WO2004033725A2 - Methods and means for the treatment of inflammatory disorders involving genotyping of the 5, 10- methylenetetrahydrofolate reductase (mthfr) gene - Google Patents
Methods and means for the treatment of inflammatory disorders involving genotyping of the 5, 10- methylenetetrahydrofolate reductase (mthfr) gene Download PDFInfo
- Publication number
- WO2004033725A2 WO2004033725A2 PCT/GB2003/004372 GB0304372W WO2004033725A2 WO 2004033725 A2 WO2004033725 A2 WO 2004033725A2 GB 0304372 W GB0304372 W GB 0304372W WO 2004033725 A2 WO2004033725 A2 WO 2004033725A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- folic acid
- vitamin
- inflammatory
- use according
- disorder
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 56
- 238000011282 treatment Methods 0.000 title claims abstract description 29
- 208000027866 inflammatory disease Diseases 0.000 title claims abstract description 21
- 108090000623 proteins and genes Proteins 0.000 title claims abstract description 13
- 101710188260 5,10-methylenetetrahydrofolate reductase Proteins 0.000 title abstract description 4
- 238000003205 genotyping method Methods 0.000 title description 2
- 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 claims abstract description 103
- 239000011724 folic acid Substances 0.000 claims abstract description 53
- 235000019152 folic acid Nutrition 0.000 claims abstract description 52
- 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 claims abstract description 51
- 229960000304 folic acid Drugs 0.000 claims abstract description 51
- 102100029684 Methylenetetrahydrofolate reductase Human genes 0.000 claims abstract description 25
- 101000587058 Homo sapiens Methylenetetrahydrofolate reductase Proteins 0.000 claims abstract 5
- 150000001875 compounds Chemical class 0.000 claims description 50
- 239000000203 mixture Substances 0.000 claims description 37
- LXNHXLLTXMVWPM-UHFFFAOYSA-N Vitamin B6 Natural products CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims description 20
- 230000000694 effects Effects 0.000 claims description 19
- 102000054765 polymorphisms of proteins Human genes 0.000 claims description 19
- 102000004190 Enzymes Human genes 0.000 claims description 16
- 108090000790 Enzymes Proteins 0.000 claims description 16
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 15
- 238000012360 testing method Methods 0.000 claims description 15
- 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 14
- 150000007523 nucleic acids Chemical group 0.000 claims description 14
- 239000003963 antioxidant agent Substances 0.000 claims description 13
- 235000006708 antioxidants Nutrition 0.000 claims description 13
- 201000004624 Dermatitis Diseases 0.000 claims description 11
- 208000010668 atopic eczema Diseases 0.000 claims description 11
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 claims description 11
- 235000019158 vitamin B6 Nutrition 0.000 claims description 11
- 239000011726 vitamin B6 Substances 0.000 claims description 11
- 229930003779 Vitamin B12 Natural products 0.000 claims description 10
- 235000019163 vitamin B12 Nutrition 0.000 claims description 10
- 239000011715 vitamin B12 Substances 0.000 claims description 10
- 229940011671 vitamin b6 Drugs 0.000 claims description 9
- 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 8
- 230000003078 antioxidant effect Effects 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 7
- 229930003268 Vitamin C Natural products 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 108091011001 folic acid binding proteins Proteins 0.000 claims description 7
- 230000002757 inflammatory effect Effects 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 208000017520 skin disease Diseases 0.000 claims description 7
- 238000011144 upstream manufacturing Methods 0.000 claims description 7
- 235000019154 vitamin C Nutrition 0.000 claims description 7
- 239000011718 vitamin C Substances 0.000 claims description 7
- 102000019197 Superoxide Dismutase Human genes 0.000 claims description 6
- 108010012715 Superoxide dismutase Proteins 0.000 claims description 6
- 208000035475 disorder Diseases 0.000 claims description 6
- 230000037353 metabolic pathway Effects 0.000 claims description 6
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 5
- 206010012442 Dermatitis contact Diseases 0.000 claims description 5
- 201000008937 atopic dermatitis Diseases 0.000 claims description 5
- 208000010247 contact dermatitis Diseases 0.000 claims description 5
- 230000000699 topical effect Effects 0.000 claims description 5
- 239000012049 topical pharmaceutical composition Substances 0.000 claims description 5
- UPYKUZBSLRQECL-UKMVMLAPSA-N Lycopene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1C(=C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=C)CCCC2(C)C UPYKUZBSLRQECL-UKMVMLAPSA-N 0.000 claims description 4
- JEVVKJMRZMXFBT-XWDZUXABSA-N Lycophyll Natural products OC/C(=C/CC/C(=C\C=C\C(=C/C=C/C(=C\C=C\C=C(/C=C/C=C(\C=C\C=C(/CC/C=C(/CO)\C)\C)/C)\C)/C)\C)/C)/C JEVVKJMRZMXFBT-XWDZUXABSA-N 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- 241001465754 Metazoa Species 0.000 claims description 4
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims description 4
- 229930003427 Vitamin E Natural products 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 claims description 4
- 235000013734 beta-carotene Nutrition 0.000 claims description 4
- 239000011648 beta-carotene Substances 0.000 claims description 4
- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 claims description 4
- 229960002747 betacarotene Drugs 0.000 claims description 4
- 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 4
- 235000012661 lycopene Nutrition 0.000 claims description 4
- 229960004999 lycopene Drugs 0.000 claims description 4
- 239000001751 lycopene Substances 0.000 claims description 4
- OAIJSZIZWZSQBC-GYZMGTAESA-N lycopene Chemical compound CC(C)=CCC\C(C)=C\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C=C(/C)CCC=C(C)C OAIJSZIZWZSQBC-GYZMGTAESA-N 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 235000001055 magnesium Nutrition 0.000 claims description 4
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 claims description 4
- 208000014999 perianal Crohn disease Diseases 0.000 claims description 4
- 238000012216 screening Methods 0.000 claims description 4
- 239000011669 selenium Substances 0.000 claims description 4
- 229910052711 selenium Inorganic materials 0.000 claims description 4
- 235000011649 selenium Nutrition 0.000 claims description 4
- ZCIHMQAPACOQHT-ZGMPDRQDSA-N trans-isorenieratene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/c1c(C)ccc(C)c1C)C=CC=C(/C)C=Cc2c(C)ccc(C)c2C ZCIHMQAPACOQHT-ZGMPDRQDSA-N 0.000 claims description 4
- 235000019165 vitamin E Nutrition 0.000 claims description 4
- 239000011709 vitamin E Substances 0.000 claims description 4
- 229940046009 vitamin E Drugs 0.000 claims description 4
- 239000011701 zinc Substances 0.000 claims description 4
- 229910052725 zinc Inorganic materials 0.000 claims description 4
- 235000016804 zinc Nutrition 0.000 claims description 4
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 claims description 4
- 102000008186 Collagen Human genes 0.000 claims description 3
- 108010035532 Collagen Proteins 0.000 claims description 3
- 102100034976 Cystathionine beta-synthase Human genes 0.000 claims description 3
- 108010073644 Cystathionine beta-synthase Proteins 0.000 claims description 3
- 108020002908 Epoxide hydrolase Proteins 0.000 claims description 3
- 102000005486 Epoxide hydrolase Human genes 0.000 claims description 3
- 102000006587 Glutathione peroxidase Human genes 0.000 claims description 3
- 108700016172 Glutathione peroxidases Proteins 0.000 claims description 3
- 102000005720 Glutathione transferase Human genes 0.000 claims description 3
- 108010070675 Glutathione transferase Proteins 0.000 claims description 3
- 102000003814 Interleukin-10 Human genes 0.000 claims description 3
- 108090000174 Interleukin-10 Proteins 0.000 claims description 3
- 102000004889 Interleukin-6 Human genes 0.000 claims description 3
- 108090001005 Interleukin-6 Proteins 0.000 claims description 3
- 102000003896 Myeloperoxidases Human genes 0.000 claims description 3
- 108090000235 Myeloperoxidases Proteins 0.000 claims description 3
- 102000008299 Nitric Oxide Synthase Human genes 0.000 claims description 3
- 108010021487 Nitric Oxide Synthase Proteins 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 108010074686 Selenoproteins Proteins 0.000 claims description 3
- 102000018594 Tumour necrosis factor Human genes 0.000 claims description 3
- 108050007852 Tumour necrosis factor Proteins 0.000 claims description 3
- 101150087698 alpha gene Proteins 0.000 claims description 3
- 229920001436 collagen Polymers 0.000 claims description 3
- 102000054766 genetic haplotypes Human genes 0.000 claims description 3
- 229940076144 interleukin-10 Drugs 0.000 claims description 3
- 229940100601 interleukin-6 Drugs 0.000 claims description 3
- 102000009310 vitamin D receptors Human genes 0.000 claims description 3
- 108050000156 vitamin D receptors Proteins 0.000 claims description 3
- 102000011848 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase Human genes 0.000 claims description 2
- 108010075604 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase Proteins 0.000 claims description 2
- 102000008114 Selenoproteins Human genes 0.000 claims description 2
- 235000021004 dietary regimen Nutrition 0.000 claims description 2
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 claims description 2
- 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 4
- 102000036215 folic acid binding proteins Human genes 0.000 claims 4
- 239000007795 chemical reaction product Substances 0.000 claims 3
- 229940091250 magnesium supplement Drugs 0.000 claims 3
- 230000001590 oxidative effect Effects 0.000 claims 3
- 230000037361 pathway Effects 0.000 claims 3
- 108010074922 Cytochrome P-450 CYP1A2 Proteins 0.000 claims 2
- 102100031476 Cytochrome P450 1A1 Human genes 0.000 claims 2
- 101710104049 Cytochrome P450 1A1 Proteins 0.000 claims 2
- 102100026533 Cytochrome P450 1A2 Human genes 0.000 claims 2
- GGLZPLKKBSSKCX-YFKPBYRVSA-N L-ethionine Chemical compound CCSCC[C@H](N)C(O)=O GGLZPLKKBSSKCX-YFKPBYRVSA-N 0.000 claims 1
- 108091028043 Nucleic acid sequence Proteins 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 claims 1
- 108020004414 DNA Proteins 0.000 description 35
- 239000000523 sample Substances 0.000 description 35
- 210000004027 cell Anatomy 0.000 description 19
- 238000009472 formulation Methods 0.000 description 17
- 102000039446 nucleic acids Human genes 0.000 description 13
- 108020004707 nucleic acids Proteins 0.000 description 13
- 238000003556 assay Methods 0.000 description 12
- 108091034117 Oligonucleotide Proteins 0.000 description 11
- 101001039269 Rattus norvegicus Glycine N-methyltransferase Proteins 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- -1 and derivatives Substances 0.000 description 10
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 8
- 239000006071 cream Substances 0.000 description 8
- 108700028369 Alleles Proteins 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 238000003752 polymerase chain reaction Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(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+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 6
- 239000003995 emulsifying agent Substances 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 6
- 239000003925 fat Substances 0.000 description 6
- 230000006872 improvement Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 239000003381 stabilizer Substances 0.000 description 6
- 230000009469 supplementation Effects 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical group CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 5
- 230000003321 amplification Effects 0.000 description 5
- 238000003199 nucleic acid amplification method Methods 0.000 description 5
- 239000002773 nucleotide Substances 0.000 description 5
- 125000003729 nucleotide group Chemical group 0.000 description 5
- 239000003883 ointment base Substances 0.000 description 5
- 238000011002 quantification Methods 0.000 description 5
- 102000053602 DNA Human genes 0.000 description 4
- 238000000018 DNA microarray Methods 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 108010022394 Threonine synthase Proteins 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 238000010448 genetic screening Methods 0.000 description 4
- 230000004968 inflammatory condition Effects 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- 239000002674 ointment Substances 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101150019913 MTHFR gene Proteins 0.000 description 3
- ZYFVNVRFVHJEIU-UHFFFAOYSA-N PicoGreen Chemical compound CN(C)CCCN(CCCN(C)C)C1=CC(=CC2=[N+](C3=CC=CC=C3S2)C)C2=CC=CC=C2N1C1=CC=CC=C1 ZYFVNVRFVHJEIU-UHFFFAOYSA-N 0.000 description 3
- 108010006785 Taq Polymerase Proteins 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000000295 complement effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000009396 hybridization Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000002493 microarray Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- 208000011231 Crohn disease Diseases 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
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 108010067770 Endopeptidase K Proteins 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 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 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 238000012408 PCR amplification Methods 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 102000005497 Thymidylate Synthase Human genes 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000002939 deleterious effect Effects 0.000 description 2
- 231100000223 dermal penetration Toxicity 0.000 description 2
- 102000004419 dihydrofolate reductase Human genes 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 235000013601 eggs Nutrition 0.000 description 2
- 239000008387 emulsifying waxe Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 210000003754 fetus Anatomy 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 239000003068 molecular probe Substances 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 244000144977 poultry Species 0.000 description 2
- 235000013594 poultry meat Nutrition 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000007894 restriction fragment length polymorphism technique Methods 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- QMMJWQMCMRUYTG-UHFFFAOYSA-N 1,2,4,5-tetrachloro-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=C(Cl)C(Cl)=CC(Cl)=C1Cl QMMJWQMCMRUYTG-UHFFFAOYSA-N 0.000 description 1
- LGEZTMRIZWCDLW-UHFFFAOYSA-N 14-methylpentadecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC(C)C LGEZTMRIZWCDLW-UHFFFAOYSA-N 0.000 description 1
- SFAAOBGYWOUHLU-UHFFFAOYSA-N 2-ethylhexyl hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(CC)CCCC SFAAOBGYWOUHLU-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 244000003416 Asparagus officinalis Species 0.000 description 1
- 235000005340 Asparagus officinalis Nutrition 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 235000011299 Brassica oleracea var botrytis Nutrition 0.000 description 1
- 235000017647 Brassica oleracea var italica Nutrition 0.000 description 1
- 240000003259 Brassica oleracea var. botrytis Species 0.000 description 1
- 239000004358 Butane-1, 3-diol Substances 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 244000060011 Cocos nucifera Species 0.000 description 1
- 235000013162 Cocos nucifera Nutrition 0.000 description 1
- 108091033380 Coding strand Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 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 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
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 244000000626 Daucus carota Species 0.000 description 1
- 235000002767 Daucus carota Nutrition 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 108060002716 Exonuclease Proteins 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- VWWQXMAJTJZDQX-UHFFFAOYSA-N Flavine adenine dinucleotide Natural products C1=NC2=C(N)N=CN=C2N1C(C(O)C1O)OC1COP(O)(=O)OP(O)(=O)OCC(O)C(O)C(O)CN1C2=NC(=O)NC(=O)C2=NC2=C1C=C(C)C(C)=C2 VWWQXMAJTJZDQX-UHFFFAOYSA-N 0.000 description 1
- 108010093223 Folylpolyglutamate synthetase Proteins 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000019687 Lamb Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 208000004155 Malabsorption Syndromes Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- 108020005187 Oligonucleotide Probes Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- 235000009337 Spinacia oleracea Nutrition 0.000 description 1
- 244000300264 Spinacia oleracea Species 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 229930003270 Vitamin B Natural products 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000037374 absorbed through the skin Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 238000007844 allele-specific PCR Methods 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000000137 annealing Methods 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003491 array Methods 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 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
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- SASYSVUEVMOWPL-NXVVXOECSA-N decyl oleate Chemical compound CCCCCCCCCCOC(=O)CCCCCCC\C=C/CCCCCCCC SASYSVUEVMOWPL-NXVVXOECSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 102000013165 exonuclease Human genes 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 210000004700 fetal blood Anatomy 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 235000019688 fish Nutrition 0.000 description 1
- 235000019162 flavin adenine dinucleotide Nutrition 0.000 description 1
- 239000011714 flavin adenine dinucleotide Substances 0.000 description 1
- 238000002795 fluorescence method Methods 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- 102000030722 folylpolyglutamate synthetase Human genes 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 1
- 235000021384 green leafy vegetables Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000008309 hydrophilic cream Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229940078545 isocetyl stearate Drugs 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 229940043348 myristyl alcohol Drugs 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
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- 238000002966 oligonucleotide array Methods 0.000 description 1
- 239000002751 oligonucleotide probe Substances 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 239000008251 pharmaceutical emulsion Substances 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 235000015277 pork Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 235000020989 red meat Nutrition 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 230000005808 skin problem Effects 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000007790 solid phase 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
- 238000010186 staining Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 208000002670 vitamin B12 deficiency Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 235000015099 wheat brans Nutrition 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4415—Pyridoxine, i.e. Vitamin B6
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
-
- 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
- A61K31/7135—Compounds containing heavy metals
- A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/28—Mercury; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/32—Manganese; Compounds thereof
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/136—Screening for pharmacological compounds
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
Definitions
- the present invention relates to the treatment of inflammatory disorders, in particular inflammatory skin disorders, and the use of genotyping to identify individuals having such disorders who are responsive to particular treatments.
- methotrexate has a number of side effects, including severe bone marrow depression, hepatotoxicicity, fibrosis and cirrhosis.
- MTHFR 10-methylenetetrahydrofolate reductase
- MTHFR is an enzyme involved in folic acid metabolism which is active in the folate-dependent methylation of DNA precursors. Low activity of this enzyme leads to an increase of uracil incorporation into DNA (instead of thymine) (Ames, B. N. PNAS USA 96(22): 12216-12218, 1999) .
- the MTHFR gene is polymorphic and has been linked to colon cancer, adult acute lymphocytic leukaemia and infant leukaemia (Ames, 1999 supra; Perera, F.P et al Carcinogenesis 21 (3): 517-524, 2000.; Potter, J. D. J. Nat. Cancer Instit. 91(11): 916-932, 1999).
- MTHFR encoding nucleic acid is further described in US6074821.
- Known polymorphisms within the MTHFR locus include C677T and A1298C substitutions.
- the C677T polymorphism of MTHFR results in the insertion of a valine residue in place of an alanine residue in the enzyme which lowers both the stability and the activity of the enzyme as measured in cell extracts (Frosst et al (1995) Nat. Genet. 10(1) 111-113).
- the A1298C polymorphism results in the insertion of a glutamate in place of an alanine residue (Viel et al (1997) Br. J. Cancer 75(8) 1105-1110) and may effect enzyme regulation by S-adenosylmethioinine ( eisberg et al (2001) 156(2) 409-415) .
- the C677T and A1298C polymorphisms can occur together; however, not in a homozygous state for both polymorphisms.
- a comparative study of genotypes of neonatal cord blood and nonviable fetal tissue revealed that 677TT with 1298CC was only found in nonviable fetal tissue as was 677CT with 1298CC, suggesting a decreased viability among foetuses with these genotypes and a possible selection disadvantage with increasing number of mutant MTHFR alleles (Isotalo et al (2000) Mol. Diagn. 5(1) 59-66).
- the present inventors have recognised that inflammatory disorders in individuals who are polymorphic for C677T and/or A1298C of the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene are responsive to treatment involving the administration of folic acid.
- MTHFR 10-methylenetetrahydrofolate reductase
- One aspect of the invention provides a method of assessing an individual having an inflammatory disorder, the method comprising; determining the presence or absence of one or both of the polymorphisms C677T and A1298C, or of haplotypes in linkage disequilibrium with one or both of said polymorphisms, in the MTHFR sequence of a nucleic acid sample obtained from said individual .
- a method may further comprise inferring from the presence of one or both of said polymorphisms or haplotypes that said individual responds to treatment comprising administration of folic acid or compounds which promote the activity or expression of MTHFR.
- An individual who is responsive to the administration of folic acid may be heterozygous at 677 (TC) and wild-type at 1298 (AA) , wild-type at 677 (CC) and heterozygous at 1298 (AC), heterozygous at both 677 (TC) and 1298 (AC) , homozygous at
- a nucleic acid sample suitable for use in such a method may be an RNA or DNA sample isolated from any suitable client or patient cell sample, for example a genomic DNA sample, or an amplification product of such a nucleic acid.
- a suitable client or patient cell sample for example a genomic DNA sample, or an amplification product of such a nucleic acid.
- the DNA is isolated from cheek (buccal) cells. This enables easy and painless collection of cells.
- ⁇ folic acid' as used herein may include folic acid, and derivatives, metabolites and prodrugs of folic acid.
- Cells may be isolated from the inside of the mouth using a disposable scraping device with a plastic or paper matrix ⁇ brush", for example, the C.E.P. SwabTM (Life Technologies).
- DNA from the cell samples may be isolated using conventional procedures. For example DNA may be immobilised onto filters, column matrices, or magnetic beads. Numerous commercial kits, such as the Qiagen QIAamp kit (Qiagen, Crawley, UK) may be used. Briefly, the cell sample may be placed in a microcentrifuge tube and combined with Proteinase K, mixed, and allowed to incubate to lyse the cells. Ethanol is then added and the lysate is transferred to a QIAamp spin column from which DNA is eluted after several washings.
- Qiagen QIAamp kit Qiagen, Crawley, UK
- the amount of DNA isolated by the particular method used may be quantified to ensure that sufficient DNA is available for the assay and to determine the dilution required to achieve the desired concentration of DNA for PCR amplification.
- the desired target DNA concentration may be in the range 10 ng and 50 ng. DNA concentrations outside this range may impact the PCR amplification of the individual alleles and thus impact the sensitivity and selectivity of the polymorphism determination step.
- the quantity of DNA obtained from a sample may be determined using any suitable technique.
- suitable techniques are well known to persons skilled in the art and include UV (Maniatis T., Fritsch E. F. , and Sambrook J., (1982) Molecular Cloning A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Springs Harbor, NY) or fluorescence based methods.
- UV methods may suffer from the interfering absorbance caused by contaminating molecules such as nucleotides, RNA, EDTA and phenol and the dynamic range and sensitivity of this technique is not as great as that of fluorescent methods, fluorescence methods are preferred.
- Commercially available fluorescence based kits such as the PicoGreen dsDNA Quantification (Molecular Probes, Eugene, Oregon, USA) .
- the nucleic acids in the sample may be selectively amplified, for example using
- PCR Polymerase Chain Reaction
- Preferred primers for use in the present invention are from 18 to 23 nucleotides in length, without internal homology or primer-primer homology.
- the two primers of a pair are preferably selected to hybridise to either side of the region of interest so that about 150 bases in length are amplified, although amplification of shorter and longer fragments may also be used.
- the site of polymorphism should be at or near the centre of the region amplified.
- Preferred examples of primer pairs which may be used for analysing the C677T and A1298C polymorphisms in the MTHFR gene are shown in Table 1, together with preferred examples of the wild-type probes and polymorphic probes used in the Taqman® assay for each gene target.
- the individual polymorphisms may be identified. Identification of the markers for the polymorphisms involves the discriminative detection of allelic forms of the MTHFR gene that differ by nucleotide substitution at position 677 and/or 1298.
- OLA Oligonucleotide ligation assay
- the polymorphisms in the MTHFR locus may be assessed via a specialised type of PCR used to detect polymorphisms, commonly referred to as the Taqman® assay and performed using an AB7700 instrument (Applied Biosystems, Warrington, UK) .
- a probe is synthesised which hybridises to a region of interest containing the polymorphism.
- the probe contains three modifications: a fluorescent reporter molecule, a fluorescent quencher molecule and a minor groove-binding chemical to enhance binding to the genomic DNA strand.
- the probe may be bound to either strand of DNA.
- the polymerase will encounter the probe and begin to remove bases from the probe one at a time using a 5' -3' exonuclease activity.
- the fluorescent molecule is no longer quenched by the quencher molecule and the molecule will begin to fluoresce.
- This type of reaction can only take place if the probe has hybridised perfectly to the matched genomic sequence. As successive cycles of amplification take place, i.e. more probes and primers are bound to the DNA present in the reaction mixture, the amount of fluorescence will increase and a positive result will be detected. If the genomic DNA does not have a sequence that matches the probe perfectly, no fluorescent signal is detected.
- hybridisation with allele specific oligonucleotides is conveniently carried out using oligonucleotide arrays, preferably microarrays, to determine the presence of a particular polymorphism.
- microarrays allow miniaturisation of assays, e.g. making use of binding agents (such as nucleic acid sequences) immobilised in small, discrete locations (microspots) and/or as arrays on solid supports or on diagnostic chips.
- binding agents such as nucleic acid sequences
- microspots discrete locations
- diagnostic chips diagnostic chips.
- These approaches may provide great sensitivity (particularly through the use of fluorescent labelled reagents) , require only very small amounts of biological sample from individuals being tested and allow a variety of separate assays to be carried out simultaneously. This latter advantage can be useful as it provides an assay for different a number of polymorphisms of one or more genes to be carried out using a single sample.
- DNA microarrays have been shown to provide appropriate discrimination for polymorphism detection (Yershov, G. et. al.(1996) PNAS USA, Genetics, Vol. 93, 4913-4918; Schena, M., 1999, DNA Microarrays "a practical approach", ISBN, 0-19- 963777-6, Oxford press, editor B. D. Hames; Cheung, V. G., et. al., 1999, Nat. Genet., vol. 21, 15-19).
- the DNA microarray may be generated using oligonucleotides that have been selected to hybridise with the specific target polymorphism.
- oligonucleotides may be applied by a robot onto a predetermined location of a glass slide, e.g. at predetermined X, Y cartesian coordinates, and immobilised.
- the PCR product e.g. fluorescently labelled RNA or DNA
- the PCR product is introduced on to the DNA microarray and a hybridisation reaction conducted so that sample RNA or DNA binds to complementary sequences of oligonucleotides in a sequence- specific manner, and allow unbound material to be washed away.
- Gene target polymorphisms can thus be detected by their ability to bind to complementary oligonucleotides on the array and produce a signal.
- the fluorescence at each coordinate can be read using a suitable automated detector in order to correlate each fluorescence signal with a particular oligonucleotide.
- the absence of a fluorescent signal for a specific oligonucleotide probe indicates that the client does not have the corresponding polymorphism.
- the method is not limited to the use of fluorescence labelling but may use other suitable labels known in the art.
- Oligonucleotides for use in the array may be selected to span the site of the polymorphism, each oligonucleotide comprising one of the following at a central location within the sequence :
- An inflammatory condition in an individual may thus be assessed using one or more oligonucleotides as described herein.
- Such nucleotides may, in some embodiments, be provided on a microarray.
- a suitable inflammatory disorder may include any disorder in which a reduction in inflammation is desirable, including an inflammatory skin disorder such as atopic dermatitis, contact dermatitis, eczema, psoriasis and other inflammatory disorders such as Perianal Crohn' s disease and rheumatoid arthritis.
- an inflammatory skin disorder such as atopic dermatitis, contact dermatitis, eczema, psoriasis and other inflammatory disorders such as Perianal Crohn' s disease and rheumatoid arthritis.
- An individual identified by a method according to this aspect of the invention may be responsive to folic acid, or derivatives, metabolites or pro-drugs thereof. Such an individual may also be responsive to compounds which either promote or reduce the activity or expression of MTHFR, including, for example, FAD, riboflavin, folic acid and vitamin B6.
- the ability of an individual to respond to folic acid may also be affected by defects or variations in antioxidant metabolism.
- a method may comprise the further step of determining the presence of polymorphisms in one or more of the following oxidation associated genes in said individual; methionine synthase, cystathionine ⁇ synthase, vitamin D receptor, collagen type 1 alpha gene, tumour necrosis factor c. and ⁇ , glutathione S-transferase, cytochro e p450 1A1 and 1A2, manganese superoxide dismutase, extracellular superoxide dismutase, epoxide hydrolase, myeloperoxidase, nitric oxide synthase, glutathione peroxidase, interleukin 10, interleukin 6 and selenoproteins .
- the presence of one or more of the polymorphisms set out in Table 2 may be determined.
- a method may comprise the further step of administering folic acid to the individual.
- Folic acid may be administered alone or in combination with one or more of vitamin B12/B6 and antioxidants, for example vitamin C, vitamin E, lycopene, beta-carotene and minerals such as magnesium, manganese, selenium and zinc.
- Administration may be in the form of a medicament such as a tablet or pill, which, for example comprises the active ingredient and a suitable excipient, or in the form of a foodstuff rich in folic acid and, optionally, vitamin B and/or antioxidants, such as, for example, vitamin C as described above .
- a method may comprise the further step of providing a dietary regime for said individual comprising foodstuffs comprising elevated levels of one or more of folic acid, vitamin B6/B12 and/or antioxidants.
- Foodstuffs with elevated levels of folic acid include beef, lamb, pork, chicken liver, deep green leafy vegetables, asparagus, broccoli, wheat bran and yeast.
- Foodstuffs with elevated levels of vitamin B12 include red meat, poultry, eggs, dairy products, yeast extract, and some soya products .
- Foodstuffs with elevated levels of vitamin B6 include poultry, fish, eggs, spinach, carrots, and wheatgerm.
- An elevated level of a nutrient is generally considered to be at least lOO ⁇ g nutrient per lOOg of foodstuff.
- composition comprising folic acid in the manufacture of a medicament for use in the treatment of an inflammatory disorder in an individual who is polymorphic for one or both of the C677T and A1298C polymorphisms in the MTHFR locus.
- Inflammatory disorders are described above.
- the treatment of psoriasis and/or Crohn's disease may be excluded.
- the individual may have a polymorphism in one or more of the oxidation associated genes described above.
- composition may further comprise vitamin B6/B12 and/or an antioxidant such as vitamin C.
- treatment as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g. in veterinary applications) , in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the inflammatory condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the inflammatory condition, and cure of the inflammatory condition.
- Treatment as a prophylactic measure i.e. prophylaxis
- prophylaxis is also included.
- x Aherapeutically-effective amount pertains to that amount of an active compound, or a material, composition or dosage from comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio.
- Folic acid or a pharmaceutical composition comprising folic acid, folic salts, pro-drugs and metabolites of folic acid, may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or at the site of desired action, including but not limited to oral (e.g. by ingestion) or, more preferably, topical (including e.g. transdermal, intranasal, ocular, buccal, and sublingual) .
- oral e.g. by ingestion
- topical including e.g. transdermal, intranasal, ocular, buccal, and sublingual
- the subject may be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent, murine, canine, feline, equine bovine, ovine or human.
- folic acid and, optionally, other active compounds such as vitamin B6/B12
- a pharmaceutical composition comprising at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents .
- the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing folic acid and, optionally, other active compounds such as vitamin B6/B12 and anti-oxidants, together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilisers, or other materials, as described herein.
- pharmaceutically acceptable refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject
- Suitable carriers, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
- Formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, lozenges, granules, powders, capsules, cachets, pills, ampoules, ointments, gels, pastes, creams, sprays, mists, foams, lotions, oils, suppositories, boluses or sustained release formulations .
- Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste.
- a tablet may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose) ; fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc, silica) ; disintegrants (e.g.
- Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
- Formulations suitable for topical administration may be formulated as an ointment, cream, suspension, lotion, powder, solution, past, gel, spray, aerosol, or oil.
- a formulation may comprise a patch or a dressing such as a bandage or adhesive plaster impregnated with active compounds and optionally one or more excipients or diluents .
- Formulations suitable for topical administration via the skin include ointments, creams, and emulsions.
- the active compound When formulated in an ointment, the active compound may optionally be employed with either a paraffinic or a water-miscible ointment base.
- the active compounds may be formulated in a cream with an oil-in-water cream base.
- the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1, 3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
- the topical formulations may desirably include a compound which enhances absorption or penetration of the active compound through the skin or other affected areas.
- dermal penetration enhancers include dimethylsulfoxide and related analogues, as well nicotine, which is known to increase blood flow to the skin.
- the oily phase may optionally comprise merely an emulsifier (otherwise known as an emulgent) , or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
- an emulsifier otherwise known as an emulgent
- a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat.
- the emulsifier (s) with or without stabiliser (s) make up the so-called emulsifying wax
- the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
- Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl onostearate and sodium lauryl sulphate.
- suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low.
- the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
- Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
- appropriate dosages of the active compounds, and compositions comprising the active compounds can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments of the present invention.
- the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient.
- the amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action that achieve the desired effect without causing substantial harmful or deleterious side-effects .
- Administration in vi vo can be effected in one dose, continuously or intermittently (e.g. in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.
- a suitable dose of folic acid or its analogue is in the range of about 200 ⁇ g to about 5 mg per day, more preferably about 800 ⁇ g per day. This may be in the form of a single bolus dose or more preferably in multiple applications or a sustained release preparation.
- Folic acid has poor oral bio-availability in some individuals (Molloy, A.M. Int J Vita Nutr Res. 2002 Jan; 72 (1 ): 46-52, Zarazaga A, et al Nutr Hosp 1991 Jul-Aug; 6 (4) : 207-266) , in particular the elderly, people living at poverty level, women taking the birth control pill and people suffering from certain diseases, including Liver disease, alcoholism and malabsorption syndromes.
- folic acid can mask the symptoms of vitamin B12 deficiency and lead to long-term complications.
- Folic acid is, however, poorly absorbed through the skin.
- FBP folate binding protein
- compositions comprising folic acid and folate binding protein (FBP) in a topical formulation for use in a method of treatment of the human or animal body.
- Folate binding protein is preferably human folate binding protein (FBP) (Swiss-Prot: P15328) .
- FBP may be produced by recombinant expression of encoding nucleic acid using conventional techniques, followed, if desired, by the isolation and/or purification of the expressed polypeptide.
- a topical formulation may comprise a dermal penetration enhancer and/or a paraffinic or a water-miscible ointment base and/or liposomes and liposomes covalently attached to proteins (Betageri G et al Liposome Drug Delivery Systems' (1993) ISBN 1-56676-030-5; New, R. Liposomes-a practical approach' Oxford University Press (1990) ISBN 0-19-963076-3) .
- the ointment base which forms the oily dispersed phase of the cream formulations, may comprise oil and/or fat and an emulsifying wax comprising an emulsifier (s) with or without stabiliser (s) .
- Such formulations are further described above.
- the pH of said formulation is between pH 6.5 and pH 7.5, more preferably about pH 7.
- Another aspect of the invention provides the use of a composition comprising folic acid and folate binding protein (FBP) in the manufacture of a medicament for topical application in the treatment of an inflammatory disorder.
- FBP folate binding protein
- a method of producing such a composition may comprise admixing folic acid and folate binding protein with a pharmaceutically acceptable carrier, such as sesame or other oils, liposomes or cyclodextrins, and, optionally, an ointment base as described above.
- a pharmaceutically acceptable carrier such as sesame or other oils, liposomes or cyclodextrins, and, optionally, an ointment base as described above.
- the inflammatory disorder may be an inflammatory skin disorder, such as atopic dermatitis, contact dermatitis (allergic and irritant) , eczema, psoriarsis, Crohn' s disease or rheumatoid arthritis.
- An individual having such a disorder who is suitable for treatment with such topical compositions may be polymorphic for one or both of the C677T and A1298C polymorphisms in the MTHFR locus.
- folic acid has an anti-inflammatory effect. Contrary to the prevailing view in the art, this indicates that anti-inflammatory factors are generated by members of the folic acid metabolism pathway upstream of the MTHFR enzyme.
- Various aspects of the invention relate to screening methods and methods for obtaining agonists of upstream FA metabolic enzymes which enhance the production of anti-inflammatory factors/or repress pro-inflammatory factors and thus exert an anti-inflammatory effect.
- An aspect of the invention provides a method of screening for an anti-inflammatory compound comprising, contacting a test compound with one or more enzymes of the folic acid metabolic pathway which act upstream of MTHFR, and; determining the activity of said one or more enzymes in the presence relative to the absence of said test compound, an increase in activity being indicative that said test compound is an anti-inflammatory compound.
- test compound enhances said activity and may therefore have an anti-inflammatory effect.
- Such a compound may thereby modulate i.e. increase or enhance the production of anti-inflammatory factors, for example by stimulating the folic acid metabolic pathway upstream of MTHFR.
- Enzymes of the folic acid metabolic pathway which act upstream of MTHFR include dihydrofolate reductase (EC 1.5.1.3), folylpolyglutamate synthetase and thymidylate synthetase (EC 2.1.1.45) .
- Activity may be determined by measuring the production of enzyme product or the depletion of enzyme substrate in the presence relative to the absence of test compound. An increase in the rate of production of product or depletion of substrate by the enzyme in the presence relative to the absence of test compound is indicative that the test compound is an agonist (i.e. an enhancer or inducer) of the enzyme.
- a method may further comprise the step of determining an increase in anti-inflammatory activity in the presence of the test compound relative to the absence.
- Anti-inflammatory activity may be determined using conventional methodologies.
- Methods according to this aspect of the invention may be in vivo cell-based methods, or in vi tro non-cell-based methods.
- In vivo methods may be performed in a cell line such as a yeast strain, insect or mammalian cell line, for example CHO, HeLa or COS cells.
- a cell line such as a yeast strain, insect or mammalian cell line, for example CHO, HeLa or COS cells.
- the precise format for performing methods of the invention may be varied by those of skill in the art using routine skill and knowledge .
- DNA was prepared from a buccal cell sample on a brush using a Qiagen QIAamp kit according to the manufacturer's instructions (Qiagen, Crawley, UK) . Briefly, the brush was cut in half and one half stored at room temperature in a sealed tube in case retesting was required. The other half of the brush is placed in a microcentrifuge tube. 400 ⁇ l PBS was added and the brush allowed to rehydrate for 45 minutes at room temperature. Qiagen lysis buffer and Proteinase K was then added, the contents mixed, and allowed to incubate at 56 C for 15 minutes to lyse the cells. Ethanol was added and the lysate transferred to a QIAamp spin column from which DNA was eluted after several washings. Quantification of DNA
- client DNA samples were prepared by transferring a 10 ⁇ l aliquot into a microcentrifuge tube with 90 ⁇ l TE . 100 ⁇ l of the working PicoGreen dsDNA quantification reagent was added, mixed well, and transferred into a black 96 well plate with flat well bottoms. The plate was then incubated for 5 minutes in the dark before a fluorescent reading was taken. The quantity of DNA present in the sample was determined by extrapolating from a calibration plot prepared using DNA standards .
- a quantity of DNA in the range of 5-50ng total was used in the subsequent PCR step. Remaining DNA sample was stored at -20°C for retesting if required.
- the modified reaction mixture contained Taq polymerase (1.25 units/ ⁇ l) , optimised PCR buffer, dNTP (200 ⁇ M each), 2mM MgCl 2 and primer pairs SEQ ID NO: 5 and 6 and polymorphism probe SEQ ID NO: 8.
- the reaction mixture was initially incubated for 10 minutes at 50°C, then 5 minutes at 95°C, followed by 40 cycles of 1 minute of annealing at between 55°C and 60°C and 30 seconds of denaturation at 95°C. Both during the cycles and at the end of the run, fluorescence of the released reporter molecules of the probe was measured by an integral CCD detection system of the AB7700 ther ocycler. The presence of a fluorescent signal which increased in magnitude through the course of the run indicated a positive result.
- the assay was then repeated with the same primer pair and wild type (wt) probe SEQ ID NO: 7. If the sample is homozygous for the polymorphism, no fluorescence signal is seen with the wt probe. However, if the sample is heterozygous for the polymorphism, a fluorescence signal is also seen with the wt probe. If single reporter results from homozygous wt, homozygous polymorphic and heterozygous polymorphic samples are plotted are plotted on an X/Y axis, the homozygous alleles will cluster at opposite ends of the axes relative to each reporter, and the heterozygous alleles will cluster at a midway region.
- the modified reaction mixture contained Taq polymerase (1.25 units/ ⁇ l), optimised PCR buffer, dNTP (200 ⁇ M each), 2mM MgCl 2 and primer pairs SEQ ID NO: 1 and 2 and polymorphism probe SEQ ID NO: 4.
- the assay was performed as described above, using SEQ ID NO: 3 as a wt probe.
- Case 1 Caucasian female, 40 years of age. History of eczema and flaky skin on hands and arms. Began taking 800 ⁇ g folic acid daily upon receiving dietary advice after identification of MTHFR C677T heterozygous polymorphism. Subject reported rapid improvement of eczema symptoms after taking the folic acid supplement.
- Case 2 Caucasian female, 25 years of age. History of severe inflammation of skin, particularly affecting hands. Genetic screening identified C677T heterozygous polymorphism.
- Case 3 Caucasian female, 21 years of age: History of eczema. Genetic screening identified C677T heterozygous polymorphism. Supplementation of daily 800 ⁇ g folic acid begun, significant improvement of symptoms reported. Symptoms reappeared upon cessation of folic acid supplementation after approximately two weeks but disappeared again when folic acid supplementation resumed.
- Case 4 Caucasian male, 67 years of age. History of mild eczema. Genetic screening identified C677T heterozygous and A1298C heterozygous polymorphisms Improvement of symptoms reported upon supplementation with daily 800 ⁇ g folic acid.
- Case 5 Caucasian female, 65 years of age. History of mild eczema. Genetic screening identified C677T heterozygous and A1298C heterozygous polymorphisms. Improvement of symptoms reported upon supplementation with daily 800 ⁇ g folic acid.
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2003285482A AU2003285482A1 (en) | 2002-10-08 | 2003-10-08 | Methods and means for the treatment of inflammatory disorders involving genotyping of the 5, 10- methylenetetrahydrofolate reductase (mthfr) gene |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0223365A GB0223365D0 (en) | 2002-10-08 | 2002-10-08 | Methods and means |
GB0223365.8 | 2002-10-08 | ||
GB0229595A GB0229595D0 (en) | 2002-12-19 | 2002-12-19 | Methods and means |
GB0229595.4 | 2002-12-19 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2004033725A2 true WO2004033725A2 (en) | 2004-04-22 |
WO2004033725A3 WO2004033725A3 (en) | 2004-07-29 |
Family
ID=32095188
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2003/004372 WO2004033725A2 (en) | 2002-10-08 | 2003-10-08 | Methods and means for the treatment of inflammatory disorders involving genotyping of the 5, 10- methylenetetrahydrofolate reductase (mthfr) gene |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU2003285482A1 (en) |
WO (1) | WO2004033725A2 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050272691A1 (en) * | 2004-06-04 | 2005-12-08 | Eaton Kevin P | Treatment of dermatological conditions |
WO2006008267A2 (en) * | 2004-07-16 | 2006-01-26 | Novo Nordisk Health Care Ag | Methods for optimizing forming viiia-based hemostatic treatment |
WO2006072239A2 (en) * | 2005-01-08 | 2006-07-13 | Regeneratio Pharma Gmbh | Use of cobalamines for treating intestinal diseases |
EP1877579A2 (en) * | 2005-04-28 | 2008-01-16 | Prometheus Laboratories, Inc. | Methods of predicting methotrexate efficacy and toxicity |
WO2009127073A1 (en) * | 2008-04-18 | 2009-10-22 | Gen Sod2 Foundation | Cosmetic preparation tailored to an individual and method for the production thereof |
CN109554465A (en) * | 2018-12-30 | 2019-04-02 | 济南齐鲁医学检验有限公司 | Noninvasive rs1801133 genotype rapid typing detection reagent box |
CN111334571A (en) * | 2020-04-13 | 2020-06-26 | 青岛智博生物科技有限公司 | Kit capable of freely combining and detecting MTHFR and MTRR gene sequences and using method thereof |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107287312B (en) * | 2017-07-07 | 2020-04-21 | 深圳市慢性病防治中心 | Molecular beacon probe, primer pair and method for detecting SNPs sites of VDR gene |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001096598A2 (en) * | 2000-06-12 | 2001-12-20 | Mcgill University | cDNA FOR HUMAN METHYLENETETRAHYDROFOLATE REDUCTASE AND USES THEREOF |
-
2003
- 2003-10-08 AU AU2003285482A patent/AU2003285482A1/en not_active Abandoned
- 2003-10-08 WO PCT/GB2003/004372 patent/WO2004033725A2/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001096598A2 (en) * | 2000-06-12 | 2001-12-20 | Mcgill University | cDNA FOR HUMAN METHYLENETETRAHYDROFOLATE REDUCTASE AND USES THEREOF |
Non-Patent Citations (11)
Title |
---|
AL TAWARI ASMA A ET AL: "An early onset form of methylenetetrahydrofolate reductase deficiency: a report of a family from Kuwait." BRAIN & DEVELOPMENT. NETHERLANDS AUG 2002, vol. 24, no. 5, August 2002 (2002-08), pages 304-309, XP002269930 ISSN: 0387-7604 * |
CHANGO A ET AL: "The effect of 677C fwdarw T and 1298A fwdarw C mutations on plasma homocysteine and 5,10-methylenetetrahydrofolate reductase activity in healthy subjects" BRITISH JOURNAL OF NUTRITION, vol. 83, no. 6, June 2000 (2000-06), pages 593-596, XP009025340 ISSN: 0007-1145 * |
CORTESE C ET AL: "MTHFR gene polymorphism, homocysteine and cardiovascular disease." PUBLIC HEALTH NUTRITION. ENGLAND APR 2001, vol. 4, no. 2B, April 2001 (2001-04), pages 493-497, XP009025166 ISSN: 1368-9800 * |
FRISO S ET AL: "A1298C methylenetetrahydrofolate reductase mutation and coronary artery disease: Relationships with C677T polymorphism and homocysteine/folate metabolism" CLINICAL AND EXPERIMENTAL MEDICINE, vol. 2, no. 1, May 2002 (2002-05), pages 7-12, XP002269931 ISSN: 1591-8890 * |
MAHMUD N ET AL: "Increased prevalence of methylenetetrahydrofolate reductase C677T variant in patients with inflammatory bowel disease, and its clinical implications" GUT, vol. 45, no. 3, September 1999 (1999-09), pages 389-394, XP009025070 ISSN: 0017-5749 * |
NAPPO FRANCESCO ET AL: "Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins" JAMA (JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION), vol. 281, no. 22, 9 June 1999 (1999-06-09), pages 2113-2118, XP009025260 ISSN: 0098-7484 * |
PAPA A ET AL: "Hyperhomocysteinemia and prevalence of polymorphisms of homocysteine metabolism-related enzymes in patients with inflammatory bowel disease." THE AMERICAN JOURNAL OF GASTROENTEROLOGY. UNITED STATES SEP 2001, vol. 96, no. 9, September 2001 (2001-09), pages 2677-2682, XP001179236 ISSN: 0002-9270 * |
SCHWAHN B ET AL: "Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences." AMERICAN JOURNAL OF PHARMACOGENOMICS: GENOMICS-RELATED RESEARCH IN DRUG DEVELOPMENT AND CLINICAL PRACTICE. NEW ZEALAND 2001, vol. 1, no. 3, 2001, pages 189-201, XP009025177 ISSN: 1175-2203 * |
STANGER O: "Physiology of folic acid in health and disease." CURRENT DRUG METABOLISM. NETHERLANDS APR 2002, vol. 3, no. 2, April 2002 (2002-04), pages 211-223, XP009025295 ISSN: 1389-2002 * |
UELAND P M ET AL: "Biological and clinical implications of the MTHFR C677T polymorphism" TRENDS IN PHARMACOLOGICAL SCIENCES, ELSEVIER TRENDS JOURNAL, CAMBRIDGE, GB, vol. 22, no. 4, 1 April 2001 (2001-04-01), pages 195-201, XP004231954 ISSN: 0165-6147 * |
WANG BAIQIU ET AL: "Study of the relationship between psoriasis and the polymorphic site C677T of methylenetetrahydrofolate reductase" CHINESE MEDICAL SCIENCES JOURNAL, vol. 15, no. 2, June 2000 (2000-06), pages 119-120, XP009025105 ISSN: 1001-9294 * |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050272691A1 (en) * | 2004-06-04 | 2005-12-08 | Eaton Kevin P | Treatment of dermatological conditions |
US20160199397A1 (en) * | 2004-06-04 | 2016-07-14 | Dan Devlin | Treatment of Dermatological Conditions |
WO2006008267A2 (en) * | 2004-07-16 | 2006-01-26 | Novo Nordisk Health Care Ag | Methods for optimizing forming viiia-based hemostatic treatment |
WO2006008267A3 (en) * | 2004-07-16 | 2006-04-13 | Novo Nordisk Healthcare Ag | Methods for optimizing forming viiia-based hemostatic treatment |
WO2006072239A2 (en) * | 2005-01-08 | 2006-07-13 | Regeneratio Pharma Gmbh | Use of cobalamines for treating intestinal diseases |
WO2006072239A3 (en) * | 2005-01-08 | 2006-09-21 | Regeneratio Pharma Gmbh | Use of cobalamines for treating intestinal diseases |
EP1877579A2 (en) * | 2005-04-28 | 2008-01-16 | Prometheus Laboratories, Inc. | Methods of predicting methotrexate efficacy and toxicity |
EP1877579A4 (en) * | 2005-04-28 | 2013-06-26 | Nestec Sa | Methods of predicting methotrexate efficacy and toxicity |
EP2722404A1 (en) * | 2005-04-28 | 2014-04-23 | Nestec S.A. | Methods of predicting methotrextrate efficacy and toxicity |
WO2009127073A1 (en) * | 2008-04-18 | 2009-10-22 | Gen Sod2 Foundation | Cosmetic preparation tailored to an individual and method for the production thereof |
CN109554465A (en) * | 2018-12-30 | 2019-04-02 | 济南齐鲁医学检验有限公司 | Noninvasive rs1801133 genotype rapid typing detection reagent box |
CN111334571A (en) * | 2020-04-13 | 2020-06-26 | 青岛智博生物科技有限公司 | Kit capable of freely combining and detecting MTHFR and MTRR gene sequences and using method thereof |
Also Published As
Publication number | Publication date |
---|---|
AU2003285482A8 (en) | 2004-05-04 |
AU2003285482A1 (en) | 2004-05-04 |
WO2004033725A3 (en) | 2004-07-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Durusu Tanriover et al. | Evaluation of the effects of vitamin D receptor and estrogen receptor 1 gene polymorphisms on bone mineral density in postmenopausal women | |
US20120277180A1 (en) | Cofactors and Methods for Use for Individuals | |
US20160215339A1 (en) | Susceptibility to bone damage | |
WO2004033725A2 (en) | Methods and means for the treatment of inflammatory disorders involving genotyping of the 5, 10- methylenetetrahydrofolate reductase (mthfr) gene | |
JP2011502510A (en) | Diagnosis of skin diseases related to aging | |
Zalsman et al. | DRD4 exon III polymorphism and response to risperidone in Israeli adolescents with schizophrenia: a pilot pharmacogenetic study | |
Gui-Yan et al. | Associations between RAS gene polymorphisms, environmental factors and hypertension in Mongolian people | |
EP2640846B1 (en) | Genetic test for liver copper accumulation in dogs and low copper pet diet | |
WO2019141627A1 (en) | Methods to predict risk of and to stratify sarcopenia and nad deficiency | |
WO2015136446A1 (en) | Methods for selecting antidepressant drug therapy to treat depression | |
DK2440049T3 (en) | GENOTYPE-SPECIFIC PROCEDURES FOR TREATING HUMAN INDIVIDUALS USING 4-METHYLPYRAZOLE | |
US20160298190A1 (en) | Influence of genotype on susceptibility to treatment with fish oil | |
US6808881B1 (en) | Method for determining susceptibility to heart disease by screening polymorphisms in the vitamin D receptor gene | |
Pérez-Bravo et al. | Lack of association between the fatty acid binding protein 2 (FABP2) polymorphism with obesity and insulin resistance in two aboriginal populations from Chile | |
WO2008127961A1 (en) | Genetic markers for assessing risk of premature birth resulting from preterm premature rupture of membranes | |
Uhl et al. | Molecular neurobiological methods in marijuana-cannabinoid research | |
Kimura et al. | No evidence of association between apolipoprotein E gene regulatory region polymorphism and Alzheimer's disease in Japanese | |
US7354712B2 (en) | Estrogen receptor alleles that are predictive of increased susceptibility to bone fracture | |
US20170037471A1 (en) | Methods for diagnosing & treating copper-dependent diseases | |
Kyte | Polymorphisms in the One-Carbon Metabolic Pathway, and the Risk and Survival of Colorectal Cancer | |
Zhang et al. | QTL-based association analyses reveal novel genes influencing pleiotropy of Metabolic | |
WO2015100300A2 (en) | Methods for diagnosing and treating copper-dependent diseases | |
WO2003091698A2 (en) | Cetp genetic markers for statin-specific changes in hdl cholesterol |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
122 | Ep: pct application non-entry in european phase | ||
NENP | Non-entry into the national phase in: |
Ref country code: JP |
|
WWW | Wipo information: withdrawn in national office |
Country of ref document: JP |