissue disease or condition can also include a skin epithelial cell disease or condition (eg, rash, acne, rosacea, atopic dermatitis, contact dermatitis, seborrheic dermatitis, lupus, scleroderma, day) Cytoes, pigmentation, melasma, vitiligo, urticaria, body lice, itchy skin, hair loss, hair changes, erythema, paronychia and nail splitting, dry skin, hypersensitivity and psoriasis), oral epithelial cell disease or Symptoms (eg, pemphigus, cold sore, herpetic stomatitis, granulomatous cheilitis, oral ulcers, pemphigoid, Shergreen's syndrome, Behcet's syndrome, and oral sarcoidosis), Nasal epithelial cell disease or condition (snoring, sinusitis, epistaxis, nasal polyps
- the epithelial tissue disease or condition associated with administration of a VEGFR inhibitor and/or VEGF inhibitor can include the disease or condition associated with endothelial cell lesions, and/or the associated with epithelial cell lesions.
- a disease or condition wherein the endothelial cell lesion and/or epithelial cell lesion is associated with inhibition of the VEGFR and/or VEGF.
- the endothelial cells can include vascular endothelial cells.
- Pathological changes in vascular endothelial cells can include endothelial dysfunction.
- the vascular endothelial cell lesion may include degenerative vascular disease (eg, atherosclerosis, arterial sclerosis, and small arteriosclerosis (eg, hyaline degeneration of arteriosclerosis and proliferative small arteriosclerosis)), inflammatory Vascular disease (eg, infectious arteritis, syphilitic arteritis, giant cell arteritis, thromboangiitis obliterans, and rheumatic arteritis), functional vascular disease (eg, Raynaud's disease, hand and foot blemishes, and red spotted limbs) Pain) and/or congenital vascular disease (eg, congenital arteriovenous fistula).
- degenerative vascular disease eg, atherosclerosis, arterial sclerosis, and small arteriosclerosis
- the epithelial cells may include skin epithelial cells, oral epithelial cells, nasal epithelial cells, gastric epithelial cells, and/or intestinal epithelial cells.
- the epithelial cell lesions may include skin epithelial cell lesions (eg, rash, acne, rosacea, atopic dermatitis, contact dermatitis, seborrheic dermatitis, lupus, scleroderma, celestial sores, pigmentation, Black spot, vitiligo, urticaria, body lice, itchy skin, hair loss, hair changes, erythema, paronychia and nail splitting, dry skin, hypersensitivity and psoriasis), oral epithelial cell pathology (eg, pemphigus, Cold sore, herpetic stomatitis, granulomatous cheilitis, oral ulcers, pemphigoid, Sherkin's syndrome, Behcet's syndrome
- VEGFR and/or VEGF causes damage to endothelial cells and endothelial tissues, thereby causing diseases or conditions of skin tissue, oral tissues, nasal tissues and/or gastrointestinal tissues.
- the disease course usually begins from the damage/lesion of endothelial cells and endothelial tissues, and the epithelial cells also have lesions and eventually inhibit with administration of VEGFR inhibitors and/or VEGF.
- Agent-associated endothelial cell lesions, and/or forms of epithelial cell lesions associated with administration of VEGFR inhibitors and/or VEGF inhibitors are manifested in the patient.
- the disease or condition associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor can include a rash associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor, with administration of a VEGFR inhibitor and/or VEGF inhibitor-associated hand-foot syndrome, pruritus associated with administration of VEGFR inhibitors and/or VEGF inhibitors, erythema associated with administration of VEGFR inhibitors and/or VEGF inhibitors, administration of VEGFR inhibitors and/or VEGF inhibitors Related skin dryness, alopecia associated with administration of a VEGFR inhibitor and/or VEGF inhibitor, paronychia associated with administration of a VEGFR inhibitor and/or VEGF inhibitor, associated with administration of a VEGFR inhibitor and/or VEGF inhibitor Pigmentation disorders, oral ulcers associated with administration of VEGFR inhibitors and/or VEGF inhibitors, dry mouth associated with administration of VEGFR inhibitors and/or VEGF inhibitors, nasal associated with administration of
- the disease or condition associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor includes hand-foot syndrome associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor.
- the severity of the disease or condition associated with administration of a VEGFR inhibitor and/or VEGF inhibitor is based on level 1 or above, level 2 or above, level 3 or above in NCI-CTCAE V5.0. , level 4 or above, and/or level 5.
- the disease or condition can include rash, hand-foot syndrome, itching, erythema, dry skin, hair loss, paronychia, pigmentation disorders, oral ulcers, dry mouth, nasal discharge, nasopharyngitis, lips Inflammation, esophageal mucositis, gastric mucositis, gastric ulcer, diarrhea, vomiting, nausea, anorexia, constipation and/or abdominal pain.
- the disease or condition includes hand-foot syndrome.
- the disease or condition associated with inhibition of VEGFR and/or VEGF is substantially incapable of being treated or alleviated by administering an agent selected from the group consisting of: 1% sildenafil, urea cream, petrolatum Ointment, urea ointment, brimonidine ointment, vitamin B6 ointment, nicotine ointment, dexamethasone ointment, hydrocortisone ointment, Vk1 ointment (0.1%), erythromycin ointment and triamcinolone acetonide ointment.
- an agent selected from the group consisting of: 1% sildenafil, urea cream, petrolatum Ointment, urea ointment, brimonidine ointment, vitamin B6 ointment, nicotine ointment, dexamethasone ointment, hydrocortisone ointment, Vk1 oin
- the term "nitrogen oxide releasing agent” generally refers to any substance capable of contributing, producing and/or releasing the production of nitric oxide.
- the nitric oxide releasing agent can directly contribute, produce, and/or release nitric oxide.
- a nitric oxide releasing agent can contribute, produce, and/or release nitric oxide by stimulating other substances.
- the nitric oxide releasing agent can act as a reactant for a chemical reaction or an enzymatic reaction by which nitric oxide is contributed, produced, and/or released.
- the nitric oxide releasing agent can act as a catalyst for chemical or enzymatic reactions by which other materials are stimulated to contribute, produce, and/or release nitric oxide.
- the nitric oxide releasing agent may also include nitric oxide itself.
- the nitric oxide releasing agent can be determined or screened by methods known in the art, for example, by detecting nitrite, NO, NO 2 -, and/or S-nitrosothiol levels to test test compound contributions.
- the nitrite, NO, NO 2 - and/or S-nitrosothiol levels can be measured using any method known in the art.
- a nitric oxide releasing agent can be determined or screened by detecting nitrite, for example, by Griess analysis (Molecular Probes), which is based on the reaction of nitrite with p-aminobenzenesulfonic acid followed by spectroscopic The reaction product was detected by photometry. It is also possible to carry out the measurement by reducing the nitrite/nitrate to NO in a reflux chamber at 95 ° C by a highly sensitive chemiluminescence technique. As another example, the nitric oxide releasing agent can be determined or screened by measuring the level of Hb-NO in the blood.
- Hb-NO paramagnetic hemoglobin-NO adduct
- red blood cells can be determined by electron paramagnetic resonance (EPR) spectroscopy to determine or screen the nitric oxide release agent.
- EPR electron paramagnetic resonance
- the nitric oxide releasing agent can be determined or screened by performing a current analysis of the NO-specific electrode. This method requires the insertion of a NO electrode into a living body or a sample.
- the nitric oxide releasing agent can be determined or screened by detecting S-nitrosothiol. Chemiluminescence detection was used in EcoMedics CLD 88 Exhalyzer (Annex, Herts, UK) to measure S-nitrosothiols of proteins (Feelisch, M. et al, Concomitant S-, N-, and heme-nitros (yl)ation in Biological tissues and fluids: implications for the fate of NO in vivo. FASEB. J 16, 1775-85 (2002)).
- the level of NO can be detected by an indirect method to determine or screen the nitric oxide releasing agent.
- non-invasive endothelial function testing is performed by the EndoPAT method to measure NO levels.
- Specific detection methods can be found in U.S. Patent No. 1,969,324. It is also possible to determine or align the nitric oxide releasing agent by using nitrate reductase to specifically reduce NO 3 - to NO 2 - , NO 2 - and a color developing agent to form a colored substance, and to measure the absorbance to indicate the serum NO content.
- the nitric oxide releasing agent is capable of producing at least one of NO + , NO - , N 2 O, NO, N 2 O 3 , NO 2 , NO 3 -, and NO 2 - .
- the nitric oxide releasing agent is capable of producing NO directly or indirectly.
- the nitric oxide releasing agent may include organic molecules, inorganic molecules, polymeric materials, nanomaterials, and/or ammonia oxidizing microorganisms (AOM).
- AOM ammonia oxidizing microorganisms
- the nitric oxide releasing agent can be NO.
- organic molecule generally means a compound containing a carbon element and does not contain an oxide of carbon, carbonic acid, carbonate, cyanide, cyanide, oxycyanide, cyanate, thiocyanate, metal carbonization. Things and so on.
- the nitric oxide releasing agent may include organic molecules, and the organic molecules may include nitroglycerin, isosorbide mononitrate, pentaerythritol tetranitrate, isosorbide dinitrate, trinitroethanolamine, nicorandil, nitrate Dihydroxybutanol, morpholamine, 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazole, isoamyl nitrite, 3,3-di(aminoethyl) 1-hydroxy-2-carbonyl-1-triazene (NOC-18), sulfonucleophilic complex disodium salt, S-nitrosoglutathione, S-nitroso-N-acetyl cyanine Moldy amine, 4-phenyl-3-furonitrile, ( ⁇ )-(E)-4-ethyl-2-(E)-indolyl-5-nitro-3-hexanamide, streptozotocin,
- the nitric oxide releasing agent may include organic molecules, and the organic molecules may include nitroglycerin, isosorbide mononitrate, and/or isosorbide dinitrate.
- the organic molecule can include nitroglycerin.
- the nitric oxide releasing agent may include inorganic molecules, and the inorganic molecules may include a nitroxyl complex, a nitrosyl complex, a metal nitrosylamino complex, a nitrate, and/or nitrous acid. salt.
- the inorganic molecule can include sodium nitroprusside.
- the nitric oxide releasing agent may have less than or equal to 2000 Daltons, less than or equal to 1500 Daltons, less than or equal to 1200 Daltons, less than or equal to 1000 Daltons, less than or equal to 900. Dalton, less than or equal to 800 Daltons, less than or equal to 700 Daltons, less than or equal to 600 Daltons, less than or equal to 500 Daltons, less than or equal to 400 Daltons, less than or equal to 300 Daltons A molecular weight of less than or equal to 200 Daltons or less than or equal to 100 Daltons.
- the nitric oxide releasing agent may be a polymer containing an NO donor group.
- Any suitable polymer can be used, including crosslinked or uncrosslinked polymers, dendrimers, metal compounds, organometallic compounds, inorganic based compounds, and other polymeric scaffolds.
- the NO-releasing polymer may include a co-condensed silica that releases NO, such as a diazoxide disulfate-functionalized polysiloxane, a NO-releasing zeolite (see US Patent Application US2006/0269620 or US2010/0331968), release a metal organic framework (MOF) of NO (see US Patent Application US 2010/0239512 or US 2011/0052650), a multi-donor compound that releases NO (see US Patent Application US 2014/0171395), a dendrimer or metal structure that releases NO ( See U.S. Patent Application No. US 2009/0214618), a NO release coating (see U.S. Patent Application No. US 2011/0086234), U.S. Patent Application No.
- the nitric oxide releasing agent can be a nanomaterial containing an NO donor group, such as nanocrystals, which is a co-condensed siloxane network formed from silica.
- the NO-releasing polymer may further include S-nitrosothiol nano silicon spheres, S-nitrosoethylene dithiol chitin, oligopropylene diamine grafted chitosan nucleophilic complex, and/or Nitric oxide releasing agent of Novan Inc. (for example, SB204, SB206, SB208, SB414 or NVN3100), and in US Pat. No. 8,282,967, US Pat. No. 8,956,658, US Pat. No. 8,962,029, US Pat. No. 9,403,851, US Pat. No. 9 438 852, US Pat. No. 1,918,501, US Pat. No. 8,981, 990, US Pat.
- S-nitrosothiol nano silicon spheres for example, SB204, SB206, SB208, SB414 or NVN3100
- Nitric oxide releasing agent of Novan Inc. for example, SB204, SB206, SB208, SB414 or NVN3100
- the oligo-propylene diamine grafted chitosan nucleophilic complex may comprise an azothanondiol salt.
- the nitric oxide releasing agent may be an oligopropylene diamine grafted chitosan NONOate.
- the nitric oxide releasing agent may include an ammoxidation microorganism (AOM), and the ammonia oxidation microorganism (AOM) may include an ammoxidation bacteria (AOB).
- AOM ammoxidation microorganism
- AOB ammoxidation bacteria
- the ammonia oxidizing microorganism (AOM) may include Nitrosomonas, Nitrosococcus, Nitrosospira, Nitrosocystis, Nitrosolobus. And/or Vibrio nitrobacter Nitrosovibrio.
- ammonia oxidizing microorganism may include a nitrogen monoxide releasing microbial population (eg, AOB101, AOB102, AOB103, AOB201, AOB201, or AOB203) of AO Biome, LLC, and US Pat. No. 7,820,420 B2, US9738870B2, WO2017004534A2, US10078054B2.
- AOM ammonia oxidizing microorganism
- polymer generally means a molecular weight greater than 2000 Daltons, greater than 3000 Daltons, greater than 4000 Daltons, greater than 5000 Daltons, greater than 6000 Daltons, greater than 7000 Daltons. Any compound having greater than 8000 Daltons, greater than 9000 Daltons, greater than 10,000 Daltons, greater than 12,000 Daltons, greater than 15,000 Daltons, or greater than 20,000 Daltons.
- small molecule generally means a molecular weight of less than or equal to 2000 Daltons, less than or equal to 1500 Daltons, less than or equal to 1200 Daltons, less than or equal to 1000 Daltons, less than or equal to 900. Dalton, less than or equal to 800 Daltons, less than or equal to 700 Daltons, less than or equal to 600 Daltons, less than or equal to 500 Daltons, less than or equal to 400 Daltons, less than or equal to 300 Daltons Any compound having a molecular weight of less than or equal to 200 Daltons or less than or equal to 100 Daltons.
- the nitric oxide releasing agent may have one or more of the following groups: azo nonanediol salt, hydroxydiazenenesulfonic acid, S-nitrosothiol, furazolium nitrogen , hydrazine, N-nitrosamines, N-hydroxy hydrazine, azo hydrazide salts, nitrates, nitrites, nitrates, nitrites, stritonimine, sedone, oxatriazole-5 - Imine, triazole-5-one, hydroxylamine, dioxadiazepine, N-hydroxynitrosamine, N-nitrosenimine, hydroxyurea and metal nitrosylamino complexes.
- the nitric oxide releasing agent may have one or more groups selected from Table 1:
- the nitric oxide releasing agent may be positively charged, neutral or negatively charged under physiological conditions.
- the nitric oxide releasing agent may have a logP between 1 and 5. For example, it can be between 1.5 and 3.5.
- nitric oxide releasing agents described herein are useful for preventing or treating the diseases or conditions associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor.
- the nitric oxide releasing agent can be used to prepare a medicament, and the medicament can be used for preventing or treating the disease or condition associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor.
- the nitric oxide releasing agent can be used for preventing or treating the rash associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor, and a hand-foot syndrome associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor.
- pruritus associated with administration of VEGFR inhibitors and/or VEGF inhibitors pruritus associated with administration of VEGFR inhibitors and/or VEGF inhibitors, erythema associated with administration of VEGFR inhibitors and/or VEGF inhibitors, skin dryness associated with administration of VEGFR inhibitors and/or VEGF inhibitors, and administration of VEGFR Inhibitors and/or VEGF inhibitor-related alopecia, paronychia associated with administration of VEGFR inhibitors and/or VEGF inhibitors, pigmentation disorders associated with administration of VEGFR inhibitors and/or VEGF inhibitors, and administration of VEGFR inhibition Oral ulcer associated with VEGF inhibitors, dry mouth associated with administration of a VEGFR inhibitor and/or VEGF inhibitor, nasal sputum associated with administration of a VEGFR inhibitor and/or VEGF inhibitor, and administration of a VEGFR inhibitor and / or VEGF inhibitor-associated nasopharyngitis, cheilitis associated with administration of VEG
- the nitric oxide releasing agent can be used for preventing or treating rash, hand and foot syndrome, itching, erythema, dry skin, hair loss, paronychia, pigmentation disorder, oral ulcer, dry mouth, nasal discharge, nose Pharyngitis, cheilitis, esophageal mucositis, gastric mucositis, gastric ulcer, diarrhea, vomiting, nausea, anorexia, constipation and/or abdominal pain.
- the nitric oxide releasing agent can be used to prevent or treat the hand and foot syndrome.
- the medicament is prepared for topical administration.
- the site of administration of the topical administration may not be the site of occurrence of cancer or a potential site of metastasis of cancer.
- the administration portion may not be the primary site of cancer.
- the administration portion may not be a metastatic site of cancer.
- the metastatic site can include sites of occurrence of cancer metastasis resulting from lymphatic metastasis, vascular metastasis, and/or implantative metastasis.
- the transfer site can include bone, brain, liver, stomach, and/or lung.
- the administration portion may not be a recurrence site of cancer.
- the concentration of the nitric oxide releasing agent may be from about 0.0001% (w/w) to about 50% (w/w), for example, may be about 0.0001% (w/w). To about 10% (w/w), about 0.0001% (w/w) to about 9.5% (w/w), about 0.0001% (w/w) to about 9% (w/w), about 0.0001% ( w/w) to about 8.5% (w/w), about 0.0001% (w/w) to about 8% (w/w), about 0.0001% (w/w) to about 7.5% (w/w), From about 0.0001% (w/w) to about 7% (w/w), from about 0.0001% (w/w) to about 6.5% (w/w), from about 0.0001% (w/w) to about 6% (w) /w), from about 0.0001% (w/w) to about 5.5% (w/w), from about 0.0001% (w/w) to about 5% (w/w), from about 0.0001% (w/w), from about
- the concentration of the nitric oxide releasing agent may be from about 0.0001% (w/w) to about 1% (w/w), from about 0.0001% (w/w) to about 0.9%. (w/w), from about 0.0001% (w/w) to about 0.6% (w/w), from about 0.05% (w/w) to about 0.5% (w/w), about 0.05% (w/w) To about 0.4% (w/w), about 0.05% (w/w) to about 0.3% (w/w), about 0.05% (w/w) to about 0.2% (w/w), about 0.1% ( w/w) varies to a range of about 0.2% (w/w) or less.
- the concentration of the nitric oxide releasing agent may be about 0.2% (w/w).
- the concentration of the nitric oxide releasing agent may be about 0.1% (w/w).
- the drug comprising the nitric oxide releasing agent may not substantially affect the therapeutic effect of the VEGFR inhibitor and/or VEGF inhibitor.
- administration of the drug comprising the nitric oxide releasing agent does not substantially reduce the need to increase the dosage of the VEGFR inhibitor and/or VEGF inhibitor to achieve substantially the same therapeutic effect.
- the medicament is prepared for topical administration.
- the medicament is prepared for topical dermal administration.
- the drug can be an ointment, lotion or cream.
- the active ingredient may refer to a monomeric compound having medical or physiological activity.
- the additional active ingredient may be selected from the group consisting of anti-inflammatory agents, analgesics, local anesthetics, antibiotics, antihistamines, preservatives, immunosuppressants, and anti-hemorrhagic agents.
- the medicament may further comprise a pharmaceutically acceptable carrier.
- the pharmaceutically acceptable carrier can be selected from the group consisting of fillers, binders, disintegrants, buffers, preservatives, lubricants, odorants, thickeners, colorants, and emulsifiers.
- the present application provides a nitric oxide releasing agent for use in preventing or treating a disease or condition associated with inhibition of VEGFR and/or VEGF (eg, epithelial tissue disease associated with inhibition of VEGFR and/or VEGF).
- a disease or condition associated with inhibition of VEGFR and/or VEGF eg, epithelial tissue disease associated with inhibition of VEGFR and/or VEGF.
- the application provides a method of preventing or treating a disease or condition associated with inhibition of VEGFR and/or VEGF in a subject.
- the method comprises administering to the subject a prophylactically or therapeutically effective amount of a nitric oxide releasing agent as described herein.
- prevention can be used interchangeably with “prophylactic treatment”.
- “Prophylaxis” as used in this application generally refers to preventing the onset, recurrence or spread of a disease or one or more of its symptoms by taking certain measures in advance.
- the term “treating” generally refers to eliminating or ameliorating a disease, or alleviating one or more symptoms associated with a disease.
- the term "subject” generally refers to a human or non-human animal (including mammals, rodents and avian animals, etc.) in need of diagnosis, prognosis, improvement, prevention and/or treatment of the disease.
- the subject can be a livestock animal (eg, cow, pig, sheep, chicken, rabbit, or horse), or a rodent (eg, rat and mouse), or a primate (eg, large Orangutans and monkeys), or domestic animals (for example, dogs and cats).
- the subject may be those subjects in need of treatment or prevention of a nitric oxide releasing agent.
- the subject can include a cancer patient.
- the subject can be administered the VEGFR inhibitor and/or the VEGF inhibitor once, in and/or in the future.
- the VEGFR inhibitor and/or VEGF inhibitor can be a VEGFR inhibitor and/or a VEGF inhibitor as described herein.
- the severity of the disease or condition can be increased following administration of the VEGFR inhibitor and/or VEGF inhibitor.
- the severity of the disease or condition can be increased by about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35. % or more, about 40% or more, about 45% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 100% or Above, about 200% or more or more.
- the subject may not have the disease or condition prior to administration of the VEGFR inhibitor and/or VEGF inhibitor.
- the term "the subject does not have the disease or condition” generally means that the subject does not have a history of the disease or condition associated with administration of a VEGFR inhibitor and/or VEGF inhibitor. .
- the present application has not been administered for more than one day, more than one week, more than one month, more than one year, more than 10 years, or the subject was born before the administration of the VEGFR inhibitor and/or VEGF inhibitor.
- the disease or condition associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor is not have the disease or condition prior to administration of the VEGFR inhibitor and/or VEGF inhibitor.
- the VEGFR inhibitor and/or VEGF inhibitor does not comprise the nitric oxide releasing agent.
- the VEGFR inhibitor and/or VEGF inhibitor does not comprise nitroglycerin.
- the term "effective amount” generally refers to an amount of a drug that can alleviate or eliminate a disease or symptom of a subject, or can prevent or prevent the occurrence of a disease or symptom. Generally, it can be based on the subject's weight, age, sex, diet, excretion rate, past medical history, current treatment, time of administration, dosage form, method of administration, route of administration, combination of drugs, health of the subject.
- the specific effective amount is determined by the potential of the condition and cross-infection, allergies, hypersensitivity and side effects, and/or the extent to which the epithelial (or endothelial) tissue disease develops. A person skilled in the art (e.g., a physician or veterinarian) may proportionally reduce or increase the dosage according to these or other conditions or requirements.
- the concentration of the nitric oxide releasing agent applied is from about 0.0001% (w/w) to about 50% (w/w), for example, from about 0.0001% (w/w) to about 10% (w/w), about 0.0001% (w/w) to about 9.5% (w/w), about 0.0001% (w/w) to about 9% (w/w), about 0.0001% (w/w) to about 8.5% (w/w), about 0.0001% (w/w) to about 8% (w/w), about 0.0001% (w/w) to about 7.5% (w/w), about 0.0001 % (w/w) to about 7% (w/w), about 0.0001% (w/w) to about 6.5% (w/w), about 0.0001% (w/w) to about 6% (w/w) ), from about 0.0001% (w/w) to about 5.5% (w/w), from about 0.0001% (w/w) to about 5% (w/w), from about 0.0001% (w/w) to about 5.5% (
- the concentration of the nitric oxide releasing agent may be from about 0.0001% (w/w) to about 1% (w/w), from about 0.0001% (w/w) to about 0.9%. (w/w), from about 0.0001% (w/w) to about 0.6% (w/w), from about 0.05% (w/w) to about 0.5% (w/w), about 0.05% (w/w) To about 0.4% (w/w), about 0.05% (w/w) to about 0.3% (w/w), about 0.05% (w/w) to about 0.2% (w/w), about 0.1% ( w/w) varies to a range of about 0.2% (w/w) or less.
- the concentration of the nitric oxide releasing agent may be about 0.2% (w/w).
- the concentration of the nitric oxide releasing agent may be about 0.1% (w/w).
- the subject can include a human or a non-human animal.
- the non-human animal can be selected from the group consisting of monkeys, chickens, geese, cats, dogs, mice, and rats.
- non-human animals may also include any animal species other than humans, such as livestock animals, or rodents, or primates, or domestic animals, or poultry animals.
- the person may be a Caucasian, African, Asian, Semitic, or other ethnic, or heterogeneous race of various races.
- the person can be an elderly person, an adult, a teenager, a child, or an infant.
- An effective amount in humans can be extrapolated based on the effective amount in the experimental animal.
- Freireich et al. describe the interrelationship between animal and human doses (based on milligrams per square meter of body surface) (Freiheim et al., Cancer Chemother. Rep. 50, 219 (1966)).
- the body surface area can be approximated from the patient's height and weight. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970).
- inhibition of the VEGFR and/or VEGF can be caused by administration of a VEGFR inhibitor and/or a VEGF inhibitor to the subject.
- the nitric oxide releasing agent can be administered prior to, concurrently with, or subsequent to administration of the VEGFR inhibitor and/or VEGF inhibitor to the subject.
- a VEGFR inhibitor and/or VEGF inhibitor as described herein is administered concurrently with the nitric oxide releasing agent, the nitric oxide releasing agent is present at about 0.0001 to 10% (eg, about 0.005-10) relative to the total dose.
- Dosage levels are administered at a dose level of -10%, about 8-10% or less.
- the nitric oxide releasing agent can be administered prior to administration of the VEGFR inhibitor and/or VEGF inhibitor Or after the interval of administration.
- the interval may be 1 minute, 2 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 Hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months or longer.
- the administration of the nitric oxide releasing agent is for external administration. In certain embodiments, the nitric oxide release agent is administered in an ointment. In certain embodiments, the nitric oxide releasing agent is co-administered with one or more other active ingredients. In certain embodiments, administration of the nitric oxide releasing agent does not substantially affect the therapeutic effect of the VEGFR inhibitor and/or VEGF inhibitor.
- the application provides a pharmaceutical combination (eg, a kit).
- the pharmaceutical combination may comprise: 1) a VEGFR inhibitor and/or a VEGF inhibitor as described herein; and, 2) a nitric oxide releasing agent as described herein.
- the VEGFR inhibitor and/or VEGF inhibitor and the nitric oxide release agent are not mixed with each other.
- the VEGFR inhibitor and/or VEGF inhibitor and the nitric oxide release agent are each independently present in a separate container.
- the pharmaceutical combination may include two or more drugs packaged separately from each other, wherein at least one of the drugs comprises a VEGFR inhibitor and/or a VEGF inhibitor as described herein, and at least one of the other
- the medicament comprises a nitric oxide releasing agent as described herein.
- the nitric oxide releasing agent of 2) is capable of preventing or treating a disease or condition associated with the VEGFR inhibitor and/or VEGF inhibitor in administration 1) ( For example, a disease or condition described herein in connection with administration of a VEGFR inhibitor and/or a VEGF inhibitor).
- the nitric oxide releasing agent of 2) does not substantially affect the therapeutic effect of the VEGFR inhibitor and/or VEGF inhibitor in 1).
- the nitric oxide releasing agent of 2) is administered prior to, simultaneously with, or after administration of the VEGFR inhibitor and/or VEGF inhibitor of 1).
- substantially unaffected may mean, as described in 2) of the use of the pharmaceutical combination or kit, as compared to the therapeutic effect of the VEGFR inhibitor and/or VEGF inhibitor alone.
- the nitric oxide releasing agent is equivalent to the therapeutic effect of the VEGFR inhibitor and/or VEGF inhibitor in 1) or does not produce a significant disadvantage.
- the nitric oxide releasing agent in 2) of the pharmaceutical combination or kit is used and compared to the therapeutic effect of using the VEGFR inhibitor and/or VEGF inhibitor alone.
- the degree of tumor volume reduction caused by the VEGFR inhibitor and/or VEGF inhibitor in 1) is the same, or the degree of reduction is not less than about 5%, not less than about 4%, not less than about 3%, Not less than about 2%, not less than about 1%, not less than about 0.5%, not less than about 0.1%, not less than about 0.01%, not less than about 0.001% or less.
- the application also provides a method comprising administering to a subject a nitric oxide releasing agent, wherein the subject has been, is being, and/or will be administered a VEGFR inhibitor and/or a VEGF inhibitor and has or Having a disease or condition associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor.
- the present application also provides a method for preventing or treating a disease or condition comprising administering a nitric oxide releasing agent to a subject susceptible to or having the disease or condition, wherein the subject has been, is VEGFR inhibitors and/or VEGF inhibitors are administered and/or in the future.
- the subject may already have a disease or condition associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor, or the subject may have a greater probability of having and administering a VEGFR inhibitor A disease or condition associated with a VEGF inhibitor.
- the term "susceptible" generally refers to a subject having a greater probability of having the disease or condition associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor.
- the greater probability may mean that a subject has an increased probability of having a disease or condition associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor by about at least 10% compared to a healthy subject. At least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200% or more.
- the present application also provides a method of preventing or treating a disease or condition comprising administering a nitric oxide releasing agent to a subject susceptible to or having the disease or condition, wherein the disease or condition is hand and foot syndrome.
- the subject can be administered a VEGFR inhibitor and/or a VEGF inhibitor once, in, and/or in the future.
- the disease or condition can be a hand-foot syndrome.
- the disease or condition can be a disease or condition associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor.
- the disease or condition can be a hand-foot syndrome associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor.
- the application also provides a method comprising the steps of: 1) monitoring one or more skin tissue, facial features and/or gastrointestinal features of a subject to whom a VEGFR inhibitor and/or a VEGF inhibitor is administered; 2) when the monitoring indicates that the subject has a skin tissue disease or disorder, a facial disease or disorder, and/or a gastrointestinal disease or disorder associated with administration of the VEGFR inhibitor and/or VEGF inhibitor, The subject administers a nitric oxide releasing agent.
- the term "skin tissue characteristics" generally refers to a feature that is capable of reflecting a disease or condition of a skin tissue.
- the features can include features that are capable of reflecting a skin tissue disease or condition associated with administration of the VEGFR inhibitor and/or VEGF inhibitor.
- the features can include a rash that is associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor, a hand-foot syndrome associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor, and administration of a VEGFR inhibitor and/or VEGF.
- Inhibitor-associated pruritus skin erythema and/or purpura associated with administration of VEGFR inhibitors and/or VEGF inhibitors, skin dryness and/or cleft palate associated with administration of VEGFR inhibitors and/or VEGF inhibitors, and administration of VEGFR Inhibitors and/or VEGF inhibitor-related alopecia, paronychia associated with administration of VEGFR inhibitors and/or VEGF inhibitors, and/or pigmentation disorders associated with administration of VEGFR inhibitors and/or VEGF inhibitors feature.
- the features may include area and extent of erythema, area and extent of purpura, number and extent of papules, number and extent of pustules, number and extent of nodules, extent and extent of skin swelling, degree of skin ulceration, dryness of the skin, cleft palate Degree, degree of keratinization of the skin, degree of skin lichenification, area and extent of skin desquamation, skin tightness, degree of skin itching, degree of vascular inflammation at the dermis and subcutaneous junction, degree of necrosis of skin tissue, degree of skin erosion ulcer, reticulate Area of bluish area, degree of skin pigmentation, number of blisters and bullae, area of hair loss/area/degree, degree of skin granulation, degree of skin dyslipidemia, degree of folliculitis, degree of peri-week swelling, degree of periungual abscess, nail week Skin pigmentation, nail bed atrophy, thinning or hypertrophy of the deck, abnormal deck color, a horizontal stripes, a longitudinal
- the term "five features" generally refers to a feature that is capable of reflecting a facial disease or condition.
- the characteristics can include features that are capable of reflecting a facial disease or condition associated with administration of the VEGFR inhibitor and/or VEGF inhibitor.
- the features can include an oral ulcer that is associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor, a dry mouth associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor, and administration of a VEGFR inhibitor and/or VEGF.
- Inhibitor-associated epistaxis nasopharyngitis associated with administration of a VEGFR inhibitor and/or VEGF inhibitor, and/or characteristics of cheilitis associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor.
- the characteristics may include degree of oral mucosal hyperemia, degree of oral mucosal edema, degree of oral mucosal herpes, degree of oral mucosal ulcer, degree of submucosal defect of the oral submucosa, degree of salivary gland atrophy of the tongue gland/sublingual gland/ parotid gland, mouth Dryness, degree of caries, degree of tongue swelling, degree of lingual dentition, frequency of nosebleeds, amount of nosebleeds, degree of mucosal edema of oropharynx and nasopharynx, degree of mucosal herpes of oropharynx and nasopharynx, oropharynx and nasopharyngeal mucosa Degree of ulceration, degree of mucosal hyperplasia of oropharynx and nasopharynx, degree of follicular hyperplasia of oropharynx and nasopharynx, degree of swelling
- gastrointestinal features generally refers to a feature that is capable of reflecting a gastrointestinal disease or condition.
- the features can include features that are capable of reflecting a gastrointestinal disease or condition associated with administration of the VEGFR inhibitor and/or VEGF inhibitor.
- the features can include an ability to reflect esophageal mucositis associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor, gastric mucositis associated with administration of a VEGFR inhibitor and/or a VEGF inhibitor, and administration of a VEGFR inhibitor and/or Or VEGF inhibitor-associated gastric ulcer, diarrhea associated with administration of a VEGFR inhibitor and/or VEGF inhibitor, vomiting associated with administration of a VEGFR inhibitor and/or VEGF inhibitor, and administration of a VEGFR inhibitor and/or VEGF inhibitor
- nausea, anorexia associated with administration of VEGFR inhibitors and/or VEGF inhibitors, constipation associated with administration of VEGFR inhibitors and/or VEGF inhibitors, and/or association with administration of VEGFR inhibitors and/or VEGF inhibitors Characteristics of abdominal pain.
- the characteristics may include degree of loss of appetite, degree of gastric hernia, degree of dysphagia, degree of post-sternal burning, degree of post-sternal pain, time of upper abdominal pain (fasting or satiety) and degree, degree of bloating, diarrhea Degree, number of bowel movements, time of defecation, abdominal pain before urgency, heavy after urgency, abnormal feces (such as black blood, blood, mucus, mucus, pus, bloody stool, egg-flower soup, etc.), frequency of vomiting, vomiting , hematemesis, nausea, malnutrition, and the lack of trace elements.
- degree of loss of appetite degree of gastric hernia, degree of dysphagia, degree of post-sternal burning, degree of post-sternal pain, time of upper abdominal pain (fasting or satiety) and degree, degree of bloating, diarrhea Degree, number of bowel movements, time of defecation, abdominal pain before urgency, heavy after urgency, abnormal feces (such as black blood, blood, mu
- the method may further comprise continuing to monitor the skin tissue disease or condition, facial disease or condition and/or gastrointestinal disease or condition, and optionally reducing or deactivating the VEGFR inhibitor and/or Or a VEGF inhibitor.
- the continued monitoring can mean about at least 1 day, at least 1 week, at least 10 days, at least 2 weeks, at least 3 weeks, at least 1 month, at least 3 after administration of the VEGFR inhibitor and/or VEGF inhibitor. Monitor for months or longer.
- the reduction or deactivation may be directed to the subject to administer the VEGFR inhibitor and/or VEGF inhibitor at a dose that is greater than the dose of the VEGFR inhibitor and/or VEGF inhibitor described in step 1) of the method. In comparison, reducing at least about 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100%.
- the severity of the disease or condition associated with administration of a VEGFR inhibitor and/or VEGF inhibitor can be increased following administration of the VEGFR inhibitor and/or VEGF inhibitor.
- the severity may be increased by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more. many.
- the VEGFR inhibitor and/or VEGF inhibitor may not comprise the nitric oxide releasing agent.
- the VEGFR inhibitor and/or VEGF inhibitor may not comprise nitroglycerin.
- the disease or condition can be an epithelial tissue disease or condition.
- administration of the VEGFR inhibitor and/or VEGF inhibitor can be used to treat cancer.
- the affected area of the disease or condition can be different from the affected area of the cancer.
- the nitric oxide releasing agent can be administered topically to the subject.
- the nitric oxide releasing agent can be administered topically to a site of the subject that is substantially free of cancer cells.
- a site that is substantially free of cancer cells generally refers to a tissue organ or site in a subject whose cancer cell content is low enough to be substantially considered to be free of cancer cells.
- the substantially free may mean that the number of the cancer cells accounts for less than 0.01% of the total cell number of the site, for example, 0.005% or less, 0.001% or less, 0.0001% or less, 0.00001% or less or less.
- the nitric oxide releasing agent can be administered to a non-cancer site in the subject.
- ** indicates P ⁇ 0.01; * indicates P ⁇ 0.05; *** indicates P ⁇ 0.001, using t-test statistical test.
- a mixture of 4 ml of (3-mercaptopropyl)trimethoxysilane and 2 ml of tetraethyl orthosilicate was injected into 30 ml of deionized water, 30 ml of ethanol and 30 ml by a syringe pump at a rate of 0.5 ml per minute.
- the reaction liquid was kept at 0 ° C during the injection.
- the reaction solution was stirred at room temperature for 2.5 hours, followed by centrifugation at 4000 rpm for 8 minutes per minute.
- the precipitate was washed once with 100 ml of ice water and 100 ml of ethanol, respectively, and dried under vacuum to obtain a thiolated nano-silica ball.
- 150 mg of thiolated nano-silica spheres were dispersed in 4 ml of methanol, the temperature was lowered to 0 ° C, and 2 ml of a mixed solution of 1 mol per liter of sodium nitrite and 1 mmol per liter of diethyltriamine pentaacetic acid was added under continuous stirring. Then add 2 ml of 5 moles per liter of aqueous hydrochloric acid. The reaction solution was stirred at 0 ° C for 2.5 hours in the dark and at 4000 ° C for 5 minutes at 4 ° C.
- the precipitate was washed once with 4 ml of a solution of 30 ml of 1 mmol of diethyltriamine pentaacetic acid per liter and 30 ml of methanol at 4 ° C, and the solid was collected by re-centrifugation.
- the dried final product was obtained by vacuum drying at -30 ° C for 30 minutes in the dark, and stored at -20 ° C until use.
- the UV-visible spectrum of the solution (detected using a Thermo Fisher EV300 UV spectrophotometer) has a characteristic absorption peak at 330 nm.
- the total amount of nitric oxide released was measured by the Biyuntian Nitric Oxide Assay Kit (Griess method, purchased from Shanghai Biyuntian Biotechnology Co., Ltd.) for 5 hours under 200-hour illumination to characterize the nitric oxide storage.
- the nitric oxide storage of the product was 1.87 ⁇ 0.55 micromoles per milligram.
- the precipitate was washed once with 300 ml of methanol, 150 ml of deionized water and 300 ml of acetone, respectively, followed by vacuum drying to obtain p-toluenesulfonylated chitin.
- the precipitate was washed once with 400 ml of methanol and 400 ml of acetone, dried in vacuo and dispersed in 25 ml of dimethyl containing 10 mmol of 1,4-dithiothreitol and N,N-diisopropylethylamine.
- the solution was stirred at room temperature for 1 hour in a solution of acetamide and filtered.
- the precipitate was washed with 400 ml of methanol and 400 ml of acetone, respectively, and dried under vacuum to give a thiolated chitin compound.
- the infrared spectrum of the final product (detected using a Nicolet 6700 infrared spectrometer) main absorption peak (wavenumber): 3600-3200, 3285, 1652, 1537, 10283360-3220, 1250-1300, 1050-1070. Its diffuse reflectance UV-visible spectrum (detected using a Thermo Fisher EV300 UV spectrophotometer) showed an absorption peak at 549 nm. The total amount of released nitric oxide was measured by the Biyuntian Nitric Oxide Assay Kit (Griess method) to characterize the nitric oxide storage. The final product had a nitric oxide storage of 0.37 ⁇ 0.08 micron. Molar per mg.
- the secondary aminated modified chitosan was dissolved in a mixed solvent of 1 ml of water and 3 ml of methanol, and the mixed solution was added to a Parr hydrogenation reactor with 100 ⁇ l of 6 mol per liter of sodium methoxide solution. .
- the high-purity nitrogen gas was replaced by multiple times to remove oxygen, and the nitrogen monoxide gas was injected, and the pressure was maintained at 10 atmospheres, and the reaction was carried out for 4 days at room temperature. After the end of the reaction, high-purity nitrogen gas was displaced several times to remove unreacted nitric oxide.
- the reaction solution was then added to 300 ml of acetone for precipitation, and the precipitate was collected by centrifugation, dried under vacuum to give the final product, which was stored at -20 ° C until use.
- the infrared spectrum of the final product (containing azo diol salt) (detected using a Nicolet 6700 infrared spectrometer) main absorption peak (wavenumber): 3600-3200, 3285, 1650, 1587, 1284, 1059.
- Its UV-visible spectrum (detected using a Thermo Fisher EV300 UV spectrophotometer) has a characteristic absorption peak at 252 nm.
- the sample was dissolved in a PBS solution, and the total amount of released nitric oxide was measured by a Biyuntian Nitric Oxide Assay Kit (Griess method) to determine a sample having a nitric oxide storage amount of 0.77 ⁇ 0.11 ⁇ mol per milliliter.
- sildenafil for the treatment of anti-VEGF multi-kinase inhibitors caused by side effects of Palmar Plantar Erythrodysesthesia (PPE) (see Kellen L. Meadows et al, Support Care Cancer. 2015 May; 23 (5): 1311 -1319).
- PPE Palmar Plantar Erythrodysesthesia
- the therapeutic effect of sildenafil on PPE caused by anti-VEGF multi-kinase inhibitors is very limited and almost ineffective.
- the effect of nitric oxide releasing agent on sildenafil was compared.
- the cultured HUVEC cells were digested and suspended, and the cells were counted and seeded in a 96-well plate, and 5000-10000 cells were planted per well.
- the wells were divided into: blank control group, VEGF/VEGFR inhibitor group, VEGF/VEGFR inhibitor + nitric oxide releasing agent group, VEGF/VEGFR inhibitor solvent group, nitric oxide releasing agent solvent control group, VEGF/VEGFR inhibition Agent + sildenafil group and sildenafil solvent control group, each well contained basal medium in each well, and each well finally contained a liquid volume of about 100 ⁇ L.
- the specific grouping situation is as follows:
- VEGF/VEGFR inhibitor group VEGF/VEGFR inhibitor solution was added (final concentration is shown in Table 1, the solvent of VEGF/VEGFR inhibitor solution is DMSO);
- VEGF/VEGFR inhibitor + nitric oxide releasing agent group adding VEGF/VEGFR inhibitor solution and nitric oxide releasing agent solution (the final concentration of VEGF/VEGFR inhibitor and nitric oxide releasing agent is shown in Table 1, And according to the solubility of the nitric oxide releasing agent, the solvent of the nitric oxide releasing agent solution is selected as ethanol or sterile water, and the total volume difference of each group is supplemented by adding the selected corresponding solvent);
- VEGF / VEGFR inhibitor solvent group added to the corresponding volume of DMSO contained in the VEGF / VEGFR inhibitor solution in group 2);
- Nitric oxide releasing agent solvent control group a solvent of the same kind (for example, ethanol or sterile water) contained in the same amount as that contained in the nitric oxide releasing agent in the group 3).
- VEGF/VEGFR inhibitor + sildenafil group first add VEGF/VEGFR inhibitor solution and then add sildenafil solution (the final concentration of VEGF/VEGFR inhibitor and sildenafil is shown in Table 2, west
- the solvent of the diazepam solution is DMSO, and the total volume difference of each group is supplemented by adding the selected corresponding solvent);
- Sildenafil solvate control group The same volume of DMSO contained in the corresponding sildenafil in group 6) was added.
- the VEGF/VEGFR inhibitor solvent group did not participate in data processing and was only used as a reference for evaluating experimental system errors.
- the nitric oxide releasing agent solvent control group and the sildenafil solvent control group were used for data correction to exclude the effect of the solvent on the results.
- the cell survival rate was determined using the Cell Counting Kit-8 (CCK-8) detection kit (C0037, Shanghai Biyuntian Biotechnology Co., Ltd., Beyotime Biotechnology) to calculate the VEGF/VEGFR inhibitor pair. Proliferative toxicity of cells and the alleviation of proliferation toxicity by nitric oxide releasing agents or sildenafil. The results were statistically analyzed and plotted using GraphPad Prism 6.0 software, t-test.
- Table 2 lists the combinations of various VEGF/VEGFR inhibitors and nitric oxide releasing agents or sildenafil, and the corresponding experimental results (where the data identification in the cell viability column is associated with the VEGF/VEGFR inhibitor group). The percentage of viable cells increased by the corresponding VEGF/VEGFR inhibitor + nitric oxide releasing agent group (or sildenafil).
- Figures 4A-4C show administration of VEGF/VEGFR inhibitor sorafenib toluene (V1) or sunitinib malate (V3) or regorafenib (V4) and nitric oxide release agent to HUVEC cells, respectively.
- Example 16-32 Nitric Oxide Release Agent attenuates VEGF/VEGFR inhibitors against human immortalized epithelial cells (HaCaT), human oral mucosal epithelial keratinocytes (HOK), human intestinal epithelial cells (FHs 74 Int), gastric epithelial cells Effect of cell proliferation toxicity of (GES-1) and its comparison with sildenafil
- HaCaT human immortalized epithelial cells
- HOK human oral mucosal epithelial keratinocytes
- Examples 25-28 used gastric epithelial cells (GES-1), and the results correspond to Table 5
- Examples 29-32 used human intestinal epithelial cells (FHs 74Int), and the results correspond to Table 6.
- the cultured cells were digested and suspended, the cells were counted, and inoculated into 96-well plates, and 5000-10000 cells were planted per well.
- the wells were divided into: blank control group, VEGF/VEGFR inhibitor group, VEGF/VEGFR inhibitor + nitric oxide releasing agent group, VEGF/VEGFR inhibitor solvent group, nitric oxide releasing agent solvent control group, VEGF/VEGFR inhibition Agent + sildenafil group, and sildenafil solvent control group, each well contained basal medium in each well, and each well finally contained a liquid volume of about 100 ⁇ L.
- the specific grouping situation is as follows:
- VEGF/VEGFR inhibitor group VEGF/VEGFR inhibitor solution was added (final concentration is shown in Table 2, the solvent of VEGF/VEGFR inhibitor solution is DMSO);
- VEGF/VEGFR inhibitor + nitric oxide releasing agent group adding VEGF/VEGFR inhibitor solution and nitric oxide releasing agent solution (the final concentration of VEGF/VEGFR inhibitor and nitric oxide releasing agent is shown in Table 2, And according to the solubility of the nitric oxide releasing agent, the solvent of the nitric oxide releasing agent solution is selected as ethanol or sterile water, and the total volume difference of each group is supplemented by adding the selected corresponding solvent);
- VEGF / VEGFR inhibitor solvent group added to the corresponding volume of DMSO contained in the VEGF / VEGFR inhibitor solution in group 2);
- Nitric oxide releasing agent solvent control group a solvent of the same kind (for example, ethanol or sterile water) contained in the same amount as that contained in the nitric oxide releasing agent in the group 3).
- VEGF/VEGFR inhibitor + sildenafil group first add VEGF/VEGFR inhibitor solution and then add sildenafil solution (the final concentration of VEGF/VEGFR inhibitor and sildenafil is shown in Table 2, west
- the solvent of the diazepam solution is DMSO, and the total volume difference of each group is supplemented by adding the selected corresponding solvent);
- Sildenafil solvate control group The same volume of DMSO contained in the corresponding sildenafil in group 6) was added.
- the VEGF/VEGFR inhibitor solvent group did not participate in data processing and was only used as a reference for evaluating experimental system errors.
- the nitric oxide releasing agent solvent control group and the sildenafil solvent control group were used for data correction to exclude the effect of the solvent on the results.
- the cell survival rate was determined using the Cell Counting Kit-8 (CCK-8) detection kit (C0037, Shanghai Biyuntian Biotechnology Co., Ltd., Beyotime Biotechnology) to calculate the VEGF/VEGFR inhibitor pair. Proliferative toxicity of cells and the alleviation of proliferation toxicity by nitric oxide releasing agents or sildenafil. The results were statistically analyzed and plotted using GraphPad Prism 6.0 software, t-test.
- Table 3 - Table 6 lists the combinations of various VEGF/VEGFR inhibitors and nitric oxide releasing agents or sildenafil, and the corresponding experimental results (where the data identification in the cell viability column is associated with VEGF/VEGFR inhibition).
- the percentage of surviving cells increased by the corresponding VEGF/VEGFR inhibitor + nitric oxide releasing agent group (or sildenafil) compared to the agent group.
- Fig. 5 shows the results of experiments on HaCaT cells
- Fig. 6 shows the results of experiments on HOK cells
- Fig. 7 shows the results of experiments on GES-1 cells
- Fig. 8 shows the results of experiments on FHs 74 Int cells.
- the abscissa indicates different experimental groups and control groups; the survival rate of cells on the ordinate table (the percentage of cells in the other experimental group or the solvent control group was calculated by the cell survival rate of the blank control group being 100%).
- 5A, 6A, 7A and 8A each show that 24 hours after administration of VEGF/VEGFR inhibitor sorafenib toluene (V1) and nitric oxide releasing agent (or sildenafil) to different cells, Exemplary results of cell proliferation toxicity as determined by the CCK-8 method;
- Figures 5B, 6B, 7B, and 8B all indicate administration of VEGF/VEGFR inhibitor sunitinib malate (V3) and nitric oxide release agent to different cell types.
- V4 feminine
- nitric oxide releasing agent or sildenafil
- the VEGF/VEGFR inhibitor has proliferative toxicity to skin cells (HaCaT), and the nitric oxide releasing agent has a significant alleviation effect on the proliferation toxicity caused by the VEGF/VEGFR inhibitor. Its relief effect is significantly better than sildenafil.
- VEGF/VEGFR inhibitors have proliferative toxicity to human oral mucosal epithelial keratinocytes (HOK), while nitric oxide releasing agents have significant proliferative toxicity to VEGF/VEGFR inhibitors.
- the mitigating effect is significantly better than sildenafil.
- VEGF/VEGFR inhibitors have proliferative toxicity to human gastric epithelial cells (GES-1), while nitric oxide releasing agents have significant proliferative toxicity to VEGF/VEGFR inhibitors.
- the mitigating effect is significantly better than sildenafil.
- VEGF/VEGFR inhibitor has proliferative toxicity to human intestinal epithelial cells (FHs 74 Int), while the nitric oxide releasing agent has obvious proliferative toxicity to VEGF/VEGFR inhibitors.
- the mitigating effect is significantly better than sildenafil.
- Examples 33-46 Determination of the effect of nitric oxide releasing agents on intracellular/external levels of nitric oxide
- the cultured HUVEC, HaCaT, HOK, FHs 74 Int or GES-1 cells were digested and counted, and the cells were counted and seeded in 24-well plates. Plant 100,000-200,000 cells per well. After the cells are attached, the nitric oxide releasing agent solution is added to a specific final concentration (as shown in Table 7 - Table 8). The control group was added with medium. At each time point (6 hours, 12 hours, 24 hours, and 48 hours, as shown in Table 7-Table 8) after the addition of the nitric oxide releasing agent, 50 ⁇ L of each group supernatant was collected for detecting the extracellular supernatant.
- the level of nitric oxide in the solution while discarding the remaining supernatant, adding the cell lysate, fully lysing and taking 50 ⁇ L of the lysate for detecting the level of nitric oxide in the cells.
- the nitric oxide content was measured using a nitric oxide detection kit (S0021, Beyotime).
- Figures 9A-9D show the relative levels of nitric oxide at 6 hours, 12 hours, 24 hours, and 48 hours after administration of nitric oxide releasing agent in HUVEC extracellular, HUVEC cells, GES-1 extracellular and GES-1 cells, respectively.
- content stands for nitroglycerin and the control group is the basal medium, reflecting physiological levels.
- Figures 10A-10D show that HUVEC extracellular, GES-1 extracellular, and HaCaT cells were treated with nitric oxide releasing agent (isosorbide dinitrate, nicorandil, morpholine, and isoamyl nitrite) for 24 hours, respectively. And the relative content of nitric oxide outside the HOK cells.
- the control group was the basal medium and reflected physiological levels.
- * indicates P ⁇ 0.05, which is significantly different from the corresponding control group; using t-test statistical test.
- Figures 11A-11D show HUVEC cells, GES-1 cells, and HaCaT cells, respectively, after treatment with a nitric oxide releasing agent (isosorbide dinitrate, nicorandil, morpholine, and isoamyl nitrite) for 24 hours. And the relative content of nitric oxide in HOK cells.
- the control group was the basal medium and reflected physiological levels.
- *** indicates P ⁇ 0.001, which is significantly different from the corresponding control group; * indicates P ⁇ 0.01, which is significantly different from the corresponding control group; * indicates P ⁇ 0.05, and corresponds to the corresponding control group.
- the ratio is significantly different; using the t-test statistical test.
- nitric oxide releasing agent can release nitric oxide and increase the level of nitric oxide in the cells.
- Examples 47-54 Sildenafil does not release nitric oxide, nor does it increase intracellular and extracellular NO levels in HUVEC, HaCaT or GES-1 cells.
- the cultured HUVEC, HaCaT or GES-1 cells were digested and counted, and the cells were counted and inoculated into a 6-well plate. Plant 500,000 to 1,000,000 cells per well. After the cells are attached, the sildenafil solution is added to a specific final concentration (as shown in Table 9-10). The control medium was supplemented with basal medium. At each time point (6 hours, 12 hours, 24 hours, and 48 hours) after the addition of sildenafil, 50 ⁇ L of each group supernatant was collected for detecting extracellular NO levels; the remaining supernatant was discarded and added. The cell lysate was fully lysed and 50 ⁇ L of the lysate was taken for the detection of intracellular NO levels. The nitric oxide content was measured using a nitric oxide detection kit (S0021, Beyotime). Figure 12-13 shows the experimental results.
- FIGS. 12A-12B show the relative NO content in extracellular and intracellular at each time point (6 hours, 12 hours, 24 hours, 48 hours) after treatment of sildenafil-treated HUVEC cells with 100 ⁇ M.
- Figures 12C-12D show the relative NO content outside and after 24 hours after sildenafil treatment of HUVEC cells at different concentrations.
- the control group was the basal medium and reflected physiological levels.
- Figures 13A-13B show the relative NO content of extracellular and intracellular, after 24 hours of silencing of 100 ⁇ M sildenafil-treated GES-1 cells, respectively.
- Figures 13C-13D show the relative NO content of extracellular and intracellular, 24 min after sildenafil treatment of HaCaT cells, respectively.
- the control group was the basal medium and reflected physiological levels.
- sildenafil could not release nitric oxide, nor could it increase the levels of NO in the cells of HUVEC, HaCaT or GES-1.
- Examples 55-108 Nitric Oxide Release Agents Can Prevent/Treat Hand-foot Syndrome Caused by Small Molecule VEGFR/VEGF Inhibitors in Vivo
- a rat animal model was constructed, and the small-molecule VEGFR/VEGF inhibitor shown in Table 11 was administered to the 8-week female SD rats by daily gavage. After several days, the paws of the rats showed symptoms of hand-foot syndrome ( As shown in Figure 14). Similar to in humans, rats develop symptoms of hand-foot syndrome after taking the VEGFR/VEGF inhibitor, and the symptoms are very similar. Therefore, rats are excellent animal models for mimicking side effects caused by VEGFR/VEGF inhibitors, such as hand-foot syndrome.
- the rats were fixed.
- the tube was fixed for 4 hours, and after 4 hours, the rats were released, and the residual drug in the application site was wiped off with water, and the rats were returned to the cage.
- the gavage frequency of the VEGFR/VEGF inhibitor is shown in Table 11, but the nitric oxide releasing agent is applied only once a day. Repeat the gavage and smear daily until the end of the test. After 15-18 days of statistical application, the number of rats with normal or significantly lighter than the non-coated side of the hand-foot syndrome was counted as the number of rats effectively inhibiting hand-foot syndrome.
- the rate of anti-cancer drug is not fixed: the rate of completion of the model of hand-foot syndrome in each group is 30%-70%, that is, about 3-7 of 10 rats have a model of hand-foot syndrome, and different drug groups In the process of achieving the hand and foot model, the rats died or the model was unsuccessful.
- the control rate refers to the proportion of rats in the experimental group who developed the hand-foot syndrome model, and the proportion of the rats whose applicator side paws were milder than the unapplied side paws.
- the nitric oxide releasing agent can effectively prevent the hand-foot syndrome caused by the VEGFR/VEGF inhibitor.
- the results of Figures 15-16 also reflect that the nitric oxide release agent is effective in preventing and treating hand-foot syndrome caused by VEGFR/VEGF inhibitors.
- Figure 15 shows that in a drug-administered group of Examples 55-100, after a left paw applicator (nitric oxide releasing agent ointment), the hand-foot syndrome of the left paw was significantly relieved;
- Figure 16 shows In a group of the administrations of Examples 101 to 108, a typical rat was subjected to a right paw applicator (nitric oxide releasing agent ointment), and the right paw of the hand and foot syndrome was also significantly relieved.
- Examples 109-110 Nitric Oxide Release Agents Can Prevent/Treat Hand-foot Syndrome Caused by Small Molecule VEGFR/VEGF Inhibitors in Vivo
- Nitrosomonas europaea (Cat. No. ATCC 19718) was inoculated into an inorganic culture solution (Cat. No. ATCC 2265) at about 200 rpm, 26 ° C, under dark conditions. Amplification culture for 3-5 days until obvious turbidity occurs, the bacterial mother liquor is obtained, and the mother liquor is diluted with the inorganic culture solution to different bacterial concentrations (eg, 10 7 , 10 8 , 10 9 , 10 10 bacteria/ml), and the bacterial concentration is determined by The cytometer was measured to obtain a nitrosomonas wash.
- an inorganic culture solution Cat. No. ATCC 2265
- Amplification culture for 3-5 days until obvious turbidity occurs, the bacterial mother liquor is obtained, and the mother liquor is diluted with the inorganic culture solution to different bacterial concentrations (eg, 10 7 , 10 8 , 10 9 , 10 10 bacteria/ml), and the bacterial concentration is determined by The cytometer was measured to obtain a nitrosomon
- a rat animal model was constructed, and the small molecule VEGFR/VEGF inhibitor shown in Table 12 was administered to the 8-week female SD rats by daily gavage, and the symptoms of hand-foot syndrome appeared in the paws of the rats several days later. Similar to humans, rats develop symptoms of hand-foot syndrome after taking the VEGFR/VEGF inhibitor, and the symptoms are very similar. Therefore, rats are excellent animal models for mimicking side effects caused by VEGFR/VEGF inhibitors, such as hand-foot syndrome.
- the gavage frequency of the VEGFR/VEGF inhibitor is shown in Table 12, but the bacterial wash is only soaked once a day. The gavage and soaking tests were repeated daily until the rats died. After 15-18 days of statistical application, the number of rats that remained normal or significantly lighter than the non-soaked hand-foot syndrome was counted as the number of rats with effective inhibition of hand-foot syndrome.
- the nitric oxide releasing agent lotion can effectively prevent the hand-foot syndrome caused by the VEGFR/VEGF inhibitor.
- Examples 111-112 Nitric Oxide Release Agents Can Prevent/Treat Hand-foot Syndrome Caused by Protein Macromolecular VEGFR/VEGF Inhibitors in Vivo
- Rammucirumab or Bevacizumab was diluted to the desired concentration with physiological saline. After the rats (about 200 g) were reared for one week, they were grouped into groups of 10, and an injection administration test was performed. The diluted remollozumab was infused intravenously for 60 minutes at a dose of 40 mg/kg once a week with paclitaxel (10 mg/kg). An ointment (about 0.05 g) containing a nitric oxide releasing agent was applied to the left paw (claw palm and claw slit) of the rat, and the right paw was used as a blank control without applying the medicine. After the application, the fixed cylinder was fixed for 4 hours, 4 hours later. The rats were released, and the residual drug in the application site was wiped off with water, and the rats were returned to the cage; the experiment was continued for 2-4 weeks, and the experimental phenomenon was observed until the death test of the experimental rats was completed.
- the rate of anti-cancer drugs is not fixed: the establishment rate of each group of hand-foot syndrome models is 10%-30%, that is, about 1-3 of 10 mice have a model of hand-foot syndrome, and different drug groups In the process of achieving the hand and foot model, the rats died or the model was unsuccessful.
- the control rate refers to the proportion of rats in the experimental group who developed the hand-foot syndrome model, and the proportion of the rats whose applicator side paws were milder than the unapplied side paws.
- Figure 15 shows the left paw, front and right paw of a typical rat in the administration group of Examples 111-112 after the left paw application (nitric oxide releasing agent ointment).
- Examples 113-124 Validation of the treatment of small molecule VEGFR/VEGF inhibitors to produce hand-foot syndrome in a rat animal model
- the dosage is shown in Table 14.
- the VEGFR/VEGF inhibitor was continuously administered daily until the hand-foot syndrome occurred in the rats, and the rats were started to undergo therapeutic experiments. During the course of treatment, VEGFR/VEGF inhibitors were administered at low frequency for intragastric administration (the frequency of gavage was as described in Table 14).
- the left paw (claw and claw joint) of rats was coated with nitric oxide releasing agent.
- the ointment about 0.05g
- the right paw as a blank control was not applied, and the fixed tube was fixed for 4 hours after the application.
- the rats were released, and the residual drug in the application site was wiped off with water, and the rats were returned to the cage.
- the gavage frequency of the VEGFR/VEGF inhibitor is shown in Table 14, but the nitric oxide releasing agent is applied only once a day. After 6-10 days of application, the number of rats in which the coated side paws returned to normal or significantly less than the non-applied side paws was counted as the number of rats in the hand and foot syndrome.
- the rate of anti-cancer drug is not fixed: the establishment rate of each group of hand-foot syndrome models is 40%-70%, that is, about 1-3 of 10 mice have a model of hand-foot syndrome, and different drug groups In the process of achieving the hand and foot model, the rats died or the model was unsuccessful.
- the control rate refers to the proportion of rats in the experimental group who developed the hand-foot syndrome model, and the proportion of the rats whose applicator side paws were milder than the unapplied side paws.
- Figure 17 shows the left paw, front and right paw of a typical rat in the administration group of Examples 113-124 after the left paw application (nitric oxide releasing agent ointment).
- Fig. 18 is a view showing the condition of the left and right paws of a typical rat in the administration group of Example 124 after administration of a right paw (nitride release agent ointment).
- Examples 125-142 Comparison of 0.2% nitroglycerin ointment with clinically available experimental drugs and other nitric oxide releasing agents in an experiment to prevent hand-foot syndrome in small molecule VEGFR/VEGF inhibitors
- the rats After the rats (about 200 g) were reared for one week, the rats were divided into 10 groups each, and then subjected to an intragastric administration test.
- nitroglycerin ointment (about 0.05g) was applied to the left paw (claw palm and claw joint) of the rat, and the right paw was also applied to apply the clinical clinical test drug or other nitric oxide release agent ointment;
- the rats were fixed with a fixed cylinder for about 4 hours. After 4 hours, the rats were released and the residual drug at the application site was wiped off with water, and the rats were returned to the cage.
- the intragastric frequency of the VEGFR/VEGF inhibitor is shown in Table 15, but other dermatological and nitric oxide releasing agents currently available in the clinic are only applied once.
- the VEGFR/VEGF inhibitor was repeatedly administered daily until the clinical trial drug (or other nitric oxide releasing agent) was applied to the symptoms of paw and foot syndrome or the rat died. After 15-18 days of application, the number of rats with flavonoids coated with nitroglycerin ointment normal or significantly lighter than those of clinical trials (or other nitric oxide releasing agents) was counted as effective in preventing hand-foot syndrome rats. Only count.
- 0.2% nitroglycerin ointment can effectively control the hand-foot syndrome caused by VEGFR inhibitors and/or VEGF inhibitors compared to 1% sildenafil;
- 0.2% nitroglycerin ointment can effectively inhibit VEGFR inhibitors and / or VEGF inhibitors Hand-foot syndrome;
- 0.2% nitroglycerin ointment is more effective in controlling hand-foot syndrome caused by VEGFR inhibitors and/or VEGF inhibitors than other nitric oxide-releasing agents.
- the concentration of 0.2% nitroglycerin ointment is much lower than the concentration of other experimental drugs available in the clinic. It can be seen that 0.2% nitroglycerin ointment has achieved unexpected technical effects.
- Example 143 Effect of nitric oxide releasing agent on therapeutic effect of said VEGFR/VEGF inhibitor
- mice hepatocellular carcinoma cell HepG2 xenografts
- the model mice were divided into 3 groups (the average tumor size of the three groups was as consistent as possible), and 10 rats in each group were administered by intragastric administration. Apply the drug test.
- Nitric oxide releasing agents alleviate the proliferation toxicity of VEGF/VEGFR inhibitors on HUVEC and HaCaT cells and their comparison with calcium channel blockers
- calcium channel blockers e.g., diltiazem
- HFS anti-VEGFR multi-kinase inhibitors
- the therapeutic effect of diltiazem against hand-foot syndrome (HFS) caused by VEGFR multi-kinase inhibitors is very limited.
- the effect of a nitric oxide releasing agent on a calcium ion channel blocker is compared.
- the cultured HUVEC and HaCaT cells were digested and suspended, and the cells were counted and seeded in a 96-well plate, and 5000 cells were seeded per well.
- the wells were divided into: blank control group, VEGF/VEGFR inhibitor group, VEGF/VEGFR inhibitor + nitric oxide releasing agent group, VEGF/VEGFR inhibitor solvent group, nitric oxide releasing agent solvent control group, VEGF/VEGFR inhibition
- the agent + calcium channel blocker group and the calcium ion channel blocker solvent control group each group contains a basal medium in each well, and each well finally contains a liquid volume of about 100 ⁇ L.
- the specific grouping situation is as follows:
- VEGF/VEGFR inhibitor group VEGF/VEGFR inhibitor solution was added (final concentration is shown in Table 16, the solvent of VEGF/VEGFR inhibitor solution is DMSO);
- VEGF/VEGFR inhibitor + nitric oxide releasing agent group adding VEGF/VEGFR inhibitor solution and nitric oxide releasing agent solution (the final concentration of VEGF/VEGFR inhibitor and nitric oxide releasing agent is shown in Table 16, And according to the solubility of the nitric oxide releasing agent, the solvent of the nitric oxide releasing agent solution is selected as ethanol or sterile water, and the total volume difference of each group is supplemented by adding the selected corresponding solvent);
- VEGF / VEGFR inhibitor solvent group added to the corresponding volume of DMSO contained in the VEGF / VEGFR inhibitor solution in group 2);
- Nitric oxide releasing agent solvent control group a solvent of the same kind (for example, ethanol or sterile water) contained in the same amount as that contained in the nitric oxide releasing agent in the group 3).
- VEGF/VEGFR inhibitor + calcium channel blocker group first add VEGF / VEGFR inhibitor solution and then add calcium channel blocker solution (the final concentration of VEGF / VEGFR inhibitor and calcium channel blocker such as Table 16 shows that the solvent of the calcium channel blocker solution is DMSO, and the total volume difference of each group is supplemented by adding the selected corresponding solvent);
- Calcium channel blocker solvent control group The same volume of DMSO contained in the calcium ion channel blocker corresponding to the group 6) was added.
- the VEGF/VEGFR inhibitor solvent group did not participate in data processing and was only used as a reference for evaluating experimental system errors.
- the nitric oxide releasing agent solvent control group and the calcium ion channel blocker solvent control group were used for data correction, thereby eliminating the influence of the solvent on the results.
- the cell survival rate was determined using the Cell Counting Kit-8 (CCK-8) detection kit (C0037, Beyotime Biotechnology) to calculate the proliferation toxicity of the VEGF/VEGFR inhibitor to the cells and the nitric oxide releasing agent. Or the alleviation of proliferation toxicity by calcium channel blockers. The results were statistically analyzed and plotted using GraphPad Prism 6.0 software, t-test.
- Table 16 lists the combinations of various VEGF/VEGFR inhibitors and nitric oxide releasing agents (or calcium channel blockers), and the corresponding experimental results (where the data identification in the cell viability column is associated with VEGF/VEGFR The percentage of viable cells increased by the corresponding VEGF/VEGFR inhibitor + nitric oxide releasing agent group (or calcium channel blocker) compared to the inhibitor group.
- Figure 20 shows exemplary results of cell proliferation toxicity measured by CCK-8 method after administration of VEGF/VEGFR inhibitor sorafenib toluene (V1) and nitric oxide releasing agent (or diltiazem) to HUVEC cells for 24 hours. .
- Figure 21 shows cell proliferation measured by CCK-8 method after administration of VEGF/VEGFR inhibitor sorafenib toluene (V1) and nitric oxide releasing agent (or calcium channel blocker) to HaCaT cells for 24 hours.
- V1 VEGF/VEGFR inhibitor sorafenib toluene
- nitric oxide releasing agent or calcium channel blocker
- the abscissa indicates different experimental groups and control groups; the survival rate of cells on the ordinate table (the percentage of cells in the other experimental group or the solvent control group was calculated by the cell survival rate of the blank control group being 100%).
- *** indicates P ⁇ 0.001
- ** indicates P ⁇ 0.01
- * indicates P ⁇ 0.05, which is significantly different from the corresponding VEGF/VEGFR inhibitor alone administration group; using t-test statistical test.
- Example 146 Determination of the effect of nitric oxide releasing agent (or calcium channel blocker) on extracellular nitric oxide levels
- nitric oxide releasing agent and calcium channel blocker were compared.
- the results showed that the calcium channel blocker could not increase the extracellular nitric oxide content and could not produce nitric oxide. Therefore, it is not a nitrogen oxide releasing agent.
- the cultured HaCaT cells were digested and suspended, and the cells were counted and seeded in 24-well plates. Plant 20,000 cells per well. After the cells were attached, a solution of nitric oxide releasing agent (or calcium channel blocker) was added to a specific final concentration (as shown in Table 17). The control medium was supplemented with basal medium. 24 h after the addition of nitric oxide releasing agent (or calcium channel blocker), 50 ⁇ L of each group supernatant was collected for detecting the level of nitric oxide in the extracellular supernatant using a nitric oxide detecting kit (S0021, Beyotime Biotechnology) detects nitric oxide levels.
- a nitric oxide detecting kit S0021, Beyotime Biotechnology
- Figure 22 shows the relative content of 24 hours of nitric oxide in a HaCaT extracellular administration of a nitric oxide releasing agent (or a calcium channel blocker).
- the control group was the basal medium and reflected physiological levels.
- *** indicates P ⁇ 0.001
- ** indicates P ⁇ 0.01
- * indicates P ⁇ 0.05, which is significantly different from the corresponding control group, and the t-test statistical test was used.
- Example 147 Determination of the effect of nitric oxide releasing agent (or calcium channel blocker) on the expression of calmodulin and calreticulin in HaCaT cells
- Calmodulin is an intermediate calcium-binding messenger protein that targets the second messenger Ca 2+ in cells (Chin D and Means AR, 2000). Calmodulin acts as part of the calcium signaling pathway and binding to Ca 2+ ions is required for its activation and is therefore often used as a marker in calcium signaling (Berchtold and Villalobo, 2014). Calreticulin (CRT) binds to Ca 2+ ions to inactivate it. (Michalak M, et al., 2002) In this application, the effects of nitric oxide releasing agents and calcium channel blockers on the expression levels of calmodulin and calreticulin in HaCaT cells were compared.
- the cultured HaCaT cells were digested and suspended, and the cells were counted and inoculated into a 6-well plate. Plant 200,000 cells per well. After the cells were attached, a solution of nitric oxide releasing agent (or calcium channel blocker) was added to a specific final concentration of 100 ⁇ M. The control medium was supplemented with basal medium. The protein was extracted by RIPA lysate (P0013C, Beyotime Biotechnology) 24 hours after the addition of nitric oxide releasing agent (or calcium channel blocker), and the expression of calmodulin and calreticulin was detected by Western Blot.
- RIPA lysate P0013C, Beyotime Biotechnology
- Figure 23 shows the expression level of calmodulin (CaM) 24 hours after administration of a nitric oxide releasing agent (or a calcium channel blocker) by HaCaT cells.
- Fig. 24 shows the results of gray scale analysis of the relative expression amount of calmodulin.
- Figure 25 shows the expression level of calreticulin (CRT) after 24 hours of administration of a nitric oxide releasing agent (or a calcium channel blocker) by HaCaT cells.
- Fig. 26 shows the results of gray value analysis of the relative expression amount of calreticulin.
- Gray value analysis was performed using Image Lab, and the results were statistically analyzed and plotted using GraphPad Prism 6.0 software and t-test. Wherein, *** indicates P ⁇ 0.001, ** indicates P ⁇ 0.01, and * indicates P ⁇ 0.05, which is significantly different from the corresponding control group, and the t-test statistical test was used.
- Fig. 23 to Fig. 24 show that there is no significant change in calmodulin in the nitric oxide releasing agent group compared with the control group, and the calmodulin in the diltiazem group of the calcium channel blocker is significantly decreased;
- Fig. 25- Fig. 26 show that: Compared with the control group, the calreticulin in the nitric oxide releasing agent group was slightly decreased, while the calcium channel protein in the nifedipine group was significantly increased. Therefore, the nitric oxide releasing agent is not a calcium ion channel blocker.
- Examples 148-159 Comparison of 0.2% nitroglycerin ointment and other nitric oxide release agents with calcium channel blockers in experiments to prevent hand-foot syndrome in small molecule VEGF/VEGFR inhibitors
- the dosage administered is shown in Table 18.
- nitroglycerin ointment (or other nitric oxide releasing agent) (about 0.05 g) was applied to the left paw (claw palm and claw joint) of the rat, and the calcium channel obstruction ointment was also applied to the right paw;
- the rats were fixed with a fixed cylinder for about 4 hours. After 4 hours, the rats were released and the residual drug at the application site was wiped off with water, and the rats were returned to the cage.
- the gavage frequency of the VEGF/VEGFR inhibitor is shown in Table 18. The VEGF/VEGFR inhibitor was repeatedly administered daily until the symptoms of the hand-foot syndrome of the calcium channel blocker ointment were observed or the rats died.
- the number of rats with nitroglycerin ointment (or other nitric oxide releasing agent) side paws normal or significantly lighter than the side of the calcium channel blocker ointment was calculated to effectively prevent hand and foot synthesis.
- the number of rats was levied.
- the rate of anti-cancer drugs is not fixed: the establishment rate of each group of hand-foot syndrome models is 30%-90%, that is, about 3-9 of 10 mice have a hand-foot syndrome model, and different drug groups In the process of achieving the hand and foot model, the rats died or the model was unsuccessful.
- the control rate refers to the proportion of rats in the experimental group who developed the hand-foot syndrome model, the symptoms of hand-foot symptoms of nitroglycerin ointment paws were lighter than those of the other drug-coated paws.
- Figure 27 shows a typical rat in the administration group of Examples 148-153 after left paw application (0.2% nitroglycerin ointment) and right paw applicator (0.2% diltiazem ointment) in the administration group, the left paw, the front and the The case of the right paw.
- Figure 28 shows a typical rat in the administration group of Example 154 after administration of a left paw (0.2% mixed isosorbide dinitrate and isosorbide monotonate) and a right paw applicator (0.2% diltiazem ointment). , the condition of the left paw, the front and the right paw.
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Abstract
Description
Claims (74)
- 一氧化氮释放剂在制备药物中的用途,所述药物用于预防或治疗受试者中与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症。
- 根据权利要求1所述的用途,其中所述疾病或病症由所述施用VEGFR抑制剂和/或VEGF抑制剂引起。
- 根据权利要求1-2中任一项所述的用途,其中至少一种所述VEGFR抑制剂直接作用于VEGFR蛋白和/或编码VEGFR蛋白的核酸。
- 根据权利要求1-3中任一项所述的用途,其中至少一种所述VEGF抑制剂直接作用于VEGF蛋白和/或编码VEGF蛋白的核酸。
- 根据权利要求1-4中任一项所述的用途,其中所述VEGFR抑制剂和/或所述VEGF抑制剂用于治疗肿瘤。
- 根据权利要求1-5中任一项所述的用途,其中所述疾病或病症的患处与肿瘤的患处不同。
- 根据权利要求1-6中任一项所述的用途,其中所述VEGFR抑制剂包括小分子VEGFR抑制剂、特异性结合VEGFR的蛋白大分子、抑制VEGFR蛋白表达的RNAi和/或抑制VEGFR蛋白表达的反义寡核苷酸。
- 根据权利要求1-7中任一项所述的用途,其中所述VEGF抑制剂包括VEGF捕获剂和/或降低VEGF表达量的试剂。
- 根据权利要求1-8中任一项所述的用途,其中所述VEGFR抑制剂抑制VEGFR1、VEGFR2和/或VEGFR3。
- 根据权利要求1-9中任一项所述的用途,其中所述VEGFR抑制剂和/或VEGF抑制剂包括雷莫芦单抗、贝伐珠单抗、瑞格非尼、普纳替尼、卡博替尼、乐伐替尼、索拉非尼、帕唑帕尼、阿帕替尼、阿西替尼、尼达尼布、凡德他尼、舒尼替尼、米哚妥林、替沃扎尼、呋喹替尼、西地尼布、布立尼布、多纳非尼、索凡替尼、安罗替尼、Famitinib、Tesevatinib、Vorolanib、莫特塞尼、Linifanib、Semaxanib、多韦替尼、orantinib、瓦它尼丁、替拉替尼、Glesatinib、德立替尼、Ilorasertib、Rebastinib、Golvatinib、Foretinib、ningetinib、Tafetinib、Altiratinib、TAS-115、Chiauranib、Henatinib、4SC-203、AAL-993、ACTB-1003、AEE-788、AMG-628、沙蟾蜍精、BAW2881、BIBF-1202、BMS-690514、BMS-794833、CEP-11981、CEP-5214、CP-547632、CYC116、DW532、ENMD-2076、FIIN-1、GFB-204、BFH-772、BMS599626、BMS690514、PP 121、MGCD 265类似物、AC480、Ki8751、KRN 633、WHI-P 154、TAK593、JI 101、AZD-2932、SCR- 1481B1、异甘草素、JNJ-26483327、KI-20227、LY2457546、ODM-203、OSI-930、PF-00337210、CGP41231、R1530、RAF265、SARi31675、Semaxinib、SIM010603、SKLB1002、SKLB610、SU 5205、SU11652、SU14813、SU-1498、SU-4312、SU5402、T-1840383、丹参酮IIA、TAS-115、TG 100572、TG 100801、TG100572HCl、Toceranib、酪氨酸磷酸化抑制剂A9、Tesevatinib、XL-844、XL999、ZD4190 HCl、ZM-306416、ZM323881 HCl、ABT-510、NVP-ACC789、ADT-OH、BMS-645737、EG 00229、XL-820、SGI-7079、内皮抑素、紫杉叶素、阿柏西普、它们的可药用盐,和/或前述的任意组合。
- 根据权利要求1-10中任一项所述的用途,其中所述VEGFR抑制剂和/或VEGF抑制剂与一种或多种其它疗法联合施用。
- 根据权利要求11所述的用途,其中所述一种或多种其它疗法包括一种或多种其它抗肿瘤疗法。
- 根据权利要求1-12中任一项所述的用途,其中所述疾病或病症是由VEGFR和/或VEGF被抑制引起的。
- 根据权利要求1-13中任一项所述的用途,其中所述疾病或病症包括与施用VEGFR抑制剂和/或VEGF抑制剂相关的皮肤组织疾病或病症、五官疾病或病症和/或胃肠道疾病或病症。
- 根据权利要求14所述的用途,其中所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的皮肤组织疾病或病症、五官疾病或病症和/或胃肠道疾病或病症包括所述皮肤组织、五官和/或胃肠道中与施用VEGFR抑制剂和/或VEGF抑制剂相关的上皮组织疾病或病症。
- 根据权利要求15所述的用途,其中所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的上皮组织疾病或病症包括与内皮细胞病变相关的所述疾病或病症,和/或与上皮细胞病变相关的所述疾病或病症,且其中所述内皮细胞病变和/或上皮细胞病变与所述施用VEGFR抑制剂和/或VEGF抑制剂相关。
- 根据权利要求16所述的用途,其中所述内皮细胞包括血管内皮细胞。
- 根据权利要求16-17中任一项所述的用途,其中所述上皮细胞包括皮肤上皮细胞、口腔上皮细胞、鼻腔上皮细胞、胃上皮细胞和/或肠上皮细胞。
- 根据权利要求1-18中任一项所述的用途,其中所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症包括与施用VEGFR抑制剂和/或VEGF抑制剂相关的皮疹、与施用VEGFR抑制剂和/或VEGF抑制剂相关的手足综合征、与施用VEGFR抑制剂 和/或VEGF抑制剂相关的瘙痒、与施用VEGFR抑制剂和/或VEGF抑制剂相关的红斑、与施用VEGFR抑制剂和/或VEGF抑制剂相关的皮肤干燥、与施用VEGFR抑制剂和/或VEGF抑制剂相关的脱发、与施用VEGFR抑制剂和/或VEGF抑制剂相关的甲沟炎、与施用VEGFR抑制剂和/或VEGF抑制剂相关的色素沉积紊乱、与施用VEGFR抑制剂和/或VEGF抑制剂相关的口腔溃疡、与施用VEGFR抑制剂和/或VEGF抑制剂相关的口干、与施用VEGFR抑制剂和/或VEGF抑制剂相关的鼻衄、与施用VEGFR抑制剂和/或VEGF抑制剂相关的鼻咽炎、与施用VEGFR抑制剂和/或VEGF抑制剂相关的唇炎、与施用VEGFR抑制剂和/或VEGF抑制剂相关的食管黏膜炎、与施用VEGFR抑制剂和/或VEGF抑制剂相关的胃黏膜炎、与施用VEGFR抑制剂和/或VEGF抑制剂相关的胃溃疡、与施用VEGFR抑制剂和/或VEGF抑制剂相关的腹泻、与施用VEGFR抑制剂和/或VEGF抑制剂相关的呕吐、与施用VEGFR抑制剂和/或VEGF抑制剂相关的恶心、与施用VEGFR抑制剂和/或VEGF抑制剂相关的厌食、与施用VEGFR抑制剂和/或VEGF抑制剂相关的便秘,和/或与施用VEGFR抑制剂和/或VEGF抑制剂相关的腹痛。
- 根据权利要求19所述的用途,其中所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症包括与施用VEGFR抑制剂和/或VEGF抑制剂相关的手足综合征。
- 根据权利要求1-20中任一项所述的用途,其中所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症的严重程度为依据NCI-CTCAE V5.0中的第1级或以上、第2级或以上、第3级或以上、第4级或以上,和/或第5级。
- 根据权利要求1-21中任一项所述的用途,其中所述一氧化氮释放剂能够产生NO +、NO -、N 2O、NO、N 2O 3、NO 2、NO 3-和NO 2-之中的至少一种。
- 根据权利要求1-22中任一项所述的用途,其中所述一氧化氮释放剂能够直接或间接产生NO。
- 根据权利要求1-23中任一项所述的用途,其中所述一氧化氮释放剂包括NO。
- 根据权利要求1-24中任一项所述的用途,其中所述一氧化氮释放剂包括有机分子、无机分子、高分子材料、纳米材料和/或氨氧化微生物(AOM)。
- 根据权利要求25所述的用途,其中所述一氧化氮释放剂包括有机分子,且所述有机分子包括硝酸甘油、单硝酸异山梨酯、季戊四醇四硝酸酯、硝酸异山梨酯、三硝乙醇胺、尼可地尔、硝二羟甲丁醇、吗多明、5-氨基-3-(4-吗啉基)-1,2,3-恶二唑、亚硝酸异戊酯、3,3-二(氨乙基)-1-羟基-2-羰基-1-三氮烯(NOC-18)、磺基亲核复合 体二钠盐、S-亚硝基谷胱甘肽、S-亚硝基-N-乙酰青霉胺、4-苯基-3-呋腈、(±)-(E)-4-乙基-2-(E)-肟基-5-硝基-3-己酰胺、链脲菌素、NG-羟基-L-精氨酸合乙酸、O2-(2,4-二硝基苯基)1-[(4-乙氧基羰基)哌嗪-1-基]1,2-二醇二氮烯-1-鎓、N-亚硝基二丁胺、3-吗啉-斯得酮亚胺、林西多明、3-(4-乙酰苯基)悉尼酮、二乙胺亲核复合体/AM和/或Itramin。
- 根据权利要求26所述的用途,其中所述一氧化氮释放剂包括有机分子,且所述有机分子包括硝酸甘油、单硝酸异山梨酯和/或硝酸异山梨酯。
- 根据权利要求26-27中任一项所述的用途,其中所述一氧化氮释放剂包括有机分子,且所述有机分子包括硝酸甘油。
- 根据权利要求25所述的用途,其中所述一氧化氮释放剂包括无机分子,且所述无机分子包括硝酰配合物、亚硝酰配合物、金属亚硝氨基络合物、硝酸盐和/或亚硝酸盐。
- 根据权利要求29所述的用途,其中所述一氧化氮释放剂包括无机分子,且所述无机分子包括硝普钠。
- 根据权利要求1-30中任一项所述的用途,其中所述一氧化氮释放剂具有小于或等于约2000道尔顿、小于或等于约1500道尔顿、小于或等于约1200道尔顿、小于或等于约1000道尔顿、小于或等于约900道尔顿、小于或等于约800道尔顿、小于或等于约700道尔顿、小于或等于约600道尔顿、小于或等于约500道尔顿、小于或等于约400道尔顿、小于或等于约300道尔顿、小于或等于约200道尔顿或者小于或等于约100道尔顿的分子量。
- 根据权利要求25所述的用途,其中所述一氧化氮释放剂包括高分子或纳米材料,且所述高分子或纳米材料包括S-亚硝基硫醇纳米硅球、S-亚硝基乙二硫醇甲壳素和/或寡聚丙二胺接枝壳聚糖NONOate。
- 根据权利要求1-32中任一项所述的用途,其中所述一氧化氮释放剂具有下述的一个或多个基团:偶氮鎓二醇盐、羟基二氮烯磺酸、S-亚硝基硫醇、呋咱氮氧、肟、N-亚硝胺、N-羟基胍、偶氮鎓二醇盐、硝酸盐、亚硝酸盐、硝酸酯、亚硝酸酯、斯得酮亚胺、斯得酮、恶三唑-5-亚胺、恶三唑-5-酮、羟胺、二氧二氮杂环丁烯、N-羟基亚硝胺、N-亚硝亚胺、羟基脲和金属亚硝氨基络合物。
- 根据权利要求25所述的用途,其中所述一氧化氮释放剂包括氨氧化微生物(AOM),且所述氨氧化微生物(AOM)包括氨氧化细菌(AOB)。
- 根据权利要求34所述的用途,其中所述一氧化氮释放剂包括氨氧化微生物(AOM), 且所述氨氧化微生物(AOM)包括亚硝化单胞菌(Nitrosomonas)、亚硝化球菌(Nitrosococcus)、亚硝化螺菌(Nitrosospira)、亚硝化囊菌(Nitrosocystis)、亚硝化叶菌(Nitrosolobus)和/或亚硝化弧菌(Nitrosovibrio)。
- 根据权利要求1-35中任一项所述的用途,其中所述药物被制备为适用于局部给药。
- 根据权利要求36所述的用途,其中所述局部给药的给药部位不为癌症的发生部位或癌症的潜在转移部位。
- 根据权利要求1-37中任一项所述的用途,其中所述药物中所述一氧化氮释放剂的浓度为约0.0001%(w/w)至约50%(w/w)。
- 根据权利要求1-38中任一项所述的用途,其中所述药物被制备为适用于外用给药。
- 根据权利要求1-39中任一项所述的用途,其中所述药物被制备为软膏剂。
- 根据权利要求1-40中任一项所述的用途,其中所述药物中还包括一种或多种其他活性成分。
- 根据权利要求1-41中任一项所述的用途,其中所述药物基本上不影响所述VEGFR抑制剂和/或VEGF抑制剂的治疗效果。
- 根据权利要求1-42中任一项所述的用途,其中所述受试者包括癌症患者。
- 根据权利要求1-43中任一项所述的用途,其中所述受试者曾经、正在和/或将来被施用所述VEGFR抑制剂和/或所述VEGF抑制剂。
- 根据权利要求1-44中任一项所述的用途,其中所述受试者患有或易患有所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症。
- 根据权利要求1-45中任一项所述的用途,其中所述疾病或病症的严重程度在所述施用VEGFR抑制剂和/或VEGF抑制剂之后增加。
- 权利要求1-46中任一项所述的用途,其中在所述施用VEGFR抑制剂和/或VEGF抑制剂之前,所述受试者未患有所述疾病或病症。
- 权利要求1-47中任一项所述的用途,其中所述VEGFR抑制剂和/或VEGF抑制剂不包含所述一氧化氮释放剂。
- 权利要求1-48中任一项所述的用途,其中所述VEGFR抑制剂和/或VEGF抑制剂不包含硝酸甘油。
- 药物组合或试剂盒,其包含:1)VEGFR抑制剂和/或VEGF抑制剂;以及2)一氧化氮释放剂。
- 根据权利要求50所述的药物组合或试剂盒,其中所述VEGFR抑制剂和/或VEGF抑 制剂与所述一氧化氮释放剂彼此不混合。
- 根据权利要求50-51中任一项所述的药物组合或试剂盒,其中所述VEGFR抑制剂和/或VEGF抑制剂与所述一氧化氮释放剂各自独立地存在于单独的容器中。
- 根据权利要求50-52中任一项所述的药物组合或试剂盒,其中所述一氧化氮释放剂被制备为适用于外用给药。
- 根据权利要求50-53中任一项所述的药物组合或试剂盒,其中所述一氧化氮释放剂被制备为软膏剂。
- 根据权利要求50-54中任一项所述的药物组合或试剂盒,其中所述一氧化氮释放剂的浓度为约0.0001%(w/w)至约50%(w/w)。
- 根据权利要求50-55中任一项所述的药物组合或试剂盒,其中2)中的所述一氧化氮释放剂能够预防或治疗与施用1)中的所述VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症。
- 根据权利要求50-56中任一项所述的药物组合或试剂盒,其中2)中的所述一氧化氮释放剂基本上不影响1)中的所述VEGFR抑制剂和/或VEGF抑制剂的治疗效果。
- 根据权利要求50-57中任一项所述的药物组合或试剂盒,其中在施用1)的所述VEGFR抑制剂和/或VEGF抑制剂之前、同时或者之后施用2)的所述一氧化氮释放剂。
- 一种方法,其包括向受试者施用一氧化氮释放剂,其中所述受试者曾经、正在和/或将来被施用VEGFR抑制剂和/或VEGF抑制剂且患有或易患有与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症。
- 一种用于预防或治疗疾病或病症的方法,包括向易患有或患有所述疾病或病症的受试者施用一氧化氮释放剂,其中所述受试者曾经、正在和/或将来被施用VEGFR抑制剂和/或VEGF抑制剂。
- 一种预防或治疗疾病或病症的方法,包括向易患有或患有所述疾病或病症的受试者施用一氧化氮释放剂,其中所述疾病或病症为手足综合征。
- 根据权利要求61所述的方法,其中所述受试者曾经、正在和/或将来被施用VEGFR抑制剂和/或VEGF抑制剂。
- 一种方法,所述方法包括下述步骤:1)监测被施用VEGFR抑制剂和/或VEGF抑制剂的受试者的一种或多种皮肤组织、五官和/或胃肠道特征;2)当所述监测显示所述受试者出现与施用所述VEGFR抑制剂和/或VEGF抑制剂相 关的皮肤组织疾病或病症、五官疾病或病症和/或胃肠道疾病或病症时,向所述受试者施用一氧化氮释放剂。
- 根据权利要求63所述的方法,其还包括继续监控所述皮肤组织疾病或病症、五官疾病或病症和/或胃肠道疾病或病症,以及任选地减少或停用所述VEGFR抑制剂和/或VEGF抑制剂。
- 根据权利要求59-64中任一项所述的方法,其中所述疾病或病症的严重程度在所述施用VEGFR抑制剂和/或VEGF抑制剂之后增加。
- 根据权利要求59-65中任一项所述的方法,其中在所述施用VEGFR抑制剂和/或VEGF抑制剂之前,所述受试者未患有所述疾病或病症。
- 根据权利要求59-66中任一项所述的方法,其中所述VEGFR抑制剂和/或VEGF抑制剂不包含所述一氧化氮释放剂。
- 根据权利要求59-67中任一项所述的方法,其中所述VEGFR抑制剂和/或VEGF抑制剂不包含硝酸甘油。
- 根据权利要求59-68中任一项所述的方法,其中所述疾病或病症为上皮组织疾病或病症。
- 根据权利要求59-69中任一项所述的方法,其中施用所述VEGFR抑制剂和/或VEGF抑制剂来治疗癌症。
- 根据权利要求59-70中任一项所述的方法,其中所述疾病或病症的患处与癌症的患处不同。
- 根据权利要求59-71中任一项所述的方法,其中向所述受试者局部施用所述一氧化氮释放剂。
- 根据权利要求59-72中任一项所述的方法,其中向所述受试者中基本不含癌细胞的部位局部施用所述一氧化氮释放剂。
- 根据权利要求59-73中任一项所述的方法,其中向所述受试者中的非癌症部位施用所述一氧化氮释放剂。
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CA3097067A1 (en) | 2019-10-24 |
US20200253915A1 (en) | 2020-08-13 |
EP3782618A1 (en) | 2021-02-24 |
AU2019254237A1 (en) | 2020-12-03 |
KR20200144116A (ko) | 2020-12-28 |
US10987336B2 (en) | 2021-04-27 |
EP3782618A4 (en) | 2022-01-26 |
TW201943428A (zh) | 2019-11-16 |
CN114028568A (zh) | 2022-02-11 |
CN111989095A (zh) | 2020-11-24 |
US20210322361A1 (en) | 2021-10-21 |
JP2021521247A (ja) | 2021-08-26 |
CN113975264A (zh) | 2022-01-28 |
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