CN103619340B - 尿苷和脱氧尿苷在治疗叶酸应答性病变中的用途 - Google Patents
尿苷和脱氧尿苷在治疗叶酸应答性病变中的用途 Download PDFInfo
- Publication number
- CN103619340B CN103619340B CN201280031365.XA CN201280031365A CN103619340B CN 103619340 B CN103619340 B CN 103619340B CN 201280031365 A CN201280031365 A CN 201280031365A CN 103619340 B CN103619340 B CN 103619340B
- Authority
- CN
- China
- Prior art keywords
- vitamin
- folic acid
- purposes according
- compositions
- main body
- 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.)
- Expired - Fee Related
Links
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 title claims abstract description 44
- 238000011282 treatment Methods 0.000 title claims abstract description 33
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 title claims description 361
- 239000011724 folic acid Substances 0.000 title claims description 198
- 235000019152 folic acid Nutrition 0.000 title claims description 197
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 title claims description 164
- 229960000304 folic acid Drugs 0.000 title claims description 164
- 230000004043 responsiveness Effects 0.000 title description 15
- 231100000915 pathological change Toxicity 0.000 title description 2
- 230000036285 pathological change Effects 0.000 title description 2
- 239000000203 mixture Substances 0.000 claims abstract description 123
- 235000005911 diet Nutrition 0.000 claims abstract description 108
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 62
- 201000011510 cancer Diseases 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 44
- 239000003814 drug Substances 0.000 claims abstract description 38
- 239000013589 supplement Substances 0.000 claims abstract description 29
- 235000012054 meals Nutrition 0.000 claims abstract description 22
- 235000007882 dietary composition Nutrition 0.000 claims abstract description 15
- 230000003203 everyday effect Effects 0.000 claims description 58
- 235000013305 food Nutrition 0.000 claims description 51
- 238000002360 preparation method Methods 0.000 claims description 24
- 239000003795 chemical substances by application Substances 0.000 claims description 23
- 229940088594 vitamin Drugs 0.000 claims description 23
- 229930003231 vitamin Natural products 0.000 claims description 23
- 235000013343 vitamin Nutrition 0.000 claims description 23
- 239000011782 vitamin Substances 0.000 claims description 23
- 208000032170 Congenital Abnormalities Diseases 0.000 claims description 22
- 206010016880 Folate deficiency Diseases 0.000 claims description 22
- 208000005016 Intestinal Neoplasms Diseases 0.000 claims description 22
- 230000007698 birth defect Effects 0.000 claims description 22
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 22
- 208000010188 Folic Acid Deficiency Diseases 0.000 claims description 21
- 229940079593 drug Drugs 0.000 claims description 19
- 235000015872 dietary supplement Nutrition 0.000 claims description 18
- 239000002775 capsule Substances 0.000 claims description 17
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 17
- 235000010755 mineral Nutrition 0.000 claims description 17
- 239000003826 tablet Substances 0.000 claims description 17
- 230000000378 dietary effect Effects 0.000 claims description 16
- 230000035935 pregnancy Effects 0.000 claims description 16
- 239000000047 product Substances 0.000 claims description 16
- 239000011707 mineral Substances 0.000 claims description 15
- 238000011275 oncology therapy Methods 0.000 claims description 15
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 14
- 206010009944 Colon cancer Diseases 0.000 claims description 13
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 13
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 claims description 13
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims description 13
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 claims description 12
- 201000002313 intestinal cancer Diseases 0.000 claims description 12
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 11
- 206010010356 Congenital anomaly Diseases 0.000 claims description 11
- 230000002265 prevention Effects 0.000 claims description 11
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 10
- 239000011573 trace mineral Substances 0.000 claims description 10
- 235000013619 trace mineral Nutrition 0.000 claims description 10
- 239000008187 granular material Substances 0.000 claims description 9
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 claims description 8
- 235000013376 functional food Nutrition 0.000 claims description 8
- 239000007937 lozenge Substances 0.000 claims description 8
- 229960003495 thiamine Drugs 0.000 claims description 8
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 claims description 8
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 7
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 7
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 claims description 7
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 claims description 7
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 claims description 7
- 229930003779 Vitamin B12 Natural products 0.000 claims description 7
- 229960002685 biotin Drugs 0.000 claims description 7
- 235000020958 biotin Nutrition 0.000 claims description 7
- 239000011616 biotin Substances 0.000 claims description 7
- 238000002512 chemotherapy Methods 0.000 claims description 7
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 7
- 229960001231 choline Drugs 0.000 claims description 7
- 229910052804 chromium Inorganic materials 0.000 claims description 7
- 239000011651 chromium Substances 0.000 claims description 7
- 229940107218 chromium Drugs 0.000 claims description 7
- 210000001072 colon Anatomy 0.000 claims description 7
- 229910052750 molybdenum Inorganic materials 0.000 claims description 7
- 239000011733 molybdenum Substances 0.000 claims description 7
- 229960003512 nicotinic acid Drugs 0.000 claims description 7
- 235000015097 nutrients Nutrition 0.000 claims description 7
- 235000008935 nutritious Nutrition 0.000 claims description 7
- 229960002477 riboflavin Drugs 0.000 claims description 7
- 230000001502 supplementing effect Effects 0.000 claims description 7
- 235000019157 thiamine Nutrition 0.000 claims description 7
- 239000011721 thiamine Substances 0.000 claims description 7
- 235000019163 vitamin B12 Nutrition 0.000 claims description 7
- 239000011715 vitamin B12 Substances 0.000 claims description 7
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 claims description 6
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 claims description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 6
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims description 6
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 claims description 6
- 229930003316 Vitamin D Natural products 0.000 claims description 6
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims description 6
- 229930003448 Vitamin K Natural products 0.000 claims description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 6
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 claims description 6
- 229910052802 copper Inorganic materials 0.000 claims description 6
- 239000010949 copper Substances 0.000 claims description 6
- 229940108928 copper Drugs 0.000 claims description 6
- 239000011777 magnesium Substances 0.000 claims description 6
- 229910052749 magnesium Inorganic materials 0.000 claims description 6
- 235000001968 nicotinic acid Nutrition 0.000 claims description 6
- 239000011664 nicotinic acid Substances 0.000 claims description 6
- 235000019161 pantothenic acid Nutrition 0.000 claims description 6
- 239000011713 pantothenic acid Substances 0.000 claims description 6
- 229940055726 pantothenic acid Drugs 0.000 claims description 6
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 claims description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 6
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 claims description 6
- 235000019192 riboflavin Nutrition 0.000 claims description 6
- 239000002151 riboflavin Substances 0.000 claims description 6
- 229910052711 selenium Inorganic materials 0.000 claims description 6
- 239000011669 selenium Substances 0.000 claims description 6
- 235000019155 vitamin A Nutrition 0.000 claims description 6
- 239000011719 vitamin A Substances 0.000 claims description 6
- 235000019158 vitamin B6 Nutrition 0.000 claims description 6
- 239000011726 vitamin B6 Substances 0.000 claims description 6
- 235000019166 vitamin D Nutrition 0.000 claims description 6
- 239000011710 vitamin D Substances 0.000 claims description 6
- 150000003710 vitamin D derivatives Chemical class 0.000 claims description 6
- 235000019168 vitamin K Nutrition 0.000 claims description 6
- 239000011712 vitamin K Substances 0.000 claims description 6
- 150000003721 vitamin K derivatives Chemical class 0.000 claims description 6
- 229940045997 vitamin a Drugs 0.000 claims description 6
- 229940011671 vitamin b6 Drugs 0.000 claims description 6
- 229940046008 vitamin d Drugs 0.000 claims description 6
- 229940046010 vitamin k Drugs 0.000 claims description 6
- 239000011701 zinc Substances 0.000 claims description 6
- 229910052725 zinc Inorganic materials 0.000 claims description 6
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 5
- 229930003268 Vitamin C Natural products 0.000 claims description 5
- 229930003427 Vitamin E Natural products 0.000 claims description 5
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 5
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 5
- 230000000474 nursing effect Effects 0.000 claims description 5
- 235000019154 vitamin C Nutrition 0.000 claims description 5
- 239000011718 vitamin C Substances 0.000 claims description 5
- 235000019165 vitamin E Nutrition 0.000 claims description 5
- 229940046009 vitamin E Drugs 0.000 claims description 5
- 239000011709 vitamin E Substances 0.000 claims description 5
- 229940100198 alkylating agent Drugs 0.000 claims description 3
- 239000002168 alkylating agent Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- 238000001959 radiotherapy Methods 0.000 claims description 3
- 229930013930 alkaloid Natural products 0.000 claims description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 claims description 2
- 239000003242 anti bacterial agent Substances 0.000 claims description 2
- 230000000340 anti-metabolite Effects 0.000 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 claims description 2
- 229940088710 antibiotic agent Drugs 0.000 claims description 2
- 229940100197 antimetabolite Drugs 0.000 claims description 2
- 239000002256 antimetabolite Substances 0.000 claims description 2
- 235000020979 dietary recommendations Nutrition 0.000 claims 2
- 229940045799 anthracyclines and related substance Drugs 0.000 claims 1
- 230000037213 diet Effects 0.000 abstract description 92
- 230000000295 complement effect Effects 0.000 abstract description 6
- 201000010193 neural tube defect Diseases 0.000 description 127
- 241000699670 Mus sp. Species 0.000 description 71
- 230000008774 maternal effect Effects 0.000 description 56
- 230000037396 body weight Effects 0.000 description 55
- 241001465754 Metazoa Species 0.000 description 54
- 210000001161 mammalian embryo Anatomy 0.000 description 49
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 45
- 238000011287 therapeutic dose Methods 0.000 description 45
- GYOZYWVXFNDGLU-XLPZGREQSA-N dTMP Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)C1 GYOZYWVXFNDGLU-XLPZGREQSA-N 0.000 description 37
- 229940014144 folate Drugs 0.000 description 33
- 230000015572 biosynthetic process Effects 0.000 description 29
- 208000035581 susceptibility to neural tube defects Diseases 0.000 description 28
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 26
- 150000001875 compounds Chemical class 0.000 description 25
- 102100021225 Serine hydroxymethyltransferase, cytosolic Human genes 0.000 description 24
- 108090000623 proteins and genes Proteins 0.000 description 24
- 101001040808 Homo sapiens Serine hydroxymethyltransferase, cytosolic Proteins 0.000 description 23
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 22
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 22
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 22
- 229940104230 thymidine Drugs 0.000 description 22
- 201000010099 disease Diseases 0.000 description 21
- 108020004414 DNA Proteins 0.000 description 18
- 239000008280 blood Substances 0.000 description 18
- 239000000843 powder Substances 0.000 description 18
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 16
- 210000004369 blood Anatomy 0.000 description 16
- 241000699666 Mus <mouse, genus> Species 0.000 description 15
- 210000002381 plasma Anatomy 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- MEFKEPWMEQBLKI-AIRLBKTGSA-N S-adenosyl-L-methioninate Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-N 0.000 description 14
- 229960001570 ademetionine Drugs 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- 230000001771 impaired effect Effects 0.000 description 14
- 239000007788 liquid Substances 0.000 description 14
- 101000888214 Flaveria pringlei Serine hydroxymethyltransferase 1, mitochondrial Proteins 0.000 description 13
- 230000002503 metabolic effect Effects 0.000 description 13
- 229940035893 uracil Drugs 0.000 description 13
- -1 MRC Vitamin Chemical class 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- 230000004060 metabolic process Effects 0.000 description 12
- 206010010411 Congenital central nervous system anomaly Diseases 0.000 description 11
- 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 11
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 11
- 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 11
- 230000008859 change Effects 0.000 description 11
- 239000000284 extract Substances 0.000 description 11
- 229960001031 glucose Drugs 0.000 description 11
- 229930182817 methionine Natural products 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 238000011160 research Methods 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 238000010521 absorption reaction Methods 0.000 description 10
- 239000000872 buffer Substances 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 239000008103 glucose Substances 0.000 description 10
- 230000003993 interaction Effects 0.000 description 10
- 230000001404 mediated effect Effects 0.000 description 10
- 235000016709 nutrition Nutrition 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- 239000000546 pharmaceutical excipient Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- QYNUQALWYRSVHF-ABLWVSNPSA-N 5,10-methylenetetrahydrofolic acid Chemical compound C1N2C=3C(=O)NC(N)=NC=3NCC2CN1C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QYNUQALWYRSVHF-ABLWVSNPSA-N 0.000 description 9
- 241000196324 Embryophyta Species 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 210000000805 cytoplasm Anatomy 0.000 description 9
- 239000002552 dosage form Substances 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 9
- 235000019197 fats Nutrition 0.000 description 9
- 230000035764 nutrition Effects 0.000 description 9
- 229920001223 polyethylene glycol Polymers 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 8
- 150000001720 carbohydrates Chemical class 0.000 description 8
- 230000006860 carbon metabolism Effects 0.000 description 8
- 239000003995 emulsifying agent Substances 0.000 description 8
- 210000003743 erythrocyte Anatomy 0.000 description 8
- 238000002513 implantation Methods 0.000 description 8
- 210000004185 liver Anatomy 0.000 description 8
- 230000007246 mechanism Effects 0.000 description 8
- 239000002773 nucleotide Substances 0.000 description 8
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 8
- 229940045145 uridine Drugs 0.000 description 8
- 241000283973 Oryctolagus cuniculus Species 0.000 description 7
- 239000002202 Polyethylene glycol Substances 0.000 description 7
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 7
- 239000000443 aerosol Substances 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 235000013361 beverage Nutrition 0.000 description 7
- 235000014633 carbohydrates Nutrition 0.000 description 7
- 238000000576 coating method Methods 0.000 description 7
- 239000000796 flavoring agent Substances 0.000 description 7
- 235000013355 food flavoring agent Nutrition 0.000 description 7
- 230000036541 health Effects 0.000 description 7
- 125000003729 nucleotide group Chemical group 0.000 description 7
- 239000006072 paste Substances 0.000 description 7
- 235000002639 sodium chloride Nutrition 0.000 description 7
- 238000000638 solvent extraction Methods 0.000 description 7
- 235000000346 sugar Nutrition 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 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 6
- 229930006000 Sucrose Natural products 0.000 description 6
- 108010022394 Threonine synthase Proteins 0.000 description 6
- 238000000540 analysis of variance Methods 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 239000011248 coating agent Substances 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 238000007069 methylation reaction Methods 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 238000010172 mouse model Methods 0.000 description 6
- 239000002417 nutraceutical Substances 0.000 description 6
- 235000021436 nutraceutical agent Nutrition 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 210000000582 semen Anatomy 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000005720 sucrose Substances 0.000 description 6
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 5
- 102000005497 Thymidylate Synthase Human genes 0.000 description 5
- 230000027326 copulation Effects 0.000 description 5
- 230000007547 defect Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 238000007689 inspection Methods 0.000 description 5
- 230000000968 intestinal effect Effects 0.000 description 5
- 239000000787 lecithin Substances 0.000 description 5
- 235000010445 lecithin Nutrition 0.000 description 5
- 229940067606 lecithin Drugs 0.000 description 5
- 229940023488 pill Drugs 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 230000002335 preservative effect Effects 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 102000011848 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase Human genes 0.000 description 4
- 108010075604 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase Proteins 0.000 description 4
- 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 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 206010071602 Genetic polymorphism Diseases 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- 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 4
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 4
- 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 4
- 108010030837 Methylenetetrahydrofolate Reductase (NADPH2) Proteins 0.000 description 4
- 102000005954 Methylenetetrahydrofolate Reductase (NADPH2) Human genes 0.000 description 4
- 101100176165 Mus musculus Shmt1 gene Proteins 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 108010073771 Soybean Proteins Proteins 0.000 description 4
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 230000005754 cellular signaling Effects 0.000 description 4
- 235000013351 cheese Nutrition 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 235000020940 control diet Nutrition 0.000 description 4
- 239000005547 deoxyribonucleotide Substances 0.000 description 4
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 210000002257 embryonic structure Anatomy 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 210000003754 fetus Anatomy 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 238000002372 labelling Methods 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 235000021416 maternal diet Nutrition 0.000 description 4
- 230000037353 metabolic pathway Effects 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 238000011321 prophylaxis Methods 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 4
- 235000019710 soybean protein Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 210000001215 vagina Anatomy 0.000 description 4
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 3
- 102100022900 Actin, cytoplasmic 1 Human genes 0.000 description 3
- 108010085238 Actins Proteins 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 3
- 241000283074 Equus asinus Species 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical group OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 102000002667 Glycine hydroxymethyltransferase Human genes 0.000 description 3
- 108010043428 Glycine hydroxymethyltransferase Proteins 0.000 description 3
- 240000007594 Oryza sativa Species 0.000 description 3
- 235000007164 Oryza sativa Nutrition 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 244000269722 Thea sinensis Species 0.000 description 3
- 108090000848 Ubiquitin Proteins 0.000 description 3
- 102000044159 Ubiquitin Human genes 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 3
- 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 3
- 230000004913 activation Effects 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
- 229940043376 ammonium acetate Drugs 0.000 description 3
- 230000003466 anti-cipated effect Effects 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 239000000440 bentonite Substances 0.000 description 3
- 229910000278 bentonite Inorganic materials 0.000 description 3
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 3
- 230000036760 body temperature Effects 0.000 description 3
- 239000001506 calcium phosphate Substances 0.000 description 3
- 229940077731 carbohydrate nutrients Drugs 0.000 description 3
- 239000003153 chemical reaction reagent Substances 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
- 239000002131 composite material Substances 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000002702 enteric coating Substances 0.000 description 3
- 238000009505 enteric coating Methods 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- 229930182470 glycoside Natural products 0.000 description 3
- 150000002338 glycosides Chemical class 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 235000013372 meat Nutrition 0.000 description 3
- 229960004961 mechlorethamine Drugs 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000011785 micronutrient Substances 0.000 description 3
- 235000013369 micronutrients Nutrition 0.000 description 3
- 235000013336 milk Nutrition 0.000 description 3
- 239000008267 milk Substances 0.000 description 3
- 210000004080 milk Anatomy 0.000 description 3
- 150000002772 monosaccharides Chemical class 0.000 description 3
- 230000016087 ovulation Effects 0.000 description 3
- 239000011505 plaster Substances 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 3
- 230000002285 radioactive effect Effects 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 235000009566 rice Nutrition 0.000 description 3
- 235000014438 salad dressings Nutrition 0.000 description 3
- 229940091258 selenium supplement Drugs 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000002269 spontaneous effect Effects 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 229940032147 starch Drugs 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000007619 statistical method Methods 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 2
- ZNOVTXRBGFNYRX-UHFFFAOYSA-N 2-[[4-[(2-amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-UHFFFAOYSA-N 0.000 description 2
- MSTNYGQPCMXVAQ-KIYNQFGBSA-N 5,6,7,8-tetrahydrofolic acid Chemical compound N1C=2C(=O)NC(N)=NC=2NCC1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-KIYNQFGBSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 101100518995 Caenorhabditis elegans pax-3 gene Proteins 0.000 description 2
- 208000005623 Carcinogenesis Diseases 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- 108010076119 Caseins Proteins 0.000 description 2
- 102000011632 Caseins Human genes 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 230000007067 DNA methylation Effects 0.000 description 2
- 208000006558 Dental Calculus Diseases 0.000 description 2
- AHCYMLUZIRLXAA-SHYZEUOFSA-N Deoxyuridine 5'-triphosphate Chemical compound O1[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)C[C@@H]1N1C(=O)NC(=O)C=C1 AHCYMLUZIRLXAA-SHYZEUOFSA-N 0.000 description 2
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 2
- 108010082495 Dietary Plant Proteins Proteins 0.000 description 2
- 102100024746 Dihydrofolate reductase Human genes 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 102000006933 Hydroxymethyl and Formyl Transferases Human genes 0.000 description 2
- 108010072462 Hydroxymethyl and Formyl Transferases Proteins 0.000 description 2
- 102000018251 Hypoxanthine Phosphoribosyltransferase Human genes 0.000 description 2
- 108010091358 Hypoxanthine Phosphoribosyltransferase Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 102000004407 Lactalbumin Human genes 0.000 description 2
- 108090000942 Lactalbumin Proteins 0.000 description 2
- 241000186660 Lactobacillus Species 0.000 description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 2
- 208000002720 Malnutrition Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 206010069666 Methylenetetrahydrofolate reductase polymorphism Diseases 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 101100518997 Mus musculus Pax3 gene Proteins 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 244000173166 Pyrus ussuriensis Species 0.000 description 2
- 235000011572 Pyrus ussuriensis Nutrition 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 230000018199 S phase Effects 0.000 description 2
- ZJUKTBDSGOFHSH-WFMPWKQPSA-N S-Adenosylhomocysteine Chemical compound O[C@@H]1[C@H](O)[C@@H](CSCC[C@H](N)C(O)=O)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZJUKTBDSGOFHSH-WFMPWKQPSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 201000010829 Spina bifida Diseases 0.000 description 2
- 208000006097 Spinal Dysraphism Diseases 0.000 description 2
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 241000218636 Thuja Species 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 239000000619 acesulfame-K Substances 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000012752 auxiliary agent Substances 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
- 239000011230 binding agent Substances 0.000 description 2
- 239000000227 bioadhesive Substances 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 229960003563 calcium carbonate Drugs 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 108010033929 calcium caseinate Proteins 0.000 description 2
- 230000036952 cancer formation Effects 0.000 description 2
- 231100000504 carcinogenesis Toxicity 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 201000002758 colorectal adenoma Diseases 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 235000014510 cooky Nutrition 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 229940109275 cyclamate Drugs 0.000 description 2
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 229960003901 dacarbazine Drugs 0.000 description 2
- 235000021185 dessert Nutrition 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 2
- 229940038472 dicalcium phosphate Drugs 0.000 description 2
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 108020001096 dihydrofolate reductase Proteins 0.000 description 2
- 239000003792 electrolyte Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000002710 external beam radiation therapy Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 230000035558 fertility Effects 0.000 description 2
- 230000001605 fetal effect Effects 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 235000013312 flour Nutrition 0.000 description 2
- 150000002224 folic acids Chemical class 0.000 description 2
- 235000012041 food component Nutrition 0.000 description 2
- 239000005417 food ingredient Substances 0.000 description 2
- 150000004675 formic acid derivatives Chemical class 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 102000054767 gene variant Human genes 0.000 description 2
- 239000003292 glue Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229940039696 lactobacillus Drugs 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 235000021056 liquid food Nutrition 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 230000001071 malnutrition Effects 0.000 description 2
- 235000000824 malnutrition Nutrition 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 230000013011 mating Effects 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 230000002906 microbiologic effect Effects 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000002366 mineral element Substances 0.000 description 2
- 229940029985 mineral supplement Drugs 0.000 description 2
- 235000020786 mineral supplement Nutrition 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 235000020772 multivitamin supplement Nutrition 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 210000000276 neural tube Anatomy 0.000 description 2
- 208000030364 neural tube closure defect Diseases 0.000 description 2
- 230000004012 neuralation Effects 0.000 description 2
- 235000019520 non-alcoholic beverage Nutrition 0.000 description 2
- 230000012223 nuclear import Effects 0.000 description 2
- 208000015380 nutritional deficiency disease Diseases 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000008488 polyadenylation Effects 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 150000004804 polysaccharides Chemical class 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 235000010241 potassium sorbate Nutrition 0.000 description 2
- 239000004302 potassium sorbate Substances 0.000 description 2
- 229940069338 potassium sorbate Drugs 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- 235000011962 puddings Nutrition 0.000 description 2
- 235000021251 pulses Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 235000015067 sauces Nutrition 0.000 description 2
- 238000010008 shearing Methods 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000014347 soups Nutrition 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 229960001052 streptozocin Drugs 0.000 description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- TYWMIZZBOVGFOV-UHFFFAOYSA-N tetracosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCO TYWMIZZBOVGFOV-UHFFFAOYSA-N 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 229940120293 vaginal suppository Drugs 0.000 description 2
- 239000006216 vaginal suppository Substances 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 210000001835 viscera Anatomy 0.000 description 2
- 239000000341 volatile oil Substances 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- 235000013618 yogurt Nutrition 0.000 description 2
- 239000011787 zinc oxide Substances 0.000 description 2
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- IRICHAOGAOFEQI-UHFFFAOYSA-N (1-bromo-2,2,2-trifluoroethyl)benzene Chemical compound FC(F)(F)C(Br)C1=CC=CC=C1 IRICHAOGAOFEQI-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- QWWVBNODQCWBAZ-WHFBIAKZSA-N (2r)-2-amino-3-[(2r)-2-carboxy-2-(methylamino)ethyl]sulfanylpropanoic acid Chemical compound CN[C@H](C(O)=O)CSC[C@H](N)C(O)=O QWWVBNODQCWBAZ-WHFBIAKZSA-N 0.000 description 1
- SPFMQWBKVUQXJV-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;hydrate Chemical compound O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O SPFMQWBKVUQXJV-BTVCFUMJSA-N 0.000 description 1
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical compound CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- ISAKRJDGNUQOIC-MPOCSFTDSA-N 1h-pyrimidine-2,4-dione Chemical compound O=C1C=C[15NH]C(=O)[15NH]1 ISAKRJDGNUQOIC-MPOCSFTDSA-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
- FCAJYRVEBULFKS-UHFFFAOYSA-N 2-(oxolan-2-yl)ethanol Chemical compound OCCC1CCCO1 FCAJYRVEBULFKS-UHFFFAOYSA-N 0.000 description 1
- QXLQZLBNPTZMRK-UHFFFAOYSA-N 2-[(dimethylamino)methyl]-1-(2,4-dimethylphenyl)prop-2-en-1-one Chemical compound CN(C)CC(=C)C(=O)C1=CC=C(C)C=C1C QXLQZLBNPTZMRK-UHFFFAOYSA-N 0.000 description 1
- YFBQXUGQIFAFMM-UHFFFAOYSA-N 2-chloro-n-methylethanamine Chemical compound CNCCCl YFBQXUGQIFAFMM-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- PMYDPQQPEAYXKD-UHFFFAOYSA-N 3-hydroxy-n-naphthalen-2-ylnaphthalene-2-carboxamide Chemical compound C1=CC=CC2=CC(NC(=O)C3=CC4=CC=CC=C4C=C3O)=CC=C21 PMYDPQQPEAYXKD-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
- UJFBVNPYHVIYBF-UHFFFAOYSA-N 5-o-(2-bromoethyl) 3-o-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCBr)C1C1=CC=CC([N+]([O-])=O)=C1 UJFBVNPYHVIYBF-UHFFFAOYSA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 1
- 235000007173 Abies balsamea Nutrition 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 229930195573 Amycin Natural products 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 239000004857 Balsam Substances 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000218645 Cedrus Species 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 240000004307 Citrus medica Species 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 1
- 239000005751 Copper oxide Substances 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 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
- 231100000277 DNA damage Toxicity 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 238000007400 DNA extraction Methods 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 208000035126 Facies Diseases 0.000 description 1
- PMVSDNDAUGGCCE-TYYBGVCCSA-L Ferrous fumarate Chemical compound [Fe+2].[O-]C(=O)\C=C\C([O-])=O PMVSDNDAUGGCCE-TYYBGVCCSA-L 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 102100025413 Formyltetrahydrofolate synthetase Human genes 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 208000031448 Genomic Instability Diseases 0.000 description 1
- 208000008051 Hereditary Nonpolyposis Colorectal Neoplasms Diseases 0.000 description 1
- 208000017095 Hereditary nonpolyposis colon cancer Diseases 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 101000897441 Homo sapiens Cyclin-O Proteins 0.000 description 1
- 101000934942 Homo sapiens Formyltetrahydrofolate synthetase Proteins 0.000 description 1
- 101000587058 Homo sapiens Methylenetetrahydrofolate reductase Proteins 0.000 description 1
- 101000807668 Homo sapiens Uracil-DNA glycosylase Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 244000018716 Impatiens biflora Species 0.000 description 1
- 206010022034 Iniencephaly Diseases 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 235000017858 Laurus nobilis Nutrition 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- LPGWZGMPDKDHEP-HLTPFJCJSA-N Leurosine Chemical compound C([C@]1([C@@H]2O1)CC)N(CCC=1C3=CC=CC=C3NC=11)C[C@H]2C[C@]1(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC LPGWZGMPDKDHEP-HLTPFJCJSA-N 0.000 description 1
- 201000005027 Lynch syndrome Diseases 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000025972 Maternal Obesity Diseases 0.000 description 1
- 208000005377 Meningomyelocele Diseases 0.000 description 1
- 102100029684 Methylenetetrahydrofolate reductase Human genes 0.000 description 1
- 206010027514 Metrorrhagia Diseases 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 101150026263 Mthfd1 gene Proteins 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 238000002944 PCR assay Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 108020002230 Pancreatic Ribonuclease Proteins 0.000 description 1
- 102000005891 Pancreatic ribonuclease Human genes 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108091036333 Rapid DNA Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000000729 Schizencephaly Diseases 0.000 description 1
- 101710084636 Serine hydroxymethyltransferase Proteins 0.000 description 1
- 101710099809 Serine hydroxymethyltransferase, cytosolic Proteins 0.000 description 1
- 101710087362 Serine hydroxymethyltransferase, mitochondrial Proteins 0.000 description 1
- 102000019394 Serine hydroxymethyltransferases Human genes 0.000 description 1
- 108050006939 Serine hydroxymethyltransferases Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 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
- 239000004283 Sodium sorbate Substances 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 244000125380 Terminalia tomentosa Species 0.000 description 1
- 235000005212 Terminalia tomentosa Nutrition 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 108010072685 Uracil-DNA Glycosidase Proteins 0.000 description 1
- 102000006943 Uracil-DNA Glycosidase Human genes 0.000 description 1
- 102100037111 Uracil-DNA glycosylase Human genes 0.000 description 1
- 229910052770 Uranium Inorganic materials 0.000 description 1
- DJJCXFVJDGTHFX-UHFFFAOYSA-N Uridinemonophosphate Natural products OC1C(O)C(COP(O)(O)=O)OC1N1C(=O)NC(=O)C=C1 DJJCXFVJDGTHFX-UHFFFAOYSA-N 0.000 description 1
- FOGRQMPFHUHIGU-UHFFFAOYSA-N Uridylic acid Natural products OC1C(OP(O)(O)=O)C(CO)OC1N1C(=O)NC(=O)C=C1 FOGRQMPFHUHIGU-UHFFFAOYSA-N 0.000 description 1
- 235000009499 Vanilla fragrans Nutrition 0.000 description 1
- 244000263375 Vanilla tahitensis Species 0.000 description 1
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 1
- 229930003451 Vitamin B1 Natural products 0.000 description 1
- 229930003471 Vitamin B2 Natural products 0.000 description 1
- 229930003537 Vitamin B3 Natural products 0.000 description 1
- 235000019498 Walnut oil Nutrition 0.000 description 1
- 239000005862 Whey Substances 0.000 description 1
- 102000007544 Whey Proteins Human genes 0.000 description 1
- 108010046377 Whey Proteins Proteins 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- FRYDSOYOHWGSMD-UHFFFAOYSA-N [C].O Chemical group [C].O FRYDSOYOHWGSMD-UHFFFAOYSA-N 0.000 description 1
- PRPAGESBURMWTI-UHFFFAOYSA-N [C].[F] Chemical compound [C].[F] PRPAGESBURMWTI-UHFFFAOYSA-N 0.000 description 1
- SXWZKIXXIJHINC-UHFFFAOYSA-N [N].C1(=CC=CC=C1)CCCC(=O)O Chemical compound [N].C1(=CC=CC=C1)CCCC(=O)O SXWZKIXXIJHINC-UHFFFAOYSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 235000010358 acesulfame potassium Nutrition 0.000 description 1
- 229960004998 acesulfame potassium Drugs 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 235000013334 alcoholic beverage Nutrition 0.000 description 1
- 229960005310 aldesleukin Drugs 0.000 description 1
- 108700025316 aldesleukin Proteins 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 206010002320 anencephaly Diseases 0.000 description 1
- 150000001454 anthracenes Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- 239000008122 artificial sweetener Substances 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 230000000680 avirulence Effects 0.000 description 1
- 235000013405 beer Nutrition 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 235000021028 berry Nutrition 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000012742 biochemical analysis Methods 0.000 description 1
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000002725 brachytherapy Methods 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000012928 buffer substance Substances 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 210000001217 buttock Anatomy 0.000 description 1
- 235000012970 cakes Nutrition 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 description 1
- 229960002079 calcium pantothenate Drugs 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 229940071162 caseinate Drugs 0.000 description 1
- 229940021722 caseins Drugs 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- 239000008370 chocolate flavor Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 239000001926 citrus aurantium l. subsp. bergamia wright et arn. oil Substances 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 1
- 229960003608 clomifene Drugs 0.000 description 1
- 229960002896 clonidine Drugs 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
- 230000000052 comparative effect Effects 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229910000431 copper oxide Inorganic materials 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- JSRLJPSBLDHEIO-SHYZEUOFSA-N dUMP Chemical compound O1[C@H](COP(O)(O)=O)[C@@H](O)C[C@@H]1N1C(=O)NC(=O)C=C1 JSRLJPSBLDHEIO-SHYZEUOFSA-N 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 208000016384 diabetic embryopathy Diseases 0.000 description 1
- 235000019621 digestibility Nutrition 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 231100001238 environmental toxicant Toxicity 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 150000002168 ethanoic acid esters Chemical class 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000007046 ethoxylation reaction Methods 0.000 description 1
- OPCRGEVPIBLWAY-QNRZBPGKSA-N ethyl (2E,4Z)-deca-2,4-dienoate Chemical compound CCCCC\C=C/C=C/C(=O)OCC OPCRGEVPIBLWAY-QNRZBPGKSA-N 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
- 229960005420 etoposide Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 235000013410 fast food Nutrition 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000011773 ferrous fumarate Substances 0.000 description 1
- 235000002332 ferrous fumarate Nutrition 0.000 description 1
- 229960000225 ferrous fumarate Drugs 0.000 description 1
- 230000004720 fertilization Effects 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 235000012020 french fries Nutrition 0.000 description 1
- 235000015203 fruit juice Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 231100000722 genetic damage Toxicity 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 101150108262 gnrh1 gene Proteins 0.000 description 1
- 235000015201 grapefruit juice Nutrition 0.000 description 1
- 235000013882 gravy Nutrition 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 235000013402 health food Nutrition 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 235000008216 herbs Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 201000009075 hydranencephaly Diseases 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 230000006607 hypermethylation Effects 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 235000015243 ice cream Nutrition 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 235000015122 lemonade Nutrition 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 229940099596 manganese sulfate Drugs 0.000 description 1
- 239000011702 manganese sulphate Substances 0.000 description 1
- 235000007079 manganese sulphate Nutrition 0.000 description 1
- SQQMAOCOWKFBNP-UHFFFAOYSA-L manganese(II) sulfate Chemical compound [Mn+2].[O-]S([O-])(=O)=O SQQMAOCOWKFBNP-UHFFFAOYSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000008268 mayonnaise Substances 0.000 description 1
- 235000010746 mayonnaise Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 235000013622 meat product Nutrition 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 210000002418 meninge Anatomy 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 235000013384 milk substitute Nutrition 0.000 description 1
- 235000020166 milkshake Nutrition 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- ZDZOTLJHXYCWBA-BSEPLHNVSA-N molport-006-823-826 Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-BSEPLHNVSA-N 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 201000003152 motion sickness Diseases 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 239000002088 nanocapsule Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N nicotinic acid amide Natural products NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000020925 non fasting Nutrition 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000012149 noodles Nutrition 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 230000037360 nucleotide metabolism Effects 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- 235000014571 nuts Nutrition 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 235000015205 orange juice Nutrition 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 235000017802 other dietary supplement Nutrition 0.000 description 1
- 238000009400 out breeding Methods 0.000 description 1
- 230000027758 ovulation cycle Effects 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 235000021400 peanut butter Nutrition 0.000 description 1
- 229960001744 pegaspargase Drugs 0.000 description 1
- 108010001564 pegaspargase Proteins 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 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
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229940013712 pineapple extract Drugs 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 208000022131 polyp of large intestine Diseases 0.000 description 1
- 208000015768 polyposis Diseases 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 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
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000004300 potassium benzoate Substances 0.000 description 1
- 235000010235 potassium benzoate Nutrition 0.000 description 1
- 229940103091 potassium benzoate Drugs 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 238000000751 protein extraction Methods 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 description 1
- 239000011764 pyridoxine hydrochloride Substances 0.000 description 1
- 229960004172 pyridoxine hydrochloride Drugs 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 239000012744 reinforcing agent Substances 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 230000009933 reproductive health Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000020509 sex determination Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 230000005586 smoking cessation Effects 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940080237 sodium caseinate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000011655 sodium selenate Substances 0.000 description 1
- 235000018716 sodium selenate Nutrition 0.000 description 1
- 229960001881 sodium selenate Drugs 0.000 description 1
- LROWVYNUWKVTCU-STWYSWDKSA-M sodium sorbate Chemical compound [Na+].C\C=C\C=C\C([O-])=O LROWVYNUWKVTCU-STWYSWDKSA-M 0.000 description 1
- 235000019250 sodium sorbate Nutrition 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 235000014214 soft drink Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 208000001916 spina bifida cystica Diseases 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 235000011496 sports drink Nutrition 0.000 description 1
- 238000000528 statistical test Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000008080 stochastic effect Effects 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000009182 swimming Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 235000015149 toffees Nutrition 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical class [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- DJJCXFVJDGTHFX-XVFCMESISA-N uridine 5'-monophosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 DJJCXFVJDGTHFX-XVFCMESISA-N 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 235000010374 vitamin B1 Nutrition 0.000 description 1
- 239000011691 vitamin B1 Substances 0.000 description 1
- 208000002670 vitamin B12 deficiency Diseases 0.000 description 1
- 235000019164 vitamin B2 Nutrition 0.000 description 1
- 239000011716 vitamin B2 Substances 0.000 description 1
- 235000019160 vitamin B3 Nutrition 0.000 description 1
- 239000011708 vitamin B3 Substances 0.000 description 1
- 239000008170 walnut oil Substances 0.000 description 1
- 210000001325 yolk sac Anatomy 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/13—Nucleic acids or derivatives thereof
-
- 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
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Pathology (AREA)
- Radiology & Medical Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及一种药物或膳食组合物,所述组合物包括脱氧尿苷和药学上或膳食上适宜的载体。本发明的另一个方面涉及一种为主体补充膳食需要的方法。该方法包括向主体施予膳食补充有效量的脱氧尿苷。本发明的又一个方面涉及一种在主体中治疗癌症的方法。该方法包括选择患有癌症的主体以及向所选择的主体施予治疗有效量的尿苷,从而治疗所选择的主体的癌症。
Description
本申请要求2011年4月25日提交的序列号为61/478,669的和2011年8月5日提交的序列号为61/515,356的美国临时专利申请的优先权,其整体通过引用并入本文。
本发明在国家卫生研究院-国家儿童保健和人类发展研究院资助的基金号为HD059120的政府支持下完成。政府对本发明拥有一定权利。
发明领域
本发明涉及包括脱氧尿苷的组合物及其使用方法。本发明还涉及包括尿苷的组合物,及使用其治疗和/或预防癌症的方法。
发明背景
叶酸介导的一碳代谢是嘌呤、胸苷酸(“dTMP”)从头生物合成和高半胱氨酸再次甲基化成甲硫氨酸(图1)所需的相互依赖的生物合成途径的代谢网络(Barry Shane,FolateChemistry and Metabolism,in FOLATE IN HEALTH AND DISEASE1-22(Lynn B.Bailey ed.,Marcel Dekker,Inc.1995))。甲硫氨酸能够转化成S-腺苷甲硫氨酸(“AdoMet”),AdoMet为用于细胞甲基化反应的主要一碳供体,所述细胞甲基化反应包括DNA、RNA、磷脂、蛋白和小分子的甲基化(Barry Shane,Folate Chemistry and Metabolism,in FOLATE IN HEALTH ANDDISEASE1-22(Lynn B.Bailey ed.,Marcel Dekker,Inc.1995);Fox等,“Folate-MediatedOne-Carbon Metabolism,”Vitam.Horm.79:1-44(2008))。因为营养缺乏和/或单核苷酸多态性造成的一碳代谢受损使dTMP合成减少,导致脱氧尿苷酸(“dUTP”)池增加、dUTP误掺入DNA的比率升高,从而造成DNA切除修复的无效循环和染色体链断裂(James等,“Diet-Induced DNA Damage and Altered Nucleotide Metabolism in Lymphocytes fromMethyl-Donor-Deficient Rats,”Carcinogenesis 10(7):1209-1214(1989);Branda等,“Folate Deficiency Increases Genetic Damage Caused by Alkylating Agents andGamma-Irradiation in Chinese Hamster Ovary Cells,”Cancer Res.53(22):5401-5408(1993);Duthie等,“DNA Instability(Strand Breakage,Uracil Misincorporation,andDefective Repair)is Increased by Folic Acid Depletion in Human Lymphocytes inVitro,”Faseb.J.12(14):1491-1497(1998))。
叶酸代谢的改变还会影响染色质的甲基化模式,包括全基因组CpG低甲基化和位点特异性高甲基化,以及组蛋白甲基化的改变,其改变基因的表达模式(Wainfan等,“Methyl Groups in Carcinogenesis:Effects on DNA Methylation and GeneExpression,”Cancer Res.52(7Suppl):2071s-2077s(1992);Friso等,“A CommonMutation in the5,10-Methylenetetrahydrofolate Reductase Gene Affects GenomicDNA Methylation Through an Interaction with Folate Status,”Proc.Natl.Acad.Sci.U.S.A.99(8):5606-5611(2002);Gaudet等,“Induction of Tumorsin Mice by Genomic Hypomethylation,”Science300(5618):489-492(2003))。
因此,基因组不稳定性增加导致的DNA完整性丧失和/或基因组甲基化改变导致的基因表达改变是叶酸介导病理学的候选病因通路。群体和临床研究已经发现由于营养缺乏和/或一碳代谢基因的突变导致的叶酸介导的一碳代谢受损会增加出生缺陷包括神经管缺损(“NTD”)、慢性疾病包括心血管疾病和某些癌症的风险。然而,尚未建立其分子机制和预测疾病风险的生物标记物。
例如,在胚胎形成过程中,通过神经胚形成神经上皮弯曲并融合形成胚胎神经管。将神经胚形成失败导致的发育谱异常统称为神经管闭合缺陷。在世界范围内人NTD的发病率范围为每10,000个新生儿<1-30(INTERNATIONALCLEARINGHOUSE FOR BIRTH DEFECTS MONITORINGSYSTEMS,WORLD ATLAS OF BIRTHDEFECTS(World Health Organization,2d ed.2003))。导致NTD风险的最强的环境决定因素之一为母体叶酸状况较低(Kirke等,“Maternal Plasma Folateand Vitamin B12are Independent Risk Factors for Neural Tube Defects,”Q.J.Med.1993;86:703–8(1993)),其与特定基因变体相互作用导致NTD风险(Relton等,“Low Erythrocyte Folate Status and Polymorphic Variation in Folate-RelatedGenes are Associated with Risk of Neural Tube Defect Pregnancy,”Mol.Genet.Metab.81:273–81(2004);Christensen等,“Genetic Polymorphisms inMethylenetetrahydrofolate Reductase and Methionine Synthase,Folate Levels inRed Blood Cells,and Risk of Neural Tube Defects,”Am.J.Med.Genet.84:1517(1999))。
母体叶酸状况较低是导致神经管缺陷风险最强的环境决定因素之一(Kirke等,“Maternal Plasma Folate and Vitamin B12are Independent Risk Factors forNeuralTube Defects,”Q.J.Med.86(11):703-708(1993))并且其与特定基因变体之间的相互作用引起NTD风险(Relton等,“Low Erythrocyte Folate Status and Polymorphic Variationin Folate-Related Genes are Associated with Risk of Neural Tube DefectPregnancy,”Mol.Genet.Metab.81(4):273-281(2004);Christensen等,“GeneticPolymorphisms in Methylenetetrahydrofolate Reductase and Methionine Synthase,Folate Levels in Red Blood Cells,and Risk of Neural Tube Defects,”Am.J.Med.Genet.84(2):151-157(1999))。推荐所有育龄妇女的叶酸摄入水平为每日400μg以减少NTD的发生(CDC,“Recommendations for the Use of Folic Acid to Reduce theNumber of Cases of Spina Bifida and Other Neural Tube Defects,”MMWRRecomm.Rep.41(1-7)(1992))。而且,在美国、加拿大和智利已引入食品叶酸强化(Honein等,“Impact of Folic Acid Fortification of the US Food Supply on theOccurrence of Neural Tube Defects,”JAMA285(23):2981-2986(2001))并且其显著降低了神经管缺陷的比率(Czeizel等,“Prevention of the First Occurrence of Neural-Tube Defects by Periconceptional Vitamin Supplementation,”N.Engl.J.Med.327(26):1832-1835(1992);Medical Research Council“Prevention of Neural TubeDefects:Results of the Medical Research Council Vitamin Study.MRC VitaminStudy Research Group,”Lancet338:131–7(1991))。然而,尚不知晓影响神经管闭合的叶酸依赖性代谢通路。预计仅有70%的NTD对膳食叶酸有应答(Berry等,“Prevention ofNeural-Tube Defects with Folic Acid in China.China-U.S.Collaborative Projectfor Neural Tube Defect Prevention,”N.Engl.J.Med.341(20):1485-1490(1999))。导致妊娠NTD的其它风险因素包括环境的和基于食物的毒素(Bhatt,“EnvironmentalInfluence on Reproductive Health,”Intl.J.Gynecology&Obstetrics70(1):69-75(2000);Hutz等,“Environmental Toxicants and Effects on Female ReproductiveFunction,”Trends Rep.Biol.2:1-11(2006))、肥胖(Leddy等,“The Impact of MaternalObesity on Maternal and Fetal Health,”Rev.Obstetrics&Gynecology1(4):170-178(2008))和母体糖尿病(Hendricks等,“Effects of Hyperinsulinemia and Obesity onRisk of Neural Tube Defects Among Mexican Americans,”Epidemiology12(6):630-635(2001))。尚不知晓对叶酸无应答的30%NTD的哪部分是由于叶酸介导的一碳代谢受损,包括维生素B12缺乏导致的代谢破坏,而引起的。尽管已经发现基因变体与叶酸状况之间的相互作用影响NTD的风险(Wlodarczyk等,“Spontaneous Neural Tube Defects inSplotch Mice Supplemented with Selected Micronutrients,”Toxicol.Appl.Pharmacol.(2005)),但是大多数的基因风险还有待鉴定(Beaudin等,“Insights into Metabolic Mechanisms Underlying Folate-Responsive Neural TubeDefects:A Minireview,”Birth Defects Res.A Clin.Mol.Teratol.85(4):274-284(2009))。
如上文所述,尚未建立揭示叶酸应答性NTD病因的代谢通路。而且,已发现补充叶酸与癌症的发生之间存在联系(Ebbing等,“Cancer Incidence and Mortality AfterTreatment With Folic Acid and Vitamin B12,”JAMA302(19):2119-2126(2009))。因此,非常有必要了解与叶酸缺乏相关的新生儿缺陷的发生和复发机制,以及提供补充叶酸的替代方案。
营养成分与遗传因子之间的相互作用在多种癌症包括结直肠癌(“CRC”)的发展过程中也起到了重要作用。已证实叶酸状况与CRC之间存在较强的负相关;与叶酸摄入最高的主体相比,膳食叶酸摄入最低主体CRC的风险增加40%至60%(Giovannucci等,“Folate,Methionine,and Alcohol intake and Risk of Colorectal Adenoma,”J.Natl.CancerInst.85:875–84(1993);Ma等,“Methylenetetrahydrofolate Reductase Polymorphism,Dietary Interactions,and Risk of Colorectal Cancer,”Cancer Res.57:1098–102(1997);Kim等,“Folate Intake and the Risk of Colorectal Cancer in a KoreanPopulation,”Eur.J.Clin.Nutr.63:1057–64(2009))。导致叶酸代谢和利用改变的变异也会影响癌症风险(Ma等,“Methylenetetrahydrofolate Reductase Polymorphism,DietaryInteractions,and Risk of Colorectal Cancer,”Cancer Res.57:1098–102(1997))。尚不知晓叶酸代谢改变CRC风险的机制,这导致了对提高膳食叶酸摄入和叶酸营养强化措施对CRC发病率潜在影响的关注(Cole等,“Folic Acid for the Prevention of ColorectalAdenomas:A Randomized Clinical Trial,”JAMA297:2351–9(2007);Logan等,“Aspirinand Folic Acid for the Prevention of Recurrent Colorectal Adenomas,”Gastroenterology134:29–38(2008))。
本发明旨在克服本领域的这些和其它缺陷。
发明概述
本发明的一个方面涉及一种药物或膳食组合物,所述组合物包括脱氧尿苷和药学上或膳食上适宜的载体。
本发明的另一个方面涉及一种补充主体膳食需要的方法。该方法包括施予主体膳食补充有效量的脱氧尿苷。
本发明的又一个方面涉及一种在主体中治疗癌症的方法。该方法包括选择患有癌症的主体和施予所选择的主体治疗有效量的尿苷,从而治疗所选择主体的癌症。
本发明证实了膳食尿苷降低对肠肿瘤敏感的小鼠的肿瘤数量,在妊娠期给小鼠母本喂养膳食尿苷增加神经管缺陷风险,在妊娠期给小鼠母本喂养膳食脱氧尿苷完全阻止了神经管缺陷。下文中的实施例证明了膳食尿苷和脱氧尿苷选择性阻止与叶酸相关的疾病。
最近,本发明人证实了在小鼠中降低SHMT1的表达增加小鼠结肠癌和出生缺陷的风险,表明该基因在叶酸相关疾病中起重要作用(Beaudin等,“Shmt1and de NovoThymidylate Biosynthesis Underlie Folate-Responsive Neural Tube Defects inMice,”Am.J.Clin.Nutr.93(4):789-798(2011);MacFarlane等,“Shmt1 HeterozygosityImpairs Folate-Dependent Thymidylate Synthesis Capacity and Modifies Risk ofApcmin-Mediated Intestinal Cancer Risk,”Cancer Res.71(6):2098-2107(2011),其通过引用整体并入本文)。这些研究还提示从尿苷酸(dUMP)合成胸苷酸(dTMP)的能力降低,其为Shmt+/-和Shmt-/-小鼠的主要代谢表型(MacFarlane等,“Cytoplasmic SerineHydroxymethyltransferase Regulates the Metabolic Partitioning ofMethylenetetrahydrofolate But is Not Essential in Mice,”J.Biol.Chem.283(38):25846-25853(2008),其通过引用整体并入本文),其为叶酸相关的出生缺陷、癌症以及其他叶酸应答性疾病的病因通路。
为更好地了解在出生缺陷和癌症风险中SHMT作用的病因机制,进行了通过在饮食中提供代谢中间体以救治Shmt+/-和Shmt-/-小鼠病症的实验。本发明(由下述实施例支持)令人惊讶地证实了使用脱氧尿苷(其为SHMT1参与的胸苷酸循环的底物)治疗小鼠,从而预防了用缺乏叶酸饮食喂养的Shmt+/-和Shmt-/-小鼠出现的出生缺陷,而尿苷(其为脱氧尿苷生物合成的前体)在用缺乏叶酸或对照饮食喂养的Shmt+/-和Shmt-/-妊娠小鼠中增加出生缺陷的比率。膳食尿苷增加出生缺陷是意想不到的,并且表明膳食尿苷在野生型胚胎中导致出生缺陷。实验数据令人惊讶地表明脱氧尿苷预防了出生缺陷。而且,在实施例14至19所示的相关研究中,给Apc-min小鼠(对肠肿瘤敏感)喂养了补充了尿苷的饮食。结果令人惊讶地显示喂养了尿苷的小鼠肿瘤减少了约50%。这些发现在预防和治疗叶酸缺乏相关疾病方面具有显著的进步。
附图说明
图1是叶酸介导的一碳代谢的示意图。四氢叶酸(“THF”)介导的一碳代谢是嘌呤、胸苷酸的合成,以及高半胱氨酸再次甲基化成甲硫氨酸所必需的。丝氨酸的羟甲基是一碳单元的主要来源,其在线粒体中以甲酸盐形式或者在细胞质中通过SHMT1的活性产生。线粒体来源的甲酸盐能够进入细胞质,并且作为用于叶酸代谢的一碳单元发挥功能。5,10-亚甲基THF能够在细胞质中由甲酸盐或丝氨酸产生,并且5,10-亚甲基THF的来源处于平衡状态。SHMT1酶还通过在细胞质中螯合5-甲基THF来抑制高半胱氨酸再次甲基化。胸苷酸合成通路涉及三种酶,即SHMT1、TYMS和DHFR。示意图中的缩写定义如下:MTHFR,亚甲基四氢叶酸还原酶;SHMT1,细胞质丝氨酸羟甲基转移酶;DHFR,二氢叶酸还原酶;TYMS,胸苷酸合成酶;MS,甲硫氨酸合成酶,AdoMet,S-腺苷甲硫氨酸;AdoHcy,S-腺苷高半胱氨酸;THF,四氢叶酸。一碳以粗体表示。
图2是显示与施予小鼠的实验饮食相关的细节的表。
图3是显示实验结果的表。特别地,在129/SvEv背景下的作为母本Shmt1基因型和饮食函数的Shmt1-缺陷胚胎的着床数、存活胚胎、死亡胚胎和神经管缺陷(NTD)频率。值以平均值±SEM表示;n=10-13胎仔,用于确定着床数以及存活胚胎、死亡胚胎和吸收。为保持一致,用于测定顶臀(CR)长度的胚胎仅考虑在妊娠第11.5天暴露的胎仔。计算CR长度作为母本饮食的函数(n=24-64)以及作为母本饮食和胚胎Shmt1基因型的函数(n=9-47)。使用用于post hoc分析的Tukey真正显著差检验通过2-因素ANOVA分析基因型、饮食和饮食x基因型相互作用之间的差异。统计学分析与C组比较。百分率列于括号中。图3所示的表中的注释如下文所示:1与C组相比,Post hoc分析未显示出死亡胚胎数和着床数上的任何显著性差异。2用于post hoc分析的Tukey真正显著差检验显示,与C饮食相比,FD和C+T饮食吸收的发生存在显著性差异。3通过使用改良的通用线性模型程序评估母本Shmt1基因型和母本饮食的主要影响。母本饮食显著影响Shmt1-/-基因型NTD的发生(χ2=43.565,P<0.0001);但不会影响Shmt1+/+基因型(P=0.21,不具有显著性(NS))。4采用独立的Fisher精确检验结合Bonferroni校正分析组间差异(饮食或基因型影响n=8,饮食x基因型影响n=16)。所有的神经管缺陷均表现为露脑畸形并且在妊娠第11.5-12.5天评估。与从用C饮食喂养的母本动物分离的胚胎相比,从用FD饮食喂养的母本动物分离的NTD数的P=0.037。与从用C饮食喂养的母本动物分离的胚胎相比,从用U饮食喂养的母本动物分离的NTD数的P=0.048。与从用C饮食喂养的母本动物分离的胚胎相比,从用FD+U饮食喂养的母本动物分离的NTD数的P=0.0021;与从用C饮食喂养的Shmt1-/-母本动物分离的胚胎相比,从用FD+U饮食喂养的Shmt1-/-母本动物分离的NTD数的P=0.042;与用FD+dU饮食喂养的母本动物分离的胚胎相比,从用FD+U饮食喂养的母本动物分离的NTD数的P=0.0133。5a从用C饮食喂养的母本动物分离的胚胎与从用FD饮食喂养的母本动物分离的胚胎存在显著性差异:(χ2=4.9669,P<0.0001)。5b从用C饮食喂养的Shmt1+/+母本动物分离的胚胎与从用C+dU喂养的Shmt1+/+母本动物分离的胚胎存在显著性差异,根据用于post hoc分析的Tukey真正显著差检验P<0.05。a=1NTD(Shmt1-/+,M);b=5NTD(均为Shmt1-/+,3M,2F)+2NTD死亡胚胎(2x Shmt1-/-,F);c=4NTD(3x Shmt1-/+,1x Shmt1+/+2M,2F)+1NTD死亡胚胎(Shmt1-/+,F);d=3(2x Shmt1-/+,1xShmt1-/-,1F,2M);e=3NTD(2x Shmt1-/+,1x Shmt1+/+,2M,1F)和1NTD死亡胚胎(Shmt1+/+,M);f=7NTD(3x Shmt1-/+,4x Shmt1-/-,5F,2M)和2NTD死亡胚胎(2x Shmt1-/-,M和F);g=2NTD(1xShmt1+/+,Shmt1-/+1M,1F);h=3NTD(2x Shmt1-/-,1x Shmt1-/+3M);F=雌性,M=雄性。
图4是显示实验结果的表。特别地,胚胎中NTD频率的结果作为母本饮食的函数表示。
图5是显示Shmt1+/+和Shmt1-/-雌性代谢水平的表。这些结果显示Shmt1+/+和Shmt1-/-小鼠显示出改变的血浆叶酸水平和血糖水平。在施予所述饮食5周后进行下述检测:肝脏DNA中的尿嘧啶;血浆中的尿苷、胸苷、脱氧尿苷和叶酸;以及血糖。施予的饮食如下文所示:AIN-93G作为对照(C);AIN-93G富含核苷酸(C+U;C+dU,C+T)和AIN-93G缺乏叶酸(FD;FD+U,FD+dU;FD+T)。组织值表示为:叶酸fmol/uL;葡萄糖mg/dL;尿嘧啶pg/ug DNA;以及尿苷、胸苷和脱氧胸苷uM。值以平均值±标准误差表示(n=4-7)。
图6是汇总结果的柱状图,其表明补充尿苷能够治疗肠肿瘤。用含0.1%脱氧尿苷的AIN93G饮食(C+dU);缺乏叶酸但含0.1%脱氧尿苷的AIN93G(FD+dU);缺乏叶酸但含0.2%胸苷的AIN93G(FD+T);缺乏叶酸但含0.6%尿苷的AIN93G(FD+U)或者缺乏叶酸的AIN93G(FD)喂养雄性Apc-min小鼠。与用FD饮食喂养的小鼠相比,用FD+U饮食喂养的小鼠的肿瘤减少接近50%(P=.02)。
发明详述
如上文所示,叶酸的功能是作为酶辅因子,其携带并化学活化用于统称为一碳代谢(“OCM”)的合成代谢通路网络的一碳。OCM是嘌呤和胸苷酸(dTMP)从头生物合成以及高半胱氨酸再次甲基化成甲硫氨酸所必需的。甲硫氨酸能够被腺苷酸化以形成S-腺苷甲硫氨酸(AdoMet),其为一种用于多种细胞甲基化反应的甲基供体(图1)。本发明人开发了首个叶酸代谢通路的基因受损导致叶酸应答性NTD的模型(Beaudin等,“Shmt1and De NovoThymidylate Biosynthesis Underlie Folate-Responsive Neural Tube Defects inMice,”Am.J.Clin.Nutr.93(4):789-798(2011),其通过引用整体并入本文)。这种基因-饮食相互作用与在人类中进行的NTD病症研究中发现的相互作用非常类似(Relton等,“LowErythrocyte Folate Status and Polymorphic Variation in Folate-Related Genesare Associated with Risk of Neural Tube Defect Pregnancy,”Mol.Genet.Metab.81(4):273-281(2004);Christensen等,“Genetic Polymorphisms inMethylenetetrahydrofolate Reductase and Methionine Synthase,Folate Levels inRed Blood Cells,and Risk of Neural Tube Defects,”Am.J.Med.Genet.84(2):151-157(1999),其通过引用整体并入本文)。Shmt1负责将丝氨酸酶解成甘氨酸产生一碳单元,其优选转移至胸苷酸的生物合成。Shmt1-/-和Shmt1+/-小鼠对叶酸应答性NTD敏感,并且表现出胸苷酸从头生物合成受损,因此其提供了一种研究NTD的基因-营养物相互作用的方法(Beaudin等,“Shmt1and De Novo Thymidylate Biosynthesis Underlie Folate-Responsive Neural Tube Defects in Mice,”Am.J.Clin.Nutr.93(4):789-798(2011),其通过引用整体并入本文)。
使用这种模型,令人惊讶地发现脱氧尿苷预防了与叶酸缺乏相关的出生缺陷以及补充尿苷导致与叶酸缺乏相关的出生缺陷。
相应地,本发明的一个方面涉及一种药物或膳食组合物,所述组合物包括脱氧尿苷。在一个实施方式中,所述组合物包括药学上或膳食上适宜的载体。
可以将本发明的化合物作为一种具有药学上或膳食上可接受载体的组合物来提供。这种剂型包括生理学上可接受的载体,所述载体自身是无毒性和无治疗作用的。此类载体的例子包括植物蛋白,大豆蛋白,离子交换剂,软凝胶,油,氧化铝,硬脂酸铝,卵磷脂,血清蛋白如人血清白蛋白,缓冲物质如磷酸盐、甘氨酸、山梨酸、山梨酸钾,饱和植物油脂肪酸部分甘油酯的混合物,水,盐,或电解质如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素物质和PEG。局部或凝胶形式的载体包括多糖如羧甲基纤维素钠或甲基纤维素、聚乙烯吡咯烷酮、聚丙烯酸酯、聚氧乙烯-聚氧丙烯嵌段共聚物、PEG和木蜡醇。在所有施予方法中,均适宜使用常规的储库形式。此类形式包括例如微囊、纳米囊、脂质体、硬膏剂、吸入形式、鼻用喷雾、舌下片和缓释制剂。
根据本发明,脱氧尿苷或尿苷(即,本发明的化合物)可以分别用于制备药品、营养食品、植物药、草药、食品补充剂、功能性食品、医疗食品、营养品、化妆品、饮料等。
相应地,在本发明的一个实施方式中,所述化合物或组合物是营养食品组合物、药物组合物、功能性食品、功能性营养品、医疗食品、医药营养品或膳食补充剂的一部分。
在某些实施方式中,本发明的化合物或组合物可以与草药组合。在其他实施方式中,本发明的化合物或组合物可以被制成植物药。植物药是由植物原料组成的产品,其可以包括植物原料、藻类、肉眼可见的真菌或其组合,其旨在用于诊断、治愈、缓解、治疗或预防人类疾病。在某些实施方式中,植物药品可以是(但不限于)溶液(例如,茶)、粉剂、片剂、胶囊、酏剂、局部用药或注射剂。
在某些实施方式中,可以将本发明的化合物或组合物制成营养食品制剂。所关注的营养食品制剂包括兽用或人用食品,包括健康食品棒、饮料和饮料补充剂等。通过引入本发明的组合物以改善这些食品。例如,在肠肿瘤的治疗中,可以定期地在患者的正常饮食中添加营养制剂。此类营养食品可以含有或不含卡路里。如本文所使用的,术语营养食品组合物包括食品、食料、膳食补充剂、营养补充剂或者食品或食料的补充剂组合。这样,在另一个实施方式中,本发明涉及一种营养食品,其中所述营养食品是一种食品、食料、膳食补充剂、营养补充剂或者食品或食料的补充剂组合。
如本文所使用的,术语食品指适于人或动物消耗的任何食物或饲料。所述食品可以是经制造和包装的食品(例如,蛋黄酱、色拉调料、面包或奶酪)或动物饲料(例如,经挤出和制粒的动物饲料、粗混饲料或宠物食品组合物)。如本文所使用的,术语食料指适于人或动物消耗的任意材料。食品或食料是,例如饮料如无酒精和酒精饮料以及加入到饮用水和液体食品中的液体制剂,无酒精饮料例如软饮料、运动饮料、果汁如橙汁、苹果汁和葡萄柚汁;柠檬水、茶、接近于水的饮料、牛奶、牛奶替代品,和其他日常饮料如酸奶,以及膳食饮料。在另一个实施方式中,食品或食料指包括本发明化合物或组合物的固体或半固体食品。这些形式可以包括但不限于烘焙食品如棒、蛋糕、饼干、布丁、奶制品、甜点、快餐或者冷冻甜点或新产品(例如,冰激凌,奶昔)、冷冻速食食品、糖果、休闲食品(例如,薯条)、液体食品如汤、涂抹酱、调味酱、色拉调料、速食肉类制品、奶酪、酸奶以及任意其他含有脂肪或油的食品和食品配料(例如,面粉)。术语食品或食料还包括功能食品和方便食品,后者指经批准供人消耗的任意预先包装的食品。术语功能食品或功能营养品指销售不受到任何限制(例如,在超市或网上)的食品或营养品。术语医疗食品或医疗营养品指需要医师处方的食品或营养品。
在某些实施方式中,可以将本发明的化合物或组合物制成膳食补充剂。本发明的膳食补充剂可以以任意适宜形式递送。在某些实施方式中,膳食补充剂制成口服递送的剂型。本发明的膳食补充剂成分包含在用于口服的可接受的赋形剂和/或载体中。所述载体可以是液体、凝胶、囊形片、胶囊、粉剂、固体片剂(包衣或未包衣)或茶等等。所述膳食补充剂优选地为片剂或胶囊形式。适宜的赋形剂和/或载体包括麦芽糖糊精、碳酸钙、磷酸氢二钙、磷酸三钙、微晶纤维素、右旋糖、米粉、硬脂酸镁、硬脂酸、交联羧甲基纤维素钠、羧甲基淀粉钠、交联聚维酮、蔗糖、植物胶、乳糖、甲基纤维素、聚维酮、羧甲基纤维素和玉米淀粉等(包括其混合物)。采用常规技术将多种成分以及赋形剂和/或载体混合并制成所需形式。可以使用在pH约6.0至7.0溶解的肠溶包衣将本发明的片剂或胶囊包衣。在小肠而非胃溶出的适宜肠溶包衣是纤维醋酸法酯。
在其他实施方式中,所述膳食补充剂是适于消费者加入食品或饮料中的粉末或液体。例如,在一些实施方式中,所述膳食补充剂可以以粉末形式施予主体,例如通过混入饮料或拌入半固体食品如布丁、浇头、调味酱、浓汤、煮熟的谷物或色拉调料中使用,例如或者以其他方式加入食品(例如,置于食品或饮料容器的盖中供使用前立即释放)。
所述膳食补充剂可以含有一种或多种惰性成分,特别是如果需要限制膳食补充剂加入饮食中的卡路里数时。例如,本发明的膳食补充剂还可以含有任选的成分包括,例如草药、维生素、矿物质、增强剂、着色剂、甜味剂、调味剂和惰性成分等等。
在其他实施方式中,本发明提供了营养补充剂(例如,能量棒或代餐棒或饮料),所述营养补充剂包括本发明的化合物或组合物。所述营养补充剂可以作为代餐品或休闲食品替代品,并且通常提供维持营养的卡路里。然而,如上文所示,还可以使用不含卡路里的补充剂。在某些实施方式中,所述营养补充剂提供处于平衡量的碳水化合物、蛋白和脂肪。所述营养补充剂可以进一步包括碳水化合物,单糖、中链糖或多糖,或者其组合。可以根据所需的感官特性选择单糖。生的玉米淀粉是复杂碳水化合物的一个例子。如果需要保持其高分子量结构,那只应包括在无需煮制或热处理的食品配方或部分中,因为加热会使复杂碳水化合物断裂成简单碳水化合物,其中简单碳水化合物是单糖或二糖。在一个实施方式中,所述营养补充剂含有三种水平链长的碳水化合物(简单、中链和复杂(例如,蔗糖、麦芽糖糊精和生玉米淀粉))的组合。
掺入本发明营养补充剂的蛋白来源可以是能够在营养配方中使用的任意适宜蛋白,并且可以包括乳清蛋白、乳清蛋白浓缩物、乳清粉、鸡蛋、大豆粉、豆奶、大豆蛋白、大豆蛋白分离物、酪蛋白酸盐(例如,酪蛋白酸钠、酪蛋白酸钙钠、酪蛋白酸钙、酪蛋白酸钾)、动物和植物蛋白及其水解产物或混合物。大豆蛋白具有几乎完美的PDCAA,蛋白消化率校正后的氨基酸得分(PDCAAS),按照此标准判断大豆蛋白能够为人体的生长和健康提供与肉和蛋相同的营养。这些蛋白具有较高的生物值(即,比例较高的必需氨基酸)。参见MODERN NUTRITION IN HEALTH AND DISEASE(Lea&Febiger,第8版1986),其通过引用整体并入本文。
所述营养补充剂还可以含有其他成分,如其他维生素、矿物质、抗氧化剂、纤维和其他膳食补充剂(例如,蛋白、氨基酸、胆碱、卵磷脂、ω-3脂肪酸和本文所述的其他膳食补充剂)中的一种或组合。一种或若干这些成分的选择与配方、设计、消费者偏好和最终使用者相关。加入本发明的膳食补充剂的这些成分的量是本领域技术人员易于知晓的。在一个实施方式中,如下文所述加入维生素和/或矿物质。
所述营养补充剂可以通过多种制备方法并且以多种形式提供。在一个实施方式中,为生产食品棒,将液态成分煮熟;在混合器中加入干成分和液体成分,并且混合直至达到面团状;将面团加入挤出机中挤出;将挤出的面团切成适当长度;将产品冷却。除了本文中特别列出的成分以外,所述食品棒可以含有其他营养物和填充剂以改善口感。
本领域技术人员易于理解,为了加工或生产营养补充剂,可以将其他成分,例如填充剂、乳化剂、防腐剂,加入到本文所述的那些中。
此外,还可以将调味剂、着色剂、香料、坚果等加入本文所述的配方中。调味剂可以是调味剂提取物、挥发油、巧克力调味剂、花生黄油调味剂、饼干屑、锅巴、香草或任意市售的调味剂形式。可使用的调味剂的例子包括但不限于纯茴香提取物、仿香蕉提取物、仿樱桃提取物、巧克力提取物、纯柠檬提取物、纯橙子提取物、纯薄荷提取物、仿菠萝提取物、仿朗姆酒提取物、仿草莓提取物、或纯香草提取物;或者挥发性油如香膏油、月桂油、佛手柑油、雪松油、核桃油、樱桃油、肉桂油、丁香油或薄荷油。
可以加入乳化剂以稳定配方。适宜乳化剂的例子包括但不限于卵磷脂(例如,来自鸡蛋或大豆的)和/或单-和二-甘油酯。其他的乳化剂对本领域技术人员而言是显而易见的,并且对适宜乳化剂的选择将部分依赖于配方和最终产品。还可以在配方中加入防腐剂以延长产品的保质期。例如,使用诸如山梨酸钾、山梨酸钠、苯甲酸钾、苯甲酸钠或EDTA二钠钙。
除了上文所述的碳水化合物以外,所述处方中还可以含有天然或人工(优选低卡路里)的甜味剂,例如糖类、甜蜜素(cyclamate)、天冬胺(aspartamine)、阿巴斯甜、安赛蜜K(acesulfame K)和/或山梨醇。如果营养补充剂预计由超重或肥胖主体或存在高血糖倾向的II型糖尿病主体消费,那么此类人工甜味剂是合乎需要的。
而且,可以在本发明的配方或组合物中加入多种维生素和矿物质补充剂以获得适量的必需营养,其在某些饮食中缺乏。多种维生素和矿物质补充物还可以用于预防疾病和防止由生活方式导致的营养损失和缺乏。
根据本发明,可以将本发明的化合物或组合物制成药物组合物,如那些可以分别专门用于治疗或预防叶酸缺乏相关疾病(例如,叶酸缺乏相关的出生缺陷)和癌症(例如,肠肿瘤)的化合物或组合物。此类组合物包括本发明的化合物(例如,脱氧尿苷和/或尿苷)或其药学上可接受的盐、生物活性代谢物、溶剂化物、水合物、前药、对映异构体或立体异构体,和药学上可接受的载体和/或赋形剂。
根据本领域所公知的,根据其预计的用途,本发明的组合物可以以多种方式施予。例如,如果本发明的组合物将被口服施予,则可以将其制成片剂、胶囊、颗粒、粉剂或喷雾。或者,本发明的制剂可以作为注射剂(静脉、肌内或皮下)、点滴输注剂或栓剂胃肠外施予。对于眼科粘膜途径应用而言,可以将本发明的组合物制成滴眼剂或眼药膏。可以采用常规方法制备这些制剂,如有需要,可以将所述组合物与任意常规的添加剂混合,如赋形剂、粘合剂、崩解剂、润滑剂、矫味剂、增溶剂、助悬剂、乳化剂或包衣剂。
在本发明的制剂中,制剂中可以存在润湿剂、乳化剂和助流剂,如十二烷基硫酸钠和硬脂酸镁,以及着色剂、脱模剂、包衣剂、甜味剂、调味和增香剂、防腐剂和抗氧化剂。
在一个实施方式中,根据本发明的化合物或组合物胃肠外施予。在本发明的另一个实施方式中,根据本发明的化合物或组合物口服施予。
在一个实施方式中,根据本发明的化合物或组合物是胶囊、片剂、颗粒或锭剂形式。
目标制剂可以适于口服、鼻内、局部(包括口腔和舌下)、直肠、***、喷雾器和/或胃肠外给药。所述制剂可以方便地以单位剂型存在,并且可以由药物领域公知的任意方法制备。与载体材料组合以生产单剂量的组合物的量可以根据治疗主体和特定给药途径而改变。
制备这些制剂的方法包括将本发明的组合物与载体以及任选地一种或多种助剂混合的步骤。在一般情况下,通过均匀和紧密地将试剂与液体载体或粉碎的固体载体或者这两者混合,如有必要的话,然后将产品成型。
适于口服给药的制剂可以是胶囊、扁囊剂、丸剂、片剂、糖锭(使用调味基质,通常是蔗糖和***胶或西黄蓍胶)、粉剂、颗粒、或者在水性或无水液体中的溶液或混悬液、或者水包油或油包水液体乳剂、或者酏剂或糖浆剂、或者锭剂(使用惰性基质,如明胶和甘油,或蔗糖和***胶),其均含有预先确定量的作为活性成分的目标组合物。本发明的组合物还可以以大丸剂、药糖剂(electuary)或糊剂形式给药。
在供口服给药的固体剂型中(胶囊、片剂、丸剂、糖锭、粉剂、颗粒等),将所述目标组合物与一种或多种药学上可接受的载体如柠檬酸钠或磷酸氢二钙,和/或任意下述组分混合:(1)填充剂或填料,如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和/或硅酸;(2)粘合剂,如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和/或***胶;(3)湿润剂,如甘油;(4)崩解剂,如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;(5)溶解延迟剂,如石蜡;(6)吸收促进剂,如季铵化合物;(7)润湿剂,如乙酰基醇和单硬脂酸甘油酯;(8)吸收剂,如高岭土和膨润土;(9)润滑剂,如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠及其混合物;和(10)着色剂。在胶囊、片剂和丸剂中,所述组合物还可以包括缓冲剂。还可以将相似类型的固体组分作为填充物使用赋形剂如乳糖或奶糖以及高分子量聚乙二醇等引入软质和硬质填充明胶胶囊中。
还可以任选地使用一种或多种助剂,通过压制或模塑制备片剂。可以使用粘合剂(例如,明胶或羟丙甲纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如,羟基乙酸淀粉钠或交联羧甲基纤维素钠)、表面活性或分散剂制备压制片。可以通过在适宜机器中将使用惰性液体稀释剂润湿的目标组合物的混合物成型制备模塑片。可以任选地将片剂和其他固体剂型如糖锭、胶囊、丸剂和颗粒进行刻字,或包衣和壳,如肠溶性包衣和药物制剂领域公知的其他包衣。
供口服给药的液体剂型包括药学上可接受的乳剂、微乳、溶液、混悬液、糖浆剂和酏剂。除了目标组合物以外,所述液体剂型还可以含有本领域常用的惰性稀释剂,如水或其他溶剂,增溶剂和乳化剂如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油(特别地,棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃甲醇、聚乙二醇和脂肪酸山梨酯、及其混合物。
除了目标组合物以外,混悬剂还可以含有助悬剂如乙氧基化异硬酯酰基醇(ethoxylated isostearyl alcohols)、聚氧乙烯山梨醇和山梨酯、微晶纤维素、偏铝酸(aluminum metahydroxide)、膨润土、琼脂和西黄蓍胶、及其混合物。
供直肠或***给药的制剂可以是栓剂,其可以通过将目标组合物与一种或多种适宜的无刺激性赋形剂或载体混合来制备,所述赋形剂或载体包括例如可可豆脂、聚乙二醇、栓剂蜡或水杨酸盐,所述栓剂在室温下是固体,但在体温下是液体,因此将在体腔内熔化并释放活性剂。适于***给药的制剂还包括***栓、棉条、乳膏、凝胶、糊剂、泡沫或喷雾制剂,其中含有本领域公知的适宜的载体。
供目标组合物透皮给药的剂型包括粉剂、喷雾、软膏、糊剂、乳膏、洗剂、凝胶、溶液、贴片和吸入剂。可以在无菌条件下将活性成分与药学上可接受的载体以及可能需要的任意防腐剂、缓冲剂或抛射剂混合。
除了目标组合物以外,软膏、糊剂、乳膏和凝胶还可以含有赋形剂,如动物和植物脂肪、油、蜡、石蜡、淀粉、西黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石粉和氧化锌、或其混合物。
除了目标组合物以外,粉剂和喷雾剂可以含有赋形剂如乳糖、滑石粉、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末、或者这些物质的混合物。喷雾剂通常还可以含有通常的抛射剂,如氯氟烃和挥发性不饱和烃如丁烷和丙烷。
或者,本发明的组合物还可以以气雾剂形式施予。通过制备含有所述化合物的水性气雾剂、脂质体制剂或固体颗粒实现。可以使用无水(例如,氟碳抛射剂)混悬剂。可以使用超声雾化器,因为其使得所述试剂受到的剪切力最小,剪切力可以导致目标组合物中所含的化合物降解。
通常地,通过将目标组合物的水性溶液或混悬液与常规的药学上可接受的载体和稳定剂制剂来制备水性气雾剂。所述载体和稳定剂随特定目标组合物的要求而改变,但是一般包括非离子表面活性剂(吐温、或聚乙二醇)、无毒的蛋白样血清白蛋白、山梨酯、油酸、卵磷脂、氨基酸如甘氨酸、缓冲剂、盐、糖或糖醇。气雾剂通常由等渗溶液制备。
适于胃肠外给药的本发明组合物包括目标组合物和一种或多种药学上可接受的无菌等渗水性或无水溶液、分散液、混悬液或乳液,或者可以在使用前在无菌注射用溶液或分散液中复溶的无菌粉末,其可以含有抗氧化剂、缓冲剂、抑菌剂、使所述制剂与目标受体的血液等渗的溶质或者悬浮或增稠剂。
可以在本发明的组合物中使用的适宜水性或无水载体的例子包括水、乙醇、多元醇(如甘油、丙二醇、聚乙二醇等)及其适宜的混合物,植物油如橄榄油,和可注射有机酯如油酸乙酯。可以通过使用包衣材料如卵磷脂,在分散液中维持所需的粒子尺寸,和使用表面活性剂维持适宜的流动性。
在某些实施方式中,将所述组合物制成片剂、丸剂、胶囊或其他适宜的可吞咽的制剂,以便使10个或更少的可吞咽制剂能提供治疗剂量。在另一个实施方式中,由20、15、10、5、4、3或2个可吞咽制剂提供治疗剂量。
本发明的组合物可以是用于肺输送的可分散干粉形式。可以使用本领域公知的方法制备干粉组合物,如冻干法和喷射研磨,参见WO91/16038和美国专利号6,921,527,其通过引用整体并入本文。可以将本发明的组合物以足以向主体提供单位剂量治疗的量置于适宜的计量容器中。所述计量容器可以是与适宜吸入设备匹配的,其使得雾化的干粉组合物分散进入气流以形成气雾剂,然后将生成的气雾剂俘获在腔室中,所述腔室带有接口供所需治疗的主体随后吸入。这种计量容器包括含有本领域公知的任意装有所述组合物的容器,如具有可除去部分的明胶或塑料胶囊,这使得气流(例如,空气)可以直接进入容器以分散所述干粉组合物。这种容器在例如美国专利号4,227,522、美国专利号4,192,309和美国专利号4,105,027中进行了描述,其通过引用整体并入本文。
透皮递送***、透皮贴片或贴片指置于皮肤上以输送定时释放的药物剂量的粘附***,其通过剂型中的通道,穿过皮肤,从而通过***循环进行分布。透皮贴片是一种用于递送多种药物的普遍接受的技术,药物包括但不限于用于治疗晕动病的东莨菪碱、用于治疗心绞痛的***、用于治疗高血压的可乐定、用于治疗绝经后适应症的***、和用于戒烟的尼古丁。适于在本发明中使用的贴片包括但不限于:(1)基质贴片;(2)储库贴片;(3)多层药物粘附贴片;和(4)单片药物粘附贴片(TRANSDERMAL AND TOPICAL DRUG DELIVER SYSTEMS(Ghosh等eds.,1997),其通过引用整体并入本文)。这些贴片是本领域所公知的,而且一般是可以购买到的。
本发明主旨的组合物可以任选地含有叶酸,以及任意其他维生素、矿物质、营养剂、治疗剂等。在一个实施方式中,所述药物或膳食组合物包括一种或多种维生素、一种或多种矿物质或其组合。
这些维生素、矿物质和微量元素包括,例如维生素A或β胡萝卜素、维生素B1(硫氨素或硝酸硫氨素)、维生素B2(核黄素)、维生素B3(烟酸)、维生素B6(吡哆醇或盐酸吡哆醇)、维生素B9(叶酸)、维生素B12(氰钴胺)、维生素H(生物素)、维生素C(抗坏血酸)、维生素D、维生素E(d1-α醋酸生育酚)、维生素K、叶酸、烟酰胺、铁(富马酸亚铁)、磷、泛酸(泛酸钙)、碘(碘化钾)、镁(氧化镁)、锌(氧化锌)、硒(硒酸钠)、铜(氧化铜)、锰(硫酸锰)、铬(氯化铬)、钼(钼酸钠)、胆碱、氟、氯、钾、钠及其混合物。此类维生素、矿物质和微量元素均可以从本领域技术人员公知的来源购买得到。可以使用上文所述的维生素和/或矿物质包括其盐的任意药学上可接受的形式制备本发明的剂型,其为本领域技术人员所公知的。
在一个实施方式中,根据本发明的药物或膳食组合物包括一种或多种选自下组的维生素、矿物质、微量元素或其组合:维生素A、维生素C、维生素D、维生素E、维生素K、硫胺素、核黄素、烟酸、叶酸、维生素B12、维生素B6、泛酸、生物素、胆碱、铬、铜、碘、钼、硒、铁、锌、镁及其组合。
如上文所述,根据本发明的组合物还可以包括叶酸或其衍生物。叶酸衍生物包括叶酸及其衍生物。叶酸衍生物包括由叶酸形成的化合物,其可以在结构上与叶酸不同,但仍保持叶酸的活性功能。此类衍生物的非限制性例子包括叶酸的盐、叶酸的碱性盐、叶酸的酯、叶酸的螯合物及其组合。
所述叶酸或其衍生物的量可以在例如约0.01mg至约5mg范围内。在某些实施方式中,根据本发明的组合物包括低于约1000μg、低于约400μg、低于约300μg、低于约200μg、或低于约100μg的叶酸或其衍生物。
在根据本发明的一个实施方式中,所述组合物包括叶酸或其衍生物,其中存在的叶酸或其衍生物的量是特定主体(例如,育龄妇女)的每日推荐摄入量。应理解,特定营养物的每日推荐摄入量已由美国国家学术出版社发布(参见National Academy of Sciences,Institute of Medicine,Food and Nutrition Board,“Dietary Reference Intakes(DRIs):Recommended Dietary Allowances and Adequate Intakes,”(2011),其通过引用整体并入本文)。在一个其他实施方式中,组合物中叶酸的量低于特定主体(例如,育龄妇女、妊娠妇女或哺乳妇女)的叶酸或其衍生物的每日推荐摄入量。在某些实施方式中,叶酸或其衍生物的量低于特定主体(例如,育龄妇女)的每日推荐摄入量至少约25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或100%。
在本发明的另一个实施方式中,所述组合物包括脱氧尿苷和其他维生素,但是所述维生素不包括叶酸。
本发明化合物(例如,脱氧尿苷和/或尿苷)的有效量根据多种不同因素而改变,包括疾病的类型和阶段、给药方式、靶点、患者的生理状态、所施予的其他药物或治疗、以及与其他医疗并发症相关的身体状况。需要对治疗剂量缓慢调整以优化安全性和疗效。
本发明的组合物可以单剂量或多剂量施予。可以采用本领域公知的方法确定所述剂量,剂量可以依赖于例如主体的年龄、敏感性、耐受性和总体的健康状况。
本发明的剂型可以涉及在24小时时间段内单剂量、在24小时时间段内双剂量、或者在24小时时间段内多于两个剂量或者在24小时时间段内以分数剂量施予本发明的组合物。双剂量或多剂量可以在24小时时间段内同时或在不同时间施予。
可以预期将本发明的组合物制成多种释放形式组合的剂型,其包括但不限于立即释放、延长释放、脉冲释放、可变释放、控制释放、定时释放、持续释放、延时释放、长效及其组合。通过本领域的普通技术人员知晓的技术和方法可以获得立即释放、延长释放、脉冲释放、可变释放、控制释放、定时释放、持续释放、延时释放、长效性质及其组合。
在一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约200mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约150mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约100mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约95mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约90mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约85mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约80mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约75mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约70mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约65mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约60mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约55mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约50mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约45mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约40mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约35mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约30mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约25mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约20mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约15mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约10mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约5mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约4mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约3mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约2mg/kg体重每天。在另一个实施方式中,所述剂量范围为约0.5mg/kg体重每天至约1mg/kg体重每天。
在某些实施方式中,所述剂量为或至少约0.1、0.2、0.3、0.4、0.5、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、125、150、175或200mg/kg体重每天。
在某些实施方式中,所述治疗剂量可以在约10mg/天至15,000mg/天之间、在约100mg/天至2,500mg/天之间、或者在250mg至约1,000mg/天之间。在其他实施方式中,可以使用其他范围包括例如50-250mg/天、250-500mg/天和500-750mg/天。将预防性治疗所需的化合物的量称为预防有效量,其通常与上文所述的有效剂量相同。
在某些实施方式中,所述有效剂量在约50mg/天至约150mg/天之间。在某些实施方式中,所述治疗剂量在约10mg/天至约20mg/天之间。在某些实施方式中,所述治疗剂量在约20mg/天至约30mg/天之间。在某些实施方式中,所述治疗剂量在约30mg/天至约40mg/天之间。在某些实施方式中,所述治疗剂量在约40mg/天至约50mg/天之间。在某些实施方式中,所述治疗剂量在约50mg/天至约60mg/天之间。在某些实施方式中,所述治疗剂量在约60mg/天至约70mg/天之间。在某些实施方式中,所述治疗剂量在约70mg/天至约80mg/天之间。在某些实施方式中,所述治疗剂量在约80mg/天至约90mg/天之间。在某些实施方式中,所述治疗剂量在约90mg/天至约100mg/天之间。在某些实施方式中,所述治疗剂量在约100mg/天至约110mg/天之间。在某些实施方式中,所述治疗剂量在约110mg/天至约120mg/天之间。在某些实施方式中,所述治疗剂量在约120mg/天至约130mg/天之间。在某些实施方式中,所述治疗剂量在约130mg/天至约140mg/天之间。在某些实施方式中,所述治疗剂量在约140mg/天至约150mg/天之间。在某些实施方式中,所述治疗剂量在约150mg/天至约160mg/天之间。在某些实施方式中,所述治疗剂量在约160mg/天至约170mg/天之间。在某些实施方式中,所述治疗剂量在约170mg/天至约180mg/天之间。在某些实施方式中,所述治疗剂量在约180mg/天至约190mg/天之间。在某些实施方式中,所述治疗剂量在约190mg/天至约200mg/天之间。在某些实施方式中,所述治疗剂量在约200mg/天至约250mg/天之间。在某些实施方式中,所述治疗剂量在约250mg/天至约300mg/天之间。在某些实施方式中,所述治疗剂量在约300mg/天至约350mg/天之间。在某些实施方式中,所述治疗剂量在约350mg/天至约400mg/天之间。在某些实施方式中,所述治疗剂量在约400mg/天至约450mg/天之间。在某些实施方式中,所述治疗剂量在约450mg/天至约500mg/天之间。在某些实施方式中,所述治疗剂量在约500mg/天至约550mg/天之间。在某些实施方式中,所述治疗剂量在约550mg/天至约600mg/天之间。在某些实施方式中,所述治疗剂量在约600mg/天至约650mg/天之间。在某些实施方式中,所述治疗剂量在约650mg/天至约700mg/天之间。在某些实施方式中,所述治疗剂量在约700mg/天至约750mg/天之间。在某些实施方式中,所述治疗剂量在约750mg/天至约800mg/天之间。在某些实施方式中,所述治疗剂量在约800mg/天至约850mg/天之间。在某些实施方式中,所述治疗剂量在约850mg/天至约900mg/天之间。在某些实施方式中,所述治疗剂量在约900mg/天至约950mg/天之间。在某些实施方式中,所述治疗剂量在约950mg/天至约1000mg/天之间。在某些实施方式中,所述治疗剂量在约1000mg/天至约1050mg/天之间。在某些实施方式中,所述治疗剂量在约1050mg/天至约1100mg/天之间。在某些实施方式中,所述治疗剂量在约1100mg/天至约1150mg/天之间。在某些实施方式中,所述治疗剂量在约1150mg/天至约1200mg/天之间。在某些实施方式中,所述治疗剂量在约1200mg/天至约1250mg/天之间。在某些实施方式中,所述治疗剂量在约1250mg/天至约1300mg/天之间。在某些实施方式中,所述治疗剂量在约1300mg/天至约1350mg/天之间。在某些实施方式中,所述治疗剂量在约1350mg/天至约1400mg/天之间。在某些实施方式中,所述治疗剂量在约1400mg/天至约1450mg/天之间。在某些实施方式中,所述治疗剂量在约1450mg/天至约1500mg/天之间。
可能需要鉴定本发明任意特定组合物的有效剂量或量,以及其对制剂给药时间选择的任意可能影响。其可以通过使用一组或多组动物进行常规实验或者,在适当情况下,通过人体试验完成。可以通过施予所述组合物,测定一种或多种适宜参数评估给药的作用,并且将给药后这些参数的值与给药前的相应参数进行比较,以评估目标组合物和治疗方法的作用。
本发明的另一个方面涉及一种为主体补充膳食需要的方法。该方法包括施予主体膳食补充有效量的脱氧尿苷。上文描述了适宜的组合物、剂量、配方、施予方式等。
在一个实施方式中,本发明方法的主体是哺乳动物。在另一个实施方式中,所述主体是人。在另一个实施方式中,所述主体是啮齿类动物。在另一个实施方式中,所述主体是实验动物。在另一个实施方式中,所述主体是雄性。在另一个实施方式中,所述主体是雌性。在另一个实施方式中,所述主体是本领域公知的任意其他主体。
在一个实施方式中,所述主体是妊娠妇女、哺乳妇女或育龄妇女。
在本发明的该实施方式中,施予所述主体脱氧尿苷预防叶酸缺乏相关出生缺陷的发生或降低其发生风险。叶酸缺乏相关出生缺陷中的一类是神经管缺陷。神经管缺陷包括但不限于无脑畸形、脑膨出、水脑畸形、枕骨裂脑露畸形、脑裂、脊柱裂、脊髓脊膜突出、脂肪脑膜突出和脊髓栓系。
在一个实施方式中,所述妇女是准备妊娠的育龄妇女。准备妊娠的育龄妇女包括例如使用辅助生殖技术(例如,体外受精(IVF))的妇女、监测生育力的妇女和一般准备怀孕的妇女。在一个实施方式中,将脱氧尿苷或包括脱氧尿苷的组合物与生育药(例如,FSH、GnRh、柠檬酸克罗米芬或HMG)结合施予。
在另一个实施方式中,所述主体是存在生产叶酸缺乏相关出生缺陷胎儿风险的妇女。其包括,例如倾向于生产患有叶酸缺乏相关出生缺陷胎儿风险的妇女。例如,由于叶酸消耗较低、肥胖和/或糖尿病,可能存在生产叶酸缺乏相关出生缺陷胎儿风险的妇女。其还包括,例如既往生产过叶酸缺陷相关出生缺陷胎儿的妇女。
而且,如下述实施例中更加详细地描述的,已发现尿苷增加叶酸缺乏相关出生缺陷的发生率。因此,在一个实施方式中,所述方法进一步包括在所述主体的饮食中降低尿苷水平。例如,其包括降低主体的尿苷消耗量。其包括,例如消除尿苷的膳食来源(例如,西红柿、啤酒、西兰花和内脏,以及补充剂、药物或其他尿苷来源)。
还提供了一种试剂盒(例如,生育试剂盒),所述试剂盒包括根据本发明的化合物和组合物。在一个实施方式中,所述试剂盒包括根据本发明的一个或多个剂量的脱氧尿苷或根据本发明的包括脱氧尿苷的组合物、***监测组件和对根据本发明的化合物和/或组合物时间选择和使用以及***时机选择以使得受孕可能达到最大的一系列说明书。所述监测组件可以包括,例如唾液电解质、基础体温或黄体激素(LH)监测器,以预测和确定***时间。在一个实施方式中,所述***监测组件包括用于编目女性典型***的基础体温表。
本发明的又一个方面涉及一种在主体中治疗和/或预防癌症的方法。在一个实施方式中,所述方法是一种在主体中治疗癌症的方法。该方法包括选择患有癌症的主体,施予所选择的主体治疗有效量的尿苷,以治疗所选择主体的癌症。
根据本发明的这个方面,所治疗的癌症包括肠肿瘤。在一个实施方式中,所述癌症是结直肠癌。在一个实施方式中,所述癌症是结肠中的肿瘤。
如本文所使用的,治疗指与未施予或施予根据本发明的化合物或组合物之前的疾病状态或状况相比,癌症的疾病状态或状况减轻。此类治疗可以是但不限于完全消除所述疾病、状况或所述疾病或状况的症状。例如,如果与同一主体或对照主体的自然水平相比,患病主体的一种或多种疾病症状(例如,肿瘤尺寸)减轻,则认为所披露的治疗癌症的方法是治疗。这样,所述的减轻可以是,与自然或对照水平相比,5、10、20、30、40、50、60、70、80、90、100%或者之间的任意减轻量。在本发明中还可以理解和预期所述治疗可以指疾病或癌症进展的任意减缓。这样,例如,如果与对照主体或治疗前同一主体的肿瘤生长速率相比,肿瘤生长速率减缓则认为所述减轻癌症作用的方法是治疗。应理解,所述的减轻可以是,与自然或对照水平相比,5、10、20、30、40、50、60、70、80、90、100%或者之间的任意减轻量。
在另一个实施方式中,根据本发明这一方面的方法是一种在主体中预防癌症的方法。所述方法包括选择存在发展为癌症的风险的主体,施予所选择的主体治疗有效量的尿苷,从而预防所选择主体的癌症。根据本发明的这一方面可预防的癌症类型如上文所述。
存在发展为肠癌的风险的主体包括,例如具有一种或多种发展为肠癌的风险因素的主体。发展为肠癌的风险因素包括,例如结直肠癌或息肉的个人病史;炎性肠病(例如,结肠慢性炎性疾病,如溃疡性结肠炎和克隆氏病);增加癌症风险的遗传症状(遗传症状如家族性腺瘤性息肉病和遗传性非息肉病性结直肠癌);肠癌家族史(例如,结肠癌和结肠息肉);糖尿病;肥胖;吸烟;大量饮酒;和癌症放疗。
在一个实施方式中,本发明方法的主体是哺乳动物。在另一个实施方式中,所述主体是人。在另一个实施方式中所述主体是啮齿类动物。在另一个实施方式中,所述主体是实验室动物。在另一个实施方式中,所述主体是雄性。在另一个实施方式中,所述主体是雌性。在另一个实施方式中,所述主体是本领域公知的其他类型的主体。在根据本发明这个方面的一个实施方式中,所选择的主体不是育龄妇女。在一个实施方式中,所述主体不是试图妊娠的育龄妇女。
根据本发明这个方面,尿苷包括尿苷及其酰基衍生物或磷酸尿苷。在一个实施方式中,磷酸尿苷是尿苷-5′-单磷酸盐(UMP)、尿苷-5′-二磷酸盐(UDP)、尿苷-5′-三磷酸盐(UTP),或者所述UMP、UDP或UTP的盐。
根据本发明的这个方面,可以按照上文所述的方式将施予所选定主体的尿苷制成组合物。特别地,包括或涉及根据本发明的化合物(例如,脱氧尿苷、尿苷和/或其衍生物)的如上文所述的适宜组合物、配方、剂型、施予方式等。包括尿苷的其他药物和膳食组合物是公知的,并且也可以根据本发明的方法进行使用(例如,Wurtman等的美国专利申请公开号2009/0105189和Renshaw的2010/0222296,其通过引用整体并入本文)。
在一个实施方式中,还施予一种或多种维生素、矿物质、微量元素或其组合。所述一种或多种维生素、矿物质、微量元素或其组合可以选自下组:维生素A、维生素C、维生素D、维生素E、维生素K、硫胺素、核黄素、烟酸、叶酸、维生素B12、维生素B6、泛酸、生物素、胆碱、铬、铜、碘、钼、硒、铁、锌、镁及其组合。
在一个实施方式中,所施予的尿苷作为选自下组的组合物的一部分:营养食品组合物、药物组合物、功能性食品、功能性营养品、医疗食品、医药营养品或膳食补充剂。
在一个实施方式中,所述施予是胃肠外给药。在另一个实施方式中,所述施予是口服。在一个实施方式中,所述尿苷以胶囊、片剂、颗粒或锭剂形式施予。
施予根据本发明的尿苷可以单独使用或与其他癌症疗法(例如,化疗剂、放疗、手术或其组合)联用。因此,在一个实施方式中,将治疗有效量的尿苷与癌症疗法联用。
在一个实施方式中,所述癌症疗法是化疗。在一个实施方式中,所述化疗选自下组:烷化剂、抗代谢药、蒽环类药物、抗肿瘤抗生素、基于铂的化学疗法和植物生物碱。
化学疗法或化学治疗的特定例子包括顺铂、达卡巴嗪(DTIC)、更生霉素、双氯乙基甲胺(氮芥)、链脲菌素、环磷酰胺、卡莫司汀(BCNU)、洛莫司汀(CCNU)、多柔比星(阿霉素)、柔红霉素、甲基苄肼、丝裂霉素、阿糖胞苷、依托泊苷、甲氨蝶呤、5-氟尿嘧啶、长春花碱、长春新碱、博来霉素、紫杉醇(泰素)、多西他赛(泰索帝)、阿地白介素、天冬酰胺酶、白消安、卡铂、克拉屈滨、达卡巴嗪、氟尿苷、氟达拉滨、羟基脲、异环磷酰胺、干扰素α、亮丙瑞林、甲地孕酮、美法仑、巯嘌呤、奥沙利铂、普卡霉素、米托坦、培门冬酶、喷司他丁、哌泊溴烷、普卡霉素、链脲菌素、他莫昔芬、替尼泊苷、睾内酯、硫鸟嘌呤、塞替派、氮芥、长春瑞滨、苯丁酸氮芥、紫杉醇及其组合。
在一个实施方式中,所述癌症疗法是放疗。所述放射源可以在所治疗患者的外部或内部。当放射源在患者外部时,所述疗法称为体外放射疗法(EBRT)。当放射源在患者内部时,所述治疗称为近程放射疗法(BT)。
在另一个实施方式中,所述癌症疗法是外科手术。
在一个实施方式中,所述治疗有效量的尿苷和癌症疗法同时施予。在另一个实施方式中,所述治疗有效量的尿苷先于癌症疗法施予。在又一个实施方式中,所述治疗有效量的尿苷在癌症疗法之后施予。
实施例
提供下述实施例以说明本发明的实施方式,但是其并非旨在限定其范围。
实施例1-小鼠模型
在129SvEv-Shmt1杂交小鼠的胎仔中(N=10只及以上)进行NTD检查。Shmt1+/-、Shmt1+/+和Shmt1-/-小鼠是由在杂交繁殖群中的Shmt1+/-繁殖对繁殖的。如下文所述,然后将Shmt1+/+和Shmt1-/-雌性小鼠与Shmt1+/-雄性小鼠交配用于定时交配实验。
实施例2-实验动物和饮食
将小鼠饲养在12-小时昼夜循环的控温动物房中。为了进行考察Shmt1受损和NTD的研究,将雌性小鼠随机分组,断奶后施予用于实验的含有叶酸(C)的AIN93G饮食或者缺乏叶酸(FD)的AIN93G饮食(图2)以及含有0.6%尿苷(Rudolph FB&Van Buren CT(1993),其通过引用整体并入本文)、0.2%胸苷(Iwasa等,“The Well-Balanced Nucleoside-NucleotideMixture‘OG-VI’for Special Medical Purposes,”Nutrition13(4):361-364(1997),其通过引用整体并入本文)或的0.1%2′-脱氧尿苷补充剂(Dyets,Bethlehem,PA)。使用这些缩写表示饮食:AIN-93G作为对照(“C”);叶酸缺乏(“FD”),C+补充0.6%尿苷(“C+U”),C+补充0.2%胸苷(“C+T”),C+补充0.1%2′-脱氧尿苷(“C+dU”),FD+补充0.6%尿苷(“FD+U”),FD+补充0.2%胸苷(“FD+T”),FD+补充0.1%2′-脱氧尿苷(“FD+dU”)。
在所有研究中,在断乳至交配期以及妊娠期间直至处死持续施予母本小鼠所述饮食。将70-120日龄未经交配的雌性小鼠与雄鼠同笼过夜。次日清晨,检查雌鼠是否存在***栓。将出现***栓那天的上午9点记为妊娠第0.5天(E0.5)。在E11.5,采用颈椎脱臼法处死妊娠雌鼠,并心脏穿刺取血。取出妊娠子宫并记录所有着床和吸收位点。检查胚胎是否存在NTD,并测定顶臂长度。收集所有卵黄囊用于随后的基因分型。提取E11.5的胚胎,并在液氮中速冻随后在-80℃下保存以供生化分析。用于检查形态异常的胚胎是在E11.5获得,并将其固定在10%的中性***缓冲液中。
实施例3-基因型分析
使用已建立的方法进行针对性别的基因分型(Clapcote等,“Simplex PCR Assayfor Sex Determination in Mice,”Biotechniques38(5):702,704,706(2005);Machado等,“Diabetic Embryopathy in C57BL/6J Mice.Altered Fetal Sex Ratio and Impactof the Splotch Allele,”Diabetes50(5):1193-1199(2001);McClive等,“Rapid DNAExtraction and PCR-Sexing of Mouse Embryos,”Mol.Reprod.Dev.60(2):225-226(2001),其通过引用整体并入本文)。使用此前已描述的方案进行针对Shmt1+/+Shmt1-/-和Shmt1+/-等位基因的基因分型(MacFarlane等,“Cytoplasmic SerineHydroxymethyltransferase Regulates the Metabolic Partitioning ofMethylenetetrahydrofolate but is Not Essential in Mice,”J.Biol.Chem.283(38):25846-25853(2008),其通过引用整体并入本文)。
实施例4-免疫印迹
对冰冻组织进行总蛋白提取和定量。使用从各母本的肝脏和胚胎中提取的15-30μg蛋白进行Western印迹分析,至少重复三次。使用4–12%的BIs-Tris梯度SDS-聚丙烯酰胺电泳分离总可溶性蛋白,并将其转移至硝酸纤维素膜。按照如下方式在封闭缓冲液中稀释用于荧光western印迹的一抗(Rockland,PA):兔抗小鼠胸苷酸合酶(TYMS)单克隆抗体(Cellsignaling,1:1000)、小鼠抗兔TK1单克隆抗体(Abcam,1:500)、兔抗小鼠Pax3多克隆抗体(Abcam1:500)、绵羊抗小鼠SHMT1多克隆抗体(1:20,000)(Liu等,“Lack of CatalyticActivity of a Murine mRNA Cytoplasmic Serine Hydroxymethyltransferase SpliceVariant:Evidence Against Alternative Splicing as a Regulatory Mechanism,”Biochemistry40(16):4932-4939(2001),其通过引用整体并入本文)、抗小鼠p-p53单克隆抗体(Cell signaling,1:1,000)、兔HPRT单克隆抗体(Acbam,1:10,000)、兔抗RRMI多克隆抗体(Thermo Scientific,1:1,000)、MTHFD(ref)、兔UNG2多克隆抗体(Abcam1:1,000)、兔HPRT多克隆抗体(Abcam1:10,000)、兔抗小鼠β-肌动蛋白单克隆抗体(Cell signaling,1:1,000)、小鼠抗小鼠β-肌动蛋白单克隆抗体(Cell signaling,1:1,000)。使用的适当的二抗:IRDye800/700-标记的驴抗小鼠IgG、IRDye800/700-标记的驴抗兔IgG和IRDye800-标记的驴抗绵羊IgG二抗(均为1:20,000)。
使用Odyssey红外扫描仪(Li-Cor)对条带进行目测检查,使用Odyssey软件对Western印迹进行光密度分析。使用抗小鼠或抗兔β-肌动蛋白对数据进行归一化处理。光密度数据以相对于用对照饮食喂养的野生型动物的平均值表示。
实施例5-血浆叶酸水平分析
使用此前描述的干酪乳酸菌微生物学检测对血浆样品中的叶酸水平进行定量(Suh等,“Purification and Properties of a Folate-Catabolizing Enzyme,”J.Biol.Chem.275(45):35646-35655(2000),其通过引用整体并入本文)。
实施例6-核DNA中的尿嘧啶含量
使用DNeasy组织和血液试剂盒(Qiagen)从25-50mg肝脏组织中提取DNA,包括使用RNase A(Sigma)和Rnase T1(Ambion)在37℃下孵育30分钟。使用1U尿嘧啶DNA糖基化酶(Epicentre)在37℃下处理10μg DNA1小时。孵育结束后,立即将10pg[15N2]尿嘧啶(Cambridge Isotopes)加入各样品中作为内标,并在干燥器内将样品彻底干燥。将50μl乙腈、10μl三乙胺和1μl3,5-双(三氟甲基)苄基溴加入各样品中,在30℃500rpm振荡下孵育25分钟。将50μl水和100μl异辛烷依次加入各样品中。将样品涡旋并离心。通过除去水相并分析有机相从而完成衍生化尿嘧啶的有机提取。如此前所述,使用气相色谱质谱联用分析核DNA中的尿嘧啶含量(MacFarlane等,“Cytoplasmic Serine HydroxymethyltransferaseRegulates the Metabolic Partitioning of Methylenetetrahydrofolate but is NotEssential in Mice,”J.Biol.Chem.283(38):25846-25853(2008),其通过引用整体并入本文)。
实施例7-血浆尿苷、脱氧尿苷和胸苷的定量
收集小鼠的血浆并将其在-80C下冻存直至通过高效液相色谱结合UV检测器对其进行分析。使用等体积的pH5.6的50mM醋酸铵将50μl血浆稀释,并掺入10μM5-氟尿苷作为内标。使用MWCO3,000Kd的Amicon Ultra离心滤器在16,000RPM下离心30分钟将经稀释的血清澄清。收集流出液,并将20μl注入使用二元缓冲***流速为1ml/分钟的SuppelcoSupelcosil LC18-T25cm x4.6mm5μ色谱柱中。缓冲液A由pH5.6的100mM醋酸铵组成,缓冲液B为100mM醋酸铵和20%甲醇。在1-30分钟采用初始时缓冲液B为0%在30min时为75%的线性梯度对核苷酸进行洗脱,随后在30-35分钟采用缓冲液B由75%降至0%的线性梯度。使用起始波长240和终止波长300nm的Shimadzu二极管阵列检测器对尿苷、脱氧尿苷和胸苷水平进行定量检测,并使用有五个点的标准曲线对各分析物和内标物进行分析。
实施例8-小鼠血液葡萄糖检测
记录妊娠第11.5-12.5天未禁食雌性小鼠的血糖水平。从各只小鼠的尾部收集血样。在使用刀片切开之前用酒精对尾尖消毒,收集10-20μL血液。使用葡萄糖计(LifeScan,Inc.)和蓝色检测试纸(LifeScan,Inc.)测定血糖水平。一次葡萄糖检测需要约3μL血液。重复进行两次葡萄糖检测并取平均值。使用方差分析(ANOVA)进行统计分析以对不同实验组之间的数据进行比较。
实施例9-统计分析
利用2-因素ANOVA结合用于post hoc分析的Tukey真正显著差检验分析NTD的发生率,包括基因型、饮食和饮食x基因型相互作用之间的差异。
利用2-因素ANOVA结合用于post hoc分析的Tukey真正显著差检验分析胚胎CR长度、总窝吸收数和着床数,其中将窝认为是随机效应。独立变量包括母本基因型和饮食。利用每窝吸收数与总着床数的比值计算吸收率,并使用对数转化将数据归一化。使用卡方分析评估与基于孟德尔遗传规律的预计基因型比例之间的偏差。利用2-因素ANOVA结合用于post hoc分析的Tukey真正显著差检验分析尿苷浓度、胸苷、脱氧尿苷、葡萄糖和叶酸。独立变量包括母本基因型和饮食。各项检验均使用8.02版的JMP(SAS institute)进行。使用ANOVA和Dunnett多重比较检验评估Western印迹分析结果。当P值≤0.05时,认为组间具有显著性差异。所有统计检验均使用适用于Windows***的GraphPad Prism4.00版(GraphPad软件,San Diego California USA)进行。
实施例10-膳食核苷酸影响叶酸应答性NTD的风险
首先,在Shmt1小鼠模型中确证了母本摄入叶酸对NTD发生率的作用。将Shmt1+/-雄性与8周龄的Shmt1+/+或Shmt1-/-雌性小鼠交配,所述雌性小鼠已断乳并用图2中所述的八种AIN-93G饮食之一喂养。母本摄入叶酸显著影响Shmt1-/-基因型NTD的发生(P<0.0001),但其对Shmt1+/+基因型没有影响(P=0.21NS)。与用C饮食喂养的母本动物相比,在用FD饮食喂养的母本动物的窝胎仔中观察到了露脑畸形(P=0.037,图3)。这确证了此前已公开的结果,表明胚胎Shmt1的受损应答母本的叶酸状态,这与此前在人体内观察到的和已公开的结果一致(Beaudin等,“Insights into Metabolic Mechanisms Underlying Folate-ResponsiveNeural Tube Defects:A Minireview,”Birth Defects Res.A Clin.Mol.Teratol.85(4):274-284(2009);Beaudin等,“Shmt1and De Novo Thymidylate Biosynthesis UnderlieFolate-Responsive Neural Tube Defects in Mice,”Am.J.Clin.Nutr.93(4):789-798(2011),其通过引用整体并入本文)。在用叶酸缺乏饮食喂养的Shmt1-/-母本动物中观察到了露脑畸形(10.6%;47个可见胚胎中有5个NTD),而在来自从用C饮食喂养的母本动物中分离的Shmt1-/-雌性小鼠的窝胎仔中未观察到NTD。在用FD饮食喂养的Shmt1+/+母本动物中仅观察到一个胚胎出现露脑畸形(2.4%)。所有受NTD影响的胚胎均缺少至少一个Shmt1等位基因,该基因来自用FD饮食喂养的Shmt1-/-杂交体。
在E11.5或E12.5时观察到的Shmt1+/+Shmt1-/-和Shmt1+/-胚胎数均未偏离各交配检测的预期值。然而,证实了此前已公开的结果(Beaudin等,“Shmt1and De NovoThymidylate Biosynthesis Underlie Folate-Responsive Neural Tube Defects inMice,”Am.J.Clin.Nutr.93(4):789-798(2011),其通过引用整体并入本文),在E11.5时母本饮食和胚胎Shmt1基因型显著影响胚胎生长(表2;图3)。与来自用C饮食喂养的母本动物的胚胎相比,从用FD饮食喂养的母本动物分离的胚胎明显更短(χ2=4.9669,P<0.0001)。饮食或基因型对雌性小鼠的体重或着床点数均没有显著影响。然而,与C饮食相比,FD饮食显著增加每窝的吸收率(P<0.05)。
施予母本补充胸苷的FD饮食不会阻止NTD发生:补充胸苷的FD饮食不会阻止NTD发生。涉及用FD+T饮食喂养的Shmt1+/+(2NTD,在49只中占4.1%)和Shmt1-/-(3NTD,在32只中占9.4%)母本动物的杂交体中均出现了NTD的胚胎。而且,报道了一例露脑畸形的Shmt1+/+胚胎,其来自涉及用FD+T饮食喂养的Shmt1+/+母本动物的杂交体(表3;图4)。在用C+T饮食喂养的母本动物中未出现NTD。与C饮食相比,施予补充胸苷的C饮食显著降低各窝的吸收率(P<0.05)。
为母本补充脱氧尿苷在Shmt1母本动物中阻止NTD:令人惊讶的是,来自用叶酸缺乏且补充脱氧尿苷饮食(FD+DU)喂养的Shmt1+/+和Shmt1-/-母本动物杂交体的胚胎未出现NTD(表3;图4)。与从用C+dU喂养的Shmt1+/+母本动物中分离的胚胎相比,从用C饮食喂养的Shmt1+/+母本动物中分离的胚胎明显更大(P<0.05,用于post hoc分析的Tukey真正显著差检验,图3)。当对用FD+dU或C+dU或C饮食喂养的母本动物的窝胎仔进行比较时,着床数、死亡胚胎出现情况和吸收率均不存在显著差异。用FD+dU和C+dU饮食喂养的母本动物的死亡胚胎数较高,但该差异尚未达到显著。与其他组相比,在断奶后施予C+dU和FD+dU的雌性小鼠中观察到的结肠大量淋巴聚集的频率较高。还观察到内脏器官水肿(dU和dUFD组共计最多4只小鼠)、胃肠道和子宫出血,以及胰脏变色。
为母本补充尿苷在Shmt1母本动物中不会阻止NTD:与用C饮食喂养的小鼠相比,在从用FD+U饮食喂养的Shmt1-/-母本动物中分离的胚胎中观察到露脑畸形的频率最高(15.9%,44个存活胚胎中有7个;P=0.042)。与从用C饮食喂养的Shmt1-/-母本动物中分离的胚胎相比,从用FD+U饮食喂养的Shmt1-/-母本动物中分离的NTD数显著更高(P=0.048)。有趣的是,在用FD+U饮食喂养的Shmt1+/+雌性小鼠中也观察到了露脑畸形的频率增加(5.4%;56个中有3个)。这表明尿苷导致了NTD,其与Shmt1基因型无关。与从施予C饮食的母本动物中分离的NTD相比,从FD+U母本动物中分离的露脑畸形的频率明显更高(P=0.0021)。
在Shmt1-/-(3NTD,占50个存活胚胎的6%)和Shmt1+/+(4NTD,占69个的5.8%)母本动物的窝胎仔中均观察到了露脑畸形。与C+U相比,在用C饮食喂养的母本动物中出现NTD影响的胚胎显著增加(P=0.048)。这些发现表明摄入尿苷导致NTD,其与Shmt1基因型和母本的叶酸状态无关。从用FD+U和C+U饮食喂养的Shmt1+/+母本动物中各分离出一例出现露脑畸形的Shmt1+/+胚胎(表3;图4)。基因型和饮食均不会显著影响妊娠后雌性小鼠的体重。
实施例11-Shmt1+/+和Shmt1-/-小鼠表现出改变的血浆叶酸水平和血糖水平
在Shmt1+/+和Shmt1-/-小鼠中测定了Shmt1基因型对血浆叶酸浓度的影响。在用叶酸缺乏饮食喂养的动物中,血浆叶酸水平显著降低(F=58.3526,P<0.0001;图5)。而且,与用对照饮食喂养的Shmt1+/+小鼠相比,断奶后施予C+T和C+dU饮食而非C+U饮食的Shmt1+/+和Shmt1-/-小鼠血浆叶酸水平显著升高(P<0.05;图5)。
用补充尿苷饮食喂养的小鼠血糖水平升高(P<0.05)。在用C+U和FD+U饮食喂养的两个基因型的母本动物中均出现血糖升高。有趣的是,用补充dU饮食喂养的母本动物具有相似的血糖水平(表4;图5)。
实施例12-Shmt1受损和补充核苷酸的饮食不会在母本肝脏DNA和其他代谢物中增加尿嘧啶的误掺入
在施予所述饮食6周后,摄入叶酸和核苷酸均不会影响母本肝脏核rDNA中的尿嘧啶水平,这表明在肝脏DNA中尿嘧啶不是NTD的生物标记物。然而,与施予C饮食的Shmt1+/+小鼠相比,用FD喂养的Shmt1-/-小鼠有增加尿嘧啶掺入DNA的趋势。在一般情况下,尿嘧啶水平的显著增加仅与母本Shmt1的受损有关(F=6.7414;P=0.0114;Shmt1-/-的平均尿嘧啶水平为0.22±0.01;Shmt1+/+的平均尿嘧啶水平为0.19±0.01(平均值±SEM))。
实施例13-在Shmt1受损的小鼠中补充脱氧尿苷阻止在母本叶酸缺乏产生应答的NTD
已确定细胞质丝氨酸羟甲基转移酶(“SHMT1”)是调节在dTMP和甲硫氨酸生物合成通路之间分配一碳单元的代谢开关(图1)(Herbig等,“Cytoplasmic SerineHydroxymethyltransferase Mediates Competition Between Folate-DependentDeoxyribonucleotide and S-Adenosylmethionine Biosyntheses,”J.Biol.Chem.277(41):38381-38389(2002),其通过引用整体并入本文)。叶酸活化的一碳可以由甲酸通过Mthfd1基因产物或由丝氨酸通过SHMT1在细胞质中产生,以支持甲硫氨酸和胸苷酸的生物合成(图1)。胸苷酸合成可以在细胞质和核中(Woeller 等,“Evidence for SmallUbiquitin-Like Modifier-Dependent Nuclear Import of the ThymidylateBiosynthesis Pathway,”J.Biol.Chem.282(24):17623-17631(2007),其通过引用整体并入本文)。当SHMT1表达时,在S期的细胞核中SHMT1优选通过小泛素样调节子(SUMO)介导的dTMP生物合成通路组件的区域化分配亚甲基四氢叶酸(亚甲基THF)进入dTMP合成通路(Herbig等,“Cytoplasmic Serine Hydroxymethyltransferase Mediates CompetitionBetween Folate-Dependent Deoxyribonucleotide and S-AdenosylmethionineBiosyntheses,”J.Biol.Chem.277(41):38381-38389(2002);Woeller等,“Evidence forSmall Ubiquitin-Like Modifier-Dependent Nuclear Import of the ThymidylateBiosynthesis Pathway,”J.Biol.Chem.282(24):17623-17631(2007),其通过引用整体并入本文)。在细胞质中,SHMT1紧密结合并螯合5-甲基THF,使其无法被甲硫氨酸循环所利用,抑制AdoMet合成并减少细胞甲基化的可能(Herbig等,“Cytoplasmic SerineHydroxymethyltransferase Mediates Competition Between Folate-DependentDeoxyribonucleotide and S-Adenosylmethionine Biosyntheses,”J.Biol.Chem.277(41):38381-38389(2002),其通过引用整体并入本文)。
如上文所示,叶酸的功能是作为酶辅因子,其携带并化学活化用于统称为一碳代谢的合成代谢通路网络的一碳。OCM是嘌呤和胸苷酸(dTMP)从头生物合成以及高半胱氨酸再次甲基化成甲硫氨酸所必需的。甲硫氨酸能够被腺苷酸化以形成S-腺苷甲硫氨酸(AdoMet),其为一种用于多种细胞甲基化反应的甲基供体(图1)。仅在150个小鼠模型的几个中确定了对母本补充叶酸的应答性(Harris等,“Mouse Mutants With Neural TubeClosure Defects and Their Role in Understanding Human Neural Tube Defects,”Birth Defects Res.A Clin.Mol.Teratol.79(3):187-210(2007),其通过引用整体并入本文),其表现出NTD(Wlodarczyk等,“Spontaneous Neural Tube Defects in Splotch MiceSupplemented with Selected Micronutrients,”Toxicol.Appl.Pharmacol.(2005);Fleming等,“Embryonic Folate Metabolism and Mouse Neural Tube Defects,”Science280(5372):2107-2109(1998);Barbera等,“Folic Acid Prevents Exencephalyin Cited2Deficient Mice,”Hum.Mol.Genet.11(3):283-293(2002);Carter等,“CrookedTail(Cd)Models Human Folate-Responsive Neural Tube Defects,”Hum.Mol.Genet.8(12):2199-2204(1999),其通过引用整体并入本文),并且其中有两个NTD模型表现出对外源性叶酸的应答。已证实splotch突变体(Pax3Sp)的OCM受损。splotch突变体的NTD能够通过补充膳食叶酸或胸苷救治,表明在这种小鼠模型中叶酸通过救治胸苷酸从头合成阻止NTD(Wlodarczyk等,“Spontaneous Neural Tube Defects in Splotch Mice Supplementedwith Selected Micronutrients,”Toxicol.Appl.Pharmacol.(2005);Fleming et al.,“Embryonic Folate Metabolism and Mouse Neural Tube Defects,”Science280(5372):2107-2109(1998),其通过引用整体并入本文)。胚胎丝氨酸羟甲基转移酶1(由Shmt1编码)的受损也能够在小鼠中导致叶酸应答性NTD。
这是首个存在叶酸代谢通路基因受损导致叶酸应答性NTD的模型(Beaudin等,“Shmt1and De Novo Thymidylate Biosynthesis Underlie Folate-Responsive NeuralTube Defects in Mice,”Am.J.Clin.Nutr.93(4):789-798(2011),其通过引用整体并入本文)。这种基因-饮食相互作用非常类似于在人体内进行的NTD病理学研究(Relton等,“LowErythrocyte Folate Status and Polymorphic Variation in Folate-Related Genesare Associated with Risk of Neural Tube Defect Pregnancy,”Mol.Genet.Metab.81(4):273-281(2004);Christensen等,“Genetic Polymorphisms inMethylenetetrahydrofolate Reductase and Methionine Synthase,Folate Levels inRed Blood Cells,and Risk of Neural Tube Defects,”Am.J.Med.Genet.84(2):151-157(1999),其通过引用整体并入本文)。Shmt1负责将丝氨酸酶解成甘氨酸产生一碳单元,其优先转移至胸苷酸的生物合成。Shmt1-/-和Shmt1+/-小鼠对叶酸应答性NTD敏感,并且已证实其胸苷酸从头生物合成受损,因此其提供了一种研究NTD的基因-营养物相互作用的方法(Beaudin等,“Shmt1and De Novo Thymidylate Biosynthesis Underlie Folate-Responsive Neural Tube Defects in Mice,”Am.J.Clin.Nutr.93(4):789-798(2011),其通过引用整体并入本文)。然而,Shmt1在小鼠中并不是必需的,因为Shmt2的表达提供了功能冗余(MacFarlane等,“Cytoplasmic Serine Hydroxymethyltransferase Regulatesthe Metabolic Partitioning of Methylenetetrahydrofolate but is Not Essentialin Mice,”J.Biol.Chem.283(38):25846-25853(2008),其通过引用整体并入本文)。尚不知晓在Shmt1小鼠模型中由于胸苷酸从头生物合成途径被破坏而导致NTD的机制。一项研究表明在splotch纯合子中补充膳食胸苷阻止NTD(Fleming等,“Embryonic Folate Metabolismand Mouse Neural Tube Defects,”Science280(5372):2107-2109(1998),其通过引用整体并入本文),而在其他模型中无法证明胸苷阻止NTD的产生。
叶酸阻止神经管闭合缺陷(NTD)的发生和复发,但是导致叶酸应答性NTD的代谢通路尚不完全清楚。如上文所述,此前发现编码丝氨酸羟甲基转移酶1(Shmt1)的基因受损使小鼠对叶酸应答性NTD敏感,叶酸应答性NTD的病因学涉及胸苷酸从头生物合成通路和DNA合成。为更好的了解叶酸在阻止NTD过程中的作用机制,考察了当存在于母本Shmt1-/-小鼠的饮食中时,补充膳食尿苷、胸苷和脱氧尿苷挽救NTD的能力。在上述实施例中已证实膳食脱氧尿苷而非胸苷阻止了响应于母本叶酸缺乏的NTD。令人惊奇的是,补充尿苷加重NTD的频率,而这与摄入叶酸和增加的母本葡萄糖无关。在饮食中存在这些核苷酸不会导致尿嘧啶在核DNA中的蓄积,但是会显著影响胚胎中Pax3的水平,这为一碳代谢受损使NTD风险增加提供了一种新的机制。
更特别的是,在用叶酸缺乏AIN93G饮食喂养的Shmt1-/-母本动物中考察了摄入核苷酸(0.6%尿苷、0.2%胸苷和0.1%2′-脱氧尿苷)影响NTD风险的能力。假设在Shmt1-/-小鼠模型中,如果缺乏细胞胸苷酸导致NTD,则摄入胸苷将阻止NTD,然而如果这些核苷/核苷酸的蓄积导致NTD,则摄入尿苷和/或脱氧尿苷将增加NTD的发生率。在上文所述实施例中得到的结果证明了母本摄入脱氧尿苷而非胸苷在叶酸缺乏Shmt1-/-母本动物中阻止NTD的产生,然而摄入尿苷导致NTD,其不依赖于Shmt1基因型和母本叶酸状况。这些发现为探索人体内叶酸应答性NTD的机制提供了新的观点。
实施例14-小鼠
根据此前的描述,产生SHMT1无(Shmt1-/+)小鼠(MacFarlane等,“CytoplasmicSerine Hydroxymethyltransferase Regulates the Metabolic Partitioning ofMethylenetetrahydrofolate but is Not Essential in Mice,”J.Biol.Chem.283(38):25846-25853(2008),其通过引用整体并入本文)并且与C57BL/6J品系最少回交10代。使用正向引物5′-GACACTGTTCACATCCCTC-3′(SEQ ID NO:1)和反向引物5′-CAAAACATTCGGGAGCCTC-3′(SEQ ID NO:2)对小鼠进行基因分型。正向引物对应于位于loxP位点5′端的内含子6序列和外显子7,反向引物对应于位于loxP位点3′端下游的内含子7序列(MacFarlane等,“Cytoplasmic Serine Hydroxymethyltransferase Regulates theMetabolic Partitioning of Methylenetetrahydrofolate but is Not Essential inMice,”J.Biol.Chem.283(38):25846-25853(2008),其通过引用整体并入本文)。获得C57BL/6J-ApcMin/J(Apcmin/+)小鼠。使用杰克逊实验室的实验方案推荐的下述引物对Apcmin /+小鼠进行基因分型:野生型正向引物5′-GCCATCCCTTCACGTTAG-3′(SEQ ID NO:3),最小正向引物5′-TTCTGAGAAAGACAGAAGTTA-3′(SEQ ID NO:4)和常规反向引物5′-TTCCACTTTGGCATAAGGC-3′(SEQ ID NO:5)。将Shmt1-/+小鼠与Apcmin/+小鼠交配。将双杂合子子代杂交以获得Apcmin/+Shmt1+/+、Apcmin/+Shmt1-/+或Apcmin/+Shmt1-/-小鼠。
实施例15-饮食
将3周龄的小鼠断乳并随机施予补充0.1%脱氧尿苷的对照(AIN-93G;Dyets,Inc.)饮食,或者缺乏叶酸的改良AIN-93G饮食、缺乏叶酸并补充0.1%脱氧尿苷的改良AIN-93G饮食、缺乏叶酸并补充0.2%胸苷的改良AIN-93G饮食、或缺乏叶酸并补充0.6%尿苷(Dyets,Inc.)的改良AIN-93G饮食。对照饮食含有2mg/kg叶酸,而叶酸缺乏饮食含有0mg/kg叶酸。施予小鼠所述饮食5周(Apc+/+)或11周(Apcmin/+)。
实施例16-肿瘤评估
如上文所述,取出小肠和结肠,使用冷PBS冲洗,纵向剖开,将内腔向上平放使用之前描述的解剖显微镜检查(Chiu等,“Sulindac Causes Rapid Regression ofPreexisting Tumors in Min/+Mice Independent of Prostaglandin Biosynthesis,”Cancer Res.57:4267–73(1997),其通过引用整体并入本文)。对肠标本的基因型处于盲态的专业病理学研究人员根据肠内位置(小肠或结肠)和测定的直径来计数肿瘤。肿瘤负荷是肿瘤数量和面积的函数,计算每只小鼠的总肿瘤面积。
实施例17-血浆和组织叶酸的测定
使用干酪乳酸菌微生物学检测对血浆和组织中的叶酸浓度进行定量(Herbig 等,“Cytoplasmic Serine Hydroxymethyltransferase Mediates Competition BetweenFolate-Dependent Deoxyribonucleotide and S-Adenosylmethionine Biosyntheses,”J.Biol.Chem.277(41):38381-38389(2002),其通过引用整体并入本文)。对蛋白浓度进行定量(Bensadoun等,“Assay of Proteins in the Presence of InterferingMaterials,”Anal.Biochem.70:241–50(1976),其通过引用整体并入本文)。
实施例18-核DNA中尿嘧啶的检测
如之前所记载的,气相/质谱测定肝脏核DNA中的尿嘧啶含量(MacFarlane 等,“Cytoplasmic Serine Hydroxymethyltransferase Regulates the MetabolicPartitioning of Methylenetetrahydrofolate but is Not Essential in Mice,”J.Biol.Chem.283(38):25846-25853(2008),其通过引用整体并入本文)。发现Shmt1-/+小鼠在肝脏核DNA中的尿嘧啶含量与在结肠核DNA中的尿嘧啶含量具有相关性。
实施例19-补充尿苷治疗肠肿瘤
通过基因与饮食的相互作用,在Apcmin/+小鼠中已发现Shmt1半合子与肠癌风险增加相关,这表明胸苷酸合成有改变Apcmin/+小鼠对肠癌的易感性的能力(MacFarlane等,“Shmt1Heterozygosity Impairs Folate-Dependent Thymidylate Synthesis Capacityand Modifies Risk of Apcmin-Mediated Intestinal Cancer Risk,”Cancer Res.71:2098-2107(2011),其通过引用整体并入本文)。在野生型中重复该研究,除了在饮食中补充0.6%尿苷0.2%胸苷或0.1%脱氧尿苷以外。汇总于图6中的结果表明在小鼠中补充尿苷治疗肠肿瘤。
特别地,依据与此前所述的相同实验方案在肠肿瘤形成(Apc-min)小鼠模型中考察了摄入脱氧尿苷(在缺乏叶酸的AIN93G饮食中加入0.1%)和尿苷(在缺乏叶酸的AIN93G饮食中加入0.6%)对肿瘤数量的影响(MacFarlane等,“Shmt1Heterozygosity ImpairsFolate-Dependent Thymidylate Synthesis Capacity and Modifies Risk of Apcmin-Mediated Intestinal Cancer Risk,”Cancer Res.71:2098-2107(2011),其通过引用整体并入本文)。用缺乏叶酸的AIN93G饮食喂养的Apc-min小鼠出现(35+/-5)肠肿瘤,而用缺乏叶酸但补充尿苷的AIN-93G饮食喂养的那些出现(18+/-2)肿瘤,用缺乏叶酸但补充脱氧尿苷的AIN-93G饮食喂养的那些出现(29+/-2.0)肿瘤。这些结果表明在这项研究中补充尿苷使肿瘤数量减少49%(p=0.02),但补充脱氧尿苷对肿瘤数量没有影响。
尽管在本文中已经详细地描述和说明了优选实施方式,但是相关领域的技术人员将理解,在不脱离本发明主旨的前提下可以对其进行多种修改、增加、替换等,因此认为由下述权利要求所定义的内容将在本发明的范围内。
Claims (43)
1.一种用于预防和治疗叶酸缺乏相关出生缺陷的药物或膳食组合物,所述组合物包括:
脱氧尿苷;和
药学上或膳食上适宜的载体;和
含量低于400μg的叶酸或其衍生物。
2.根据权利要求1所述的药物或膳食组合物,其中所述组合物是营养食品组合物、药物组合物、功能性食品、功能性营养品、医疗食品、医药营养品或膳食补充剂的一部分。
3.根据权利要求1所述的药物或膳食组合物,其进一步包括:
一种或多种维生素、矿物质、微量元素或其组合。
4.根据权利要求3所述的药物或膳食组合物,其中所述一种或多种维生素、矿物质、微量元素或其组合选自下组:维生素A、维生素C、维生素D、维生素E、维生素K、硫胺素、核黄素、烟酸、叶酸、维生素B12、维生素B6、泛酸、生物素、胆碱、铬、铜、碘、钼、硒、铁、锌、镁及其组合。
5.根据权利要求1所述的药物或膳食组合物,其中所述叶酸或其衍生物的含量低于300μg。
6.根据权利要求1所述的药物或膳食组合物,所述叶酸或其衍生物含量低于200μg。
7.根据权利要求1所述的药物或膳食组合物,所述叶酸或其衍生物含量低于100μg。
8.根据权利要求1所述的药物或膳食组合物,其中所述叶酸或其衍生物的含量低于育龄妇女每日饮食推荐摄取量的至少50%。
9.根据权利要求1所述的药物或膳食组合物,其中所述组合物是胶囊、片剂、颗粒或锭剂形式。
10.脱氧尿苷在制备用于补充主体膳食需要的组合物中的用途,其中所述组合物用于预防和治疗叶酸缺乏相关出生缺陷,并且能够用于一种方法,所述方法包括:
施予主体膳食补充有效量的所述组合物。
11.根据权利要求10所述的用途,其中所述主体是人。
12.根据权利要求10所述的用途,其中所述主体是妊娠妇女、哺乳妇女或育龄妇女。
13.根据权利要求12所述的用途,其中所述妇女是计划妊娠的育龄妇女。
14.根据权利要求10所述的用途,其中将所述组合物作为营养食品组合物、药物组合物、功能性食品、功能性营养品、医疗食品、医疗营养品或膳食补充剂的一部分施予。
15.根据权利要求10所述的用途,其中所述施予进一步包括:
施予一种或多种维生素、矿物质、微量元素或其组合。
16.根据权利要求15所述的用途,其中所述一种或多种维生素、矿物质、微量元素或其组合选自下组:维生素A、维生素C、维生素D、维生素E、维生素K、硫胺素、核黄素、烟酸、叶酸、维生素B12、维生素B6、泛酸、生物素、胆碱、铬、铜、碘、钼、硒、铁、锌、镁及其组合。
17.根据权利要求10所述的用途,其中所述施予进一步包括:
施予主体含量低于1000μg的叶酸或其衍生物。
18.根据权利要求10所述的用途,其中所述施予进一步包括:
施予主体含量低于400μg的叶酸或其衍生物。
19.根据权利要求10所述的用途,其中所述施予进一步包括:
施予主体含量低于300μg的叶酸或其衍生物。
20.根据权利要求10所述的用途,其中所述施予进一步包括:
施予主体含量低于200μg的叶酸或其衍生物。
21.根据权利要求10所述的用途,其中所述施予进一步包括:
施予主体含量低于100μg的叶酸或其衍生物。
22.根据权利要求10所述的用途,其中所述施予进一步包括:
施予主体含量低于育龄妇女每日饮食推荐剂量至少50%的叶酸或其衍生物。
23.根据权利要求10所述的用途,其中所述组合物是以胶囊、片剂、颗粒或锭剂形式施予。
24.根据权利要求10所述的用途,其中所述施予是胃肠外的。
25.根据权利要求10所述的用途,其中所述施予是口服。
26.尿苷在制备用于在主体中治疗肠癌的组合物中的用途,其中所述组合物能够用于一种方法,所述方法包括:
选择患有肠癌的主体;和
施予所选择的主体治疗有效量的所述组合物,从而治疗所选择主体的肠癌。
27.根据权利要求26所述的用途,其中所述癌症是结直肠癌。
28.根据权利要求26所述的用途,其中所述癌症是结肠中的肿瘤。
29.根据权利要求26所述的用途,其中所选择的主体是人。
30.根据权利要求26所述的用途,其中所述组合物作为组合物的一部分施予,所述组合物选自下组:营养食品组合物、药物组合物、功能性食品、功能性营养品、医疗食品、医疗营养品或膳食补充剂。
31.根据权利要求26所述的用途,其中所述施予进一步包括:
施予所选择的主体一种或多种维生素、矿物质、微量元素或其组合。
32.根据权利要求31所述的用途,其中所述一种或多种维生素、矿物质、微量元素或其组合选自下组:维生素A、维生素C、维生素D、维生素E、维生素K、硫胺素、核黄素、烟酸、叶酸、维生素B12、维生素B6、泛酸、生物素、胆碱、铬、铜、碘、钼、硒、铁、锌、镁及其组合。
33.根据权利要求26所述的用途,其中所述组合物是以胶囊、片剂、颗粒或锭剂形式施予。
34.根据权利要求26所述的用途,其中所述施予是胃肠外的。
35.根据权利要求26所述的用途,其中所述施予是口服。
36.根据权利要求26所述的用途,其进一步包括:
联合向所述所选择的主体施予癌症疗法和所述治疗有效量的所述组合物。
37.根据权利要求36所述的用途,其中所述癌症疗法是放疗。
38.根据权利要求36所述的用途,其中所述癌症疗法是外科手术。
39.根据权利要求36所述的用途,其中所述癌症疗法是化疗。
40.根据权利要求39所述的用途,其中所述化疗选自下组:烷化剂、抗代谢药、蒽环类药物、抗肿瘤抗生素、基于铂的化学疗法和植物生物碱。
41.根据权利要求36所述的用途,其中所述治疗有效量的所述组合物和癌症疗法同时施予。
42.根据权利要求36所述的用途,其中所述治疗有效量的所述组合物在癌症疗法之前施予。
43.根据权利要求36所述的用途,其中所述治疗有效量的所述组合物在癌症疗法之后施予。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161478669P | 2011-04-25 | 2011-04-25 | |
US61/478,669 | 2011-04-25 | ||
US201161515356P | 2011-08-05 | 2011-08-05 | |
US61/515,356 | 2011-08-05 | ||
PCT/US2012/034963 WO2012148998A1 (en) | 2011-04-25 | 2012-04-25 | Use of uridine and deoxyuridine to treat folate-responsive pathologies |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103619340A CN103619340A (zh) | 2014-03-05 |
CN103619340B true CN103619340B (zh) | 2016-08-17 |
Family
ID=47072721
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201280031365.XA Expired - Fee Related CN103619340B (zh) | 2011-04-25 | 2012-04-25 | 尿苷和脱氧尿苷在治疗叶酸应答性病变中的用途 |
Country Status (4)
Country | Link |
---|---|
US (1) | US9579337B2 (zh) |
EP (1) | EP2701712B1 (zh) |
CN (1) | CN103619340B (zh) |
WO (1) | WO2012148998A1 (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB201211135D0 (en) * | 2012-06-22 | 2012-08-08 | Ucl Business Plc | Treatment |
WO2018033382A1 (en) * | 2016-08-15 | 2018-02-22 | F. Hoffmann-La Roche Ag | Method of isolating nucleic acids for long sequencing reads |
CA3128973A1 (en) | 2019-03-04 | 2020-09-10 | Bhaskar Bhattacharyya | Data compression and communication using machine learning |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070114476A1 (en) * | 2005-11-04 | 2007-05-24 | Williams Christopher P | Low radiocarbon nucleotide and amino acid dietary supplements |
CN101019880A (zh) * | 2007-03-13 | 2007-08-22 | 西安交通大学 | 一种肝靶向氟尿苷纳米粉针剂及其制备方法 |
WO2008003514A2 (en) * | 2006-07-06 | 2008-01-10 | Apogenix Gmbh | Human il-4 muteins in combination with chemotherapeutics or pro-apoptotic agents in cancer therapy |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1521000A (en) | 1975-06-13 | 1978-08-09 | Syntex Puerto Rico Inc | Inhalation device |
US4192309A (en) | 1978-09-05 | 1980-03-11 | Syntex Puerto Rico, Inc. | Inhalation device with capsule opener |
US4227522A (en) | 1978-09-05 | 1980-10-14 | Syntex Puerto Rico, Inc. | Inhalation device |
JPS5735516A (en) * | 1980-08-11 | 1982-02-26 | Yamasa Shoyu Co Ltd | Agent for increasing radiosensitivity or agent for increasing effect of substance having activity similar to radiation |
JPH05963A (ja) | 1990-04-13 | 1993-01-08 | Toray Ind Inc | ポリペプチド類組成物 |
US6335434B1 (en) * | 1998-06-16 | 2002-01-01 | Isis Pharmaceuticals, Inc., | Nucleosidic and non-nucleosidic folate conjugates |
US6582728B1 (en) | 1992-07-08 | 2003-06-24 | Inhale Therapeutic Systems, Inc. | Spray drying of macromolecules to produce inhaleable dry powders |
US8518882B2 (en) | 1998-07-31 | 2013-08-27 | Massachusetts Institute Of Technology | Methods and compositions for ameliorating or inhibiting decline in memory or intelligence or improving same |
US20060280776A1 (en) * | 2003-09-02 | 2006-12-14 | Masafumi Koide | Diet food |
WO2005122767A1 (en) | 2004-06-10 | 2005-12-29 | Mclean Hospital Corporation | Pyrimidines, such as uridine, in treatments for patients with bipolar disorder |
WO2009002146A1 (en) | 2007-06-26 | 2008-12-31 | N.V. Nutricia | Supporting activities of daily living |
-
2012
- 2012-04-25 US US14/113,858 patent/US9579337B2/en active Active
- 2012-04-25 WO PCT/US2012/034963 patent/WO2012148998A1/en active Application Filing
- 2012-04-25 CN CN201280031365.XA patent/CN103619340B/zh not_active Expired - Fee Related
- 2012-04-25 EP EP12777418.0A patent/EP2701712B1/en not_active Not-in-force
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070114476A1 (en) * | 2005-11-04 | 2007-05-24 | Williams Christopher P | Low radiocarbon nucleotide and amino acid dietary supplements |
WO2008003514A2 (en) * | 2006-07-06 | 2008-01-10 | Apogenix Gmbh | Human il-4 muteins in combination with chemotherapeutics or pro-apoptotic agents in cancer therapy |
CN101019880A (zh) * | 2007-03-13 | 2007-08-22 | 西安交通大学 | 一种肝靶向氟尿苷纳米粉针剂及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
EP2701712A4 (en) | 2015-05-27 |
EP2701712B1 (en) | 2017-06-21 |
WO2012148998A1 (en) | 2012-11-01 |
US20140080784A1 (en) | 2014-03-20 |
US9579337B2 (en) | 2017-02-28 |
CN103619340A (zh) | 2014-03-05 |
EP2701712A1 (en) | 2014-03-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Isbrucker et al. | Risk and safety assessment on the consumption of Licorice root (Glycyrrhiza sp.), its extract and powder as a food ingredient, with emphasis on the pharmacology and toxicology of glycyrrhizin | |
CN102470154B (zh) | 用于毛发护理的甜菊提取物或甜菊醇 | |
JP2017506651A (ja) | 脂肪肝の低減または予防のための組成物および方法 | |
CN109069462A (zh) | 缺乏至少两种非必需氨基酸的膳食产品 | |
CN102264222B (zh) | 抗病毒补剂 | |
JP6177688B2 (ja) | 組成物、及び糖代謝改善剤、並びに組成物の使用 | |
CN104306617B (zh) | 含有玛咖和阿萨伊果的组合物及其制备方法和应用 | |
WO2020262325A1 (ja) | 雌の抗老化剤 | |
Diogo et al. | Voluntary oral administration of losartan in rats | |
CN102695514A (zh) | 具有增强的生物利用度的s-腺苷甲硫氨酸配制物 | |
EP2397039A1 (en) | Compositions for delaying progression of diabetes using Salacia oblonga extract | |
JP2002528507A (ja) | 神経疾患および病態心理学的疾患の治療および予防用の組成物 | |
CN103619340B (zh) | 尿苷和脱氧尿苷在治疗叶酸应答性病变中的用途 | |
CN109452651B (zh) | 耐力组合物 | |
CN105142648A (zh) | 用于癌症的镁组合物及其用途 | |
KR20160132134A (ko) | 당 대사 개선제 및 당 대사 개선 조성물 | |
WO2024015453A1 (en) | Methods for increasing the bioavailability of nucleoside medicinal agents | |
CN101662956A (zh) | 羟基酪醇和含有羟基酪醇的橄榄提取物/浓缩物的新颖用途 | |
CN105451730A (zh) | 用于增强认知性能的方法和组合物 | |
KR20160121023A (ko) | 패오니플로린을 유효성분으로 포함하는 불임증 예방 또는 치료용 조성물 | |
US20190298721A1 (en) | Stable pro-vitamin derivative compounds, pharmaceutical and dietary compositions, and methods of their use | |
US11684618B2 (en) | Compositions comprising mixtures of compounds and uses thereof | |
WO2022094916A1 (zh) | 一种提高烟酰胺磷酸核糖转移酶活性的方法及其组合物 | |
US20220323470A1 (en) | Composition and use thereof in the manufacture of medicament for treating cancer | |
EP3053575B1 (en) | Agent for preventing or ameliorating renal dysfunction |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1195493 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1195493 Country of ref document: HK |
|
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160817 Termination date: 20190425 |