CN104602688A - 用于治疗脑转移的维利帕尼与全脑放疗的组合 - Google Patents
用于治疗脑转移的维利帕尼与全脑放疗的组合 Download PDFInfo
- Publication number
- CN104602688A CN104602688A CN201380025598.3A CN201380025598A CN104602688A CN 104602688 A CN104602688 A CN 104602688A CN 201380025598 A CN201380025598 A CN 201380025598A CN 104602688 A CN104602688 A CN 104602688A
- Authority
- CN
- China
- Prior art keywords
- acid
- brain
- benzimidazole
- carboxamide
- methylpyrrolidin
- Prior art date
- Legal status (The legal status 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 status listed.)
- Pending
Links
- 210000004556 brain Anatomy 0.000 title claims abstract description 49
- 238000011282 treatment Methods 0.000 title claims abstract description 21
- 238000001959 radiotherapy Methods 0.000 title claims description 10
- JNAHVYVRKWKWKQ-CYBMUJFWSA-N veliparib Chemical compound N=1C2=CC=CC(C(N)=O)=C2NC=1[C@@]1(C)CCCN1 JNAHVYVRKWKWKQ-CYBMUJFWSA-N 0.000 title abstract description 5
- 208000003174 Brain Neoplasms Diseases 0.000 title abstract description 4
- 206010059282 Metastases to central nervous system Diseases 0.000 title abstract 2
- 229950011257 veliparib Drugs 0.000 title description 4
- 238000000034 method Methods 0.000 claims abstract description 32
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims abstract description 23
- 230000005855 radiation Effects 0.000 claims abstract description 10
- 230000008569 process Effects 0.000 claims description 7
- 230000004083 survival effect Effects 0.000 description 19
- 206010028980 Neoplasm Diseases 0.000 description 16
- 239000000203 mixture Substances 0.000 description 15
- 239000002253 acid Substances 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 12
- -1 alkali metal salt Chemical class 0.000 description 10
- 206010006187 Breast cancer Diseases 0.000 description 9
- 208000026310 Breast neoplasm Diseases 0.000 description 9
- 230000002354 daily effect Effects 0.000 description 9
- 238000011160 research Methods 0.000 description 9
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 201000008275 breast carcinoma Diseases 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000008859 change Effects 0.000 description 5
- 230000003203 everyday effect Effects 0.000 description 5
- 206010027476 Metastases Diseases 0.000 description 4
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 4
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 4
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 4
- 210000003169 central nervous system Anatomy 0.000 description 4
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 210000000582 semen Anatomy 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 239000000783 alginic acid Substances 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 229960001126 alginic acid Drugs 0.000 description 3
- 150000004781 alginic acids Chemical class 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- 230000009401 metastasis Effects 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- 231100000915 pathological change Toxicity 0.000 description 3
- 230000036285 pathological change Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 229910052688 Gadolinium Inorganic materials 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 239000012661 PARP inhibitor Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229940126534 drug product Drugs 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 2
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 2
- 208000018389 neoplasm of cerebral hemisphere Diseases 0.000 description 2
- 230000000474 nursing effect Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- OBSLWIKITOYASJ-AZEWMMITSA-N (2r,3s,4s,5r,6s)-6-(hydroxymethyl)-3-(methylamino)oxane-2,4,5-triol Chemical compound CN[C@@H]1[C@H](O)O[C@@H](CO)[C@H](O)[C@H]1O OBSLWIKITOYASJ-AZEWMMITSA-N 0.000 description 1
- LSPHULWDVZXLIL-LDWIPMOCSA-N (?)-Camphoric acid Chemical compound CC1(C)[C@@H](C(O)=O)CC[C@@]1(C)C(O)=O LSPHULWDVZXLIL-LDWIPMOCSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- BSFDDBUSIZRAPB-VHEBQXMUSA-N (e)-2-octadecanoylbut-2-enedioic acid Chemical class CCCCCCCCCCCCCCCCCC(=O)C(\C(O)=O)=C/C(O)=O BSFDDBUSIZRAPB-VHEBQXMUSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 208000006313 Delayed Hypersensitivity Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 208000009847 Eye Foreign Bodies Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000021309 Germ cell tumor Diseases 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Natural products OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000019025 Hypokalemia Diseases 0.000 description 1
- 206010021036 Hyponatraemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 208000033240 Progressive symmetric erythrokeratodermia Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 244000173166 Pyrus ussuriensis Species 0.000 description 1
- 235000011572 Pyrus ussuriensis Nutrition 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 240000002825 Solanum vestissimum Species 0.000 description 1
- 235000018259 Solanum vestissimum Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940023476 agar Drugs 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940024545 aluminum hydroxide Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000004596 appetite loss Effects 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- BNFRJXLZYUTIII-UHFFFAOYSA-N efaproxiral Chemical compound CC1=CC(C)=CC(NC(=O)CC=2C=CC(OC(C)(C)C(O)=O)=CC=2)=C1 BNFRJXLZYUTIII-UHFFFAOYSA-N 0.000 description 1
- 229960000925 efaproxiral Drugs 0.000 description 1
- 229950005627 embonate Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N glycerol 1-phosphate Chemical compound OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 208000013210 hematogenous Diseases 0.000 description 1
- ULLYUYLDAISRDE-SSPAHAAFSA-N heptanoic acid (2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanal Chemical compound C(CCCCCC)(=O)O.O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO ULLYUYLDAISRDE-SSPAHAAFSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 230000001709 ictal effect Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 208000003849 large cell carcinoma Diseases 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 1
- 229960003538 lonidamine Drugs 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- OBBCSXFCDPPXOL-UHFFFAOYSA-N misonidazole Chemical compound COCC(O)CN1C=CN=C1[N+]([O-])=O OBBCSXFCDPPXOL-UHFFFAOYSA-N 0.000 description 1
- 229950010514 misonidazole Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- AARXZCZYLAFQQU-UHFFFAOYSA-N motexafin gadolinium Chemical compound [Gd].CC(O)=O.CC(O)=O.C1=C([N-]2)C(CC)=C(CC)C2=CC(C(=C2C)CCCO)=NC2=CN=C2C=C(OCCOCCOCCOC)C(OCCOCCOCCOC)=CC2=NC=C2C(C)=C(CCCO)C1=N2 AARXZCZYLAFQQU-UHFFFAOYSA-N 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 235000020925 non fasting Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000008008 oral excipient Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- LCLHHZYHLXDRQG-ZNKJPWOQSA-N pectic acid Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)O[C@H](C(O)=O)[C@@H]1OC1[C@H](O)[C@@H](O)[C@@H](OC2[C@@H]([C@@H](O)[C@@H](O)[C@H](O2)C(O)=O)O)[C@@H](C(O)=O)O1 LCLHHZYHLXDRQG-ZNKJPWOQSA-N 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 208000024896 potassium deficiency disease Diseases 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011809 primate model Methods 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000002673 radiosurgery Methods 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- HCWPIIXVSYCSAN-UHFFFAOYSA-N radium atom Chemical compound [Ra] HCWPIIXVSYCSAN-UHFFFAOYSA-N 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- YRWWOAFMPXPHEJ-OFBPEYICSA-K sodium L-ascorbic acid 2-phosphate Chemical compound [Na+].[Na+].[Na+].OC[C@H](O)[C@H]1OC(=O)C(OP([O-])([O-])=O)=C1[O-] YRWWOAFMPXPHEJ-OFBPEYICSA-K 0.000 description 1
- 229940048058 sodium ascorbyl phosphate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 208000005809 status epilepticus Diseases 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000011521 systemic chemotherapy Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N2005/1092—Details
- A61N2005/1098—Enhancing the effect of the particle by an injected agent or implanted device
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pathology (AREA)
- Radiology & Medical Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种用于治疗主体中来自非小细胞肺癌的脑转移的方法，包括给予主体有效量的2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺或其可药用盐以及有效量的全脑放射。
Description
相关申请的交叉引用
本申请要求2012年5月15日提交的美国临时申请系列号61/647,329的优先权，将其全部内容通过引用并入本文。
发明领域
本发明涉及维利帕尼(veliparib)与全脑放疗(WBRT)的组合用于治疗患有脑转移的患者的用途。
发明背景
据估计，全球每年超过240,000人诊断患有脑转移。由于全身性癌症的血行播散导致在患有转移的癌症患者中约20-25％出现脑转移。由于全身疾病的较好控制，该发病率可能会升高。超过50％的患者确诊患有1-3脑转移。脑转移最通常与肺癌一起出现，但是也经常会在乳腺癌、皮肤癌(黑素瘤)、肾癌和结肠癌中出现。
在Southwest Oncology Group(SWOG)试验的分析中，据发现，在422名患有非小细胞肺癌(NSCLC)的患者中，约64％会经历进行性疾病。在患有进行性疾病的患者中，26％在脑中有发展(20％仅在脑中，6％在脑和其他部位中)。脑转移的中位时间为约6.5个月，其中在初期治疗期间接近25％显示有脑转移。(Gasper et al，J Clin Oncol.2005；23(13)：2955-61)。
因为脑的坚硬外层、与其他身体腔相比相对小尺寸的颅骨、及脑对颅内压升高的高敏感性，在脑中比其他部位来自转移的症状发展快速。脑转移产生症状比如头痛、恶心、呕吐和局部神经缺损如运动乏力和不同组合的局部和广泛性发作。
对于患有NSCLC的患者，已经显示脑转移会导致预后不良。对于患有来自NSCLC的多发性脑转移的患者，已经报道了中位存活期在3至4.9个月之间。(Horton et al.，Am J Roentgenol Radium Ther Nucl Med.1971；3：334-35)。患有来自NSCLC的脑转移的患者中接近一半发展为进行性神经问题，仅仅10％至15％的患者在诊断为脑转移之后存活超过1年。具有高至2个转移性器官部位的患者的存活率可能取决于对脑转移的足够控制。
脑转移的控制包括症状疗法和脑定向疗法。脑定向疗法包括WBRT、立体定向放射外科(SRS)和神经外科作为护理标准，以单独或不同组合形式，取决于脑转移的部位、大小和数量。目前可用的治疗模式中没有一个在大型随机化试验中显示相对彼此具有存活优势。(Regine et al.，Int J Radiat Oncol Biol Phys，2002；52(2)：333-8)。症状疗法通常包括减轻瘤周水肿的类固醇治疗和预防复发性发作的抗惊厥药。全身性化疗在该情形中具有的功效有限。
对于大多数患有脑转移的患者，WBRT是护理标准。非随机化的研究表明与没有治疗约1个月的中位存活时间和单独用类固醇治疗的2个月中位存活时间相比，WBRT增加中位存活时间至3至4个月。尽管WBRT对于患有NSCLC的脑转移患者的响应速率可变化，但是据报道该速率通常在25％-30％的范围内。(Tsao et al.，Cochrane Database Syst Rev.2006；3：CD003869)。
多种方法已用于改善单独的WBRT的结果，特别是通过在临床前模型中加入疑似具有放射敏感性效应的试剂。已经在随机、对照研究中研究了下述放射敏感剂，这些在局部脑肿瘤控制或总存活率方面均没能提供益处：氯尼达明、甲硝唑、米索硝唑、莫特沙芬钆(motexafm gadolinium)、溴脱氧尿苷和乙丙昔罗。
仍然需要治疗和缓解脑转移及其症状的有效方法。本发明提供通常解决该需求的治疗方法。
发明简述
本发明涉及一种用于治疗主体中来自非小细胞肺癌的脑转移的方法，包括给予主体有效量的2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺(维利帕尼或ABT-888)或其可药用盐以及全脑放疗。
附图简述
图1显示与维利帕尼(ABT-888)组合的WBRT日程表。
图2显示患有脑转移的患者在WBRT之后维利帕尼的初期平均药代动力学参数。
图3显示口服给予维利帕尼之后初期平均血浆浓度-时间曲线。
图4显示最佳肿瘤大小自基线的变化百分比(患有NSCLC的患者)。
图5显示最佳肿瘤大小自基线的变化百分比(患有乳腺癌的患者)。
图6显示最佳肿瘤大小自基线的变化百分比(患有其它类型癌症的患者)。
图7显示患有NSCLC的患者的总存活率(13个事件)。
图8显示应答者相对于无应答者的总存活率(患有NSCLC的患者)。
图9显示患有乳腺癌的患者的总存活率(13个事件)。
图10显示应答者相对于无应答者的总存活率(患有乳腺癌的患者)。
图11显示患有NSCLC的患者的观察的总存活率相对于预期总存活率(20个事件)。
图12显示患有乳腺癌的患者的观察的总存活率相对于预期总存活率(18个事件)。
发明详述
定义
术语“治疗(treat，treating，treatment)”指减缓或消除疾病和/或其伴随症状的方法。
“可药用的”指必须与制剂的其它成分相容而对其接受者无害的载体、稀释剂或赋形剂。
“主体”在本文中定义为包括动物，比如哺乳动物，包括但不限于灵长类动物(例如人)、母牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠等。在优选的实施方案中，主体为人。
全脑放疗(WBRT)是给予全脑的放射，通常为期数周。该放射以单位戈瑞(Gy)测量，戈瑞为电离辐射的吸收的辐射剂量的单位。
关于2-[(2R)-2-甲基吡咯烷2-基]-1H-苯并咪唑-4-甲酰胺的“有效量”或“药学上有效量”指足够在主体中诱导期望的生物学、药理学或治疗结果的量。
脑转移(metastasis或metastases)是从原发肿瘤扩散到脑的癌症，即非CNS原发性实体恶性肿瘤。
本发明提供一种用于治疗主体中来自非小细胞肺癌的脑转移的方法，包括给予主体有效量的2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺或其可药用盐以及有效量的全脑放射。
在本发明中，主体患有非小细胞肺癌(NSCLC)的原发性实体恶性肿瘤。NSCLC可以为鳞状细胞癌、腺癌或大细胞癌。主体也患有脑转移。在一个实施方案中，主体具有至少一处病变。另外，主体可以具有2处或更多处病变。在一个实施方案中，主体具有来自NSCLC的1个转移部位，即脑转移。在另一个实施方案中，主体具有来自NSCLC的2个转移部位，即脑转移和在一个其他器官***中的转移。
2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺是聚(ADP-核糖)聚合酶(PARP)的抑制剂，之前描述在WO 2006-110816中。聚(ADP-核糖)聚合酶在促进DNA修复、控制RNA转录、介导细胞死亡和调节免疫反应中具有重要作用。这些作用使得PARP抑制剂靶向广谱的病症。(Virag L.，et al，Pharmacol.Rev.200254(3)：375-429)。在各种临床前癌症模型和人临床试验中，已经显示PARP抑制剂可通过增加癌细胞的细胞凋亡、限制肿瘤生长、减少转移和延长带有肿瘤主体的存活率而增强放射和化疗。(WO 2007-084532；Donawho C.K.，et al，ClinCancer Res 200713(9)：2728-37；Kummar S.，et al，J Clin Oncol.200927(16)：2705-11)。
在治疗恶性脑肿瘤中，血脑屏障可以显著地影响药剂的功效。在临床前研究中，已显示2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺穿过血脑屏障且累积在脑肿瘤组织中。另外，在非人灵长类动物模型的临床前研究中，在CSF中测得2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺是在已显示在人类体内抑制PARP活性的范围内。(Muscal et al.Cancer Chemother Pharmacol.2010；65(3)419-25)。
本发明也部分涉及2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺的所有盐及其使用方法。化合物的盐可由于所述盐的一种或多种性质而是有利的，例如在不同温度和湿度下增加的药物稳定性或在水或其它溶剂中期望的溶解度。当预期向患者给予盐(例如与用于体外情形相反)时，所述盐优选地为可药用的和/或生理学相容的。在本专利申请中作为形容词使用的术语“可药用的”指修饰的名词适于用作药物产品或用作药物产品的一部分。可药用盐包括通常用于形成碱金属盐和形成游离酸或游离碱的加成盐的盐。通常，这些盐通常可以通过常规方法，例如通过由合适的酸或碱与本发明的化合物反应来制备。
2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺的可药用酸加成盐可以由无机酸或有机酸制备。通常适合的无机酸的实例包括盐酸、氢溴酸、氢碘酸、硝酸、碳酸、硫酸和磷酸。适合的有机酸通常包括例如有机酸的脂族酸、脂环族酸、芳香族酸、芳香脂族(araliphatic)酸、杂环酸、羧酸和磺酸种类。通常适合的有机酸的具体实例包括乙酸、三氟乙酸、甲酸、丙酸、琥珀酸、羟乙酸、葡糖酸、二葡糖酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、葡糖醛酸、马来酸、富马酸、丙酮酸、天冬氨酸、谷氨酸、苯甲酸、邻氨基苯甲酸、甲磺酸、硬脂酸、水杨酸、对-羟基苯甲酸、苯乙酸、扁桃酸、双羟萘酸(embonate，pamoate)、乙磺酸、苯磺酸、泛酸、2-羟基乙磺酸、磺胺酸、环己基氨基磺酸、海藻酸、β-羟基丁酸、半乳糖二酸(galactarate)、半乳糖醛酸、己二酸、海藻酸、重硫酸、丁酸、樟脑酸、樟脑磺酸、环戊烷丙酸、十二烷基硫酸、葡糖庚酸(glycoheptanoate)、甘油磷酸、庚酸、己酸、烟酸、草酸、巴莫酸(palmoate)、果胶酸、2-萘磺酸、3-苯基丙酸、苦味酸、新戊酸、硫氰酸、甲苯磺酸和十一酸。
2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺的可药用碱加成盐包括例如金属盐和有机盐。优选的金属盐包括碱金属(Ia族)盐、碱土金属(IIa族)盐、及其它生理学可接受的金属盐。这样的盐可以由铝、钙、锂、镁、钾、钠和锌制备。优选的有机盐可以由胺制备，比如氨丁三醇、二乙胺、N，N′-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、葡甲胺(N-甲基葡糖胺)和普鲁卡因。碱性含氮基团可以利用下述试剂进行季胺化：比如低级烷基(C1-C6)卤化物(例如，甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物)、二烷基硫酸盐(例如，二甲基、二乙基、二丁基和二戊基的硫酸盐)、长链卤化物(例如，癸基、十二烷基、十四烷基和十八烷基的氯化物、溴化物和碘化物)、芳基烷基卤化物(例如，苄基和苯乙基溴化物)等。
本发明还部分涉及2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺的所有组合物及其使用方法。2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺可以在存在或不存在赋形剂下给予。赋形剂包括，但不限于包封剂和添加剂比如吸收加速剂、抗氧化剂、粘合剂、缓冲剂、包衣剂、着色剂、稀释剂、崩解剂、乳化剂、增量剂、填充剂、矫味剂、湿润剂、润滑剂、香料、防腐剂、推进剂、释放剂、杀菌剂、甜味剂、增溶剂、润湿剂、其混合物等。
用于制备待口服给予的包含2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺的组合物的赋形剂包括，但不限于琼脂、海藻酸、氢氧化铝、苯甲醇、苯甲酸苄酯、1，3-丁二醇、卡波姆、蓖麻油、纤维素、乙酸纤维素、胶体二氧化硅、可可脂、玉米淀粉、玉米油、棉籽油、交联聚维酮、甘油二酯、乙醇、乙基纤维素、月桂酸乙酯、油酸乙酯、脂肪酸酯、明胶、胚芽油、葡萄糖、甘油、花生油、羟丙基甲基纤维素、异丙醇、等渗盐水、乳糖、氢氧化镁、硬脂酸镁、麦芽、甘露醇、微晶纤维素、甘油单酯、橄榄油、花生油、磷酸钾盐、马铃薯淀粉、聚维酮、丙二醇、林格溶液、红花油、芝麻油、羧甲基纤维素钠、磷酸钠盐、十二烷基硫酸钠、山梨醇钠、大豆油、硬脂酸、硬脂酰富马酸盐、蔗糖、表面活性剂、滑石、二氧化钛、黄蓍胶、四氢糠醇、甘油三酯、水、其混合物等。
以单剂量或分剂量向人类或其它哺乳动物宿主给予的本发明的组合物的总日剂量可以为例如每日0.0001-300mg/kg体重，且更通常1-300mg/kg体重的量。可以每天两次给予0.0001-300mg/kg体重的剂量。
在本发明的一个实施方案中，2-[(2R)-2-甲基吡咯烷2-基]-1H-苯并咪唑-4-甲酰胺或其可药用盐或溶剂化物的剂量是在20-600mg的范围内，或在60-400mg的范围内。在本发明的一个进一步的实施方案中，2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺或其可药用盐或溶剂化物的剂量为约30mg、50mg、80mg、100mg、150mg、200mg或300mg。该剂量可以每天1次或每天2次给予。在一个实施方案中，每天两次给予该剂量。
本发明进一步包括向主体给予全脑放射的步骤。通常，WBRT由向全脑给予的常规体外放射治疗组成。
WBRT可以以任何治疗有效剂量给予。通常，WBRT作为每日治疗期的过程，例如分次，给予。在本发明的一个实施方案中，累积剂量为约20Gy至约40Gy。在另一个实施方案中，累积剂量为约20Gy、约30Gy、约35Gy或约37.5Gy。
WBRT的给药日程表呈现在图1中。
在本发明的一个实施方案中，30Gy的累积剂量是以每天一次3.0Gy每次(3.0Gy fractions)总共10次递送的。在另一个实施方案中，30Gy的累积剂量是以10次3.0Gy每次递送的，经两周时间(周一-周五×2周)。
在本发明的一个实施方案中，37.5Gy的累积剂量是以每天一次2.5Gy每次总共15次递送的。在另一个实施方案中，37.5Gy的累积剂量是以15次2.5Gy每次递送的，经三周时间(周一-周五×3周)。
在本发明的一个实施方案中，35Gy的累积剂量是以每天一次2.5Gy每次总共14次递送的。
可以在给予WBRT之前、之前立即、期间、之后立即或之后，给予2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺或其可药用盐或溶剂化物、及其组合物和制剂。
在一个实施方案中，在开始WBRT的当天给予2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺及其组合物和制剂。在另一个实施方案中，在开始WBRT之前至少一天给予2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺及其组合物和制剂。在另一个实施方案中，在开始WBRT之前给予2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺及其组合物和制剂两天。在另一个实施方案中，在开始WBRT之前给予2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺及其组合物和制剂一周。
在一个实施方案中，在WBRT的过程期间，每天或每天两次连续给予2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰安及其组合物和制剂。
在一个实施方案中，在WBRT过程完成之后，给予2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺及其组合物和制剂。在另一个实施方案中，在WBRT过程的最后一天之后，给予2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺及其组合物和制剂一天。
在一个实施方案中，在第1-13天给予2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺及其组合物和制剂，而在第1-5天和第8-12天给予WBRT治疗。在另一个实施方案中，WBRT的累积剂量为30Gy，且每天两次以200mg的剂量给予2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。在另一个实施方案中，WBRT的累积剂量为30Gy，且每天两次以50mg的剂量给予2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。
在一个实施方案中，在第1-20天给予2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺及其组合物和制剂，而在第1-5天和第8-12天及第15-19天给予WBRT治疗。在另一个实施方案中，WBRT的累积剂量为37.5Gy，且每天两次以200mg的剂量给予2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。在另一个实施方案中，WBRT的累积剂量为37.5Gy，且每天两次以50mg的剂量给予2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。
将本文引用的所有参考文献，包括出版物、专利申请和专利，都以如同每个参考文献分别和特别地指出通过引用并入本文并且在本文中列出全部内容一样通过引用并入本文。
在描述本发明的上下文(特别是在下述权利要求的上下文)中，使用的术语“一个(a)”、“一个(an)”和“该(the)”和类似的指示词应当解释为包括单数和复数，除非本文中另有说明或明显与上下文矛盾。除非另有说明，否则术语“包括”、“具有”、“包含”和“含有”应当看作是开放式术语(即，指“包括，但不限于”)。除非本文另有说明，否则本文记载的数值范围仅仅意图充当分别提及落入所述范围的每个单独值的简写方法，将每个单独的值如同其分别在本文中记载一样并入说明书。除非本文另有说明或者明显与上下文矛盾，否则本文描述的所有方法都可以以任何合适的顺序进行。除非另有说明，否则使用本文提供的任何和所有实施例或示例性语言(例如“比如”)仅仅意图更好地阐述本发明，而并没有提出对本发明范围的限制。在说明书中任何语言都不应当被看作是指对于实施本发明所需的任何未主张的要素。
本文中描述了本发明的优选的实施方案，包括本发明人已知用于实施本发明的最佳方式。在阅读前面的描述时，这些优选实施方案的变化对本领域普通技术人员而言变得显而易见。本发明人预期本领域技术人员根据需要实施这样的变化，并且本发明人意图按照除了本文具体描述的之外的方式实施本发明。因此，本发明包括所有在附加权利要求中记载的主题的修饰和同等物，如适用法律所允许的。而且，除非本文另有说明，或者明显与上下文矛盾，否则本发明包括上述要素以其所有可能变化的任何组合。
实施例
实施例1
该实施例是评价与常规WBRT同时给予的维利帕尼在患有实体原发肿瘤向脑转移的主体中的安全性、耐受性和药代动力学的1期多中心剂量递增研究。
纳入标准
患有组织学或细胞学证实非CNS原发性实体癌及病理学或放射摄影学证实脑转移性疾病的患者适于该研究。患有不可测量的病变(包括软脑膜癌病)的主体也是合格的。除了预防性治疗之外，WBRT是临床上指定的。患者具有大于或等于70分的卡氏行为表现状态(Kamofsky Performance Status，KPS)和足够的血液学、肾脏和肝脏功能。
排除标准
脑转移继发于生殖细胞肿瘤或恶性淋巴瘤。原发性中枢神经***(CNS)瘤。之前或同时给予下述疗法或治疗：(a)之前用WBRT治疗；(b)在WBRT D1之前少于14天进行SRS，或者规定发生在WBRT最后期的30天之内；(c)在WBRTD1之前的少于14天进行最后一次给予化疗、免疫疗法、生物疗法或研究性治疗。没有限制地允许二膦酸盐、激素改良疗法和曲妥单抗。来自先前给予另一种研究性药物和/或先前抗癌治疗的未解决的或不稳定的严重毒性。不受控制的已知发作性病症(癫痫持续状态)，或上个月期间发作每周大于或等于3次。如果是女性，主体处于怀孕或哺乳期。临床上显著且不受控制的主要心脏、呼吸道、肾脏、肝脏、胃肠、血液学或神经病学/精神病学疾病或病症，包括但不限于：(a)活动性不受控制的感染；(b)有症状的充血性心力衰竭、不稳定的心绞痛、或心律失常；和(c)任何其它可加重潜在的毒性、混淆安全性评价、控制需要排除治疗、或限制研究要求的顺应性的病态条件。不能吞咽和保持口服药物。增加MRI和CT的已知禁忌症，包括但不限于：(a)体内存在金属物体，比如心脏起搏器、植入心脏除颤器、脑动脉瘤夹、耳蜗植入物、眼异物或弹片，及(b)速发性或迟发性超敏反应的病史或其它针对造影剂(包括但不限于钆和碘)的禁忌症。之前入选该研究或另一涉及研究维利帕尼的研究，除了接受单次剂量的研究药物之外。
入选
从2008年5月至2012年4月对66名患者给药。62名患者结束研究治疗。56名患者完成至少80％的维利帕尼给药方案，58名患者完成整个WBRT过程，且4名患者仍在进行中。
将基线特征显示在表1中。
表1.患者和疾病特征
患者接受每天一次(QD)以2.5Gy每次总共15次递送的WBRT，或以3.0Gy每次QD总共10次递送的WBRT。
在整个WBRT过程中，维利帕尼剂量以每天两次(BID)从10mg开始递增，且增加至20、30、50、80、100、150、200和300mg(表2)；在最后一次WBRT之后，再给予一天的维利帕尼。
通过RECIST评价PK、安全性和肿瘤反应。
PK
为了确定维利帕尼的PK，在WBRT日程表的第1天(第15天和第10天)，在下述时间点进行密集的PK采样：0、30分钟、1、2、6和24小时。也在两个WBRT日程表第6天的下述时间点进行PK采样：0、30分钟、1、2和6小时。对于日程表的第15天，在第15天的0、30分钟、1、2和6小时进行采样。对于日程表的第10天，仅采集0小时的样品。在最后一次给予维利帕尼之后24-72小时，采集两个WBRT日程表的治疗后样品。
维利帕尼被快速吸收，平均Tmax值为1至2小时。
随着维利帕尼剂量增加的维利帕尼暴露(C max和AUC)的增加在10至150mg BID剂量范围内为近似与剂量成比例关系，口服清除率为21.6±14.2L/h(平均值±SD，n＝45；图2)。
第1天、第6天和第15天维利帕尼的Cmax和AUC值的比较证实维利帕尼在BID给予后的累积最小(图3)。
在第6天(禁食)和第15天(非禁食)的维利帕尼暴露是可比较的，表明食物对维利帕尼口服生物利用度没有显著影响。
安全性
通过NCI CTCAE v3.0评价AE。
最常见的(≥10％)的可能或也许与维利帕尼有关的治疗突发性AE显示在表3中。
表3.在≥10％的患者中发生的可能或也许与维利帕尼有关的治疗-突发性所有等级AE和所有等级3/4AE；N＝66
| 事件 | 任何等级n(％) | 等级3/4n(％) |
| 任何事件 | 37(56) | 10(15) |
| 疲劳 | 22(33.3) | 3(5) |
| 恶心 | 13(19.7) | 1(2) |
| 呕吐 | 8(12) | - |
| 食欲减退 | 8(12) | - |
在10、20、30、50、80、100、200和300mg剂量水平下没有观察到剂量限制性毒性(DLT)。
在150mg的维利帕尼BID下，1名患者经历DLT为等级3的低钾血症，第二名患者经历DLT为等级3的低钠血症。8(12％)名患者具有导致研究药物停用的AE。2(3％)名患者具有导致研究药物停用的可能或也许与维利帕尼有关的AE。
功效
在3个月的间隔时间长达2年的最后一次探视后开始生存随访评价，并且在每次随访探视时进行肿瘤评估和简单精神状态检查。在基线、最后探视和每隔3个月间隔(WBRT后)，使用颅钆-增强的MRI对所有患者进行脑放射影像评价。使用RECIST，根据研究者的评价，评价疾病反应/进展。
给予的66名患者中，54名在基线时患有可测量的疾病。对于患有NSCLC(图4)、乳腺癌(图5)及其它肿瘤类型(图6)的患者，呈现最佳脑肿瘤反应数据。
除了对于NSCLC患者(图7)和乳腺癌患者(图9)估计的中位生存时间，也对患有NSCLC(图8)和乳腺癌(图10)的患者估计了应答者相对于非应答者的中位生存时间。
截至2013年3月，总共81名患者入选。最终基线特征显示在表4中。
表4.最终患者和疾病特征
将NSCLC患者(图11)和乳腺癌患者(图12)的观察的总存活率相对于预期存活率绘图。使用个体化预测脑转移患者的存活率的列线图估计预期存活率(参见Neuro-Oncology，2012)。
Claims (16)
1.一种用于治疗主体中来自非小细胞肺癌的脑转移的方法，包括给予所述主体有效量的2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺或其可药用盐以及有效量的全脑放射。
2.权利要求1的方法，其中2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺的量为约30-约600mg/天。
3.权利要求1或2的方法，其中2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺的量为约60-约400mg/天。
4.权利要求1-3中任一项的方法，其中2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺的量为约100mg/天。
5.权利要求1-3中任一项的方法，其中2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺的量为约400mg/天。
6.权利要求1-5中任一项的方法，其中每天两次给予2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。
7.权利要求1-6中任一项的方法，其中全脑放射的量为约20Gy-约40Gy的累积剂量。
8.权利要求7的方法，其中所述累积剂量为约30Gy。
9.权利要求8的方法，其中所述累积剂量是以每天一次约3.0Gy每次递送的，总共10次。
10.权利要求7的方法，其中所述累积剂量为约37.5Gy。
11.权利要求10的方法，其中所述累积剂量是以每天一次约2.5Gy每次递送的，总共15次。
12.权利要求7的方法，其中所述累积剂量为约35Gy。
13.权利要求12的方法，其中所述累积剂量是以每天一次约2.5Gy每次递送的，总共14次。
14.权利要求1-13中任一项的方法，其中在给予全脑放疗之前，给予2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。
15.权利要求1-13中任一项的方法，其中与给予全脑放疗同时给予2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。
16.权利要求1-13中任一项的方法，其中在给予全脑放疗之后，给予2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261647329P | 2012-05-15 | 2012-05-15 | |
| US61/647329 | 2012-05-15 | ||
| PCT/US2013/041095 WO2013173428A1 (en) | 2012-05-15 | 2013-05-15 | Veliparib in combination with whole brain radiation therapy for the treatment of brain metastases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104602688A true CN104602688A (zh) | 2015-05-06 |
Family
ID=48576528
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201380025598.3A Pending CN104602688A (zh) | 2012-05-15 | 2013-05-15 | 用于治疗脑转移的维利帕尼与全脑放疗的组合 |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US20130310625A1 (zh) |
| EP (1) | EP2849750A1 (zh) |
| JP (1) | JP2015521188A (zh) |
| KR (1) | KR20150017355A (zh) |
| CN (1) | CN104602688A (zh) |
| AU (1) | AU2013262906A1 (zh) |
| BR (1) | BR112014028618A2 (zh) |
| CA (1) | CA2873119A1 (zh) |
| CL (1) | CL2014003072A1 (zh) |
| DO (1) | DOP2014000258A (zh) |
| HK (1) | HK1207984A1 (zh) |
| IL (1) | IL235389A0 (zh) |
| MX (1) | MX2014013903A (zh) |
| PH (1) | PH12014502464A1 (zh) |
| RU (1) | RU2014150506A (zh) |
| SG (1) | SG11201407498RA (zh) |
| TW (1) | TW201400113A (zh) |
| WO (1) | WO2013173428A1 (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2017003304A (es) * | 2014-09-16 | 2017-08-15 | Abbvie Inc | Veliparib en combinacion con carboplatino y paclitaxel para el tratamiento de cancer de pulmon de celulas no pequeñas en fumadores. |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI375673B (en) | 2005-04-11 | 2012-11-01 | Abbott Lab | 1h-benzimidazole-4-carboxamides substituted with a quaternary carbon at the 2-position are potent parp inhibitors |
| JP5289060B2 (ja) | 2006-01-17 | 2013-09-11 | アボット・ラボラトリーズ | Ｐａｒｐインヒビターとの組合せ療法 |
| US20130030237A1 (en) * | 2010-04-15 | 2013-01-31 | Charles Theuer | Potentiation of anti-cancer activity through combination therapy with ber pathway inhibitors |
-
2013
- 2013-05-15 JP JP2015512782A patent/JP2015521188A/ja active Pending
- 2013-05-15 CA CA2873119A patent/CA2873119A1/en not_active Abandoned
- 2013-05-15 KR KR1020147035036A patent/KR20150017355A/ko not_active Application Discontinuation
- 2013-05-15 EP EP13726934.6A patent/EP2849750A1/en not_active Withdrawn
- 2013-05-15 TW TW102117250A patent/TW201400113A/zh unknown
- 2013-05-15 CN CN201380025598.3A patent/CN104602688A/zh active Pending
- 2013-05-15 BR BR112014028618A patent/BR112014028618A2/pt not_active Application Discontinuation
- 2013-05-15 AU AU2013262906A patent/AU2013262906A1/en not_active Abandoned
- 2013-05-15 RU RU2014150506A patent/RU2014150506A/ru unknown
- 2013-05-15 WO PCT/US2013/041095 patent/WO2013173428A1/en active Application Filing
- 2013-05-15 US US13/894,555 patent/US20130310625A1/en not_active Abandoned
- 2013-05-15 SG SG11201407498RA patent/SG11201407498RA/en unknown
- 2013-05-15 MX MX2014013903A patent/MX2014013903A/es unknown
-
2014
- 2014-10-29 IL IL235389A patent/IL235389A0/en unknown
- 2014-11-05 PH PH12014502464A patent/PH12014502464A1/en unknown
- 2014-11-12 CL CL2014003072A patent/CL2014003072A1/es unknown
- 2014-11-14 DO DO2014000258A patent/DOP2014000258A/es unknown
-
2015
- 2015-09-07 HK HK15108693.6A patent/HK1207984A1/zh unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BR112014028618A2 (pt) | 2017-06-27 |
| HK1207984A1 (zh) | 2016-02-19 |
| DOP2014000258A (es) | 2015-01-15 |
| EP2849750A1 (en) | 2015-03-25 |
| IL235389A0 (en) | 2014-12-31 |
| RU2014150506A (ru) | 2016-07-10 |
| TW201400113A (zh) | 2014-01-01 |
| US20130310625A1 (en) | 2013-11-21 |
| SG11201407498RA (en) | 2014-12-30 |
| PH12014502464A1 (en) | 2014-12-22 |
| MX2014013903A (es) | 2015-01-16 |
| KR20150017355A (ko) | 2015-02-16 |
| JP2015521188A (ja) | 2015-07-27 |
| WO2013173428A1 (en) | 2013-11-21 |
| CA2873119A1 (en) | 2013-11-21 |
| CL2014003072A1 (es) | 2015-02-27 |
| AU2013262906A1 (en) | 2014-11-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107001326B (zh) | 抗非小细胞肺癌的喹啉衍生物 | |
| US10111868B2 (en) | Antineoplastic combinations containing HKI-272 and vinorelbine | |
| CN109475524A (zh) | 用于减少中性粒细胞减少症的组合物和方法 | |
| CN104349771A (zh) | 用于***疾病的17α-羟化酶(C17,20-裂解酶)抑制剂和特定PI-3K抑制剂的组合 | |
| US20230330106A1 (en) | Treatment of breast cancer using combination therapies comprising an atp competitive akt inhibitor, a cdk4/6 inhibitor, and fulvestrant | |
| CN104602688A (zh) | 用于治疗脑转移的维利帕尼与全脑放疗的组合 | |
| WO2020029918A1 (zh) | 用于治疗结外nk/t细胞淋巴瘤的喹啉衍生物 | |
| Jeremić et al. | Concurrent hyperfractionated radiation therapy and chemotherapy in locally advanced (Stage III) non-small-cell lung cancer: single institution experience with 600 patients | |
| JP5590560B2 (ja) | 組合せ抗がん剤 | |
| CN115038447A (zh) | 用于治疗癌症的组合疗法 | |
| CN106999485B (zh) | 抗肺鳞癌的喹啉衍生物 | |
| CN104334192A (zh) | 使用pi3k抑制剂和mek抑制剂治疗癌症的方法 | |
| CN103221050A (zh) | 用于治疗增生性障碍的贝伐单抗与2,2-二甲基-N-((S)-6-氧代-6,7-二氢-5H-二苯并[b,d]氮杂*-7-基)-N`-(2,2,3,3,3-五氟-丙基)-丙二酰胺的组合 | |
| WO2011139867A2 (en) | Method of treating brain cancer | |
| AU2017232057B2 (en) | Antineoplastic Combinations Containing HKI-272 and Vinorelbine | |
| Mirmiran et al. | Phase I/II study of IV topotecan in combination with whole brain radiation for the treatment of brain metastases | |
| Colella et al. | Radiochemotherapy for unresectable glioblastoma multiforme: a mono-institutional experience | |
| MX2013013406A (es) | Medicamentos y metodos para tratar cancer. | |
| CN115463143A (zh) | 非天然人参皂苷3β,12β-Di-O-Glc-PPD治疗脑瘤的用途 | |
| Shen | Retrospective comparison of outcomes in patients with recurrent or refractory ovarian cancer treated with pegylated liposomal doxorubicin at an academic medical center | |
| NZ788180A (en) | Combination therapy with notch and pd-1 or pd-l1 inhibitors | |
| DUTTA et al. | PROSPECTIVE EVALUATION OF RADIOTHERAPY WITH CONCURRENT AND ADJUVANT TEMOZOLOMIDE IN CHILDREN WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA RAKESH JALALI, MD,* NIRMAL RAUT, MD,* BRIJESH ARORA, DM, y TEJPAL GUPTA, MD | |
| CN105228611A (zh) | 用于治疗或预防头颈癌的pi3激酶抑制剂与紫杉醇的组合 | |
| AU2013202963A1 (en) | Antineoplastic Combinations Containing HKI-272 and Vinorelbine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150506 |