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 PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
inhibitor
vegfr
vegf
administration
nitric oxide
Prior art date
Application number
PCT/CN2019/082623
Other languages
English (en)
French (fr)
Inventor
张诗宜
吴兆宇
刘超
杨立楠
陈乐颖
罗洁
Original Assignee
上海岸阔医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海岸阔医药科技有限公司 filed Critical 上海岸阔医药科技有限公司
Priority to EP19789251.6A priority Critical patent/EP3782618A4/en
Priority to AU2019254237A priority patent/AU2019254237A1/en
Priority to CN201980025735.0A priority patent/CN111989095A/zh
Priority to CA3097067A priority patent/CA3097067A1/en
Priority to KR1020207032592A priority patent/KR20200144116A/ko
Priority to JP2020558446A priority patent/JP2021521247A/ja
Publication of WO2019201195A1 publication Critical patent/WO2019201195A1/zh
Priority to US16/855,677 priority patent/US10987336B2/en
Priority to US17/216,594 priority patent/US20210322361A1/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/04—Nitro compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6923—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Nanotechnology (AREA)
  • Immunology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Ceramic Engineering (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

本发明公开了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与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症。本申请还提供预防或者治疗与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症的方法，所述方法可包括向有需要的受试者施用预防或治疗有效量的一氧化氮释放剂。

Description

预防或治疗肿瘤疗法副作用的方法 技术领域
本申请涉及疾病治疗领域，例如一种预防或治疗与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症的方法。
背景技术
血管内皮生长因子受体(Vascular endothelial growth factor receptor，VEGFR)的突变或过表达已被发现与多种癌症相关，并且可以通过抑制VEGFR和/或VEGF的疗法(例如，施用VEGFR抑制剂和/或VEGF抑制剂)来治疗患有此类肿瘤的患者。然而，这类治疗经常会引起严重的副作用，特别是在皮肤，五官和胃肠道发生的副作用。抑制VEGFR和/或VEGF的疗法引起的严重副作用会损害患者的生活质量，引起患者用药的依从性和耐受性降低，导致VEGFR/VEGF抑制剂的停药或剂量不足，从而对治疗效果产生不利影响，甚至导致疾病进展加速，患者生存期缩短。
目前，尚没有有效的治疗方案来控制与施用VEGFR抑制剂和/或VEGF抑制剂相关的副作用。因此，迫切需要能够成功控制该等副作用的治疗方案。
发明内容
本申请提供了一种用于预防或治疗与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病的方法。具体而言，本申请涉及使用一氧化氮释放剂来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，其可有效控制由VEGFR抑制剂和/或VEGF抑制剂所引起的副作用，如与施用VEGFR抑制剂和/或VEGF抑制剂相关的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等。
与已报道的使用较高剂量(例如，约2％)的一氧化氮释放剂(例如，硝酸甘油)来预防或治疗心绞痛的情况不同，在本申请中，令人惊讶地，所使用的一氧化氮释放剂(例如，硝酸甘油)的有效剂量可以低至0.5％或以下，例如可以为0.45％以下，可以为0.4％以下，可以为0.3％以下，可以为0.25％以下，可以为0.2％以下，可以为0.15％以下，或者，可以为0.1％以下，且发挥预防或治疗肿瘤疗法副作用的作用，例如，发挥预防或治疗与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症的作用，例如，发挥预防或治疗与施用VEGFR抑制剂和/或VEGF抑制剂相关的皮肤组织疾病或病症、与施用VEGFR抑制剂和/或VEGF抑制剂相关的五官疾病或病症和/或与施用VEGFR抑制剂和/或VEGF抑制剂相关的胃肠道疾病 或病症等的作用。在本申请之前，一氧化氮释放剂没有被用于治疗上述疾病。
一方面，本申请提供了一氧化氮释放剂在制备药物中的用途。所述药物可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。例如，所述疾病或病症可由所述施用VEGFR抑制剂和/或VEGF抑制剂引起。在某些实施方式中，所述VEGFR抑制剂和/或所述VEGF抑制剂用于治疗肿瘤。在某些实施方式中，所述所述疾病或病症的患处与肿瘤的患处不同。在某些实施方式中，所述药物被制备为适用于局部给药。在某些实施方式中，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。在某些实施方式中，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)。在某些实施方式中，所述药物被制备为适用于外用给药。在某些实施方式中，所述药物被制备为软膏剂。在某些实施方式中，所述药物中还包括一种或多种其他活性成分。在某些实施方式中，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(例如治疗癌症的效果)。
另一方面，本申请提供了一种一氧化氮释放剂，其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。例如，所述疾病或病症可由所述施用VEGFR抑制剂和/或VEGF抑制剂引起。
另一方面，本申请提供了一种预防或治疗受试者中与施用VEGFR抑制剂和/或VEGF抑制剂相关的的疾病或病症的方法，所述方法包括向所述受试者施用预防或治疗有效量的一氧化氮释放剂。在某些实施方式中，所述受试者包括人或非人动物。例如，所述非人动物可包括选自下组的动物：猴、鸡、鹅、猫、狗、小鼠和大鼠。在某些实施方式中，所述受试者包括癌症患者。在某些实施方式中，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。在某些实施方式中，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。在某些实施方式中，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。在某些实施方式中，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。在某些实施方式中，所述VEGFR抑制剂和/或VEGF抑制剂不包含所述一氧化氮释放剂。在某些实施方式中，所述VEGFR抑制剂和/或VEGF抑制剂不包含硝酸甘油。在某些实施方式中，所述疾病或病症由向所述受试者施用VEGFR抑制剂和/或VEGF抑制剂引起。例如，可在向所述受试者施用VEGFR抑制剂和/或VEGF抑制剂之前、同时或者之后施用所述一氧化氮释放剂。在某些实施方式中，所述VEGFR抑制剂和/或所述VEGF抑制剂用于治疗肿瘤。在某些实施方式中，所述所述疾病或病症的患处与肿瘤的患处不同。在某些实施方式中，所述一氧化氮释 放剂的施用为局部给药。在某些实施方式中，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。在某些实施方式中，所施用的所述一氧化氮释放剂的浓度为约0.0001％(w/w)至约50％(w/w)。在某些实施方式中，所述一氧化氮释放剂的施用为外用给药。在某些实施方式中，所述一氧化氮释放剂被包含在软膏剂中施用。在某些实施方式中，所述一氧化氮释放剂与一种或多种其他活性成分共同施用。在某些实施方式中，所述一氧化氮释放剂的施用基本上不影响所述VEGFR抑制剂和/或VEGF抑制剂的治疗效果。
另一方面，本申请提供了一种药物组合或试剂盒。所述药物组合或试剂盒可包含：1)VEGFR抑制剂和/或VEGF抑制剂；以及2)一氧化氮释放剂。在某些实施方式中，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。在某些实施方式中，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。在某些实施方式中，所述一氧化氮释放剂被制备为适用于外用给药。在某些实施方式中，所述一氧化氮释放剂被制备为软膏剂。在某些实施方式中，所述一氧化氮释放剂的浓度为约0.0001％(w/w)至约50％(w/w)。在某些实施方式中，2)中的所述一氧化氮释放剂能够预防或治疗1)中的所述VEGFR抑制剂和/或VEGF抑制剂引起的疾病或病症。在某些实施方式中，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。在某些实施方式中，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。
另一方面，本申请提供了一种方法，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。
另一方面，本申请提供了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。
另一方面，本申请提供了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。
在某些实施方式中，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。
另一方面，本申请提供了一种方法，其包括下述步骤：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。
在某些实施方式中，所述方法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。
在某些实施方式中，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。
在某些实施方式中，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。
在某些实施方式中，所述VEGFR抑制剂和/或VEGF抑制剂不包含所述一氧化氮释放剂。在某些实施方式中，所述VEGFR抑制剂和/或VEGF抑制剂不包含硝酸甘油。
在某些实施方式中，所述疾病或病症为上皮组织疾病或病症。
在某些实施方式中，施用所述VEGFR抑制剂和/或VEGF抑制剂来治疗癌症。在某些实施方式中，所述疾病或病症的患处与癌症的患处不同。
在某些实施方式中，向所述受试者局部施用所述一氧化氮释放剂。
在某些实施方式中，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。在某些实施方式中，向所述受试者中的非癌症部位施用所述一氧化氮释放剂。
在某些实施方式中，至少一种本申请所述的VEGFR抑制剂直接作用于VEGFR蛋白和/或编码VEGFR蛋白的核酸。
在某些实施方式中，至少一种本申请所述的VEGF抑制剂直接作用于VEGF蛋白和/或编码VEGF蛋白的核酸。
在某些实施方式中，本申请所述的VEGFR抑制剂和/或本申请所述的VEGF抑制剂用于治疗肿瘤。
在某些实施方式中，本申请所述的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。
在某些实施方式中，本申请所述的VEGF抑制剂包括VEGF捕获剂和/或降低VEGF表达量的试剂。
在某些实施方式中，本申请所述的VEGFR抑制剂抑制VEGFR1、VEGFR2和/或VEGFR3。
在某些实施方式中，本申请所述的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、Ki 8751、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、SAR131675、Semaxinib、SIM010603、SKLB1002、SKLB610、SU5205、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、ZD4190HCl、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。
在某些实施方式中，本申请所述的VEGFR抑制剂和/或VEGF抑制剂与一种或多种其它疗法联合施用。所述一种或多种其它疗法可包括一种或多种其它抗肿瘤疗法。
在某些实施方式中，本申请所述疾病或病症是由VEGFR和/或VEGF被抑制引起的。
在某些实施方式中，本申请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。
在某些实施方式中，本申请所述的与施用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。
在某些实施方式中，本申请所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的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/或上皮细胞病变与施用VEGFR抑制剂和/或VEGF抑制剂相关。所述内皮细胞可包括血管内皮细胞。所述上皮细胞可包括皮肤上皮细胞、口腔上皮细胞、鼻腔上皮细胞、胃上皮细胞和/或肠上皮细胞。
在某些实施方式中，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选自下组的疾病或病症：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与施用VEGFR抑制剂和/或VEGF抑制剂相关的腹痛。在某些实施方式中，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。在某些实施方式中，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。
在某些实施方式中，所述一氧化氮释放剂能够产生选自下组的物质：NO +、NO -、N 2O、NO、N 2O 3、NO 2、NO 3 -和NO 2 -。例如，所述一氧化氮释放剂能够直接或间接产生NO。在某些实施方式中，所述一氧化氮释放剂包括NO。
在某些实施方式中，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)。
在某些实施方式中，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、O 2-(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。例如，所述有机分子可选自下组：硝酸甘油、单硝酸异 山梨酯、硝酸异山梨酯以及它们的任意组合。在某些实施方式中，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。
在某些实施方式中，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。在某些实施方式中，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。
在某些实施方式中，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)。在某些实施方式中，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)。
在某些实施方式中，所述一氧化氮释放剂具有小于或等于2000道尔顿、小于或等于1500道尔顿、小于或等于1200道尔顿、小于或等于1000道尔顿、小于或等于900道尔顿、小于或等于800道尔顿、小于或等于700道尔顿、小于或等于600道尔顿、小于或等于500道尔顿、小于或等于400道尔顿、小于或等于300道尔顿、小于或等于200道尔顿或小于或等于100道尔顿的分子量。
在某些实施方式中，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。
在某些实施方式中，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。
本领域技术人员能够从下文的详细描述中容易地洞察到本公开的其它方面和优势。下文的详细描述中仅显示和描述了本公开的示例性实施方式。如本领域技术人员将认识到的，本公开的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地，本申请的附图和说明书中的描述仅仅是示例性的，而非为限制性的。
附图说明
本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明书 如下：
图1显示了S-亚硝基硫醇纳米硅球的示例性合成路线。
图2显示了S-亚硝基乙二硫醇甲壳素的示例性合成路线。
图3显示了寡聚丙二胺接枝壳聚糖NONOate的示例性合成路线。
图4A-4C显示了向HUVEC细胞施用一氧化氮释放剂(或西地那非)后测定的细胞增殖毒性的示例性结果。
图5A-5C显示了向HaCaT细胞施用一氧化氮释放剂(或西地那非)后测定的细胞增殖毒性的示例性结果。
图6A-6C显示了向HOK细胞施用一氧化氮释放剂(或西地那非)后测定的细胞增殖毒性的示例性结果。
图7A-7C显示了向GES-1细胞施用一氧化氮释放剂(或西地那非)后测定的细胞增殖毒性的示例性结果。
图8A-8C显示了向FHs 74 Int细胞施用一氧化氮释放剂(或西地那非)后测定的细胞增殖毒性的示例性结果。
图9A-9D显示了HUVEC和GES-1细胞内、外一氧化氮的相对含量。
图10A-10D显示了用一氧化氮释放剂处理24小时后细胞外一氧化氮的相对含量。
图11A-11D显示了用一氧化氮释放剂处理24小时后细胞内一氧化氮的相对含量。
图12A-12B显示了用西地那非处理HUVEC细胞后，各时间点细胞外、内一氧化氮的相对含量。
图12C-12D显示了用不同浓度的西地那非处理HUVEC细胞24小时后，细胞外、内一氧化氮的相对含量。
图13A-13B显示了用100μM的西地那非处理GES-1细胞24小时后，细胞外、内一氧化氮的相对含量。
图13C-13D显示了用100μM的西地那非处理HaCaT细胞24小时后，细胞外、内的相对NO一氧化氮的相对含量。
图14显示了VEGFR和/或VEGF被抑制导致手足综合征的大鼠模型的左爪放大图、左右爪正面图、右爪放大图。
图15显示了本申请实施例55-100、实施例111-112的给药组中一只典型大鼠(左爪涂药)的左爪放大图、左右爪正面图、右爪放大图。
图16显示了本申请实施例101-108的给药组中一只典型大鼠(右爪涂药)的左爪放大图、 左右爪正面图、右爪放大图。
图17显示了本申请实施例113-123的给药组中一只典型大鼠(左爪涂药)的左爪放大图、左右爪正面图、右爪放大图。
图18显示了本申请实施例124的给药组中一只典型大鼠(右爪涂药)的左爪放大图、左右爪正面图、右爪放大图。
图19显示了外用施用本申请实施例143中的一氧化氮释放剂时，对用VEGFR/VEGF抑制剂治疗的带瘤鼠中瘤体积变化的影响。
图20显示了向HUVEC细胞施用一氧化氮释放剂(或地尔硫卓)后测定的细胞增殖毒性的示例性结果。
图21显示了向HaCaT细胞施用一氧化氮释放剂(或钙离子通道阻滞剂)后测定的细胞增殖毒性的示例性结果。
图22显示了向HaCaT细胞施用一氧化氮释放剂(或钙离子通道阻滞剂)后一氧化氮的相对含量。
图23显示了向HaCaT细胞给予一氧化氮释放剂(或钙离子通道阻滞剂)后钙调蛋白(CaM)的表达水平。
图24显示了向HaCaT细胞给予一氧化氮释放剂(或钙离子通道阻滞剂)后钙调蛋白相对表达量的灰度值分析结果。
图25显示了向HaCaT细胞给予一氧化氮释放剂(或钙离子通道阻滞剂)后钙网蛋白的表达水平。
图26显示了向HaCaT细胞给予一氧化氮释放剂(或钙离子通道阻滞剂)后钙网蛋白相对表达量的灰度值分析结果。
图27显示了本申请实施例148-153的给药组中一只典型大鼠经左爪涂药和右爪涂药后，其左爪放大图、左右爪正面图、右爪放大图。
图28显示了本申请实施例154的给药组中一只典型大鼠经左爪涂药和右爪涂药后，其左爪放大图、左右爪正面图、右爪放大图。
具体实施方式
以下由特定的具体实施例说明本申请发明的实施方式，熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
VEGFR抑制剂、VEGF抑制剂
在本申请中，术语“VEGFR”通常是指血管内皮生长因子受体(Vascular Endothelial Grow Factor Receptor)，属于酪氨酸激酶受体Receptor tyrosine kinases(RTKs))家族。据报道其包括三种主要的亚型，分别为VEGFR1，VEGFR2和VEGFR3。其中VEGFR1和VEGFR2主要分布在肿瘤血管内皮表面，调解肿瘤血管的生成，VEGFR3主要分布于淋巴内皮表面，调解肿瘤淋巴管的生成。据报道VEGFR2是血管新生和有丝分裂过程主要的VEGF信号转导受体。VEGF家族包括VEGF-A，VEGF-B，VEGF-C，VEGF-D，VEGF-E和胎盘生长因子(PGF)。据报道VEGF-A与VEGFR-1和VEGFR-2结合，可以调节几乎所有的对VEGF的细胞应答。VEGFR-2在内皮细胞上的激活导致细胞的增殖，迁移，存活率增加以及血管通透性的提高(参见Waldner，Maximilian J.等人，The Journal of Experimental Medicine 207.13，2010)。VEGFR的表达或其激酶活性的增加与一系列人类癌症相关。
在本申请中，术语“VEGF”通常是指血管内皮生长因子(Vascular Endothelial Grow Factor)，据报道，其被认为是病理性血管生成信号通路所需的关键内皮细胞特异性生长因子，VEGF受体酪氨酸激酶信号通路的抑制阻断了肿瘤生长中新血管的形成，导致血管生成肿瘤的停滞或消退(参见Gerald McMahon，The Oncologist 2000，5：3-10)。
在本申请中，术语“VEGFR抑制剂”通常是指本领域中已知的或将来发现的任何能够引起VEGFR的表达、数量或活性降低的物质或试剂，包括任何当其被施用至受试者时，导致了受试者中与VEGFR活性相关的生物活性的抑制(包括任何VEGFR与其天然配体结合产生的下游生物效应的抑制)的任何物质。在某些实施方式中，VEGFR抑制剂可以包括在治疗癌症过程中任何能够阻断VEGFR活性或其任何下游生物效应的试剂。例如，所述VEGFR抑制剂可用于治疗肿瘤。例如，所述VEGFR抑制剂可以直接抑制VEGFR的一种或多种功能。例如，所述VEGFR抑制剂可以与编码VEGFR的核酸序列结合。例如，所述VEGFR抑制剂可以降低VEGFR蛋白的转录水平。
在本申请中，术语“VEGF抑制剂”通常是指本领域中已知的或将来发现的任何能够引起VEGF的表达、数量或活性降低的物质或试剂，包括任何当其被施用至受试者时，导致了受试者中与VEGF活性相关的生物活性的抑制的任何物质。在某些实施方式中，VEGF抑制剂可以包括任何能够阻断VEGF活性或其任何下游生物效应的试剂。在某些实施方式中，VEGF抑制剂可以包括在治疗癌症过程中任何能够阻断VEGF活性或其任何下游生物效应的试剂。例如，所述VEGF抑制剂可用于治疗肿瘤。例如，所述VEGF抑制剂可以直接抑制VEGF的一种或多种功能。例如，所述VEGF抑制剂可以与编码VEGF的核酸序列结合。例如，所述VEGF抑制剂可以降低VEGF蛋白的转录水平。
在本申请中，无论在体内还是体外，检测和/或评价所述VEGF和/或VEGFR被抑制的水平的方法在本领域是常见的，并且所述方法也可用于鉴定、标准、筛选和/或评价本申请所述的VEGF抑制剂和/或VEGFR抑制剂。
在本申请中，术语“与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症”通常是指与向受试者施用VEGFR抑制剂和/或VEGF抑制剂存在一定相关性的疾病或病症。例如，所述疾病或病症可以是因向受试者施用所述VEGFR抑制剂和/或所述VEGF抑制剂而引起的疾病或病症。例如，所述疾病或病症可以包括与施用VEGFR抑制剂和/或VEGF抑制剂相关的皮肤组织疾病或病症、与施用VEGFR抑制剂和/或VEGF抑制剂相关的五官疾病或病症和/或与施用VEGFR抑制剂和/或VEGF抑制剂相关的胃肠道疾病或病症。又例如，所述疾病或病症可以包括与施用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与施用VEGFR抑制剂和/或VEGF抑制剂相关的腹痛。在本申请中，所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症可以为与施用VEGFR抑制剂和/或VEGF抑制剂相关的手足综合征。
在本申请中，术语“肿瘤”通常是指机体在各种致瘤因子作用下，局部组织细胞增生所形成的新生物，由于这种新生物多呈占位性块状凸起，也称赘生物。根据新生物的细胞特性及对机体的危害程度，又将肿瘤分为良性肿瘤和恶性肿瘤两类，癌症是恶性肿瘤的总称。所述的肿瘤可以选自下组：上皮的恶性肿瘤(上皮来源的癌)、肺癌(例如，非小细胞肺癌)、乳腺癌、皮肤癌、膀胱癌、结肠癌、肠道癌、前列腺癌、胰腺癌、子宫癌、宫颈癌、卵巢癌、食 管癌、头颈部癌、胃癌和喉癌。例如，所述肿瘤可以为肝癌、肾癌、结直肠癌、胃癌、食道癌或甲状腺癌。
在本申请中，本领域已知的方法可以被用来确定或者筛选VEGFR抑制剂和/或VEGF抑制剂，例如通过检测施用候选物质/试剂之后VEGFR和/或VEGF表达水平或活性的变化。检测VEGFR和/或VEGF的表达水平也可以通过本领域已知的方法，例如，免疫组织化学方法、PCR、RT-PCR、原位杂交、Southern blot，Western blot，Northern blot、分光光度法和ELISA等。
在本申请中，至少一种(例如，可以为至少1种、至少2种、至少3种、至少4种、至少5种、至少6种、至少7种、至少8种、至少9种、至少10种或更多)所述VEGFR抑制剂可以直接作用于VEGFR蛋白和/或编码VEGFR蛋白的核酸。
在本申请中，至少一种(例如，可以为至少1种、至少2种、至少3种、至少4种、至少5种、至少6种、至少7种、至少8种、至少9种、至少10种或更多)所述VEGF抑制剂可以直接作用于VEGF蛋白和/或编码VEGF蛋白的核酸。
例如，所述VEGFR抑制剂可包括小分子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。
在本申请中，术语“小分子VEGFR抑制剂”可以包括与VEGFR可逆或不可逆结合的小分子VEGFR抑制剂或者是特异性结合突变的VEGFR的小分子VEGFR抑制剂。例如，所述小分子VEGFR抑制剂可以包括瑞格非尼、普纳替尼、卡博替尼、乐伐替尼、索拉非尼、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、Ki 8751、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、SAR131675、Semaxinib、SIM010603、SKLB1002、SKLB610、SU5205、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、ZD4190HCl、ZM-306416、ZM323881HCl、ABT-510、NVP-ACC789、ADT-OH、BMS-645737、EG 00229、XL-820、SGI-7079、内皮抑素(Endostatin)和/或紫杉叶素。
在本申请中，术语“特异性结合”通常是指在复杂混合物中，所述VEGFR抑制剂可以特异性地识别并结合VEGFR，而基本上不识别或结合该复杂混合物中的其他组分。例如，所述抑制剂与VEGFR的亲和力可以为其与其他非特异性结合组分的亲和力的至少2倍(例如，至少2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍或更多)。在某些实施方式中，所述VEGFR抑制剂与VEGFR结合的平衡解离常数的数值小于或等于10 -6(例如，可以小于或等于10 -7M、小于或等于10 -8M、小于或等于10 -9M、小于或等于10 -10M或更小)。
在本申请中，所述特异性结合VEGFR的蛋白大分子可以是针对VEGFR的抗体、抗体变体、融合蛋白、衍生物或其片段。例如，其可以是特异性结合VEGFR的抗体或其抗原结合片段。
在本申请中，所述抗体通常是指一种能够特异性识别和/或中和特定抗原的多肽分子。例如，抗体可包含通过二硫键相互连接的至少两条重(H)链和两条轻(L)链组成的免疫球蛋白，并且包括任何包含其抗原结合部分的分子。术语“抗体”可包括单克隆抗体、抗体片段或抗体衍生物，包括但不限于人抗体(全人源抗体)、人源化抗体、嵌合抗体、单链抗体(例如，scFv)，以及与抗原结合的抗体片段(例如，Fab、Fab’和(Fab) 2片段)。其中，所述嵌合抗体可以为重链或轻链氨基酸序列的一部分与来自于一个物种的抗体中相应氨基酸序列同源，或者属于特定的类别，而该链的其余区段则与另一物种中的相应序列同源的抗体。其中，所述人源化抗体可以指一种嵌合抗体，其含有较少的来自非人免疫球蛋白的序列，从而降低异种抗体引入到人类中时的免疫原性，同时保持抗体的完全抗原结合亲和力和特异性。其中，所述全人源抗体可以指包含对应于由人或人免疫细胞产生的、或从例如利用人源抗体库的转基因非人动物等非人来源衍生的抗体的氨基酸序列，或者其他编码人源抗体的序列的抗体。
在本申请中，所述抗原结合片段抗体可以为发挥特异性结合抗原功能的一个或多个片段。抗体的抗原结合功能可通过抗体的全长片段来实现。抗体的抗原结合功能也可通过以下来实现：包括Fv、ScFv、dsFv、Fab、Fab’或F(ab’) 2的片段的重链，或者，包括Fv、ScFv、dsFv、Fab、Fab’或F(ab’) 2的片段的轻链。(1)Fab片段，即由VL、VH、CL和CH结构域组成的一价片段；(2)F(ab’) 2片段，包含通过铰链区处的二硫键连接的两个Fab片段的二价片段；(3)由VH和CH结构域组成的Fd片段；(4)由抗体单臂的VL和VH结构域组成的 Fv片段；(5)由VH结构域组成的dAb片段(Ward等，(1989)Nature 341：544-546)；(6)分离的互补决定区(CDR)；(7)可任选地通过接头连接的两个或以上分离的CDR的组合；(8)骆驼化单域抗体(Camelized single domain antibody)，包含两个重链可变区而不含有轻链的抗体和(9)纳米抗体，包含重链可变区、CH2和CH3。此外，还可包括由VL和VH配对形成的一价单链分子Fv(scFv)(参见Bird等(1988)Science242：423-426；以及Huston等(1988)Proc.Natl.Acad.Sci.85：5879-5883)。所述”抗原结合部分”还可包括免疫球蛋白融合蛋白，所述融合蛋白包含选自以下的结合结构域：(1)与免疫球蛋白铰链区多肽融合的结合结构域多肽；(2)与铰链区融合的免疫球蛋白重链CH2恒定区；和(3)与CH2恒定区融合的免疫球蛋白重链CH3恒定区。
例如，所述特异性结合VEGFR的蛋白大分子可以为雷莫芦单抗，其抗原结合片段或其功能性变体。
在本申请中，术语“VEGF捕获剂”通常是指能够通过结合VEGF而将其捕获的试剂。例如，所述VEGF捕获剂可以选自下组：贝伐珠单抗和阿柏西普。
在本申请中，术语“降低VEGF表达量的试剂”通常是指能够直接或间接降低受试者中VEGF表达量的物质。例如，所述降低VEGF表达量的试剂可以选自下组：坦西莫斯(Temsirolimus)和沙利度胺(Thalidomide)。
在本申请中，术语“RNAi”通常是指RNA干扰(RNA interference)，其通常是外源或内源的双链RNA分子或小分子RNA，一般通过靶向mRNA并将其特异性降解而抑制目标基因的表达或翻译。通常，RNAi包括两种小分子RNA：微型RNA(miRNA)和小干扰RNA(siRNA)，这些小RNA能够结合其他mRNA分子，进而提高或降低其活性，例如阻止mRNA被翻译成蛋白质。在真核动物中，RNAi途径通过RNaseIII酶(例如，Dicer、DCL或Drosha)将长的双链RNA(dsRNA)切割成为长度为约20-23个核苷酸的siRNA双链片段。每个siRNA被拆分成两个单链RNA(ssRNA)，即过客(passenger)链和引导(guide)链。过客(passenger)链被降解，而引导链整合进RNA诱导的沉默复合物(RISC)。当引导链与mRNA分子互补时，RISC切割该mRNA分子，从而导致该mRNA分子的降解。
在本申请中，抑制VEGFR蛋白表达的RNAi可以通过靶向编码VEGFR的mRNA，从而将该mRNA特异性降解来抑制VEGFR的表达或翻译。在本申请中，抑制VEGF蛋白表达的RNAi可以通过靶向编码VEGF的mRNA，从而将该mRNA特异性降解来抑制VEGF的表达或翻译。
在本申请中，术语“寡核苷酸”通常是指核糖核酸(RNA)或脱氧核糖核酸(DNA)或其 任何模拟物或结构修饰的核酸的低聚物或聚合物。所述寡核苷酸可包括由天然存在的核碱基、糖和共价核苷(主链)间键组成的寡核苷酸，以及具有类似功能的非天然存在的寡核苷酸。经过修饰或取代的寡核苷酸通常优于天然形式，因为其具有例如增强的细胞摄取、对靶核酸的增强的亲和性以及在核酸酶存在下的增加的稳定性。
在本申请中，术语“反义寡核苷酸”通常是指具有允许与靶核酸的对应区域或片段至少部分地杂交的核碱基序列的单链寡核苷酸。在本申请中，所述反义寡核苷酸可包含约8至约50个核碱基。
在本申请中，所述VEGFR抑制剂可抑制VEGFR1、VEGFR2和/或VEGFR3。例如，所述VEGFR抑制剂可抑制VEGFR1、VEGFR2和VEGFR3中的一种、两种或三种。
在某些实施方式中，所述VEGFR抑制剂和/或VEGF抑制剂可包括雷莫芦单抗、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、Ki 8751、KRN633、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、SAR131675、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、ZD4190HCl、ZM-306416、ZM323881HCl、ABT-510、NVP-ACC789、ADT-OH、BMS-645737、EG 00229、XL-820、SGI-7079、内皮抑素(Endostatin)、紫杉叶素、阿柏西普、和/或，上述VEGFR抑制剂和/或VEGF抑制剂的可药用盐。
在本申请中，所述“可药用盐”可以指所述化合物在药学上可接受的盐。在某些实施方式中，所述可药用盐可以选自下组：索拉非尼甲苯磺酸盐、舒尼替尼苹果酸盐、帕唑帕尼盐酸盐和Dovitinib(TKI258)乳酸盐。
在本申请中，所述VEGFR抑制剂和/或VEGF抑制剂可以与一种或多种其他疗法联合施 用。在某些实施方式中，所述一种或多种其他疗法可以包括一种或多种其他抗肿瘤疗法。例如，所述其他抗肿瘤疗法可以包括细胞毒抗癌剂、免疫治疗抗癌剂和/或激素治疗抗癌剂。所述其他抗肿瘤疗法也可以包括放射治疗或手术治疗。
在本申请中，在将VEGFR抑制剂和/或VEGF抑制剂与其他抗肿瘤疗法组合使用的情况下，它们可以同时施用于受试者，或者以一定间隔分开施用。例如，所述其他抗肿瘤疗法可以是单一药剂的一部分，其与所述的VEGFR抑制剂和/或VEGF抑制剂混合成为单一组合物。又例如，所述其他抗肿瘤疗法可以是单独的药剂，其与所述的VEGFR抑制剂和/或VEGF抑制剂分别施用。在本申请中，如果所述其他抗肿瘤疗法与所述VEGFR抑制剂和/或VEGF抑制剂作为单一组合物，所述VEGFR抑制剂和/或VEGF抑制剂可以以相对于总剂量约1-99％(例如约5-95％、约1％、约5％、约10％、约20％、约30％、约40％、约50％、约60％、约70％、约80％、约90％、约95％或约99％)的剂量水平存在和/或被施用。
在治疗癌症中使用的细胞毒抗癌剂可以包括烷基化剂如氮芥、氮芥N-氧化物盐酸盐、苯丁酸氮芥、环磷酰胺、异环磷酰胺、噻替派、异硫氰酸酯、白消安、盐酸尼莫司汀、米托溴铵、美法仑、达卡巴嗪、雷莫司汀、丙米酚磷酸钠、亚乙基三胺、卡莫司汀、洛莫司汀、链脲佐菌素、哌泊溴烷(pipobroman)、依托格鲁(ethoglucid)、卡铂、顺铂、米铂、奈达铂、替奈特胺、奥莫司汀、二氯吡啶、氟匹司坦、泼尼匹昔汀、嘌嘧替派(pumitepa)、盐酸苯达莫司汀(Ribomustin)、替莫唑胺、双氯芬酸、曲伐沙星、津诺他汀、辛伐他汀、青霉烯素、半胱胺亚硝脲(cystemustine)和比折来新(bizelesin)；抗代谢药物如巯嘌呤、6-巯基嘌呤核糖苷、硫代肌苷、甲氨蝶呤、培美曲塞、恩替西汀、阿糖胞苷、奥沙利铂、盐酸替沙巴汀、5-FU及其衍生物(例如，氟尿嘧啶、替加氟、UFT、多西葫芦、卡莫氟、卡培他滨等)、氨基喋呤、奈唑硫胺、甲酰四氢叶酸钙、小叶菌、叶酸钙、左派芬酸钙、克拉屈滨、埃米特福尔、氟达拉滨、吉西他滨、羟基脲、喷司他丁、吡曲克辛(piritrexim)、碘尿苷、米托胍酮、噻唑呋喃、维马司他和苯达莫司汀；抗肿瘤抗生素如放线菌素D、放线菌素C、丝裂霉素C、色霉素A3、博来霉素盐酸盐、硫酸博莱霉素、盐酸西替霉素、盐酸柔比星、盐酸米托蒽醌和盐酸伊达比星；和/或，依托泊苷、依托泊甙磷酸盐、硫酸长春碱、硫酸长春新碱、替尼泊苷、紫杉醇、多西他赛和长春瑞滨等植物来源的细胞毒抗癌药物；VEGF抑制剂如贝伐珠单抗、以及在PCT专利申请WO 2005/012359、WO 2005/044853、WO 98/45332、WO 96/30046、WO 94/10202、美国专利US7,060,269、US6,582,959、US6,703,020、US6,054,297、美国专利申请US2006/009360、US2005/0186208、US2003/0206899、US2003/0190317、US2003/0203409和US2005/0112126中公开的那些VEGF抑制剂。
在治疗癌症中使用的免疫治疗抗癌剂可以包括布比奈尼、克雷司汀、依托呋喃、香菇多糖、乌苯美辛、干扰素、白细胞介素、巨噬细胞集落刺激因子、粒细胞集落刺激因子、红细胞生成素、淋巴毒素、BCG疫苗、小棒状杆菌、依维莫司、左旋咪唑、多糖K、丙考达唑(procodazole)和/或免疫检查点抑制剂(例如，CTLA4抑制剂、TIM-3抑制剂、PD-1抑制剂(例如，Nivolumab(纳武单抗)、Pembrolizumab(派姆单抗)、Pidilizumab、AMP514(Amplimmune)、AMP-224、以及在PCT专利申请WO2006/121168、WO2009/114335、WO2009/101611、美国专利US 8609089、美国专利申请US2010/028330、US2012/0114649中公开的其它PD-1抑制剂)、PD-L1抑制剂(例如，YW243.55.S70、MPDL3280A、MEDI-4736、MSB-0010718C、MDX-1105、以及在PCT专利申请WO2010/077634和美国专利US7,943,743中公开的其它PD-L1抑制剂))。
在治疗癌症中使用的激素治疗抗癌剂可以包括夫司他丁、己烯雌酚、氯代木香烯、醋酸甲羟孕酮、乙酸甲地孕酮、乙酸环丙孕酮、醋酸环丙孕酮、丹那唑、烯丙雌醇、孕酮、美帕曲星(mepartricin)、雷洛昔芬或美洛昔芬、左旋氧氟沙星、抗雌激素(例如，他莫昔芬柠檬酸盐、托瑞米芬柠檬酸盐等)、避孕药、前列环烷烷、睾酮内酯、氨基丁二酰亚胺、LH-RH激动剂(例如，醋酸戈舍瑞林、布舍瑞林、亮丙瑞林等)、屈洛昔芬、表雄甾烷醇、炔雌醇磺酸酯、盐酸呋苯唑、阿那曲唑、来曲唑、依西美坦、伏罗唑、抗雄激素(例如，氟他胺、比卡鲁胺、尼鲁他胺等)、5α-还原酶抑制剂(例如，非那雄胺、爱普列特(Epristeride))、皮质类固醇(例如，地塞米松、泼尼松龙、倍他米松、曲安奈德等)和/或雄激素合成抑制剂(例如，阿比特龙等)。
与VEGFR和/或VEGF被抑制相关的疾病或病症
在本申请中，所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症可以与VEGFR和/或VEGF的抑制存在统计学上显著的相关性。在某些实施方式中，所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症可以是由VEGFR和/或VEGF被抑制引起的。例如，所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症可包括与施用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。例如，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可以包括所述皮肤组织、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。在某些实施方式中，所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症可包括因施用VEGFR抑制剂和/或VEGF抑制剂而引起的副作用或不良反应。
在本申请中，所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症可以为一种新的适应症，其可以不同于以往的任意一种其他的疾病或病症。例如，所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症的诊断方式、治疗方式和/或症状均是独特的。例如，红霉素软膏可以治疗皮疹，但是对与施用VEGFR抑制剂和/或VEGF抑制剂相关的皮疹没有治疗作用。
在本申请中，术语”皮肤组织疾病或病症”通常是指皮肤(包括毛发和甲)的形态、结构和/或功能发生的病理性变化。例如，所述所述皮肤组织疾病或病症可包括但不限于皮疹、手足综合征、瘙痒、红斑、皮肤干燥、脱发、甲沟炎、色素沉积紊乱等。
在本申请中，术语”皮疹”通常是指会影响皮肤颜色、外观或纹理的皮肤变化。皮疹可以仅局限在在身体的一部分，或影响整个皮肤。皮疹还包括荨麻疹。
在本申请中，术语”手足综合征”又称为Hand Foot Syndrome(HFS)，或Palmar Plantar Erythrodysesthesia(PPE)或Hand-foot skin reaction(HFSR)，其是由哈佛医学院新英格兰戴肯尼斯医院的Jacob Lokich和Cery Moor于1984年首次描述的。典型的临床表现呈进展性，临床主要表现为指(趾)热、痛、红斑性肿胀，严重者发展至脱屑、溃疡和剧烈疼痛等。HFS的病理表现主要包括，例如基底角质细胞空泡变性、皮肤血管周围淋巴细胞浸润、角质细胞凋亡和皮肤水肿等。例如，HFS可包括手掌、足底感觉迟钝或化疗引起的肢端红斑等。肿瘤患者在接受化疗或者分子靶向治疗(如VEGFR抑制剂和/或VEGF抑制剂)的过程中可能出现相应症状。
手足综合征(HFS)目前有多种分级方法，其中以美国国立癌症研究所(NCI)分级标准较为常用，该分级将手足综合征分为3级：1级为轻微的皮肤改变或皮炎伴感觉异常(如指纹消失、色素沉着、红斑、脱皮、感觉异常、感觉迟钝、皮肤麻木等)，但不影响日常活动；2级为皮肤改变同1级，并伴疼痛，轻度影响日常活动，皮肤表面完整；3级为溃疡性皮炎或皮肤改变伴剧烈疼痛，严重影响日常生活，具有明显的组织破坏，(如脱屑、水疱、出血、水肿等)。
此外，世界卫生组织(WHO)对HFS的分级则为4级：1级为手和脚感觉迟钝、感觉异常或刺痛感；2级为在持物和走路时的不舒适、无痛肿胀或红斑；3级为疼痛的红斑和水肿的手掌和脚底，甲周的红斑和肿胀；4级为脱皮、溃烂、起庖及剧烈的疼痛。
在本申请中，术语“红斑”通常是指真皮乳头层毛细血管网局限性或全身性扩张而产生局部的或全身性的红色斑疹。
在本申请中，术语“甲沟炎”通常是指指(趾)甲周围软组织的感染性病变，通常是细菌通 过甲旁皮肤的微小破损侵袭至皮下并发生繁殖引起的，临床表现为患处红肿疼痛，伴炎性渗出及肉芽组织增生等。
在本申请中，术语“色素沉积紊乱”通常是指皮肤比正常情况下颜色更浅或更深、产生斑点或变色的病症。色素沉积不足(hypopigmentation)是由于身体无法产生足够多的色素，色素沉积过度(hyperpigmentation)是由于身体产生过多的色素。
在本申请中，术语“五官疾病或病症”通常是指耳、眉、眼、鼻、口等器官的形态、结构和/或功能发生的病理性变化。例如，所述五官疾病或病症可包括但不限于口腔溃疡(oral Mucositis)、口干(dry mouth)、鼻衄(epistaxis)、鼻咽炎和/或唇炎。
在本申请中，术语“鼻咽炎”通常是指鼻咽部黏膜、黏膜下和淋巴组织的炎症反应，可分为急性鼻咽炎和慢性鼻咽炎。症状包括但不限于鼻咽干燥不适，有黏稠分泌物不易咳出，常伴有恶心，严重者有声嘶、咽痛、头痛、头晕、乏力、消化不良、低热等局部或全身症状。鼻咽部检查见黏膜慢性充血、增生、肥厚，覆以分泌物或干痂等。
在本申请中，术语“唇炎”通常是指发生于唇部的炎症性疾病或病症。例如，其可包括口周皮肤、朱红边界、和/或唇粘膜的炎症等。根据病程可分为急性唇炎和慢性唇炎，根据临床症状特征可分为糜烂性唇炎、湿疹性唇炎、脱屑性唇炎，根据病因病理可分为慢性非特异性唇炎、腺性唇炎、良性淋巴增生性唇炎、肉芽肿性唇炎、梅-罗综合征、光化性唇炎和变态反应性唇炎等。
在本申请中，术语“胃肠道疾病或病症”通常是指胃或肠道组织(例如，从胃幽门至肛门的消化管组织)的形态、结构和/或功能发生的病理性变化。例如，所述胃肠道疾病或病症可包括但不限于腹泻(diarrhea)、呕吐(vomitting)、恶心(nausea)、厌食(anorexia)、便秘(constipation)和/或腹痛(abdominal pain)等。
在本申请中，所述VEGFR抑制剂和/或所述VEGF抑制剂可用于治疗肿瘤。例如，所述疾病或病症的患处与肿瘤的患处不同。
在本申请中，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可以包括所述皮肤组织、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。
在本申请中，术语“上皮组织”包括一层或多层覆盖整个身体的自由和封闭表面的细胞，包括皮肤、粘液、腔、浆液和腺体空间。所有上皮层都包含两个特殊的结构域：面向粘膜(或腔)空间的顶端结构域和面向浆膜(或深层)空间的基底外侧膜。因此，上皮组织的重要功能是提供适当的屏障功以分离和控制这两个空间之间的许多生理过程。上皮组织包括上皮细 胞以及内皮细胞。
在本申请中，术语“上皮组织疾病或病症”通常是指上皮细胞和/或内皮细胞病变引起的疾病或病症。例如，所述上皮组织疾病或病症可以包括皮疹、痤疮、皮肤瘙痒、脱发、毛发改变、红斑、皮肤脱落(skin exfoliation)、疱脓疹、多毛症、色素沉着(hyper-pigmentation)、指甲疾病(nail disorders)、甲沟炎及甲裂、皮肤干燥、超敏反应、黏膜炎、鼻咽炎、鼻出血、口腔干燥、唇炎、口腔溃疡和/或胃肠道粘膜损伤。又例如，所述上皮组织疾病或病症还可以包括皮肤上皮细胞疾病或病症(例如，皮疹、痤疮、酒糟鼻、异位性皮炎、接触性皮炎、脂溢性皮炎、狼疮、硬皮病、天胞疮、色素沉淀、黑斑病、白癜风、荨麻疹、体癣、皮肤瘙痒、脱发、毛发改变、红斑、甲沟炎及甲裂、皮肤干燥、超敏反应以及牛皮癣)、口腔上皮细胞疾病或病症(例如，天疱疮、唇疱疹、疱疹性口炎、肉芽肿性唇炎、口腔溃疡、类天疱疮、舍格林氏综合征、贝赫切特综合征以及口腔结节病等)、鼻腔上皮细胞疾病或病症(鼻衄、鼻窦炎、鼻疖以及鼻息肉等)、胃上皮细胞疾病或病症(例如，胃炎、肠化生、胃穿孔、胃瘘、胃溃疡以及胃肠道息肉)和/或小肠上皮细胞疾病或病症(例如，肠炎、克罗恩病、肠穿孔、肠瘘、肠溃疡、溃疡性结肠炎以及NSAIDs肠病)。
在本申请中，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可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，其中所述内皮细胞病变和/或上皮细胞病变与所述VEGFR和/或VEGF被抑制相关。
例如，所述内皮细胞可以包括血管内皮细胞。血管内皮细胞的病变可包括内皮功能障碍。例如，所述血管内皮细胞病变可以包括退行性变性血管疾病(例如，动脉粥样硬化、动脉中层硬化以及小动脉硬化(例如，透明变性型小动脉硬化和增生型小动脉硬化))、炎症性血管疾病(例如，感染性动脉炎、梅毒性动脉炎、巨细胞性动脉炎、血栓闭塞性脉管炎以及风湿性动脉炎)、功能性血管疾病(例如，雷诺氏病、手足发绀以及红斑肢痛症)和/或先天性血管疾病(例如，先天性动静脉瘘)等。
在本申请中，所述上皮细胞可包括皮肤上皮细胞、口腔上皮细胞、鼻腔上皮细胞、胃上皮细胞和/或肠上皮细胞。例如，所述上皮细胞病变可以包括皮肤上皮细胞病变(例如，皮疹、痤疮、酒糟鼻、异位性皮炎、接触性皮炎、脂溢性皮炎、狼疮、硬皮病、天胞疮、色素沉淀、黑斑病、白癜风、荨麻疹、体癣、皮肤瘙痒、脱发、毛发改变、红斑、甲沟炎及甲裂、皮肤干燥、超敏反应以及牛皮癣)、口腔上皮细胞病变(例如，天疱疮、唇疱疹、疱疹性口炎、肉芽肿性唇炎、口腔溃疡、类天疱疮、舍格林氏综合征、贝赫切特综合征以及口腔结节病等)、鼻腔上皮细胞病变(鼻衄、鼻窦炎、鼻疖以及鼻息肉等)、胃上皮细胞病变(例如，胃炎、肠化 生、胃穿孔、胃瘘、胃溃疡以及胃肠道息肉)和/或小肠上皮细胞病变(例如，肠炎、克罗恩病、肠穿孔、肠瘘、肠溃疡、溃疡性结肠炎以及NSAIDs肠病)等。
本申请的发明人发现，VEGFR和/或VEGF的抑制会导致内皮细胞、内皮组织受损，从而引起皮肤组织、口腔组织、鼻腔组织和/或胃肠道组织的疾病或病症。在这些疾病或病症的发生及发展过程中，通常从内皮细胞、内皮组织的受损/病变开始发展病程，而上皮细胞也会有病变表现，并最终以与施用VEGFR抑制剂和/或VEGF抑制剂相关的内皮细胞病变，和/或与施用VEGFR抑制剂和/或VEGF抑制剂相关的上皮细胞病变的形式表现于患者。
在某些实施方式中，所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症可以包括与施用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。例如，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。例如，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。
在某些实施方式中，所述疾病或病症可以包括皮疹、手足综合征、瘙痒、红斑、皮肤干燥、脱发、甲沟炎、色素沉积紊乱、口腔溃疡、口干、鼻衄、鼻咽炎、唇炎、食管黏膜炎、胃黏膜炎、胃溃疡、腹泻、呕吐、恶心、厌食、便秘和/或腹痛。例如，所述疾病或病症包括手足综合征。
在某些实施方式中，所述与VEGFR和/或VEGF被抑制相关的疾病或病症基本上无法通过施用选自下组的药剂而被治疗或缓解：1％西地那非、尿素霜、凡士林软膏、尿素软膏、溴莫尼定软膏、维生素B6软膏、尼古丁软膏、地塞米松软膏、氢化可的松软膏、Vk1软膏(0.1％)、红霉素软膏和曲安奈德软膏。
一氧化氮释放剂
在本申请中，术语”一氧化氮释放剂”通常是指任何能够贡献、产生和/或释放一氧化氮产生的物质。在某些实施方式中，一氧化氮释放剂可以直接贡献、生产和/或释放一氧化氮。例如，一氧化氮释放剂可以通过刺激其他物质来贡献、生产和/或释放一氧化氮。例如，一氧化氮释放剂可以作为化学反应或酶催化反应的反应物，通过该等反应贡献、生产和/或释放一氧化氮。在某些实施方式中，一氧化氮释放剂可以作为化学反应或酶催化反应的催化剂，通过该等反应来刺激其他物质贡献、生产和/或释放一氧化氮。一氧化氮释放剂也可以包括一氧化氮本身。
可以通过本领域已知的方法来确定或筛选所述一氧化氮释放剂，例如，可以通过检测亚硝酸盐、NO、NO 2 -和/或S-亚硝基硫醇水平来检测测试化合物贡献、产生、释放和/或直接或间接转移一氧化氮的能力。可以使用本领域已知的任何方法测量亚硝酸盐、NO、NO 2 -和/或S-亚硝基硫醇水平。例如，可以通过检测亚硝酸盐来确定或筛选一氧化氮释放剂，例如，通过Griess分析(Molecular Probes)来分析亚硝酸盐，其是基于亚硝酸盐与对氨苯磺酸反应，随后通过分光光度法检测反应产物。还可以通过高灵敏度的化学发光技术在95℃的回流室中将亚硝酸盐/硝酸盐还原为NO进而进行测量。又例如，可以通过测定血液中的Hb-NO水平来确定或筛选一氧化氮释放剂。已知NO与血红蛋白(Hb)紧密结合，NO与Hb的相互作用被认为是血管中NO代谢的主要途径。因此，血液中的Hb-NO水平是内源性NO产生的良好指标。在一些实施方式中，可以通过电子顺磁共振(EPR)光谱法来测定全血和红细胞中的顺磁性血红蛋白-NO加合物(Hb-NO)，从而确定或筛选所述一氧化氮释放剂。又例如，可以通过进行NO特异性电极的电流分析来确定或筛选所述一氧化氮释放剂。这种方法需要将NO电极插入生物体内或样本中。又例如，可以通过检测S-亚硝基硫醇来确定或筛选所述一氧化氮释放剂。在EcoMedics CLD 88 Exhalyzer(Annex，Herts，UK)中使用化学发光检测来测量蛋白的S-亚硝基硫醇(Feelisch，M.等，ConcomitantS-，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))。又例如，可以通过间接方法检测NO水平，从而确定或筛选所述一氧化氮释放剂。例如，通过EndoPAT方法进行非侵入式内皮功能检测以测量NO水平。具体检测方法可见于美国专利 US9696324。还可以通过采用硝酸还原酶特异性将NO 3 -还原为NO 2 -，NO 2 -与显色剂作用生成有色物质，测定吸光度来指示血清NO含量，从而确定或筛选一氧化氮释放剂。
在本申请中，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。例如，所述一氧化氮释放剂能够直接或间接产生NO。
在本申请中，所述一氧化氮释放剂可以包括有机分子、无机分子、高分子材料、纳米材料和/或氨氧化微生物(AOM)。例如，所述一氧化氮释放剂可为NO。
在本申请中，术语“有机分子”通常是指含碳元素的化合物，且不包含碳的氧化物、碳酸、碳酸盐、氰、氰化物、氧氰、氰酸盐、硫氰、金属碳化物等。
例如，所述一氧化氮释放剂可以包括有机分子，且所述有机分子可包括硝酸甘油、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、O 2-(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。例如，所述一氧化氮释放剂可以包括有机分子，且所述有机分子可以包括硝酸甘油、单硝酸异山梨酯和/或硝酸异山梨酯。在某些实施方式中，所述有机分子可以包括硝酸甘油。
在本申请中，所述一氧化氮释放剂可以包括无机分子，且所述无机分子可以包括硝酰配合物、亚硝酰配合物、金属亚硝氨基络合物、硝酸盐和/或亚硝酸盐。例如，所述无机分子可以包括硝普钠。
在本申请中，所述一氧化氮释放剂可以具有小于或等于2000道尔顿、小于或等于1500道尔顿、小于或等于1200道尔顿、小于或等于1000道尔顿、小于或等于900道尔顿、小于或等于800道尔顿、小于或等于700道尔顿、小于或等于600道尔顿、小于或等于500道尔顿、小于或等于400道尔顿、小于或等于300道尔顿、小于或等于200道尔顿或小于或等于100道尔顿的分子量。
在本申请中，所述一氧化氮释放剂可以是含有NO供体基团的高分子。可以使用任何合适的高分子，包括交联或未交联的聚合物、树枝状高分子、金属化合物、有机金属化合物、无机基化合物和其它高分子支架。释放NO的高分子可以包括，释放NO的共缩合二氧化硅，如二氮嗪二硫酸酯官能化聚硅氧烷、释放NO的沸石(参见美国专利申请US2006/0269620或 US2010/0331968)、释放NO的金属有机骨架(MOF)(参见美国专利申请US2010/0239512或US2011/0052650)、释放NO的多供体化合物(参见美国专利申请US2014/0171395)、释放NO的树枝状高分子或金属结构(参见美国专利申请US2009/0214618)、NO释放涂层(参见美国专利申请US2011/0086234)、美国专利申请US2010/0098733以及PCT专利申请WO2012/100174中描述的化合物。上述参考文献的公开内容通过引用整体并入本申请。在一些实施方式中，一氧化氮释放剂可以是含有NO供体基团的纳米材料，例如纳米晶体，其为由二氧化硅形成的共缩合硅氧烷网络。
又例如，释放NO的高分子还可以包括S-亚硝基硫醇纳米硅球、S-亚硝基乙二硫醇甲壳素、寡聚丙二胺接枝壳聚糖亲核复合体和/或Novan Inc.的一氧化氮释放剂(例如SB204、SB206、SB208、SB414或NVN3100)以及在美国专利US8282967、US8956658、US8962029、US9403851、US9403852、US9187501、US8399005、US8981139、US9713652、US9238038、US9669041、US8591876、US9526738、US9737561、US9427605、美国专利申请US2009/0214618、US2012/0021055、US2012/0034169、US2014/0005426、US2014/0058124、US2015/0182543、US2016/0060279、US2014/0065200、US2015/0225488、US2010/0297200、US2013/0196951、US2013/0344334、US2014/0017121、US2011/0086234、US2014/0134321、US2010/0098733、US2012/0230921、US2014/0171395、US2016/0083339、US2016/0199295、US2014/0255318、US2017/0246205、US2012/0136323、US2012/0156163、US2014/0057001、US2012/0134951、US2017/0056437、US2017/0312307、US2017/0216197、US2015/0024052、US2008/0311163、US2016/0256366、US2015/0111973、US2017/0196905、PCT专利申请WO2017/079268、WO2004/009253、WO2017/151905、WO2016/160089以及WO2017/019614中所描述的那些。
在本申请中，寡聚丙二胺接枝壳聚糖亲核复合体可以包含偶氮鎓二醇盐。例如，一氧化氮释放剂可以为寡聚丙二胺接枝壳聚糖NONOate。在本申请中，NONOate可以指包含化学式R 1R 2N-(NO -)-N＝O的化合物，其中R 1和R 2都为烷基。
在本申请中，一氧化氮释放剂可以包括氨氧化微生物(AOM)，且所述氨氧化微生物(AOM)可以包括氨氧化细菌(AOB)。例如，所述氨氧化微生物(AOM)可以包括亚硝化单胞菌(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/或亚硝基弧菌亚硝化弧菌(Nitrosovibrio)。例如，所述氨氧化微生物(AOM)可以包括AOBiome，LLC的释放一氧化氮的微生物群(例如AOB101、AOB102、AOB103、AOB201、AOB201或AOB203)，以及在美国专利US7820420B2、US9738870B2、WO2017004534A2、US10078054B2、US2017189454A1、 US20170191109A1、US20180092948A1、WO2018057710A1、WO2018017583A1、WO2018111888A1、US20070148136A1、US2005106126A1、US20170037363A1、CN1997731A、US20170189454A1和WO2017004557A1中公开的那些。
在本申请中，术语“高分子”通常是指分子量为大于2000道尔顿、大于3000道尔顿、大于4000道尔顿、大于5000道尔顿、大于6000道尔顿、大于7000道尔顿、大于8000道尔顿、大于9000道尔顿、大于10000道尔顿、大于12000道尔顿、大于15000道尔顿或大于20000道尔顿的任何化合物。
在本申请中，术语“小分子”通常是指分子量小于或等于2000道尔顿、小于或等于1500道尔顿、小于或等于1200道尔顿、小于或等于1000道尔顿、小于或等于900道尔顿、小于或等于800道尔顿、小于或等于700道尔顿、小于或等于600道尔顿、小于或等于500道尔顿、小于或等于400道尔顿、小于或等于300道尔顿、小于或等于200道尔顿或小于或等于100道尔顿的分子量的任何化合物。
在本申请中，所述一氧化氮释放剂可以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。
例如，所述一氧化氮释放剂可以具有选自表1的一个或多个基团：
表1
Figure PCTCN2019082623-appb-000001
Figure PCTCN2019082623-appb-000002
Figure PCTCN2019082623-appb-000003
在本申请中，所述一氧化氮释放剂在生理条件下可以带正电、中性或者带负电。在本申请中，所述一氧化氮释放剂的logP可以在1-5之间。例如，可以在1.5-3.5之间。
本申请所述的一氧化氮释放剂可用于预防或治疗所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症。
预防和/或治疗疾病的方法及相关用途
在本申请中，所述一氧化氮释放剂可用于制备药物，且所述药物可用于预防或治疗所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症。
在本申请中，所述一氧化氮释放剂可用于预防或治疗所述与施用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，和与施用VEGFR抑制剂和/或VEGF抑制剂相关的腹痛。例如，所述的一氧化氮释放剂可用于预防或治疗所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的手足综合征。
在本申请中，所述一氧化氮释放剂可用于预防或治疗皮疹、手足综合征、瘙痒、红斑、皮肤干燥、脱发、甲沟炎、色素沉积紊乱、口腔溃疡、口干、鼻衄、鼻咽炎、唇炎、食管黏膜炎、胃黏膜炎、胃溃疡、腹泻、呕吐、恶心、厌食、便秘和/或腹痛。例如，所述的一氧化氮释放剂可用于预防或治疗所述手足综合征。
在某些实施方式中，所述药物被制备为适用于局部给药。在一些实施方式中，所述局部给药的给药部位可以不为癌症的发生部位或癌症的潜在转移部位。例如，所述给药部分可以不为癌症的原发部位。又例如，所述给药部分可以不为癌症的转移部位。例如，所述转移部位可以包括淋巴转移、血管转移和/或种植性转移导致的癌症转移的发生部位。在一些实施方式中，所述转移部位可以包括骨、脑、肝、胃和/或肺。又例如，所述给药部分可以不为癌症的复发部位。在本申请的所述药物中，所述一氧化氮释放剂的浓度可以为约0.0001％(w/w)至约50％(w/w)，例如，可以在约0.0001％(w/w)至约10％(w/w)、约0.0001％(w/w)至约9.5％(w/w)、约0.0001％(w/w)至约9％(w/w)、约0.0001％(w/w)至约8.5％(w/w)、约0.0001％(w/w)至约8％(w/w)、约0.0001％(w/w)至约7.5％(w/w)、约0.0001％(w/w)至约7％(w/w)、约0.0001％(w/w)至约6.5％(w/w)、约0.0001％(w/w)至约6％(w/w)、约0.0001％(w/w)至约5.5％(w/w)、约0.0001％(w/w)至约5％(w/w)、约0.0001％(w/w)至约4.5％(w/w)、约0.0001％(w/w)至约4％(w/w)、约0.0001％(w/w)至约3.5％(w/w)、约0.0001％(w/w)至约3％(w/w)、约0.0001％(w/w)至约2.5％(w/w)、约0.0001％(w/w)至约2％(w/w)、约0.0001％(w/w)至约1.5％(w/w)、约0.0001％(w/w)至约1％(w/w)、约0.0001％(w/w)至约0.5％(w/w)、约0.0001％(w/w)至约0.01％(w/w)或更小的范围内变动。在本申请的所述药物中，所述一氧化氮释放剂的浓度可以为约0.0001％(w/w)至约1％(w/w)、约0.0001％(w/w)至约0.9％(w/w)、约0.0001％(w/w)至约0.6％(w/w)、约0.05％(w/w)至约0.5％(w/w)、约0.05％(w/w)至约0.4％(w/w)、约0.05％(w/w)至约0.3％(w/w)、约0.05％(w/w)至约0.2％(w/w)、约0.1％(w/w)至约0.2％(w/w)或更小的范围内变动。例如，所述一氧化氮释放剂的浓度可以为约0.2％(w/w)。或者，所述一氧化氮释放剂的浓度可以为约0.1％(w/w)。
在本申请中，包含所述一氧化氮释放剂的所述药物可基本上不影响所述VEGFR抑制剂 和/或VEGF抑制剂的治疗效果。例如，施用包含所述一氧化氮释放剂的所述药物基本上不会使得需要增加施用所述VEGFR抑制剂和/或VEGF抑制剂的剂量，以达到基本上相同的治疗效果。
在某些实施方式中，所述药物被制备为适用于外用给药。
在某些实施方式中，所述药物被制备为适于局部皮肤施用。例如，所述药物可以为软膏剂，洗剂或霜剂。
在本申请中，所述药物中还可以包括一种或多种其他活性成分。例如，所述活性成分可以指具有医疗效用或者生理活性的单体化合物。例如，所述其他活性成分可以选自下组：抗炎剂、止痛剂、局部麻醉剂、抗生素、抗组胺剂、防腐剂、免疫抑制剂和抗出血剂。
在本申请中，所述药物还可以包括药学上可接受的载体。例如，所述药学上可接受的载体可以选自下组：填充剂、粘合剂、崩解剂、缓冲液、防腐剂、润滑剂、搅味剂、增稠剂、着色剂和乳化剂。
另一方面，本申请提供了一氧化氮释放剂，其用于预防或治疗与VEGFR和/或VEGF被抑制相关的疾病或病症(例如与VEGFR和/或VEGF被抑制相关的上皮组织疾病)。
另一方面，本申请提供了一种预防或治疗受试者中所述与VEGFR和/或VEGF被抑制相关的疾病或病症的方法。所述方法包括向所述受试者施用预防或治疗有效量的本申请所述的一氧化氮释放剂。
在本申请中，术语“预防”可以与“预防性治疗”互换地使用。在本申请中“预防”通常是指通过预先采取某些措施而防止疾病或其一种或多种症状的发作，复发或扩散。在本申请中，术语”治疗”通常是指消除或改善疾病，或缓解与疾病相关的一种或多种症状。
在本申请中，术语“受试者”通常是指需要接受疾病的诊断、预后、改善、预防和/或治疗的人或非人动物(包括哺乳动物，啮齿类动物和禽类动物等)。例如，所述受试者可以为家畜动物(例如，牛、猪、羊、鸡、兔或马)，或啮齿类动物(例如，大鼠和小鼠)，或灵长类动物(例如，大猩猩和猴子)，或家养动物(例如，狗和猫)。在本申请中，所述受试者可以是需要一氧化氮释放剂治疗或预防的那些受试者。在本申请中，所述受试者可以包括癌症患者。例如，所述受试者可以曾经、正在和/或将来被施用所述VEGFR抑制剂和/或所述VEGF抑制剂。例如，所述VEGFR抑制剂和/或VEGF抑制剂可以为本申请所述的VEGFR抑制剂和/或VEGF抑制剂。
在本申请中，所述疾病或病症的严重程度可以在所述施用VEGFR抑制剂和/或VEGF抑制剂之后增加。例如，所述疾病或病症的严重程度可以增加约5％或以上，约10％或以上，约 15％或以上，约20％或以上，约25％或以上，约30％或以上，约35％或以上，约40％或以上，约45％或以上，约50％或以上，约60％或以上，约70％或以上，约80％或以上，约90％或以上，约100％或以上，约200％或以上或更多。
在本申请中，在所述施用VEGFR抑制剂和/或VEGF抑制剂之前，所述受试者可以未患有所述疾病或病症。在本申请中，术语“所述受试者未患有所述疾病或病症”通常是指受试者没有涉及所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症的既往病史。例如，在所述施用VEGFR抑制剂和/或VEGF抑制剂之前1天以上、1周以上、1个月以上、1年以上、10年以上或所述受试者出生以来，未患有本申请所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症。
在本申请中，所述VEGFR抑制剂和/或VEGF抑制剂不包含所述一氧化氮释放剂。例如，所述VEGFR抑制剂和/或VEGF抑制剂不包含硝酸甘油。
在本申请中，术语“有效量”通常是指可以缓解或者消除受试者的疾病或症状，或者可以预防性地抑制或防止疾病或症状发生的药物的量。通常，可根据受试者的体重、年龄、性别、饮食、排泄速率、过往病史、现用治疗、给药时间、剂型、给药方法、给药途径、药物组合、所述受试者的健康状况和交叉感染的潜力、过敏、超敏和副作用、和/或上皮(或内皮)组织疾病发展的程度等来确定具体的有效量。本领域技术人员(例如，医生或兽医)可根据这些或其它条件或要求按比例降低或升高剂量。
在某些实施方式中，所施用的所述一氧化氮释放剂的浓度为约0.0001％(w/w)至约50％(w/w)，例如，约0.0001％(w/w)至约10％(w/w)、约0.0001％(w/w)至约9.5％(w/w)、约0.0001％(w/w)至约9％(w/w)、约0.0001％(w/w)至约8.5％(w/w)、约0.0001％(w/w)至约8％(w/w)、约0.0001％(w/w)至约7.5％(w/w)、约0.0001％(w/w)至约7％(w/w)、约0.0001％(w/w)至约6.5％(w/w)、约0.0001％(w/w)至约6％(w/w)、约0.0001％(w/w)至约5.5％(w/w)、约0.0001％(w/w)至约5％(w/w)、约0.0001％(w/w)至约4.5％(w/w)、约0.0001％(w/w)至约4％(w/w)、约0.0001％(w/w)至约3.5％(w/w)、约0.0001％(w/w)至约3％(w/w)、约0.0001％(w/w)至约2.5％(w/w)、约0.0001％(w/w)至约2％(w/w)、约0.0001％(w/w)至约1.5％(w/w)、约0.0001％(w/w)至约1％(w/w)、约0.0001％(w/w)至约0.5％(w/w)、约0.0001％(w/w)至约0.01％(w/w)或在更小的范围内变化。在本申请的所述药物中，所述一氧化氮释放剂的浓度可以为约0.0001％(w/w)至约1％(w/w)、约0.0001％(w/w)至约0.9％(w/w)、约0.0001％(w/w)至约0.6％(w/w)、约0.05％(w/w)至约0.5％(w/w)、约0.05％(w/w)至约0.4％(w/w)、约0.05％(w/w)至约0.3％(w/w)、 约0.05％(w/w)至约0.2％(w/w)、约0.1％(w/w)至约0.2％(w/w)或更小的范围内变动。例如，所述一氧化氮释放剂的浓度可以为约0.2％(w/w)。或者，所述一氧化氮释放剂的浓度可以为约0.1％(w/w)。
在本申请中，所述受试者可以包括人或非人动物。例如，所述非人动物可以选自下组：猴、鸡、鹅、猫、狗、小鼠和大鼠。此外，非人动物也可以包括任何除人以外的动物物种，例如家畜动物，或啮齿类动物，或灵长类动物，或家养动物，或家禽动物。所述人可以是高加索人、非洲人、亚洲人、闪族人，或其他种族，或各种种族的杂合体。又例如，所述人可以是老年、成年、青少年、儿童或者婴儿。
可以根据在实验动物中的有效量推测在人类中的有效量。例如，Freireich等人描述了动物和人的剂量的相互关系(基于每平方米身体表面的毫克数)(Freireich et al.，Cancer Chemother.Rep.50，219(1966))。身体表面积可以从患者的身高和体重近似确定。参见例如Scientific Tables，Geigy Pharmaceuticals，Ardsley，N.Y.，537(1970)。
在本申请的所述方法中，所述VEGFR和/或VEGF被抑制可以由向所述受试者施用VEGFR抑制剂和/或VEGF抑制剂引起。
例如，可以在向所述受试者施用所述VEGFR抑制剂和/或VEGF抑制剂之前、同时或者之后施用所述一氧化氮释放剂。当本申请所述的VEGFR抑制剂和/或VEGF抑制剂与所述一氧化氮释放剂同时施用时，所述一氧化氮释放剂以相对于总剂量约0.0001-10％(例如约0.005-10％、约0.01-10％、约0.05-10％、约0.1-10％、约0.2-10％、约0.3-10％、约0.4-10％、约0.5-10％、约0.6-10％、约0.7-10％、约0.8-10％、约0.9-10％、约0.95-10％、约1-10％、约2-10％、约3-10％、约5-10％、约6-10％、约8-10％或更小范围)的剂量水平施用。在所述一氧化氮释放剂与所述VEGFR抑制剂和/或VEGF抑制剂间隔给药的实施方式中，所述一氧化氮释放剂可以在施用所述VEGFR抑制剂和/或VEGF抑制剂之前或之后间隔给药。所述间隔的时间可以为1分钟、2分钟、5分钟、10分钟、20分钟、30分钟、45分钟、1小时、2小时、3小时、4小时、5小时、6小时、12小时、18小时、1天、2天、3天、1周、2周、3周、1个月、2个月、3个月或更长。
在某些实施方式中，所述一氧化氮释放剂的施用为外用给药。在某些实施方式中，所述一氧化氮释放剂被包含在软膏剂中施用。在某些实施方式中，所述一氧化氮释放剂与一种或多种其他活性成分共同施用。在某些实施方式中，所述一氧化氮释放剂的施用基本上不影响所述VEGFR抑制剂和/或VEGF抑制剂的治疗效果。
另一方面，本申请提供了一种药物组合(例如，药剂盒)。所述药物组合可包含：1)本 申请所述的VEGFR抑制剂和/或VEGF抑制剂；以及，2)本申请所述的一氧化氮释放剂。在某些实施方式中，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。
在某些实施方式中，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。例如，所述药物组合中可以包括2种或更多种彼此独立包装的药物，其中至少一种所述药物包含本申请所述的VEGFR抑制剂和/或VEGF抑制剂，且其中至少一种另外的药物包含本申请所述的一氧化氮释放剂。
在所述药物组合的某些实施方式中，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(例如，本申请所述的与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症)。在某些实施方式中，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。在某些实施方式中，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。
本申请中，所述“基本上不影响”可以指，与单独使用所述VEGFR抑制剂和/或VEGF抑制剂的治疗效果相比，使用所述药物组合或试剂盒的2)中的所述一氧化氮释放剂和1)中的所述VEGFR抑制剂和/或VEGF抑制剂的治疗效果相当，或者不产生显著的劣势。例如，对任意的受试者，与单独使用所述VEGFR抑制剂和/或VEGF抑制剂的治疗效果相比，使用所述药物组合或试剂盒的2)中的所述一氧化氮释放剂和1)中的所述VEGFR抑制剂和/或VEGF抑制剂所导致的肿瘤体积减少的程度是相同的，或者，减少的程度不小于约5％、不小于约4％、不小于约3％、不小于约2％、不小于约1％、不小于约0.5％、不小于约0.1％、不小于约0.01％、不小于约0.001％或更小。
本申请还提供一种方法，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。
本申请还提供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。
在本申请中，所述受试者可以已经患有与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症，或者，所述受试者可具备较大概率患有与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症。
在本申请中，术语“易患有”通常是指受试者具备较大概率患有所述与施用VEGFR抑制 剂和/或VEGF抑制剂相关的疾病或病症。例如，所述较大概率可以指与健康的受试者相比，一个受试者患有所述与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症的概率提高了大约至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％、至少100％、至少150％、至少200％或更多。
本申请还提供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。
例如，所述受试者可以曾经、正在和/或将来被施用VEGFR抑制剂和/或VEGF抑制剂。
例如，所述疾病或病症可以为手足综合征。例如，所述疾病或病症可以为与施用VEGFR抑制剂和/或VEGF抑制剂相关的疾病或病症。例如，所述疾病或病症可以为与施用VEGFR抑制剂和/或VEGF抑制剂相关的手足综合征。
本申请还提供一种方法，其包括下述步骤：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。
在本申请中，术语“皮肤组织特征”通常是指能够反映皮肤组织疾病或病症的特征。例如，所述特征可以包括能够反映与施用所述VEGFR抑制剂和/或VEGF抑制剂相关的皮肤组织疾病或病症的特征。例如，所述特征可以包括能够反映与施用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抑制剂相关的皮肤瘙痒、与施用VEGFR抑制剂和/或VEGF抑制剂相关的皮肤红斑和/或紫癜、与施用VEGFR抑制剂和/或VEGF抑制剂相关的皮肤干燥和/或皲裂、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，和/或，与施用VEGFR抑制剂和/或VEGF抑制剂相关的色素沉积紊乱的特征。例如，所述特征可以包括红斑面积和程度、紫癜面积和程度、丘疹数量与程度、脓疱数量与程度、结节数量与程度、皮肤肿胀范围与程度、皮肤溃疡程度、皮肤干燥程度、皮肤皲裂程度、皮肤角化程度、皮肤苔藓化程度、皮肤脱屑面积与程度、皮肤紧绷状态、皮肤瘙痒程度、真皮与皮下交界处血管炎症程度、皮肤组织的坏死程度、皮肤糜烂溃疡程度、网状青斑面积、皮肤色素沉着程度、水疱与大疱数量、毛发脱失部位/面积/程度、皮肤肉芽增生程度、皮肤脂溢程度，毛囊炎程度、甲周红肿程度、甲周脓肿程度、甲周皮肤色素沉着、甲床萎缩程度、甲板变薄或肥厚、甲板颜色异常、甲横纹、甲纵脊、甲翼状胬肉等。
在本申请中，术语“五官特征”通常是指能够反映五官疾病或病症的特征。例如，所述特 征可以包括能够反映与施用所述VEGFR抑制剂和/或VEGF抑制剂相关的五官疾病或病症的特征。例如，所述特征可以包括能够反映与施用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，和/或，与施用VEGFR抑制剂和/或VEGF抑制剂相关的唇炎的特征。例如，所述特征可以包括口腔粘膜充血程度、口腔粘膜水肿程度、口腔黏膜疱疹程度、口腔黏膜溃疡程度、口腔粘膜下层腺周缺损程度、舌腺/舌下腺/腮腺等唾液腺体萎缩程度、口干程度、龋齿程度、舌肿胀程度、舌周齿痕程度、鼻血发生频率、鼻血量、口咽和鼻咽部黏膜水肿程度、口咽和鼻咽部黏膜疱疹程度、口咽和鼻咽部黏膜溃疡程度、口咽和鼻咽部黏膜增生程度、口咽及鼻咽部滤泡增生程度、唇及唇周肿胀程度、唇及唇周疱疹程度、唇及唇周红斑程度、唇及唇周皮肤脱屑程度、唇及唇周皮肤苔藓化程度和唇及唇周皮肤糜烂程度等。
在本申请中，术语“胃肠道特征”通常是指能够反映胃肠道疾病或病症的特征。例如，所述特征可以包括能够反映与施用所述VEGFR抑制剂和/或VEGF抑制剂相关的胃肠道疾病或病症的特征。例如，所述特征可以包括能够反映与施用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抑制剂相关的腹痛的特征。例如，所述特征可以包括食欲减退程度、胃脘嗳气程度、吞咽困难程度、胸骨后烧灼感程度、胸骨后疼痛程度、上腹部疼痛的时间(空腹或饱腹时)和程度、腹胀程度、腹泻程度、排便次数、排便时间、便前腹痛、里急后重、粪便异常(如黑血便、鲜血便、粘液便、粘液脓血便、稀水样便、蛋花汤样便等)、呕吐频次、呕吐物情况、呕血情况、恶心、营养不良程度、微量元素缺乏程度等。
在本申请中，所述方法还可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。例如，所述继续监控可以指在施用所述VEGFR抑制剂和/或VEGF抑制剂之后约至少1天、至少1周、至少10天、至少2周、至少3周、至少1个月、至少3个月或更长时间进行监控。例如，所述减少或停用可以指向所述受试者施用所述VEGFR抑制剂和/或VEGF抑制剂的剂量较所述方法步骤1)中所述VEGFR抑制剂和/或VEGF抑制剂的剂量相比，减少约至少5％、 至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％、至少95％、至少99％或100％。
在本申请中，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可以在所述施用VEGFR抑制剂和/或VEGF抑制剂之后增加。例如，所述严重程度可以为增加至少5％、至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％或更多。
在本申请中，在所述施用VEGFR抑制剂和/或VEGF抑制剂之前，所述受试者可以未患有所述疾病或病症。
在本申请中，所述VEGFR抑制剂和/或VEGF抑制剂可以不包含所述一氧化氮释放剂。例如，所述VEGFR抑制剂和/或VEGF抑制剂可以不包含硝酸甘油。
在本申请中，所述疾病或病症可以为上皮组织疾病或病症。
在本申请中，施用所述VEGFR抑制剂和/或VEGF抑制剂可以来治疗癌症。例如，所述疾病或病症的患处可以与癌症的患处不同。
在本申请中，可以向所述受试者局部施用所述一氧化氮释放剂。例如，可以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。
在本申请中，术语“基本不含癌细胞的部位”通常是指受试者中癌细胞含量低至基本上被认为不含癌细胞的组织器官或部位。例如，所述基本上不含可以指所述癌细胞的数量占该部位的总细胞数量的0.01％以下，例如，0.005％以下，0.001％以下，0.0001％以下，0.00001％以下或更低。
又例如，可以向所述受试者中的非癌症部位施用所述一氧化氮释放剂。
在本申请中，术语“非癌症部位”通常是指受试者中非癌症病灶且非癌症转移区域的部位。例如，所述癌症病灶可以为癌症的原发部位。例如，所述癌症转移区域可以为与原发部位肿瘤类型相同的肿瘤的所在区域。例如，所述癌症转移区域可以经淋巴道转移、血管转移或种植性转移而形成。
在本申请中，术语“一(a)”和“一个(an)”和“所述(the)”和“至少一种”以及相似指示词的使用应理解为包括单数和复数。除非在本文中另有说明或者与上下文明显矛盾，当使用的术语”至少一种”后接一项或多项列举项(例如，“至少一种A和B”)时，应理解为表示选自所列项的一项(A或B)或者所列项中两项或多项的任意组合(A和B)。
在本申请中，除非另有注明，术语“包含”、“具有”、“包括”以及“含有”都应理解为开放性术语(即，意思是”包括，但不限于”)。
不欲被任何理论所限，下文中的实施例仅仅是为了阐释本申请的装置、方法和系统的工作方式，而不用于限制本申请发明的范围。
实施例
在本申请实施例的结果中，**表示P＜0.01；*表示P＜0.05；***表示P＜0.001，利用t-test统计检验。
实施例1：S-亚硝基硫醇纳米硅球的合成
将4毫升(3-巯基丙基)三甲氧基硅烷和2毫升原硅酸四乙酯的混合液通过注射泵以0.5毫升每分钟的速度注入到30毫升去离子水、30毫升乙醇和30毫升氨水的混合溶液中，在注射过程中反应液保持0摄氏度。注射完成后反应液在室温下搅拌2.5小时，随后4000转每分钟离心8分钟。沉淀物分别用100毫升冰水和100毫升乙醇洗涤一次，真空干燥得到巯基化纳米硅球。
将150毫克巯基化纳米硅球用4毫升甲醇分散，将温度降至0摄氏度，持续搅拌下加入2毫升1摩尔每升亚硝酸钠和1毫摩尔每升二乙基三胺五乙酸的混合溶液，再加入2毫升5摩尔每升盐酸水溶液。反应液在避光和0摄氏度下搅拌2.5小时，在4摄氏度下，4000转每分钟离心5分钟。沉淀物分别用4摄氏度30毫升1毫摩尔每升二乙基三胺五乙酸水溶液和4摄氏度30毫升甲醇洗涤一次，并重新离心收集固体。在避光，-30摄氏度下真空干燥30分钟得到干燥的最终产物，在-20摄氏度下保存待用。
将最终产物溶于pH＝7.4的PBS缓冲溶液中，用ZS90型纳米粒度电位分析仪测得产物的流体力学半径为423nm，多分散系数为0.061。该溶液的紫外可见光谱(使用Thermo Fisher EV300型紫外分光光度计检测)具有特征的330纳米处的吸收峰。在200w光照5小时条件下，用碧云天一氧化氮检测试剂盒(Griess法，购自上海碧云天生物技术有限公司)检测释放的一氧化氮总量来表征一氧化氮储存量，测得最终产物的一氧化氮储存量为1.87±0.55微摩尔每毫克。
实施例2：S-亚硝基乙二硫醇甲壳素的合成
将2克甲壳素和5克氯化锂分散于50毫升二甲基乙酰胺中，在0摄氏度下加入20毫升N，N-二异丙基乙胺。将20克对甲苯磺酰氯溶于20毫升二甲基乙酰胺中，将其加入到前述含甲壳素的溶液中。将混合溶液在4摄氏度下搅拌反应20小时，随后倒入至300毫升丙酮中沉淀，过滤。沉淀物分别用300毫升甲醇、150毫升去离子水和300毫升丙酮清洗各洗涤一次，随后真空干燥得到对甲苯磺酰化甲壳素。
将1克对甲苯磺酰化甲壳素和2.5克氯化锂分散于40毫升二甲基乙酰胺中，随后加入3毫升N，N-二异丙基乙胺和1.5毫升1，2-乙二硫醇。将混合溶液在60摄氏度并在氮气保护下搅拌24小时，随后倒入至400毫升丙酮中沉淀，过滤。沉淀物用400毫升甲醇和400毫升丙酮各清洗一次，真空干燥后分散于25毫升含10毫摩尔每升1，4-二硫代苏糖醇和N，N-二异丙基乙胺的二甲基乙酰胺溶液中，室温下搅拌1小时，过滤。沉淀物分别用400毫升甲醇和400毫升丙酮洗涤，真空干燥得到巯基化甲壳素化合物。将200毫克巯基化甲壳素化合物分散于5毫升二甲基乙酰胺/甲醇混合溶剂(体积比3/1)，加入1毫升亚硝酸特丁酯，室温下搅拌12小时，随后将混合溶液加入到100毫升甲醇中搅拌30分钟，过滤，真空干燥得到最终产物。
最终产物的红外光谱(使用Nicolet 6700型红外光谱仪检测)主要吸收峰(波数)：3600-3200，3285，1652，1537，10283360-3220，1250-1300，1050-1070。其漫反射紫外可见光谱(使用Thermo Fisher EV300型紫外分光光度计检测)特征显示具有在549纳米的吸收峰。在200w光照5小时条件下，用碧云天一氧化氮检测试剂盒(Griess法)检测释放的一氧化氮总量来表征一氧化氮储存量，最终产物的一氧化氮储存量为0.37±0.08微摩尔每毫克。
实施例3：寡聚丙二胺接枝壳聚糖NONOate的合成
将250微升2-甲基氮丙啶与300微升1摩尔每升盐酸水溶液混合，逐滴加入到10毫升20毫克每毫升的壳聚糖水溶液中。混合溶液在室温下搅拌4天，之后在78摄氏度搅拌20小时，随后倒入至300毫升丙酮中沉淀，离心。沉淀物用甲醇清洗2次，真空干燥得到仲胺化改性壳聚糖。核磁氢谱(使用Bruker Avance III型核磁共振波谱仪，400MHz，CD 3OD)显示的峰位置：0.8-1.1，1.9，2.3-2.7，3.3-4.0，4.4。
将50毫克仲胺化改性壳聚糖溶于1毫升水和3毫升甲醇的混合溶剂，将该混合溶液与100微升6摩尔每升的甲醇钠溶液一起加入到Parr加氢摇摆反应釜中。多次置换高纯氮气除氧，注入一氧化氮气体，保持10个大气压力，室温下反应4天。反应结束后多次置换高纯氮气除去未反应的一氧化氮。随后将反应液加入到300毫升丙酮中沉淀，离心收集沉淀，真空干燥得到最终产物，在-20摄氏度下保存待用。
最终产物(包含偶氮鎓二醇盐)的红外光谱(使用Nicolet 6700型红外光谱仪检测)主要吸收峰(波数)：3600-3200，3285，1650，1587，1284，1059。其紫外可见光谱(使用Thermo Fisher EV300型紫外分光光度计检测)具有特征的252纳米处的吸收峰。将样品溶于PBS溶液，用碧云天一氧化氮检测试剂盒(Griess法)检测释放得到的一氧化氮的总量测得样品的一氧化氮储存量为0.77±0.11微摩尔每毫升。
实施例4-15：一氧化氮释放剂缓解VEGF/VEGFR抑制剂对HUVEC细胞增殖毒性的效果及其与西地那非的对比
有报道尝试使用西地那非治疗抗VEGF多激酶抑制剂所引起的副作用掌足红肿(Palmar Plantar Erythrodysesthesia，PPE)(参见Kellen L.Meadows等，Support Care Cancer.2015 May；23(5)：1311-1319)。然而，西地那非对抗VEGF多激酶抑制剂所引起的PPE的治疗效果非常有限，几乎无效。在本申请中，将一氧化氮释放剂与西地那非的效果进行了对比。
消化悬浮经培养的HUVEC细胞，对细胞进行计数，并接种到96孔板中，每孔种植5000-10000个细胞。将各孔分成：空白对照组、VEGF/VEGFR抑制剂组、VEGF/VEGFR抑制剂+一氧化氮释放剂组、VEGF/VEGFR抑制剂溶剂组、一氧化氮释放剂溶剂对照组、VEGF/VEGFR抑制剂+西地那非组以及西地那非溶剂对照组，各组的每个孔中均含有基础培养基，每个孔最终含有的液体体积约为100μL。具体分组情况如下：
1)空白对照组：除正常更换培养基以外不额外加入任何溶液；
2)VEGF/VEGFR抑制剂组：加入VEGF/VEGFR抑制剂溶液(最终浓度如表1所示，VEGF/VEGFR抑制剂溶液的溶剂为DMSO)；
3)VEGF/VEGFR抑制剂+一氧化氮释放剂组：加入VEGF/VEGFR抑制剂溶液以及一氧化氮释放剂溶液(VEGF/VEGFR抑制剂和一氧化氮释放剂的最终浓度如表1所示，并根据一氧化氮释放剂的溶解性，选择一氧化氮释放剂溶液的溶剂为乙醇或无菌水，各分组的总体积细微差异通过加入所选择的相应溶剂补齐)；
4)VEGF/VEGFR抑制剂溶剂组：加入与组2)中对应所述VEGF/VEGFR抑制剂溶液中所含有的、等体积的DMSO；
5)一氧化氮释放剂溶剂对照组：加入与组3)中对应所述一氧化氮释放剂中所含有的、同体积同种类的溶剂(例如，乙醇或无菌水)。
6)VEGF/VEGFR抑制剂+西地那非组：先加入VEGF/VEGFR抑制剂溶液再加入西地那非溶液(VEGF/VEGFR抑制剂和西地那非的最终浓度如表2所示，西地那非溶液的溶剂为DMSO，各分组的总体积细微差异通过加入所选择的相应溶剂补齐)；
7)西地那非溶剂对照组：加入与组6)中对应所述西地那非中所含有的、同体积的DMSO。
VEGF/VEGFR抑制剂溶剂组不参与数据处理，仅作为评价实验系统误差的参考。一氧化氮释放剂溶剂对照组、西地那非溶剂对照组用于数据校正，从而排除溶剂对结果的影响。
继续培养24-48小时后，使用Cell Counting Kit-8(CCK-8)检测试剂盒(C0037，上海碧 云天生物科技有限公司，Beyotime Biotechnology)测定细胞的存活率，从而计算VEGF/VEGFR抑制剂对细胞的增殖毒性以及一氧化氮释放剂或西地那非对增殖毒性的缓解作用。使用GraphPad Prism 6.0软件、t检验对结果进行统计分析和画图。
表2列出了各种VEGF/VEGFR抑制剂和一氧化氮释放剂或西地那非的组合，以及相应的实验结果(其中，细胞存活率栏的数据标识是与VEGF/VEGFR抑制剂组相比，相应的VEGF/VEGFR抑制剂+一氧化氮释放剂组(或西地那非)所增加的存活细胞的百分比)。图4A-4C分别表示向HUVEC细胞给予VEGF/VEGFR抑制剂甲苯磺酸索拉非尼(V1)或苹果酸舒尼替尼(V3)或瑞格非尼(V4)和一氧化氮释放剂(或西地那非)的24小时后，通过CCK-8法测定的细胞增殖毒性的示例性结果。其中，横坐标表示不同的实验组和对照组；纵坐标表细胞的存活率(以空白对照组的细胞存活率为100％计算其他实验组或溶剂对照组中细胞的存活百分率)。其中，***表示P＜0.001，与相应的VEGF/VEGFR抑制剂单独给药组相比具有显著差异；**表示P＜0.01，与相应的VEGF/VEGFR抑制剂单独给药组相比具有显著差异；*表示P＜0.05，与相应的VEGF/VEGFR抑制剂单独给药组相比具有显著差异；利用t-test统计检验。
表2实施例4-15的实验条件和实验结果
Figure PCTCN2019082623-appb-000004
Figure PCTCN2019082623-appb-000005
Figure PCTCN2019082623-appb-000006
Figure PCTCN2019082623-appb-000007
从表2和图4A-4C中的结果可以看出：一氧化氮释放剂对增殖毒性有明显的缓解作用，其缓解效果明显优于西地那非。
实施例16-32：一氧化氮释放剂缓解VEGF/VEGFR抑制剂对人永生化表皮细胞(HaCaT)、人口腔黏膜上皮角质细胞(HOK)、人小肠上皮细胞(FHs 74 Int)、胃上皮细胞(GES-1)的细胞增殖毒性的效果及其与西地那非的对比
培养多种上皮细胞用于实验，其中：实施例16-20使用人永生化表皮细胞(HaCaT)，结果对应表3；实施例21-24使用人口腔黏膜上皮角质细胞(HOK)，结果对应表4；实施例25-28使用胃上皮细胞(GES-1)，结果对应表5；实施例29-32使用人小肠上皮细胞(FHs 74Int)，结果对应表6。
消化悬浮经培养的细胞，对细胞进行计数，接种到96孔板中，每孔种植5000-10000个细胞。将各孔分成：空白对照组、VEGF/VEGFR抑制剂组、VEGF/VEGFR抑制剂+一氧化氮释放剂组、VEGF/VEGFR抑制剂溶剂组、一氧化氮释放剂溶剂对照组、VEGF/VEGFR抑制剂+西地那非组、以及西地那非溶剂对照组，各组的每个孔中均含有基础培养基，每个孔最终含有的液体体积约为100μL。具体分组情况如下：
1)空白对照组：除正常更换培养基以外不额外加入任何溶液；
2)VEGF/VEGFR抑制剂组：加入VEGF/VEGFR抑制剂溶液(最终浓度如表2所示，VEGF/VEGFR抑制剂溶液的溶剂为DMSO)；
3)VEGF/VEGFR抑制剂+一氧化氮释放剂组：加入VEGF/VEGFR抑制剂溶液以及一氧化氮释放剂溶液(VEGF/VEGFR抑制剂和一氧化氮释放剂的最终浓度如表2所示，并根据一氧化氮释放剂的溶解性，选择一氧化氮释放剂溶液的溶剂为乙醇或无菌水，各分组的总体积细微差异通过加入所选择的相应溶剂补齐)；
4)VEGF/VEGFR抑制剂溶剂组：加入与组2)中对应所述VEGF/VEGFR抑制剂溶液中所含有的、等体积的DMSO；
5)一氧化氮释放剂溶剂对照组：加入与组3)中对应所述一氧化氮释放剂所中所含有的、同体积同种类的溶剂(例如，乙醇或无菌水)。
6)VEGF/VEGFR抑制剂+西地那非组：先加入VEGF/VEGFR抑制剂溶液再加入西地那非溶液(VEGF/VEGFR抑制剂和西地那非的最终浓度如表2所示，西地那非溶液的 溶剂为DMSO，各分组的总体积细微差异通过加入所选择的相应溶剂补齐)；
7)西地那非溶剂对照组：加入与组6)中对应所述西地那非中所含有的、同体积的DMSO。
VEGF/VEGFR抑制剂溶剂组不参与数据处理，仅作为评价实验系统误差的参考。一氧化氮释放剂溶剂对照组、西地那非溶剂对照组用于数据校正，从而排除溶剂对结果的影响。
继续培养24-48小时后，使用Cell Counting Kit-8(CCK-8)检测试剂盒(C0037，上海碧云天生物科技有限公司，Beyotime Biotechnology)测定细胞的存活率，从而计算VEGF/VEGFR抑制剂对细胞的增殖毒性以及一氧化氮释放剂或西地那非对增殖毒性的缓解作用。使用GraphPad Prism 6.0软件、t检验对结果进行统计分析和画图。
表3-表6列出了各种VEGF/VEGFR抑制剂和一氧化氮释放剂或西地那非的组合，以及相应的实验结果(其中，细胞存活率栏的数据标识是与VEGF/VEGFR抑制剂组相比，相应的VEGF/VEGFR抑制剂+一氧化氮释放剂组(或西地那非)所增加的存活细胞的百分比)。图5表示HaCaT细胞上的实验结果，图6表示HOK细胞上的实验结果，图7表示GES-1细胞上的实验结果，图8表示FHs 74 Int细胞上的实验结果。其中，横坐标表示不同的实验组和对照组；纵坐标表细胞的存活率(以空白对照组的细胞存活率为100％计算其他实验组或溶剂对照组中细胞的存活百分率)。其中图5A、6A、7A和8A均表示对不同种细胞施用VEGF/VEGFR抑制剂甲苯磺酸索拉非尼(V1)和一氧化氮释放剂(或西地那非)的24小时后，通过CCK-8法测定的细胞增殖毒性的示例性结果；图5B、6B、7B和8B均表示对不同种细胞表示施用VEGF/VEGFR抑制剂苹果酸舒尼替尼(V3)和一氧化氮释放剂(或西地那非)的24小时后，通过CCK-8法测定的细胞增殖毒性的示例性结果；图5C、6C、7C和8C均表示对不同种细胞表示施用VEGF/VEGFR抑制剂瑞格非尼(V4)和一氧化氮释放剂(或西地那非)的24小时后，通过CCK-8法测定的细胞增殖毒性的示例性结果。其中，***表示P＜0.001，与相应的VEGF/VEGFR抑制剂单独给药组相比具有显著差异；**表示P＜0.01，与相应的VEGF/VEGFR抑制剂单独给药组相比具有显著差异；*表示P＜0.05，与相应的VEGF/VEGFR抑制剂单独给药组相比具有显著差异；利用t-test统计检验。
表3实施例16-20的实验条件和实验结果
Figure PCTCN2019082623-appb-000008
Figure PCTCN2019082623-appb-000009
从表3和图5中的结果可以看出：VEGF/VEGFR抑制剂对皮肤细胞(HaCaT)有增殖毒性，而一氧化氮释放剂对VEGF/VEGFR抑制剂引起的增殖毒性有明显的缓解作用，其缓解效果明显优于西地那非。
表4实施例21-24的实验条件和实验结果
Figure PCTCN2019082623-appb-000010
Figure PCTCN2019082623-appb-000011
从表4和图6中的结果可以看出：VEGF/VEGFR抑制剂对人口腔黏膜上皮角质细胞(HOK)有增殖毒性，而一氧化氮释放剂对VEGF/VEGFR抑制剂引起的增殖毒性有明显的缓解作用，其缓解效果明显优于西地那非。
表5实施例25-28的实验条件和实验结果
Figure PCTCN2019082623-appb-000012
Figure PCTCN2019082623-appb-000013
从表5和图7中的结果可以看出：VEGF/VEGFR抑制剂对人胃上皮细胞(GES-1)有增殖毒性，而一氧化氮释放剂对VEGF/VEGFR抑制剂引起的增殖毒性有明显的缓解作用，其缓解效果明显优于西地那非。
表6实施例29-32的实验条件和实验结果
Figure PCTCN2019082623-appb-000014
从表6和图8中的结果可以看出：VEGF/VEGFR抑制剂对人小肠上皮细胞(FHs 74 Int)有增殖毒性，而一氧化氮释放剂对VEGF/VEGFR抑制剂引起的增殖毒性有明显的缓解作用，其缓解效果明显优于西地那非。
实施例33-46：测定一氧化氮释放剂对细胞内/外一氧化氮水平的影响
消化悬浮经培养的HUVEC、HaCaT、HOK、FHs 74 Int或GES-1细胞，对细胞进行计数， 并接种到24孔板中。每孔种植100，000-200，000个细胞。待细胞贴壁后，加入一氧化氮释放剂溶液至特定最终浓度(如表7-表8所示)。对照组加培养基。分别在加入一氧化氮释放剂后的各时间点(6小时、12小时、24小时和48小时，如表7-表8所示)，收集各组上清液50μL用于检测细胞外上清液中一氧化氮水平；同时弃去剩余上清液，加入细胞裂解液，充分裂解后取裂解液50μL用于检测细胞内一氧化氮水平。使用一氧化氮检测试剂盒(S0021，Beyotime公司)检测一氧化氮含量。
其中，图9A-9D分别表示HUVEC细胞外、HUVEC细胞内、GES-1细胞外和GES-1细胞内给予一氧化氮释放剂的6小时、12小时、24小时、48小时一氧化氮的相对含量。NTG代表硝酸甘油，对照组为基础培养基，反映生理水平。
图10A-10D分别表示用一氧化氮释放剂(硝酸异山梨酯、尼可地尔、吗多明和亚硝酸异戊酯)处理24小时后，HUVEC细胞外、GES-1细胞外、HaCaT细胞外和HOK细胞外一氧化氮的相对含量。对照组为基础培养基，反映生理水平。其中，**表示P＜0.01，与相应的对照组相比具有显著差异；*表示P＜0.05，与相应的对照组相比具有显著差异；利用t-test统计检验。
图11A-11D分别表示用一氧化氮释放剂(硝酸异山梨酯、尼可地尔、吗多明和亚硝酸异戊酯)处理24小时后，HUVEC细胞内、GES-1细胞内、HaCaT细胞内和HOK细胞内一氧化氮的相对含量。对照组为基础培养基，反映生理水平。其中，***表示P＜0.001，与相应的对照组相比具有显著差异；*表示P＜0.01，与相应的对照组相比具有显著差异；*表示P＜0.05，与相应的对照组相比具有显著差异；利用t-test统计检验。
从表7-8和图9-11的结果可以看出：一氧化氮释放剂可以释放一氧化氮并提高细胞内一氧化氮水平。
表7实施例33-39的实验条件和实验结果
Figure PCTCN2019082623-appb-000015
Figure PCTCN2019082623-appb-000016
表8实施例40-46的实验条件和实验结果
Figure PCTCN2019082623-appb-000017
Figure PCTCN2019082623-appb-000018
实施例47-54：西地那非不能释放一氧化氮，也不能提高HUVEC、HaCaT或GES-1细胞内和细胞外的NO水平
消化悬浮经培养的HUVEC、HaCaT或GES-1细胞，对细胞进行计数，并接种到6孔板中。每孔种植500,000～1,000,000个细胞。待细胞贴壁后，加入西地那非溶液至特定最终浓度(如表9-10所示)。对照组加基础培养基。分别在加入西地那非后的各时间点(6小时、12小时、24小时和48小时)，收集各组上清液50μL用于检测细胞外NO水平；同时弃去剩余上清液，加入细胞裂解液，充分裂解后取裂解液50μL用于检测细胞内NO水平。使用一氧化氮检测试剂盒(S0021，Beyotime公司)检测一氧化氮含量。图12-13列出了实验结果。
其中图12A-12B分别表示100μM的西地那非处理HUVEC细胞后各时间点(6小时、12小时、24小时、48小时)细胞外、内的相对NO含量。图12C-12D分别表示不同浓度的西地那非处理HUVEC细胞后24小时后细胞外、内的相对NO含量。对照组为基础培养基，反映生理水平。
图13A-13B分别表示100μM的西地那非处理GES-1细胞24小时后细胞外、内的相对NO含量。图13C-13D分别表示100μM的西地那非处理HaCaT细胞24小时后细胞外、内的相对NO含量。对照组为基础培养基，反映生理水平。
根据这些结果可知西地那非不能释放一氧化氮，也不能提高HUVEC、HaCaT或GES-1细胞内和细胞外的NO水平。
表9实施例47-50的实验条件和实验结果
Figure PCTCN2019082623-appb-000019
Figure PCTCN2019082623-appb-000020
表10实施例51-54的实验条件和实验结果
Figure PCTCN2019082623-appb-000021
实施例55-108：一氧化氮释放剂能够在体内预防/治疗小分子VEGFR/VEGF抑制剂引起的手足综合征
构建大鼠动物模型，通过每日灌胃的方式向8周雌性的SD大鼠分别施用表11中所示的小分子VEGFR/VEGF抑制剂，若干天后，大鼠的爪子出现手足综合征症状(如图14所示)。与在人体上类似，大鼠在服用所述VEGFR/VEGF抑制剂之后会出现手足综合征症状，且症状非常相似。因此，大鼠是很好的用于模拟VEGFR/VEGF抑制剂引起的副作用(例如手足综合征)的动物模型。
将所述大鼠(约200g)饲养适应一周后，将其分组，每组10只，进行灌胃给药试验。将各种小分子VEGFR/VEGF抑制剂溶解在蓖麻油∶乙醇＝1∶1的混合溶液中，灌胃前用PBS将所述VEGFR/VEGF抑制剂药物溶液稀释至所需浓度(用PBS溶液稀释约3倍)，每次灌胃量不超过2mL，给药剂量如表11所示。灌胃后，对大鼠左爪(爪掌及爪缝)涂抹包含一氧化氮释放剂的药膏(约0.05g)，右爪作为空白对照不进行涂药，涂药后将大鼠置于固定筒内固定4小时，4小时后放出大鼠，并用清水擦去涂药部位残留药物，放鼠回笼。VEGFR/VEGF抑制剂的灌胃频率如表11所示，但一氧化氮释放剂每天只涂药一次。每日重复灌胃和涂抹操作，直到试验结束。统计涂药15-18天后，将涂药侧保持正常或明显轻于非涂药侧手足综合征的大鼠只数统计为有效抑制手足综合征大鼠的只数。
表11列出了各VEGFR/VEGF抑制剂和一氧化氮释放剂药膏的动物实验组合，以及相应的实验结果(其中，控制率栏的数值＝每组有效抑制手足综合征大鼠的只数/每组手足综合征模型建成的只数×100％，每组手足综合征模型建成率在30％-70％，即10只鼠里面约3-7只出现手足综合征模型，不同药物组大鼠在实现手足模型过程中均有个别大鼠死亡或模型不成功等情况)。
表11实施例55-108的实验条件和实验结果
Figure PCTCN2019082623-appb-000022
Figure PCTCN2019082623-appb-000023
Figure PCTCN2019082623-appb-000024
表注：抗癌药物的成模率并非固定不变：每组手足综合征模型建成率在30％-70％，即10只鼠里面约3-7只出现手足综合征模型，不同药物组大鼠在实现手足模型过程中均有个别大鼠死亡或模型不成功等情况。控制率是指实验组建成手足综合征模型的大鼠中，出现涂药侧爪子症状轻于未涂药侧爪子的大鼠所占的比重。
从表11的结果可以看出：所述一氧化氮释放剂能够有效地防治VEGFR/VEGF抑制剂引起的手足综合征。同时，图15-16的结果也能反映出所述一氧化氮释放剂能够有效地防治VEGFR/VEGF抑制剂引起的手足综合征。图15显示了实施例55-100的给药组中一只典型大鼠经过左爪涂药(一氧化氮释放剂药膏)后，其左爪的手足综合征得到了显著的缓解；图16显示了实施例101-108的给药组中一只典型大鼠经过右爪涂药(一氧化氮释放剂药膏)后，其右爪的手足综合征也得到了显著的缓解。
实施例109-110：一氧化氮释放剂能够在体内预防/治疗小分子VEGFR/VEGF抑制剂引起的手足综合征
亚硝化单胞菌洗液的配置：将亚硝化单胞菌(Nitrosomonas europaea，货号：ATCC 19718)接种至无机培养液(货号：ATCC 2265)中，约200转每分钟，26℃，黑暗条件下扩增培养3-5天至出现明显浑浊，得到细菌母液，将母液用所述无机培养液稀释至不同细菌浓度(如10 7、10 8、10 9、10 10细菌/毫升)，细菌浓度由血细胞计数器测得，即得到亚硝化单胞菌洗液。
构建大鼠动物模型，通过每日灌胃的方式向8周雌性的SD大鼠分别施用表12中所示的小分子VEGFR/VEGF抑制剂，若干天后，大鼠的爪子出现手足综合征症状。与在人体上类 似，大鼠在服用所述VEGFR/VEGF抑制剂之后会出现手足综合征症状，且症状非常相似。因此，大鼠是很好的用于模拟VEGFR/VEGF抑制剂引起的副作用(例如手足综合征)的动物模型。
将所述大鼠(约200g)饲养适应一周后，将其分组，每组10只，进行灌胃给药试验。将各种小分子VEGFR/VEGF抑制剂溶解在蓖麻油∶乙醇＝1∶1的混合溶液，灌胃前用PBS将所述VEGFR/VEGF抑制剂药物溶液稀释至所需浓度(用PBS溶液稀释约3倍)，每次灌胃量不超过2mL，给药剂量如表12所示。灌胃后，将大鼠用固定筒固定，将左爪用细菌洗液浸泡，10分钟后放出大鼠，每天一次，右爪作为空白对照不进行浸泡。VEGFR/VEGF抑制剂的灌胃频率如表12所示，但细菌洗液每天只浸泡一次。每日重复灌胃和浸泡试验，直到大鼠死亡。统计涂药15-18天后，将浸泡侧保持正常或明显轻于非浸泡侧手足综合征的大鼠只数统计为有效抑制手足综合征大鼠的只数。
表12列出了施用各VEGFR/VEGF抑制剂和一氧化氮释放剂药膏的动物实验，以及相应的实验结果(其中，控制率栏的数值＝每组有效抑制手足综合征大鼠的只数/每组手足综合征模型建成的只数×100％，每组手足综合征模型建成率在30％-70％，即10只鼠里面约有3-7只出现手足综合征模型，不同药物组大鼠在实现手足模型过程中均有个别大鼠死亡或模型不成功等情况)。
表12实施例109-110的实验条件和实验结果
Figure PCTCN2019082623-appb-000025
从表12的结果可以看出：一氧化氮释放剂洗液能够有效的防治VEGFR/VEGF抑制剂引起的手足综合征。
实施例111-112：一氧化氮释放剂能够在体内预防/治疗蛋白质大分子VEGFR/VEGF抑制剂引起的手足综合征
将雷莫芦单抗(Ramucirumab)或贝伐珠单抗(Bevacizumab)用生理盐水稀释至所需浓度。将所述大鼠(约200g)饲养适应一周后，将其分组，每组10只，进行注射给药试验。静脉输注稀释后的雷莫芦单抗，输注60分钟，施用剂量为40mg/kg，每周施用1次，同时联用紫杉醇(10mg/kg)。对大鼠左爪(爪掌及爪缝)涂抹包含一氧化氮释放剂的软膏(约0.05g)， 右爪作为空白对照不进行涂药，涂药后固定筒内固定4小时，4小时后放出大鼠，并用清水擦去涂药部位残留药物，放鼠回笼；实验持续2-4周，观察实验现象，至实验大鼠死亡实验结束。
表13列出了施用各VEGFR/VEGF抑制剂和一氧化氮释放剂药膏的动物实验，以及相应的实验结果(其中，控制率栏的数值＝每组有效抑制手足综合征大鼠的只数/每组手足综合征模型建成的只数×100％，每组手足综合征模型建成率在10％-30％，即10只鼠里面约1-3只出现手足综合征模型)。
表13实施例111-112的实验条件和实验结果
Figure PCTCN2019082623-appb-000026
表注：抗癌药物的成模率并非固定不变：每组手足综合征模型建成率在10％-30％，即10只鼠里面约1-3只出现手足综合征模型，不同药物组大鼠在实现手足模型过程中均有个别大鼠死亡或模型不成功等情况。控制率是指实验组建成手足综合征模型的大鼠中，出现涂药侧爪子症状轻于未涂药侧爪子的大鼠所占的比重。
图15显示了实施例111-112的给药组中一只典型大鼠经左爪涂药(一氧化氮释放剂药膏)后，其左爪、正面和右爪的情况。
从表13和图15的结果可以看出：一氧化氮释放剂药膏能够有效的预防单抗类VEGFR/VEGF抑制剂引起的手足综合征。
实施例113-124：在大鼠动物模型上验证治疗小分子VEGFR/VEGF抑制剂产生手足综合征的实验
将所述大鼠(约200g)饲养适应一周后，将大鼠分成每组10只，进行灌胃给药试验。将VEGFR/VEGF抑制剂溶解在蓖麻油∶乙醇＝1∶1的混合溶液中，灌胃前用PBS稀释至所需浓度(用PBS溶液稀释约3倍)，灌胃量不超过2mL，给药剂量如表14所示。每天持续灌胃VEGFR/VEGF抑制剂，直至大鼠出现手足综合征，此时开始对大鼠进行治疗实验。治疗实验过程中，持续低频率灌胃VEGFR/VEGF抑制剂(灌胃频率按表14所述操作)，灌胃后，对大鼠左爪(爪掌及爪缝)涂一氧化氮释放剂的药膏(约0.05g)，右爪作为空白对照不进行 涂药，涂药后固定筒内固定4小时，4小时后放出大鼠，并用清水擦去涂药部位残留药物，放鼠回笼。VEGFR/VEGF抑制剂的灌胃频率如表14所示，但一氧化氮释放剂每天只涂药一次。涂药6-10天后，将涂药侧爪恢复正常或明显轻于非涂药侧爪的大鼠只数统计为有效治疗手足综合征大鼠的只数。
表14列出了施用各小分子VEGFR/VEGF抑制剂和一氧化氮释放剂药膏的动物实验，以及相应的实验结果(其中，缓解率栏的数值＝每组有效治疗手足综合征大鼠的只数/每组手足综合征模型建成的只数×100％)。
表14实施例113-124的实验条件和实验结果
Figure PCTCN2019082623-appb-000027
Figure PCTCN2019082623-appb-000028
表注：抗癌药物的成模率并非固定不变：每组手足综合征模型建成率在40％-70％，即10只鼠里面约1-3只出现手足综合征模型，不同药物组大鼠在实现手足模型过程中均有个别大鼠死亡或模型不成功等情况。控制率是指实验组建成手足综合征模型的大鼠中，出现涂药侧爪子症状轻于未涂药侧爪子的大鼠所占的比重。
图17显示了实施例113-124的给药组中一只典型大鼠经左爪涂药(一氧化氮释放剂药膏)后，其左爪、正面和右爪的情况。图18显示了实施例124的给药组中一只典型大鼠经右爪涂药(一氧化氮释放剂药膏)后，其左爪和右爪的情况。
从表14和图17-18中的结果可以看出：一氧化氮释放剂药膏能够有效地治疗小分子VEGFR抑制剂引起的手足综合征。
实施例125-142：在预防小分子VEGFR/VEGF抑制剂产生手足综合征的实验中，0.2％硝酸甘油软膏与临床现有试验性用药和其他一氧化氮释放剂对比
将所述大鼠(约200g)饲养适应一周后，将大鼠分成每组10只，然后进行灌胃给药试验。VEGFR抑制剂溶解在蓖麻油∶乙醇＝1∶1的混合溶液中，灌胃前用PBS稀释至所需浓度(用PBS溶液稀释约3倍)，每次灌胃量不超过2mL，给药剂量如表15所示。灌胃后，对大鼠左爪(爪掌及爪缝)涂硝酸甘油软膏(约0.05g)，右爪同样操作涂临床临床现有试验性用药或者其他一氧化氮释放剂软膏；涂药后用固定筒将大鼠固定约4小时，4小时后放出大鼠并用清水擦去涂药部位残留药物，放鼠回笼。VEGFR/VEGF抑制剂的灌胃频率如表15所示，但临床上现有的其它皮肤用药和一氧化氮释放剂只涂药一次。每日重复用VEGFR/VEGF抑制剂灌胃，直到涂临床试验性用药(或其他一氧化氮释放剂)爪子手足综合征症状出现或大鼠死亡。涂药15-18天后，将涂硝酸甘油软膏侧爪子正常或明显轻于涂临床试验性用药(或其他一氧化氮释放剂)侧爪子的大鼠只数统计为有效预防手足综合征大鼠的只数。
表15列出了0.2％硝酸甘油软膏与临床试验性用药(或其他一氧化氮释放剂)实验组合，以及相应的实验结果(其中，相对缓解率栏的数值＝左爪手足综合征明显轻于右爪手足综合征大鼠只数/每组中手足综合征出现的只数×100％)。
表15实施例125-142的实验条件和实验结果
Figure PCTCN2019082623-appb-000029
从表15中的结果可以看出：相比于1％的西地那非，0.2％硝酸甘油软膏能有效地控制VEGFR抑制剂和/或VEGF抑制剂所导致的手足综合征；相比于临床现有其他的试验性用药(几乎对VEGFR抑制剂和/或VEGF抑制剂所导致的手足综合征没有治疗作用)，0.2％硝酸甘油软膏能有效抑制VEGFR抑制剂和/或VEGF抑制剂所导致的手足综合征；相比于其他一氧化氮释放剂药膏，0.2％硝酸甘油软膏能更有效地控制VEGFR抑制剂和/或VEGF抑制剂所导致的手足综合征。硝酸甘油软膏0.2％的浓度远远低于临床现有其他的试验性用药的浓度， 可见0.2％硝酸甘油软膏达到了预料不到的技术效果。
实施例143：一氧化氮释放剂对所述VEGFR/VEGF抑制剂治疗效果的影响
建立BALB/C裸鼠(肝癌细胞HepG2移植瘤)模型，模型稳定后，将模型鼠分成3组(3组鼠肿瘤大小平均值尽可能保持一致)，每组10只，进行灌胃给药及涂抹药物试验。
VEGFR抑制剂溶解在蓖麻油∶乙醇＝1∶1(体积比)的混合溶液中，灌胃前用PBS稀释至所需浓度(用PBS溶液稀释约3倍)，灌胃量不超过0.2mL，给药剂量为每天30mg/kg。每天带瘤老鼠口服索拉非尼来控制或者缩小肿瘤。同时，通过外用给药的方式，在小鼠背部涂抹治疗副作用的药物(具体分组如下：A组：灌胃+涂赋形剂；B组：灌胃+涂0.15％硝酸甘油软膏；C组：灌胃+涂0.2％硝酸甘油软膏；用记号笔标记出约为5.8平方厘米涂抹面积，并且，该被涂抹的区域不能是小鼠嘴能触碰到的区域，也不能是紧挨着肿瘤的区域)。在每日灌胃结束后，在模型鼠背部标定的区域，用棉签涂抹空白药膏，涂抹均匀，保证皮肤润湿即可；涂药后，每只老鼠在一个相对独立的空间中保持4小时；4小时后，用纸巾，或者沾水的纸巾轻轻擦去小鼠背部残留的药膏；然后小鼠可以回到之前饲养的笼子中正常活动。每2天测量并记录肿瘤的尺寸。实验20天结束后，解剖老鼠，取出肿瘤，称量并记录，观察不同实验组瘤体积变化情况。
实验结果参见图19。从图19的实验结果可以看出，在不同实验组中，涂软膏组(B组或C组)的肿瘤体积小于赋形剂组(A组)，且C组的肿瘤体积接近或略小于B组的肿瘤体积，可见一氧化氮释放剂的外用软膏不会降低VEGFR/VEGF抑制剂对肿瘤的效果。
实施例144-145：一氧化氮释放剂缓解VEGF/VEGFR抑制剂对HUVEC、HaCaT细胞增殖毒性的效果及其与钙离子通道阻滞剂的对比
有报道称，钙离子通道阻滞剂(如：地尔硫卓Diltiazem)可以治疗抗VEGFR多激酶抑制剂所引起的副作用手足综合征(HFS)(参见美国专利申请US2016/0101114A1)。然而，地尔硫卓对抗VEGFR多激酶抑制剂所引起的手足综合征(HFS)的治疗效果非常有限。在本申请中，将一氧化氮释放剂与钙离子通道阻滞剂的效果进行了对比。
消化悬浮经培养的HUVEC、HaCaT细胞，对细胞进行计数，并接种到96孔板中，每孔种植5000个细胞。将各孔分成：空白对照组、VEGF/VEGFR抑制剂组、VEGF/VEGFR抑制剂+一氧化氮释放剂组、VEGF/VEGFR抑制剂溶剂组、一氧化氮释放剂溶剂对照组、VEGF/VEGFR抑制剂+钙离子通道阻滞剂组、以及钙离子通道阻滞剂溶剂对照组，各组的每个孔中均含有基础培养基，每个孔最终含有的液体体积约为100μL。具体分组情况如下：
1)空白对照组：除正常更换培养基以外不额外加入任何溶液；
2)VEGF/VEGFR抑制剂组：加入VEGF/VEGFR抑制剂溶液(最终浓度如表16所示，VEGF/VEGFR抑制剂溶液的溶剂为DMSO)；
3)VEGF/VEGFR抑制剂+一氧化氮释放剂组：加入VEGF/VEGFR抑制剂溶液以及一氧化氮释放剂溶液(VEGF/VEGFR抑制剂和一氧化氮释放剂的最终浓度如表16所示，并根据一氧化氮释放剂的溶解性，选择一氧化氮释放剂溶液的溶剂为乙醇或无菌水，各分组的总体积细微差异通过加入所选择的相应溶剂补齐)；
4)VEGF/VEGFR抑制剂溶剂组：加入与组2)中对应所述VEGF/VEGFR抑制剂溶液中所含有的、等体积的DMSO；
5)一氧化氮释放剂溶剂对照组：加入与组3)中对应所述一氧化氮释放剂所中所含有的、同体积同种类的溶剂(例如，乙醇或无菌水)。
6)VEGF/VEGFR抑制剂+钙离子通道阻滞剂组：先加入VEGF/VEGFR抑制剂溶液再加入钙离子通道阻滞剂溶液(VEGF/VEGFR抑制剂和钙离子通道阻滞剂的最终浓度如表16所示，钙离子通道阻滞剂溶液的溶剂均为DMSO，各分组的总体积细微差异通过加入所选择的相应溶剂补齐)；
7)钙离子通道阻滞剂溶剂对照组：加入与组6)中对应所述钙离子通道阻滞剂中所含有的、同体积的DMSO。
VEGF/VEGFR抑制剂溶剂组不参与数据处理，仅作为评价实验系统误差的参考。一氧化氮释放剂溶剂对照组、钙离子通道阻滞剂溶剂对照组用于数据校正，从而排除溶剂对结果的影响。
继续培养24小时后，使用Cell Counting Kit-8(CCK-8)检测试剂盒(C0037，Beyotime Biotechnology)测定细胞的存活率，从而计算VEGF/VEGFR抑制剂对细胞的增殖毒性以及一氧化氮释放剂或钙离子通道阻滞剂对增殖毒性的缓解作用。使用GraphPad Prism 6.0软件、t检验对结果进行统计分析和画图。
表16列出了各种VEGF/VEGFR抑制剂和一氧化氮释放剂(或钙离子通道阻滞剂)的组合，以及相应的实验结果(其中，细胞存活率栏的数据标识是与VEGF/VEGFR抑制剂组相比，相应的VEGF/VEGFR抑制剂+一氧化氮释放剂组(或钙离子通道阻滞剂)所增加的存活细胞的百分比)。图20表示向HUVEC细胞给予VEGF/VEGFR抑制剂甲苯磺酸索拉非尼(V1)和一氧化氮释放剂(或地尔硫卓)24小时后，通过CCK-8法测定的细胞增殖毒性的示例性结果。图21表示向HaCaT细胞给予VEGF/VEGFR抑制剂甲苯磺酸索拉非尼(V1) 和一氧化氮释放剂(或钙离子通道阻滞剂)24小时后，通过CCK-8法测定的细胞增殖毒性的示例性结果。其中，横坐标表示不同的实验组和对照组；纵坐标表细胞的存活率(以空白对照组的细胞存活率为100％计算其他实验组或溶剂对照组中细胞的存活百分率)。其中，***表示P＜0.001，**表示P＜0.01，*表示P＜0.05，与相应的VEGF/VEGFR抑制剂单独给药组相比具有显著差异；利用t-test统计检验。
表16实施例144-145的实验条件和实验结果
Figure PCTCN2019082623-appb-000030
实施例146：测定一氧化氮释放剂(或钙离子通道阻滞剂)对细胞外一氧化氮水平的影响
将一氧化氮释放剂与钙离子通道阻滞剂对细胞外一氧化氮的含量影响进行了对比，结果表明钙离子通道阻滞剂不能使细胞外一氧化氮含量增加，不能产生一氧化氮，因此不属于一氧化氮释放剂。
消化悬浮经培养的HaCaT细胞，对细胞进行计数，并接种到24孔板中。每孔种植20，000个细胞。待细胞贴壁后，加入一氧化氮释放剂(或钙离子通道阻滞剂)溶液至特定最终浓度(如表17所示)。对照组加基础培养基。在加入一氧化氮释放剂(或钙离子通道阻滞剂)后的24h，收集各组上清液50μL用于检测细胞外上清液中一氧化氮水平使用一氧化氮检测试剂盒(S0021，Beyotime Biotechnology)检测一氧化氮含量。
图22表示HaCaT细胞外给予一氧化氮释放剂(或钙离子通道阻滞剂)的24小时一氧化氮的相对含量。对照组为基础培养基，反映生理水平。其中，***表示P＜0.001，**表示P＜0.01，*表示P＜0.05，与相应的对照组相比具有显著差异，利用t-test统计检验。
表17实施例146的实验条件和实验结果
Figure PCTCN2019082623-appb-000031
Figure PCTCN2019082623-appb-000032
实施例147：测定一氧化氮释放剂(或钙离子通道阻滞剂)对HaCaT细胞中钙调蛋白、钙网蛋白表达水平的影响
钙调蛋白(CaM)是一种中间钙结合信使蛋白，是第二信使Ca 2+在细胞内的靶标(Chin D and Means AR，2000)。钙调蛋白作为钙信号传导途径中的一部分，与Ca 2+离子的结合是其活化所必需的，因此常作为钙信号传导中的标志物(Berchtold and Villalobo，2014)。钙网蛋白(CRT)与Ca 2+离子结合使其失活。(Michalak M，et al.，2002)在本申请中，将一氧化氮释放剂与钙离子通道阻滞剂对HaCaT细胞中钙调蛋白、钙网蛋白表达水平的影响进行对比。
消化悬浮经培养的HaCaT细胞，对细胞进行计数，并接种到6孔板中。每孔种植200，，000个细胞。待细胞贴壁后，加入一氧化氮释放剂(或钙离子通道阻滞剂)溶液至特定最终浓度100μM。对照组加基础培养基。在加入一氧化氮释放剂(或钙离子通道阻滞剂)后的24h，采用RIPA裂解液(P0013C，Beyotime Biotechnology)提取蛋白，通过Western Blot检测钙调蛋白、钙网蛋白的表达变化。
图23表示HaCaT细胞给予一氧化氮释放剂(或钙离子通道阻滞剂)24小时后，钙调蛋白(CaM)的表达水平。图24表示钙调蛋白的相对表达量灰度值分析结果。图25表示HaCaT细胞给予一氧化氮释放剂(或钙离子通道阻滞剂)24小时后，钙网蛋白(CRT)的表达水平。图26表示钙网蛋白的相对表达量灰度值分析结果。
使用Image Lab进行灰度值分析，采用GraphPad Prism 6.0软件、t检验对结果进行统计分析和画图。其中，***表示P＜0.001，**表示P＜0.01，*表示P＜0.05，与相应的对照组相比具有显著差异，利用t-test统计检验。
图23-图24结果表明：与对照组相比，一氧化氮释放剂组钙调蛋白无明显变化，而钙离子通道阻滞剂地尔硫卓组钙调蛋白显著降低；图25-图26结果表明：与对照组相比，一氧化氮释放剂组钙网蛋白稍有降低，而钙离子通道阻滞剂硝苯地平组钙网蛋白表达显著升高。因此，一氧化氮释放剂不属于钙离子通道阻滞剂。
实施例148-159：在预防小分子VEGF/VEGFR抑制剂产生手足综合征的实验中，0.2％硝酸甘油软膏和其他一氧化氮释放剂与钙离子通道阻滞剂的对比
将所述大鼠(约200g)饲养适应一周后，将大鼠分成每组10只，然后进行灌胃给药试 验。VEGF/VEGFR抑制剂溶解在蓖麻油∶乙醇＝1∶1的混合溶液中，灌胃前用PBS定容稀释至所需浓度(用PBS溶液稀释约3倍)，每次灌胃量不超过2mL，给药剂量如表18所示。灌胃后，对大鼠左爪(爪掌及爪缝)涂硝酸甘油软膏(或者其他一氧化氮释放剂)(约0.05g)，右爪同样操作涂钙离子通道阻滞剂软膏；涂药后用固定筒将大鼠固定约4小时，4小时后放出大鼠并用清水擦去涂药部位残留药物，放鼠回笼。VEGF/VEGFR抑制剂的灌胃频率如表18所示。每日重复用VEGF/VEGFR抑制剂灌胃，直到涂钙离子通道阻滞剂软膏爪子手足综合征症状出现或大鼠死亡。涂药15-18天后，将涂硝酸甘油软膏(或其他一氧化氮释放剂)侧爪子正常或明显轻于涂钙离子通道阻滞剂软膏侧爪子的大鼠只数计算统计为有效预防手足综合征大鼠的只数。
表18列出了0.2％硝酸甘油软膏(或其他一氧化氮释放剂)与钙离子通道阻滞剂软膏实验组合，以及相应的实验结果(其中，相对缓解率栏的数值＝左爪手足综合征明显轻于右爪手足综合征大鼠只数/每组中手足综合征出现的只数×100％)。
表18实施例148-159的实验条件和实验结果
Figure PCTCN2019082623-appb-000033
Figure PCTCN2019082623-appb-000034
表注：抗癌药物的成模率并非固定不变：每组手足综合征模型建成率在30％-90％，即10只鼠里面约3-9只出现手足综合征模型，不同药物组大鼠在实现手足模型过程中均有个别大鼠死亡或模型不成功等情况。控制率是指实验组建成手足综合征模型的大鼠中，涂硝酸甘油软膏爪子的手足症状轻于另一只涂其他药物爪子的症状的大鼠所占的比重。
图27显示了实施例148-153的给药组中一只典型大鼠经左爪涂药(0.2％硝酸甘油软膏)和右爪涂药(0.2％地尔硫卓软膏)后，其左爪、正面和右爪的情况。图28显示了实施例154的给药组中一只典型大鼠经左爪涂药(0.2％硝酸异山梨酯和单硝酸异山梨酯混合软膏)和右爪涂药(0.2％地尔硫卓软膏)后，其左爪、正面和右爪的情况。
从表18和图27中的结果可以看出：相比于0.2％的钙离子通道阻滞剂软膏，0.2％硝酸甘油软膏和其他一氧化氮释放剂软膏能有效地控制VEGF/VEGFR抑制剂所导致的手足综合征。
本文描述了本申请的优选实施方式，包括发明人所知晓的实施本申请的最佳方式。在对上述说明书阅读的基础上，那些优选实施方式的变体对本领域普通技术人员而言是显而易见的。发明人预期熟练技术人员可以根据需要应用这样的变体，且发明人有意以本文中具体描述的方式以外的方式实施本申请。因此，本申请包括由适用法律所准许的本申请所附权利要求中所述主题的所有修饰和等同。而且，除非在本文中另有说明或者与上下文明显矛盾，本申请包括以上所述元素的所有可能的变体的任意组合。

Claims (74)

  1. 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。
  2. 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。
  3. 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。
  4. 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。
  5. 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。
  6. 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。
  7. 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。
  8. 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。
  9. 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。
  10. 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。
  11. 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。
  12. 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。
  13. 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。
  14. 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。
  15. 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。
  16. 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。
  17. 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。
  18. 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。
  19. 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。
  20. 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。
  21. 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。
  22. 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。
  23. 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。
  24. 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。
  25. 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)。
  26. 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。
  27. 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。
  28. 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。
  29. 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。
  30. 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。
  31. 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。
  32. 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。
  33. 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。
  34. 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)。
  35. 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)。
  36. 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。
  37. 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。
  38. 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)。
  39. 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。
  40. 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。
  41. 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。
  42. 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。
  43. 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。
  44. 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。
  45. 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。
  46. 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。
  47. 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。
  48. 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。
  49. 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。
  50. 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。
  51. 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。
  52. 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。
  53. 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。
  54. 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。
  55. 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)。
  56. 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。
  57. 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。
  58. 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。
  59. 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。
  60. 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。
  61. 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。
  62. 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。
  63. 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。
  64. 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。
  65. 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。
  66. 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。
  67. 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。
  68. 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。
  69. 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。
  70. 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。
  71. 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。
  72. 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。
  73. 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。
  74. 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。
PCT/CN2019/082623 2018-04-16 2019-04-15 预防或治疗肿瘤疗法副作用的方法 WO2019201195A1 (zh)

Priority Applications (8)

Application Number Priority Date Filing Date Title
EP19789251.6A EP3782618A4 (en) 2018-04-16 2019-04-15 METHOD OF PREVENTING OR TREATING SIDE EFFECTS OF CANCER THERAPY
AU2019254237A AU2019254237A1 (en) 2018-04-16 2019-04-15 Method for preventing or treating side effects of cancer therapy
CN201980025735.0A CN111989095A (zh) 2018-04-16 2019-04-15 预防或治疗肿瘤疗法副作用的方法
CA3097067A CA3097067A1 (en) 2018-04-16 2019-04-15 Method for preventing or treating side effects of cancer therapy
KR1020207032592A KR20200144116A (ko) 2018-04-16 2019-04-15 암 치료의 부작용을 예방하거나 치료하기 위한 방법
JP2020558446A JP2021521247A (ja) 2018-04-16 2019-04-15 腫瘍療法の副作用の予防または治療方法
US16/855,677 US10987336B2 (en) 2018-04-16 2020-04-22 Method of preventing or treating side effect of tumor therapy
US17/216,594 US20210322361A1 (en) 2018-04-16 2021-03-29 Method of preventing or treating side effect of tumor therapy

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810339975 2018-04-16
CN201810339975.5 2018-04-16

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/855,677 Continuation US10987336B2 (en) 2018-04-16 2020-04-22 Method of preventing or treating side effect of tumor therapy

Publications (1)

Publication Number Publication Date
WO2019201195A1 true WO2019201195A1 (zh) 2019-10-24

Family

ID=68239371

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/082623 WO2019201195A1 (zh) 2018-04-16 2019-04-15 预防或治疗肿瘤疗法副作用的方法

Country Status (9)

Country Link
US (2) US10987336B2 (zh)
EP (1) EP3782618A4 (zh)
JP (1) JP2021521247A (zh)
KR (1) KR20200144116A (zh)
CN (3) CN111989095A (zh)
AU (1) AU2019254237A1 (zh)
CA (1) CA3097067A1 (zh)
TW (1) TW201943428A (zh)
WO (1) WO2019201195A1 (zh)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111569078A (zh) * 2020-06-18 2020-08-25 上海馨颖生物技术有限公司 Sirt1抑制剂在vegfr抑制剂与免疫检查点抑制剂联用引起的副作用上的应用
WO2021073535A1 (zh) * 2019-10-16 2021-04-22 上海岸阔医药科技有限公司 预防或治疗与vegfr和/或vegf被抑制相关疾病的方法
WO2022052874A1 (zh) * 2020-09-09 2022-03-17 深圳微芯生物科技股份有限公司 西奥罗尼联合免疫检查点抑制剂在抗肿瘤治疗中的应用
WO2023142996A1 (zh) * 2022-01-28 2023-08-03 上海岸阔医药科技有限公司 预防或治疗与抗肿瘤剂相关的疾病或病症的方法

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102511934B1 (ko) * 2021-04-27 2023-03-21 재단법인 아산사회복지재단 피부 색소침착의 예방, 개선, 또는 치료용 조성물
WO2023182856A1 (ko) * 2022-03-24 2023-09-28 서울대학교산학협력단 로-키나제 억제제를 포함하는 켈로이드 등 피부 섬유화 질환의 예방 또는 치료용 약학적 조성물 및 그의 용도
CN117180246B (zh) * 2023-11-02 2024-01-26 西北农林科技大学深圳研究院 异甘草素在制备防治虾白斑综合征药物中的应用

Citations (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2833010A (en) 1954-02-01 1958-05-06 Rosenthal Harry Laundry clip
WO1994010202A1 (en) 1992-10-28 1994-05-11 Genentech, Inc. Vascular endothelial cell growth factor antagonists
WO1996030046A1 (en) 1995-03-30 1996-10-03 Genentech, Inc. Vascular endothelial cell growth factor antagonists
WO1998045332A2 (en) 1997-04-07 1998-10-15 Genentech, Inc. Humanized antibodies and methods for forming humanized antibodies
US6054297A (en) 1991-06-14 2000-04-25 Genentech, Inc. Humanized antibodies and methods for making them
US6582959B2 (en) 1991-03-29 2003-06-24 Genentech, Inc. Antibodies to vascular endothelial cell growth factor
US20030190317A1 (en) 1997-04-07 2003-10-09 Genentech, Inc. Anti-VEGF antibodies
US20030206899A1 (en) 1991-03-29 2003-11-06 Genentech, Inc. Vascular endothelial cell growth factor antagonists
WO2004009253A1 (en) 2002-07-19 2004-01-29 University Of North Carolina At Chapel Hill Surface-localized release of an anti-biofouling agent via micropatterning
US6703020B1 (en) 1999-04-28 2004-03-09 Board Of Regents, The University Of Texas System Antibody conjugate methods for selectively inhibiting VEGF
WO2005012359A2 (en) 2003-08-01 2005-02-10 Genentech, Inc. Anti-vegf antibodies
US20050106126A1 (en) 2002-01-11 2005-05-19 Whitlock David R. Compositions including ammonia oxidizing bacteria and methods of using same
WO2005044853A2 (en) 2003-11-01 2005-05-19 Genentech, Inc. Anti-vegf antibodies
US20050112126A1 (en) 1997-04-07 2005-05-26 Genentech, Inc. Anti-VEGF antibodies
US20050186208A1 (en) 2003-05-30 2005-08-25 Genentech, Inc. Treatment with anti-VEGF antibodies
US20060009360A1 (en) 2004-06-25 2006-01-12 Robert Pifer New adjuvant composition
WO2006121168A1 (en) 2005-05-09 2006-11-16 Ono Pharmaceutical Co., Ltd. Human monoclonal antibodies to programmed death 1(pd-1) and methods for treating cancer using anti-pd-1 antibodies alone or in combination with other immunotherapeutics
US20060269620A1 (en) 2003-07-03 2006-11-30 Morris Russell E Zeolites for delivery of nitric oxide
US20070148136A1 (en) 2003-09-26 2007-06-28 Whitlock David R Methods of using ammonia oxidizing bacteria
CN1997731A (zh) 2003-09-26 2007-07-11 大卫·R·怀特洛克 使用氨氧化细菌的方法
US20080311163A1 (en) 2005-03-24 2008-12-18 Tor Peters Cosmetic Treatment With Nitric Oxide, Device For Performing Said Treatment And Manufacturing Method Therefor
WO2009101611A1 (en) 2008-02-11 2009-08-20 Curetech Ltd. Monoclonal antibodies for tumor treatment
US20090214618A1 (en) 2005-05-27 2009-08-27 Schoenfisch Mark H Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
WO2009114335A2 (en) 2008-03-12 2009-09-17 Merck & Co., Inc. Pd-1 binding proteins
US20100098733A1 (en) 2008-10-16 2010-04-22 Novan, Inc. Nitric oxide releasing particles for oral care applications
WO2010077634A1 (en) 2008-12-09 2010-07-08 Genentech, Inc. Anti-pd-l1 antibodies and their use to enhance t-cell function
US20100239512A1 (en) 2006-08-17 2010-09-23 Russell Edward Morris Adsorption and release of nitric oxide in metal organic frameworks
US7820420B2 (en) 2000-08-11 2010-10-26 Whitlock David R Compositions including ammonia oxidizing bacteria to increase production of nitric oxide and nitric oxide precursors and methods of using same
US20100297200A1 (en) 2007-10-12 2010-11-25 The University Of North Carolina Atchapel Hill Use of nitric oxide to enhance the efficacy of silver and other topical wound care agents
US20110052650A1 (en) 2008-04-01 2011-03-03 Centre National De La Recherche Scientifique - CNR S Porous crystalline hybrid solid for adsorbing and releasing gas of biological interest
US20110086234A1 (en) 2009-10-13 2011-04-14 Nathan Stasko Nitric oxide-releasing coatings
US7943743B2 (en) 2005-07-01 2011-05-17 Medarex, Inc. Human monoclonal antibodies to programmed death ligand 1 (PD-L1)
US20120114649A1 (en) 2008-08-25 2012-05-10 Amplimmune, Inc. Delaware Compositions of pd-1 antagonists and methods of use
US20120136323A1 (en) 2009-08-21 2012-05-31 Nathan Stasko Wound Dressings, Methods of Using the Same and Methods of Forming the Same
US20120134951A1 (en) 2009-08-21 2012-05-31 Nathan Stasko Topical Gels and Methods of Using the Same
US20120156163A1 (en) 2010-12-15 2012-06-21 Susanne Bauman Methods of decreasing sebum production in the skin
WO2012100174A1 (en) 2011-01-20 2012-07-26 Novan, Inc. Temperature controlled sol-gel co-condensation
US20130344334A1 (en) 2011-02-28 2013-12-26 The University Of North Carolina At Chapel Hill Nitric oxide-releasing s-nitrosothiol-modified silica particles and methods of making the same
US20140065200A1 (en) 2012-08-28 2014-03-06 The University Of North Carolina At Chapel Hill Nitric oxide-releasing nanorods and their methods of use
US20140171395A1 (en) 2011-08-24 2014-06-19 The University Of North Carolina At Chapel Hill Tunable Nitric Oxide-Releasing Macromolecules Having Multiple Nitric Oxide Donor Structures
US20140255318A1 (en) 2011-10-27 2014-09-11 Novan, Inc. Nitric oxide releasing bath compositions and methods of using the same
US20150024052A1 (en) 2012-03-14 2015-01-22 Novan, Inc. Nitric Oxide Releasing Pharmaceutical Compositions
US20150111973A1 (en) 2012-03-13 2015-04-23 Novan, Inc. Methods of modulating steroid hormone activity
US20150225488A1 (en) 2012-08-17 2015-08-13 The University Of North Carolina At Chapel Hill Water soluble nitric oxide-releasing polyglucosamines and uses thereof
EP2978412A2 (en) * 2013-03-25 2016-02-03 Sloan Kettering Institute For Cancer Research Articles and methods for preventing and treating dermatologic adverse events
US20160199295A1 (en) 2013-08-08 2016-07-14 Novan, Inc. Topical compositions and methods of using the same
WO2016160089A1 (en) 2015-03-27 2016-10-06 Novan, Inc. Topical antiviral compositions, delivery systems, and methods of using the same
WO2017004557A1 (en) 2015-07-02 2017-01-05 Aobiome Llc Ammonia oxidizing bacteria for treatment of acne
WO2017004534A2 (en) 2015-07-02 2017-01-05 Aobiome Llc Microbiome-compatible cosmetics
WO2017019614A1 (en) 2015-07-28 2017-02-02 Novan, Inc. Combinations and methods for the treatment and/or prevention of fungal infections
US20170037363A1 (en) 2014-04-15 2017-02-09 Aobiome Llc Ammonia-oxidizing nitrosomonas eutropha strain d23
WO2017079268A1 (en) 2015-11-02 2017-05-11 University Of North Carolina- Chapel Hill Functionalized mesoporous silica via an aminosilane surfactant ion exchange reaction: controlled scaffold design and nitric oxide release
US9696324B2 (en) 2011-12-27 2017-07-04 L'université Catholique De Louvain Method for measuring nitric oxide in blood
US20170189454A1 (en) 2014-05-22 2017-07-06 Aobiome Llc Systems and methods for storage and delivery of ammonia oxidizing bacteria
US20170191109A1 (en) 2014-05-22 2017-07-06 Aobiome Llc Methods of preparing materials with ammonia oxidizing bacteria and testing materials for ammonia oxidizing bacteria
US20170196905A1 (en) 2014-07-14 2017-07-13 Novan, Inc. Nitric oxide releasing nail coating compositions, nitric oxide releasing nail coatings, and methods of using the same
US20170216197A1 (en) 2014-07-11 2017-08-03 Novan, Inc. Topical antiviral compositions and methods of using the same
WO2017151905A1 (en) 2016-03-02 2017-09-08 Novan, Inc. Compositions for treating inflammation and methods of treating the same
WO2018017583A1 (en) 2016-07-19 2018-01-25 Aobiome Llc Ammonia oxidizing microorganisms for use and delivery to the gastrointestinal system
WO2018057710A1 (en) 2016-09-21 2018-03-29 Aobiome Llc Ammonia oxidizing microorganisms for use and delivery to the intranasal system
US20180092948A1 (en) 2015-04-02 2018-04-05 Aobiome Llc Production of nitro-fatty acids and nitro-hydrocarbons by ammonia oxidizing bacteria
WO2018111888A1 (en) 2016-12-12 2018-06-21 Aobiome Llc Ammonia oxidizing microorganisms for the regulation of blood pressure
US10078054B2 (en) 2014-05-08 2018-09-18 Aobiome Llc Systems and methods for detecting nitric oxide

Family Cites Families (81)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1163561A (en) 1979-11-06 1984-03-13 Cyril Boroda Preparation containing nitroglycerine and optionally other medicaments and preparation thereof
US4450175A (en) 1982-09-23 1984-05-22 Warshaw Thelma G Method and compositions for treating acne
US5698589A (en) 1993-06-01 1997-12-16 International Medical Innovations, Inc. Water-based topical cream containing nitroglycerin and method of preparation and use thereof
US5504117A (en) 1994-05-27 1996-04-02 Neptune Pharmaceutical Corporation Pharmacologic preparation for the treatment of anal disorders
ATE196082T1 (de) 1994-05-27 2000-09-15 Cellegy Pharma Inc Stickstoffoxyd abgebendes präparat zur behandlung von analen erkrankungen
GB9802078D0 (en) 1998-01-30 1998-03-25 Futura Medical Limited Preparation for treatment of erectile dysfunction
US6103275A (en) 1998-06-10 2000-08-15 Nitric Oxide Solutions Systems and methods for topical treatment with nitric oxide
GB9818524D0 (en) 1998-08-25 1998-10-21 Futura Medical Limited Inorgasmia treatment
US6492398B1 (en) 1999-03-04 2002-12-10 Smithkline Beechman Corporation Thiazoloindolinone compounds
GB9904930D0 (en) 1999-03-04 1999-04-28 Glaxo Group Ltd Thiazoloindolinone compounds
US20040191276A1 (en) 1999-11-30 2004-09-30 Cutispharma, Inc. Compositions and kits for compounding pharmaceuticals
AU2727701A (en) 1999-12-15 2001-06-25 Cellegy Pharmaceuticals, Inc. Nitroglycerin ointment for treatment of pain associated with anal disease
US6620818B1 (en) 2000-03-01 2003-09-16 Smithkline Beecham Corporation Method for reducing the severity of side effects of chemotherapy and/or radiation therapy
WO2001070255A2 (en) 2000-03-20 2001-09-27 Pfizer Products, Inc. Combined treatment with keratinocyte growth factor and epidermal growth factor inhibitor
EP1278547B1 (en) * 2000-04-26 2004-11-03 Cellegy Pharmaceuticals, Inc Formulations and methods of using nitric oxide mimetics against a malignant cell phenotype
EP1286654A1 (de) 2000-05-24 2003-03-05 MERCK PATENT GmbH Verwendung von aryloximen zur prophylaxe und/oder behandlung von erythembildung und/oder entzündungsreaktionen der haut
US6780849B2 (en) 2000-12-21 2004-08-24 Scimed Life Systems, Inc. Lipid-based nitric oxide donors
WO2002069906A2 (en) 2001-03-06 2002-09-12 Cellegy Pharmaceuticals, Inc. Compounds and methods for the treatment of urogenital disorders
US7816366B2 (en) 2002-02-12 2010-10-19 Asymmetric Therapeutics, Llc Compositions and methods for treating and preventing dermatoses
US6995165B2 (en) 2002-02-12 2006-02-07 Ford John P Methods, compositions, and kits for organ protection during systemic anticancer therapy
US6979688B2 (en) 2002-02-12 2005-12-27 Ford John P Treatment method against side-effects of chemotherapy
US20030203915A1 (en) 2002-04-05 2003-10-30 Xinqin Fang Nitric oxide donors, compositions and methods of use related applications
AU2005216192B2 (en) 2004-02-23 2010-11-04 Strategic Science & Technologies, Llc Topical delivery of a nitric oxide donor to improve body and skin appearance
CN1568943A (zh) 2004-04-26 2005-01-26 江苏省药物研究所 硝酸甘油软膏及其制备方法和应用
EP1704876A1 (en) 2005-03-24 2006-09-27 NOLabs AB Cosmetic treatment, device for performing said treatment and manufacturing method thereof
EP1871353B1 (en) 2005-04-15 2010-12-22 ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIVERSITY, a division of YESHIVA UNIVERSITY Vitamin k for prevention and treatment of skin rash secondary to anti-egfr therapy
WO2006127591A2 (en) 2005-05-23 2006-11-30 Nitromed, Inc. Organic nitric oxide enhancing salts of nonsteroidal antiinflammatory compounds, compositions and methods of use
KR20080068848A (ko) 2005-10-11 2008-07-24 메르크 파텐트 게엠베하 케모카인 발현의 ｅｇｆｒ 의존적 조절 및 그의 종양 및부작용의 치료 및 진단효과
US20070172847A1 (en) 2005-11-15 2007-07-26 The Regents Of The University Of California Molecular signaling pathways triggered by rituximab: prognostic, diagnostic, and therapeutic uses
MX2008015266A (es) 2006-06-01 2009-02-10 Nobera Pharma Sl Uso del alopurinol para el tratamiento de la eritrodisestesia palmo-plantar.
CA2656613A1 (en) 2006-07-03 2008-01-10 Genmab A/S Prevention of rash in patients undergoing anti-egfr therapy
US20090196833A1 (en) 2008-02-06 2009-08-06 Adherex Technologies Inc. Compositions comprising topical dpd inhibitors and methods of using same in the treatment of hand-foot syndrome
US8815953B2 (en) 2008-03-13 2014-08-26 Spectrum Pharmaceuticals, Inc. Formulations of vitamin K analogs for topical use
US20100016446A1 (en) 2008-07-21 2010-01-21 Sylvia Gonda Stable water-based topical pharmaceutical creams and methods of making and using same
WO2010037095A2 (en) * 2008-09-29 2010-04-01 Nometics Agents and methods for the treatment of cancer
EP2201942A1 (de) 2008-12-23 2010-06-30 Intendis GmbH Zusammensetzung mit Hanföl für die Behandlung topischer Erkrankungen
EP2246057A1 (en) * 2009-04-29 2010-11-03 Nobera Pharma, S.L. Use of allopurinol for the treatment of hand foot skin reaction
WO2010148572A1 (en) * 2009-06-26 2010-12-29 Asan Laboratories Co., Ltd. Method for treating or ameliorating mucocutaneous or ocular toxicities
ES2600909T3 (es) 2009-06-30 2017-02-13 Derman Biomedicine Co. Ltd. Composiciones que contienen berberina o análogos de la misma para tratar rosácea o trastornos de la piel relacionados con enrojecimiento de la cara
JP2013508295A (ja) 2009-10-16 2013-03-07 デューク・ユニヴァーシティ 薬物誘発性手足症候群を治療するための組成物および方法
US20110190244A1 (en) 2010-02-01 2011-08-04 Peter Maccallum Cancer Institute Method of treatment of egfr inhibitor toxicity
WO2011097358A1 (en) 2010-02-05 2011-08-11 Deland M Maitland Led treatment of dermatologic toxicities associated with vascular endothelial growth factor inhibitors
WO2011097360A1 (en) 2010-02-05 2011-08-11 Deland M Maitland Led treatment of dermatologic toxicities associated with epidermal growth factor receptor inhibitors
WO2011097354A1 (en) 2010-02-05 2011-08-11 Deland M Maitland Led treatment of dermatologic toxicities associated with multikinase inhibitors
EP2368549A1 (en) 2010-03-25 2011-09-28 BioAlliance Pharma Treating hand-foot syndrome and related pathologies using clonidine or its derivatives
ES2604705T3 (es) 2010-03-31 2017-03-08 Ono Pharmaceutical Co., Ltd. Agente preventivo y/o remedio para el síndrome mano-pie
WO2012055057A1 (en) 2010-10-29 2012-05-03 Neurotune Ag Therapeutic use of dimiracetam to prevent the hand & foot syndrome caused by sorafenib
EP2701700A4 (en) 2011-04-27 2015-10-21 Univ Yale Inc PHARMACEUTICAL THERAPY FOR INHIBITING CHEMOTHERAPY-INDUCED SIDE EFFECTS AND CORRESPONDING PHARMACEUTICAL COMPOSITIONS, DIAGNOSTICS, SCREENING METHOD AND KITS
WO2012153331A2 (en) 2011-05-09 2012-11-15 Topical Therapeutic Agent (Tta) Ltd. Nitric oxide-sequestering topical formulations
WO2013009535A1 (en) 2011-07-08 2013-01-17 Merck Sharp & Dohme Corp. Il-23 antagonists for treatment or prevention of skin rash associated with treatment with p13k/akt pathway inhibitors
US20130330244A1 (en) 2011-12-05 2013-12-12 Nioxx Llc Compositions and methods for topical nitric oxide generation
EP2601965A1 (en) 2011-12-06 2013-06-12 Apeiron Biologics AG Compositions for preventing or treating adverse reactions of EGFR inhibition
WO2013157891A1 (ko) 2012-04-19 2013-10-24 부산대학교 산학협력단 Ｅｇｆｒ 억제제 유발 피부 부작용의 예방 또는 치료용 국소용 약학 조성물
CN103446261B (zh) 2012-06-05 2015-04-15 中国医学科学院肿瘤医院 一种预防和/或治疗肿瘤治疗相关皮肤损害的中药组合物
EP2700413B1 (en) 2012-08-20 2015-10-14 Bionoox Suisse SA Composition comprising dihydroquercetin, alpha-tocopherol and bisabolol
US8871254B2 (en) 2012-09-19 2014-10-28 Transdermal Biotechnology, Inc. Systems and methods for treatment of acne vulgaris and other conditions with a topical nitric oxide delivery system
US8871256B2 (en) 2012-09-19 2014-10-28 Transdermal Biotechnology, Inc. Methods and systems for treatment of inflammatory diseases with nitric oxide
US9855211B2 (en) 2013-02-28 2018-01-02 Novan, Inc. Topical compositions and methods of using the same
GB201305947D0 (en) 2013-04-02 2013-05-15 Univ Sheffield New method 1
US20150313896A1 (en) 2013-07-26 2015-11-05 Galderma Research & Development Method for treating cell proliferation disorders
US10206947B2 (en) 2013-08-08 2019-02-19 Novan, Inc. Topical compositions and methods of using the same
TW201538156A (zh) 2013-12-19 2015-10-16 Twi Biotechnology Inc 小蘗鹼配方及其用途
US20160263092A1 (en) 2013-12-19 2016-09-15 Twi Biotechnology, Inc. Therapeutic uses of berberine formulations
CN106659768A (zh) 2014-05-29 2017-05-10 株式会社大熊制药 用于预防或治疗皮疹的药物组合物
MX2016016650A (es) 2014-06-24 2017-04-13 Galderma Sa Metodo para tratar el sindrome de mano-pie y sintomas asociados con el mismo.
CN107206071A (zh) * 2014-09-13 2017-09-26 诺华股份有限公司 Alk抑制剂的联合疗法
EP3034092A1 (en) * 2014-12-17 2016-06-22 Université de Lausanne Adoptive immunotherapy for treating cancer
CN204411249U (zh) 2014-12-26 2015-06-24 朴瑛 一种肿瘤患者化疗后手足综合症的多功能康复装置
EP3313520A4 (en) 2015-06-24 2019-01-02 TWI Biotechnology, Inc. Therapeutic uses of berberine formulations
WO2017009824A1 (en) 2015-07-16 2017-01-19 Neotech-Kordan Group Ltd. Formulation methods and ointment formulations therein containing uracil, thymine, and/or their derivatives for treatment and prevention of hand-and-foot syndrome
WO2017029647A1 (en) 2015-08-20 2017-02-23 Meir Eini Tetracycline management of egfr inhibitor associated dermatoses
CN105381070A (zh) 2015-12-22 2016-03-09 浙江大学 犀角地黄药物组合物在制备预防及治疗表皮生长因子受体抑制剂所致相关皮疹药物中的用途
CA3016311C (en) 2016-03-10 2021-01-05 Lutris Pharma Ltd. Use of braf inhibitors for treating cutaneous reactions
CA3018341A1 (en) 2016-03-21 2017-09-28 Mayo Foundation For Medical Education And Research Methods for reducing toxicity of a chemotherapeutic drug
US11148999B2 (en) 2016-06-22 2021-10-19 MedChem Partners, LLC Nitric oxide donors
CN106539924A (zh) 2016-12-22 2017-03-29 张丽燕 一种预防和缓解化疗所致手足综合症的中药手套和袜子
CN107158287A (zh) 2017-03-25 2017-09-15 许进秀 缓解吉非替尼/厄洛替尼引起的皮肤毒性的中药
CN107412455A (zh) 2017-04-21 2017-12-01 曹师磊 一种治疗皮疹的天然外用药物组合物及其制备方法
CN107198718A (zh) 2017-05-04 2017-09-26 常州桐树生物科技有限公司 一种外用治疗皮疹的中药组合物及其制备方法和应用
JP7103363B2 (ja) 2017-09-21 2022-07-20 味の素株式会社 手足症候群の予防または改善用組成物
JP2021506958A (ja) 2017-12-13 2021-02-22 オンクォリティ ファーマシューティカルズ チャイナ エルティーディーＯｎｑｕａｌｉｔｙ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｃｈｉｎａ Ｌｔｄ． Ｅｇｆｒ阻害に関連する疾患を予防又は治療する方法

Patent Citations (100)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2833010A (en) 1954-02-01 1958-05-06 Rosenthal Harry Laundry clip
US6582959B2 (en) 1991-03-29 2003-06-24 Genentech, Inc. Antibodies to vascular endothelial cell growth factor
US20030203409A1 (en) 1991-03-29 2003-10-30 Genentech, Inc. Antibodies to vascular endothelial cell growth factor
US20030206899A1 (en) 1991-03-29 2003-11-06 Genentech, Inc. Vascular endothelial cell growth factor antagonists
US6054297A (en) 1991-06-14 2000-04-25 Genentech, Inc. Humanized antibodies and methods for making them
WO1994010202A1 (en) 1992-10-28 1994-05-11 Genentech, Inc. Vascular endothelial cell growth factor antagonists
WO1996030046A1 (en) 1995-03-30 1996-10-03 Genentech, Inc. Vascular endothelial cell growth factor antagonists
US20050112126A1 (en) 1997-04-07 2005-05-26 Genentech, Inc. Anti-VEGF antibodies
WO1998045332A2 (en) 1997-04-07 1998-10-15 Genentech, Inc. Humanized antibodies and methods for forming humanized antibodies
US20030190317A1 (en) 1997-04-07 2003-10-09 Genentech, Inc. Anti-VEGF antibodies
US7060269B1 (en) 1997-04-07 2006-06-13 Genentech, Inc. Anti-VEGF antibodies
US6703020B1 (en) 1999-04-28 2004-03-09 Board Of Regents, The University Of Texas System Antibody conjugate methods for selectively inhibiting VEGF
US7820420B2 (en) 2000-08-11 2010-10-26 Whitlock David R Compositions including ammonia oxidizing bacteria to increase production of nitric oxide and nitric oxide precursors and methods of using same
US20050106126A1 (en) 2002-01-11 2005-05-19 Whitlock David R. Compositions including ammonia oxidizing bacteria and methods of using same
WO2004009253A1 (en) 2002-07-19 2004-01-29 University Of North Carolina At Chapel Hill Surface-localized release of an anti-biofouling agent via micropatterning
US20050186208A1 (en) 2003-05-30 2005-08-25 Genentech, Inc. Treatment with anti-VEGF antibodies
US20060269620A1 (en) 2003-07-03 2006-11-30 Morris Russell E Zeolites for delivery of nitric oxide
US20100331968A1 (en) 2003-07-03 2010-12-30 Russell Edward Morris Zeolites for Delivery of Nitric Oxide
WO2005012359A2 (en) 2003-08-01 2005-02-10 Genentech, Inc. Anti-vegf antibodies
US20070148136A1 (en) 2003-09-26 2007-06-28 Whitlock David R Methods of using ammonia oxidizing bacteria
CN1997731A (zh) 2003-09-26 2007-07-11 大卫·R·怀特洛克 使用氨氧化细菌的方法
WO2005044853A2 (en) 2003-11-01 2005-05-19 Genentech, Inc. Anti-vegf antibodies
US20060009360A1 (en) 2004-06-25 2006-01-12 Robert Pifer New adjuvant composition
US9427605B2 (en) 2005-03-24 2016-08-30 Novan, Inc. Cosmetic treatment with nitric oxide, device for performing said treatment and manufacturing method therefor
US20160256366A1 (en) 2005-03-24 2016-09-08 Novan, Inc. Cosmetic treatment with nitric oxide, device for performing said treatment and manufacturing method therefor
US20080311163A1 (en) 2005-03-24 2008-12-18 Tor Peters Cosmetic Treatment With Nitric Oxide, Device For Performing Said Treatment And Manufacturing Method Therefor
WO2006121168A1 (en) 2005-05-09 2006-11-16 Ono Pharmaceutical Co., Ltd. Human monoclonal antibodies to programmed death 1(pd-1) and methods for treating cancer using anti-pd-1 antibodies alone or in combination with other immunotherapeutics
US20160060279A1 (en) 2005-05-27 2016-03-03 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8282967B2 (en) 2005-05-27 2012-10-09 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8962029B2 (en) 2005-05-27 2015-02-24 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US20140005426A1 (en) 2005-05-27 2014-01-02 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US20150182543A1 (en) 2005-05-27 2015-07-02 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US9403852B2 (en) 2005-05-27 2016-08-02 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US8956658B2 (en) 2005-05-27 2015-02-17 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US9403851B2 (en) 2005-05-27 2016-08-02 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US20120021055A1 (en) 2005-05-27 2012-01-26 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US20120034169A1 (en) 2005-05-27 2012-02-09 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US20140058124A1 (en) 2005-05-27 2014-02-27 The University Of North Carolina At Chapel Hill Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US20090214618A1 (en) 2005-05-27 2009-08-27 Schoenfisch Mark H Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications
US7943743B2 (en) 2005-07-01 2011-05-17 Medarex, Inc. Human monoclonal antibodies to programmed death ligand 1 (PD-L1)
US20100239512A1 (en) 2006-08-17 2010-09-23 Russell Edward Morris Adsorption and release of nitric oxide in metal organic frameworks
US8399005B2 (en) 2007-10-12 2013-03-19 University Of North Carolina At Chapel Hill Use of nitric oxide to enhance the efficacy of silver and other topical wound care agents
US20130196951A1 (en) 2007-10-12 2013-08-01 University Of North Carolina At Chapel Hill Use of nitric oxide to enhance the efficacy of silver and other topical wound care agents
US20100297200A1 (en) 2007-10-12 2010-11-25 The University Of North Carolina Atchapel Hill Use of nitric oxide to enhance the efficacy of silver and other topical wound care agents
WO2009101611A1 (en) 2008-02-11 2009-08-20 Curetech Ltd. Monoclonal antibodies for tumor treatment
WO2009114335A2 (en) 2008-03-12 2009-09-17 Merck & Co., Inc. Pd-1 binding proteins
US20110052650A1 (en) 2008-04-01 2011-03-03 Centre National De La Recherche Scientifique - CNR S Porous crystalline hybrid solid for adsorbing and releasing gas of biological interest
US20120114649A1 (en) 2008-08-25 2012-05-10 Amplimmune, Inc. Delaware Compositions of pd-1 antagonists and methods of use
US8609089B2 (en) 2008-08-25 2013-12-17 Amplimmune, Inc. Compositions of PD-1 antagonists and methods of use
US20120230921A1 (en) 2008-10-16 2012-09-13 Nathan Stasko Nitric oxide releasing particles for oral care applications
US20100098733A1 (en) 2008-10-16 2010-04-22 Novan, Inc. Nitric oxide releasing particles for oral care applications
WO2010077634A1 (en) 2008-12-09 2010-07-08 Genentech, Inc. Anti-pd-l1 antibodies and their use to enhance t-cell function
US9526738B2 (en) 2009-08-21 2016-12-27 Novan, Inc. Topical gels and methods of using the same
US9737561B2 (en) 2009-08-21 2017-08-22 Novan, Inc. Topical gels and methods of using the same
US20120136323A1 (en) 2009-08-21 2012-05-31 Nathan Stasko Wound Dressings, Methods of Using the Same and Methods of Forming the Same
US20120134951A1 (en) 2009-08-21 2012-05-31 Nathan Stasko Topical Gels and Methods of Using the Same
US20170056437A1 (en) 2009-08-21 2017-03-02 Novan, Inc. Topical gels and methods of using the same
US20170312307A1 (en) 2009-08-21 2017-11-02 Novan, Inc. Topical gels and methods of using the same
US20140134321A1 (en) 2009-10-13 2014-05-15 The University Of North Carolina At Chapel Hill Nitric oxide-releasing coatings
US20110086234A1 (en) 2009-10-13 2011-04-14 Nathan Stasko Nitric oxide-releasing coatings
US8591876B2 (en) 2010-12-15 2013-11-26 Novan, Inc. Methods of decreasing sebum production in the skin
US20140057001A1 (en) 2010-12-15 2014-02-27 Novan, Inc. Methods of decreasing sebum production in the skin
US20120156163A1 (en) 2010-12-15 2012-06-21 Susanne Bauman Methods of decreasing sebum production in the skin
WO2012100174A1 (en) 2011-01-20 2012-07-26 Novan, Inc. Temperature controlled sol-gel co-condensation
US20140017121A1 (en) 2011-02-28 2014-01-16 The University Of North Carolina At Chapel Hill Tertiary s-nitrosothiol-modified nitricoxide-releasing xerogels and methods of using the same
US20130344334A1 (en) 2011-02-28 2013-12-26 The University Of North Carolina At Chapel Hill Nitric oxide-releasing s-nitrosothiol-modified silica particles and methods of making the same
US8981139B2 (en) 2011-02-28 2015-03-17 The University Of North Carolina At Chapel Hill Tertiary S-nitrosothiol-modified nitric—oxide-releasing xerogels and methods of using the same
US9713652B2 (en) 2011-02-28 2017-07-25 The University Of North Carolina At Chapel Hill Nitric oxide-releasing S-nitrosothiol-modified silica particles and methods of making the same
US20160083339A1 (en) 2011-08-24 2016-03-24 The University Of North Carolina At Chapel Hill Tunable nitric oxide-releasing macromolecules having multiple nitric oxide donor structures
US9238038B2 (en) 2011-08-24 2016-01-19 The University Of North Carolina At Chapel Hill Tunable nitric oxide-releasing macromolecules having multiple nitric oxide donor structures
US20140171395A1 (en) 2011-08-24 2014-06-19 The University Of North Carolina At Chapel Hill Tunable Nitric Oxide-Releasing Macromolecules Having Multiple Nitric Oxide Donor Structures
US20170246205A1 (en) 2011-10-27 2017-08-31 Novan, Inc. Nitric oxide releasing bath compositions and methods of using the same
US9669041B2 (en) 2011-10-27 2017-06-06 Novan, Inc. Nitric oxide releasing bath compositions and methods of using the same
US20140255318A1 (en) 2011-10-27 2014-09-11 Novan, Inc. Nitric oxide releasing bath compositions and methods of using the same
US9696324B2 (en) 2011-12-27 2017-07-04 L'université Catholique De Louvain Method for measuring nitric oxide in blood
US20150111973A1 (en) 2012-03-13 2015-04-23 Novan, Inc. Methods of modulating steroid hormone activity
US20150024052A1 (en) 2012-03-14 2015-01-22 Novan, Inc. Nitric Oxide Releasing Pharmaceutical Compositions
US20150225488A1 (en) 2012-08-17 2015-08-13 The University Of North Carolina At Chapel Hill Water soluble nitric oxide-releasing polyglucosamines and uses thereof
US9187501B2 (en) 2012-08-28 2015-11-17 The University Of North Carolina At Chapel Hill Nitric oxide-releasing nanorods and their methods of use
US20140065200A1 (en) 2012-08-28 2014-03-06 The University Of North Carolina At Chapel Hill Nitric oxide-releasing nanorods and their methods of use
US20160101114A1 (en) 2013-03-25 2016-04-14 Sloan-Kettering Institute For Cancer Research Articles and methods for preventing and treating dermatologic adverse events
EP2978412A2 (en) * 2013-03-25 2016-02-03 Sloan Kettering Institute For Cancer Research Articles and methods for preventing and treating dermatologic adverse events
US20160199295A1 (en) 2013-08-08 2016-07-14 Novan, Inc. Topical compositions and methods of using the same
US9738870B2 (en) 2014-04-15 2017-08-22 Aobiome Llc Ammonia oxidizing bacteria for treatment of acne
US20170037363A1 (en) 2014-04-15 2017-02-09 Aobiome Llc Ammonia-oxidizing nitrosomonas eutropha strain d23
US10078054B2 (en) 2014-05-08 2018-09-18 Aobiome Llc Systems and methods for detecting nitric oxide
US20170191109A1 (en) 2014-05-22 2017-07-06 Aobiome Llc Methods of preparing materials with ammonia oxidizing bacteria and testing materials for ammonia oxidizing bacteria
US20170189454A1 (en) 2014-05-22 2017-07-06 Aobiome Llc Systems and methods for storage and delivery of ammonia oxidizing bacteria
US20170216197A1 (en) 2014-07-11 2017-08-03 Novan, Inc. Topical antiviral compositions and methods of using the same
US20170196905A1 (en) 2014-07-14 2017-07-13 Novan, Inc. Nitric oxide releasing nail coating compositions, nitric oxide releasing nail coatings, and methods of using the same
WO2016160089A1 (en) 2015-03-27 2016-10-06 Novan, Inc. Topical antiviral compositions, delivery systems, and methods of using the same
US20180092948A1 (en) 2015-04-02 2018-04-05 Aobiome Llc Production of nitro-fatty acids and nitro-hydrocarbons by ammonia oxidizing bacteria
WO2017004534A2 (en) 2015-07-02 2017-01-05 Aobiome Llc Microbiome-compatible cosmetics
WO2017004557A1 (en) 2015-07-02 2017-01-05 Aobiome Llc Ammonia oxidizing bacteria for treatment of acne
WO2017019614A1 (en) 2015-07-28 2017-02-02 Novan, Inc. Combinations and methods for the treatment and/or prevention of fungal infections
WO2017079268A1 (en) 2015-11-02 2017-05-11 University Of North Carolina- Chapel Hill Functionalized mesoporous silica via an aminosilane surfactant ion exchange reaction: controlled scaffold design and nitric oxide release
WO2017151905A1 (en) 2016-03-02 2017-09-08 Novan, Inc. Compositions for treating inflammation and methods of treating the same
WO2018017583A1 (en) 2016-07-19 2018-01-25 Aobiome Llc Ammonia oxidizing microorganisms for use and delivery to the gastrointestinal system
WO2018057710A1 (en) 2016-09-21 2018-03-29 Aobiome Llc Ammonia oxidizing microorganisms for use and delivery to the intranasal system
WO2018111888A1 (en) 2016-12-12 2018-06-21 Aobiome Llc Ammonia oxidizing microorganisms for the regulation of blood pressure

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
BIRD ET AL., SCIENCE, vol. 242, 1988, pages 423 - 426
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, vol. 16, 2002, pages 1775 - 85
FREIREICH ET AL., CANCER CHEMOTHER. REP., vol. 50, 1966, pages 219
GERALD MCMAHON, THE ONCOLOGIST, vol. 5, 2000, pages 3 - 10
HUSTON ET AL., PROC.NATL.ACAD.SCI., vol. 85, 1988, pages 5879 - 5883
KELLEN L. MEADOWS ET AL., SUPPORT CARE CANCER., vol. 5, 23 May 2015 (2015-05-23), pages 1311 - 1319
See also references of EP3782618A4
WALDNER, MAXIMILIAN J. ET AL., JOURNAL OF EXPERIMENTAL MEDICINE, vol. 207, 2010, pages 13
WARD ET AL., NATURE, vol. 341, 1989, pages 544 - 546

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021073535A1 (zh) * 2019-10-16 2021-04-22 上海岸阔医药科技有限公司 预防或治疗与vegfr和/或vegf被抑制相关疾病的方法
CN111569078A (zh) * 2020-06-18 2020-08-25 上海馨颖生物技术有限公司 Sirt1抑制剂在vegfr抑制剂与免疫检查点抑制剂联用引起的副作用上的应用
WO2022052874A1 (zh) * 2020-09-09 2022-03-17 深圳微芯生物科技股份有限公司 西奥罗尼联合免疫检查点抑制剂在抗肿瘤治疗中的应用
WO2023142996A1 (zh) * 2022-01-28 2023-08-03 上海岸阔医药科技有限公司 预防或治疗与抗肿瘤剂相关的疾病或病症的方法

Also Published As

Publication number Publication date
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

Similar Documents

Publication Publication Date Title
WO2019201195A1 (zh) 预防或治疗肿瘤疗法副作用的方法
US20210077510A1 (en) Compositions and methods for inhibiting arginase activity
JP6182313B2 (ja) 癌治療のためのチオキサントンをベースとしたオートファジー阻害剤療法
EP3574904A1 (en) Pharmaceutical combinations comprising a b-raf inhibitor, an egfr inhibitor and optionally a pi3k-alpha inhibitor
JP2019511204A (ja) コパンリシブバイオマーカー
Fenn et al. Phase 1 study of erlotinib and metformin in metastatic triple-negative breast cancer
JP2019512003A (ja) コパンリシブバイオマーカー
US10583111B2 (en) Method for preventing or treating diseases associated with the inhibition of EGFR
JP2023025214A (ja) がんを治療するためのｍｄｍ２阻害剤の投与計画
US20230035892A1 (en) Methods and compositions for treating cancer
JP2023022190A (ja) 癌治療
WO2022143628A1 (zh) 预防或治疗抗肿瘤剂相关疾病或病症的方法
US20210071180A1 (en) Microrna 584-5p compositions and methods for treating cancer
RU2782033C2 (ru) Способ профилактики или лечения побочного эффекта опухолевой терапии
WO2021073535A1 (zh) 预防或治疗与vegfr和/或vegf被抑制相关疾病的方法
US20190133998A1 (en) Treatment of tumors with inhibitors of cxcl12 signaling and subtherapeutic amounts of chemotherapeutic agents
WO2023142996A1 (zh) 预防或治疗与抗肿瘤剂相关的疾病或病症的方法
JP2022137317A (ja) 大腸がんを治療及び／又は予防する医薬組成物
CN116211789A (zh) 组合物及其用途
US20240009160A1 (en) Use of (s)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid in the treatment of cancer
TW202140057A (zh) 環孢素類似物於治療癌症之用途
JP2022143194A (ja) 抗癌剤
TWI590825B (zh) 治療癌症的基於硫□酮之自體吞噬抑制劑治療

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19789251

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3097067

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2020558446

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 20207032592

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2019789251

Country of ref document: EP

Effective date: 20201116

ENP Entry into the national phase

Ref document number: 2019254237

Country of ref document: AU

Date of ref document: 20190415

Kind code of ref document: A