US20110077194A1 - Method for Treating or Preventing a Functional Vitamin B12 Deficiency in an Individual and to Medical Compositions for Use in Said Method - Google Patents
Method for Treating or Preventing a Functional Vitamin B12 Deficiency in an Individual and to Medical Compositions for Use in Said Method Download PDFInfo
- Publication number
- US20110077194A1 US20110077194A1 US12/706,411 US70641110A US2011077194A1 US 20110077194 A1 US20110077194 A1 US 20110077194A1 US 70641110 A US70641110 A US 70641110A US 2011077194 A1 US2011077194 A1 US 2011077194A1
- Authority
- US
- United States
- Prior art keywords
- disease
- vitamin
- cobalamin
- folate
- deficiency
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 38
- 239000000203 mixture Substances 0.000 title claims abstract description 28
- 208000002670 vitamin B12 deficiency Diseases 0.000 title description 6
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims abstract description 144
- 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 abstract description 118
- 229960003180 glutathione Drugs 0.000 claims abstract description 69
- 239000011715 vitamin B12 Substances 0.000 claims abstract description 66
- 108010024636 Glutathione Proteins 0.000 claims abstract description 60
- 230000007812 deficiency Effects 0.000 claims abstract description 43
- 230000036542 oxidative stress Effects 0.000 claims abstract description 37
- 230000003834 intracellular effect Effects 0.000 claims abstract description 26
- 239000002243 precursor Substances 0.000 claims abstract description 25
- 239000003446 ligand Substances 0.000 claims abstract description 22
- 238000012545 processing Methods 0.000 claims abstract description 13
- 208000019553 vascular disease Diseases 0.000 claims abstract description 12
- 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 description 58
- 208000024827 Alzheimer disease Diseases 0.000 claims description 54
- 235000019152 folic acid Nutrition 0.000 claims description 50
- 239000011724 folic acid Substances 0.000 claims description 50
- 229940014144 folate Drugs 0.000 claims description 42
- 230000000694 effects Effects 0.000 claims description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- 201000010099 disease Diseases 0.000 claims description 20
- 230000004060 metabolic process Effects 0.000 claims description 19
- 208000024891 symptom Diseases 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 18
- NZRCMFDUKLMQKD-UHFFFAOYSA-K 2-[(4-amino-4-carboxybutanoyl)amino]-3-(carboxymethylamino)-3-oxopropane-1-thiolate;cobalt(3+);[5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] 1-[3-[2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,1 Chemical compound [Co+3].OC(=O)C(N)CCC(=O)NC(C[S-])C(=O)NCC(O)=O.OCC1OC(N2C3=CC(C)=C(C)C=C3N=C2)C(O)C1OP([O-])(=O)OC(C)CNC(=O)CCC1(C)C(CC(N)=O)C2[N-]\C1=C(C)/C(C(C\1(C)C)CCC(N)=O)=N/C/1=C\C(C(C/1(CC(N)=O)C)CCC(N)=O)=N\C\1=C(C)/C1=NC2(C)C(C)(CC(N)=O)C1CCC(N)=O NZRCMFDUKLMQKD-UHFFFAOYSA-K 0.000 claims description 13
- 208000010877 cognitive disease Diseases 0.000 claims description 13
- 108700005155 glutathionylcobalamin Proteins 0.000 claims description 12
- MEFKEPWMEQBLKI-AIRLBKTGSA-N S-adenosyl-L-methioninate Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-N 0.000 claims description 10
- 229960001570 ademetionine Drugs 0.000 claims description 9
- 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 description 8
- 229960000304 folic acid Drugs 0.000 claims description 8
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims description 8
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 claims description 6
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 claims description 6
- 229960003237 betaine Drugs 0.000 claims description 6
- 201000006417 multiple sclerosis Diseases 0.000 claims description 6
- WRRSSUKQMMVXTQ-UHFFFAOYSA-K 2-amino-3-hydroxy-3-oxopropane-1-thiolate;cobalt(3+);[5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] 1-[3-[(4z,9z)-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-2,7,12,17-tetra Chemical compound [Co+3].[S-]CC(N)C(O)=O.OCC1OC(N2C3=CC(C)=C(C)C=C3N=C2)C(O)C1OP([O-])(=O)OC(C)CNC(=O)CCC1(C)C(CC(N)=O)C2[N-]\C1=C(C)/C(C(C\1(C)C)CCC(N)=O)=N/C/1=C\C(C(C/1(CC(N)=O)C)CCC(N)=O)=N\C\1=C(C)/C1=NC2(C)C(C)(CC(N)=O)C1CCC(N)=O WRRSSUKQMMVXTQ-UHFFFAOYSA-K 0.000 claims description 5
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 claims description 5
- 201000004810 Vascular dementia Diseases 0.000 claims description 5
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 claims description 5
- ZNOVTXRBGFNYRX-STQMWFEESA-N (6S)-5-methyltetrahydrofolic acid Chemical compound C([C@@H]1N(C=2C(=O)N=C(N)NC=2NC1)C)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-STQMWFEESA-N 0.000 claims description 4
- PHIQHXFUZVPYII-ZCFIWIBFSA-O (R)-carnitinium Chemical compound C[N+](C)(C)C[C@H](O)CC(O)=O PHIQHXFUZVPYII-ZCFIWIBFSA-O 0.000 claims description 4
- 206010039966 Senile dementia Diseases 0.000 claims description 4
- 230000007000 age related cognitive decline Effects 0.000 claims description 4
- 229960004203 carnitine Drugs 0.000 claims description 4
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 4
- 229960001231 choline Drugs 0.000 claims description 4
- 229960003208 levomefolic acid Drugs 0.000 claims description 4
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 claims description 4
- 235000019158 vitamin B6 Nutrition 0.000 claims description 4
- 239000011726 vitamin B6 Substances 0.000 claims description 4
- 229940011671 vitamin b6 Drugs 0.000 claims description 4
- 208000027061 mild cognitive impairment Diseases 0.000 claims 2
- 208000031889 Vascular Depression Diseases 0.000 claims 1
- 150000002224 folic acids Chemical class 0.000 claims 1
- 206010012289 Dementia Diseases 0.000 abstract description 31
- 230000005856 abnormality Effects 0.000 abstract description 14
- 238000011260 co-administration Methods 0.000 abstract description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract description 5
- 239000005864 Sulphur Substances 0.000 abstract description 5
- 230000002265 prevention Effects 0.000 abstract description 5
- 230000008238 biochemical pathway Effects 0.000 abstract description 2
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 79
- YOZNUFWCRFCGIH-BYFNXCQMSA-L hydroxocobalamin Chemical compound O[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=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 YOZNUFWCRFCGIH-BYFNXCQMSA-L 0.000 description 38
- 210000002966 serum Anatomy 0.000 description 26
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 25
- 229960004308 acetylcysteine Drugs 0.000 description 24
- 230000006872 improvement Effects 0.000 description 24
- 230000001149 cognitive effect Effects 0.000 description 20
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 20
- 235000018417 cysteine Nutrition 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 19
- 235000004867 hydroxocobalamin Nutrition 0.000 description 19
- 239000011704 hydroxocobalamin Substances 0.000 description 19
- 229960001103 hydroxocobalamin Drugs 0.000 description 19
- 238000002347 injection Methods 0.000 description 18
- 239000007924 injection Substances 0.000 description 18
- 230000001537 neural effect Effects 0.000 description 17
- 210000001519 tissue Anatomy 0.000 description 16
- 108010075604 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase Proteins 0.000 description 14
- 102000011848 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase Human genes 0.000 description 14
- 102000004190 Enzymes Human genes 0.000 description 14
- 108090000790 Enzymes Proteins 0.000 description 14
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 14
- 229940088598 enzyme Drugs 0.000 description 14
- 230000002489 hematologic effect Effects 0.000 description 13
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 11
- ZUKPVRWZDMRIEO-VKHMYHEASA-N L-cysteinylglycine Chemical compound SC[C@H]([NH3+])C(=O)NCC([O-])=O ZUKPVRWZDMRIEO-VKHMYHEASA-N 0.000 description 11
- 208000007502 anemia Diseases 0.000 description 11
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 description 10
- 108010016616 cysteinylglycine Proteins 0.000 description 10
- 230000002503 metabolic effect Effects 0.000 description 10
- 235000007672 methylcobalamin Nutrition 0.000 description 10
- 239000011585 methylcobalamin Substances 0.000 description 10
- JEWJRMKHSMTXPP-BYFNXCQMSA-M methylcobalamin Chemical compound C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=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 JEWJRMKHSMTXPP-BYFNXCQMSA-M 0.000 description 10
- 230000037361 pathway Effects 0.000 description 10
- 230000032683 aging Effects 0.000 description 9
- AGBQKNBQESQNJD-UHFFFAOYSA-N alpha-Lipoic acid Natural products OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 9
- 150000001867 cobalamins Chemical class 0.000 description 9
- 230000006999 cognitive decline Effects 0.000 description 9
- 206010016256 fatigue Diseases 0.000 description 9
- 238000011835 investigation Methods 0.000 description 9
- 235000019136 lipoic acid Nutrition 0.000 description 9
- 229960002663 thioctic acid Drugs 0.000 description 9
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 229940010007 cobalamins Drugs 0.000 description 8
- 230000003920 cognitive function Effects 0.000 description 8
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=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 RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 8
- 210000003989 endothelium vascular Anatomy 0.000 description 8
- 210000002569 neuron Anatomy 0.000 description 8
- 206010020772 Hypertension Diseases 0.000 description 7
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 7
- 229940109239 creatinine Drugs 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 230000015654 memory Effects 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 208000033892 Hyperhomocysteinemia Diseases 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- FEZWOUWWJOYMLT-DSRCUDDDSA-M cobalt;[(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-2,7,1 Chemical compound [Co].[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 FEZWOUWWJOYMLT-DSRCUDDDSA-M 0.000 description 6
- 230000007423 decrease Effects 0.000 description 6
- 230000006866 deterioration Effects 0.000 description 6
- 230000003225 hyperhomocysteinemia Effects 0.000 description 6
- 230000001771 impaired effect Effects 0.000 description 6
- 206010025382 macrocytosis Diseases 0.000 description 6
- 230000003340 mental effect Effects 0.000 description 6
- 229960004452 methionine Drugs 0.000 description 6
- 230000006403 short-term memory Effects 0.000 description 6
- 230000000391 smoking effect Effects 0.000 description 6
- 238000003860 storage Methods 0.000 description 6
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 description 5
- 239000004471 Glycine Substances 0.000 description 5
- 206010025476 Malabsorption Diseases 0.000 description 5
- 208000004155 Malabsorption Syndromes Diseases 0.000 description 5
- 235000006279 cobamamide Nutrition 0.000 description 5
- 239000011789 cobamamide Substances 0.000 description 5
- ZIHHMGTYZOSFRC-UWWAPWIJSA-M cobamamide Chemical compound C1(/[C@](C)(CCC(=O)NC[C@H](C)OP(O)(=O)OC2[C@H]([C@H](O[C@@H]2CO)N2C3=CC(C)=C(C)C=C3N=C2)O)[C@@H](CC(N)=O)[C@]2(N1[Co+]C[C@@H]1[C@H]([C@@H](O)[C@@H](O1)N1C3=NC=NC(N)=C3N=C1)O)[H])=C(C)\C([C@H](C/1(C)C)CCC(N)=O)=N\C\1=C/C([C@H]([C@@]\1(CC(N)=O)C)CCC(N)=O)=N/C/1=C(C)\C1=N[C@]2(C)[C@@](C)(CC(N)=O)[C@@H]1CCC(N)=O ZIHHMGTYZOSFRC-UWWAPWIJSA-M 0.000 description 5
- 235000000639 cyanocobalamin Nutrition 0.000 description 5
- 239000011666 cyanocobalamin Substances 0.000 description 5
- 229960003067 cystine Drugs 0.000 description 5
- 230000006735 deficit Effects 0.000 description 5
- 230000003511 endothelial effect Effects 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 206010027175 memory impairment Diseases 0.000 description 5
- ZIYVHBGGAOATLY-UHFFFAOYSA-N methylmalonic acid Chemical compound OC(=O)C(C)C(O)=O ZIYVHBGGAOATLY-UHFFFAOYSA-N 0.000 description 5
- 230000000474 nursing effect Effects 0.000 description 5
- 230000036470 plasma concentration Effects 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 239000013589 supplement Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- RSPCKAHMRANGJZ-UHFFFAOYSA-N thiohydroxylamine Chemical compound SN RSPCKAHMRANGJZ-UHFFFAOYSA-N 0.000 description 5
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 230000003078 antioxidant effect Effects 0.000 description 4
- 201000007201 aphasia Diseases 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 230000007278 cognition impairment Effects 0.000 description 4
- 238000003745 diagnosis Methods 0.000 description 4
- 238000000611 regression analysis Methods 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 4
- 235000019156 vitamin B Nutrition 0.000 description 4
- 239000011720 vitamin B Substances 0.000 description 4
- 230000003442 weekly effect Effects 0.000 description 4
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 3
- 208000000044 Amnesia Diseases 0.000 description 3
- 206010002064 Anaemia macrocytic Diseases 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 206010016880 Folate deficiency Diseases 0.000 description 3
- 206010019233 Headaches Diseases 0.000 description 3
- FFEARJCKVFRZRR-UHFFFAOYSA-N L-Methionine Natural products CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- 229930182816 L-glutamine Natural products 0.000 description 3
- 229930195722 L-methionine Natural products 0.000 description 3
- 208000002720 Malnutrition Diseases 0.000 description 3
- 208000026139 Memory disease Diseases 0.000 description 3
- 208000006011 Stroke Diseases 0.000 description 3
- 102000011409 Transcobalamins Human genes 0.000 description 3
- 108010023603 Transcobalamins Proteins 0.000 description 3
- 102000004357 Transferases Human genes 0.000 description 3
- 108090000992 Transferases Proteins 0.000 description 3
- 229930003779 Vitamin B12 Natural products 0.000 description 3
- 230000001594 aberrant effect Effects 0.000 description 3
- 150000004347 all-trans-retinol derivatives Chemical class 0.000 description 3
- 125000005365 aminothiol group Chemical group 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 238000001949 anaesthesia Methods 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 108010042865 aquacobalamin reductase Proteins 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- 238000004820 blood count Methods 0.000 description 3
- 230000036765 blood level Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- -1 but not limited to Substances 0.000 description 3
- 230000002490 cerebral effect Effects 0.000 description 3
- 208000026106 cerebrovascular disease Diseases 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000000544 cholinesterase inhibitor Substances 0.000 description 3
- 229960002104 cyanocobalamin Drugs 0.000 description 3
- 230000003412 degenerative effect Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 230000003001 depressive effect Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 206010013395 disorientation Diseases 0.000 description 3
- 230000002526 effect on cardiovascular system Effects 0.000 description 3
- 230000004907 flux Effects 0.000 description 3
- 229930195712 glutamate Natural products 0.000 description 3
- 230000003394 haemopoietic effect Effects 0.000 description 3
- 231100000869 headache Toxicity 0.000 description 3
- 201000006437 macrocytic anemia Diseases 0.000 description 3
- 235000000824 malnutrition Nutrition 0.000 description 3
- 230000001071 malnutrition Effects 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 229930182817 methionine Natural products 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 208000015380 nutritional deficiency disease Diseases 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 230000035807 sensation Effects 0.000 description 3
- 230000035882 stress Effects 0.000 description 3
- 230000009469 supplementation Effects 0.000 description 3
- 238000006491 synthase reaction Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- 229940088594 vitamin Drugs 0.000 description 3
- 229930003231 vitamin Natural products 0.000 description 3
- 235000013343 vitamin Nutrition 0.000 description 3
- 239000011782 vitamin Substances 0.000 description 3
- 235000019163 vitamin B12 Nutrition 0.000 description 3
- 150000003722 vitamin derivatives Chemical class 0.000 description 3
- LJUQGASMPRMWIW-UHFFFAOYSA-N 5,6-dimethylbenzimidazole Chemical compound C1=C(C)C(C)=CC2=C1NC=N2 LJUQGASMPRMWIW-UHFFFAOYSA-N 0.000 description 2
- 229910000497 Amalgam Inorganic materials 0.000 description 2
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 description 2
- 208000028698 Cognitive impairment Diseases 0.000 description 2
- YPWSLBHSMIKTPR-UHFFFAOYSA-N Cystathionine Natural products OC(=O)C(N)CCSSCC(N)C(O)=O YPWSLBHSMIKTPR-UHFFFAOYSA-N 0.000 description 2
- 108010073644 Cystathionine beta-synthase Proteins 0.000 description 2
- ILRYLPWNYFXEMH-UHFFFAOYSA-N D-cystathionine Natural products OC(=O)C(N)CCSCC(N)C(O)=O ILRYLPWNYFXEMH-UHFFFAOYSA-N 0.000 description 2
- 208000020401 Depressive disease Diseases 0.000 description 2
- 206010017577 Gait disturbance Diseases 0.000 description 2
- 208000004547 Hallucinations Diseases 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- ILRYLPWNYFXEMH-WHFBIAKZSA-N L-cystathionine Chemical compound [O-]C(=O)[C@@H]([NH3+])CCSC[C@H]([NH3+])C([O-])=O ILRYLPWNYFXEMH-WHFBIAKZSA-N 0.000 description 2
- 208000004552 Lacunar Stroke Diseases 0.000 description 2
- 238000000585 Mann–Whitney U test Methods 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
- RDHQFKQIGNGIED-MRVPVSSYSA-N O-acetyl-L-carnitine Chemical compound CC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C RDHQFKQIGNGIED-MRVPVSSYSA-N 0.000 description 2
- 108090000854 Oxidoreductases Proteins 0.000 description 2
- 102000004316 Oxidoreductases Human genes 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 206010034568 Peripheral coldness Diseases 0.000 description 2
- 241000364021 Tulsa Species 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229960001009 acetylcarnitine Drugs 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 230000003542 behavioural effect Effects 0.000 description 2
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 2
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- ZFLASALABLFSNM-QBOHGLHMSA-L carbanide;cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2s)-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-oc Chemical compound [CH3-].[Co+3].[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 ZFLASALABLFSNM-QBOHGLHMSA-L 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229910017052 cobalt Inorganic materials 0.000 description 2
- 239000010941 cobalt Substances 0.000 description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 2
- IUJJHFFFUXMHFY-UHFFFAOYSA-K cobalt(3+);[5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] 1-[3-[(4z,9z)-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-2,7,12,17-tetrahydro-1h-corrin-21-id-3-yl]propanoylamino] Chemical compound [Co+3].OS([O-])=O.OCC1OC(N2C3=CC(C)=C(C)C=C3N=C2)C(O)C1OP([O-])(=O)OC(C)CNC(=O)CCC1(C)C(CC(N)=O)C2[N-]\C1=C(C)/C(C(C\1(C)C)CCC(N)=O)=N/C/1=C\C(C(C/1(CC(N)=O)C)CCC(N)=O)=N\C\1=C(C)/C1=NC2(C)C(C)(CC(N)=O)C1CCC(N)=O IUJJHFFFUXMHFY-UHFFFAOYSA-K 0.000 description 2
- 238000002591 computed tomography Methods 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 108010068906 gamma-glutamylcysteine Proteins 0.000 description 2
- 208000027700 hepatic dysfunction Diseases 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000001631 hypertensive effect Effects 0.000 description 2
- 208000002780 macular degeneration Diseases 0.000 description 2
- 206010025482 malaise Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000006984 memory degeneration Effects 0.000 description 2
- 208000023060 memory loss Diseases 0.000 description 2
- 230000006996 mental state Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 230000000926 neurological effect Effects 0.000 description 2
- 235000020925 non fasting Nutrition 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000004792 oxidative damage Effects 0.000 description 2
- 208000035824 paresthesia Diseases 0.000 description 2
- 230000003950 pathogenic mechanism Effects 0.000 description 2
- 230000002688 persistence Effects 0.000 description 2
- 210000003800 pharynx Anatomy 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000000272 proprioceptive effect Effects 0.000 description 2
- 208000020016 psychiatric disease Diseases 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000009601 thyroid function test Methods 0.000 description 2
- 210000003556 vascular endothelial cell Anatomy 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 208000030401 vitamin deficiency disease Diseases 0.000 description 2
- 208000016261 weight loss Diseases 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- 230000036642 wellbeing Effects 0.000 description 2
- RITKHVBHSGLULN-CRCLSJGQSA-N γ-glutamylcysteine Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@H](CS)C(O)=O RITKHVBHSGLULN-CRCLSJGQSA-N 0.000 description 2
- TZBGSHAFWLGWBO-ABLWVSNPSA-N (2s)-2-[[4-[(2-amino-4-oxo-5,6,7,8-tetrahydro-1h-pteridin-6-yl)methylamino]benzoyl]amino]-5-methoxy-5-oxopentanoic acid Chemical group C1=CC(C(=O)N[C@@H](CCC(=O)OC)C(O)=O)=CC=C1NCC1NC(C(=O)NC(N)=N2)=C2NC1 TZBGSHAFWLGWBO-ABLWVSNPSA-N 0.000 description 1
- OAJLVMGLJZXSGX-SLAFOUTOSA-L (2s,3s,4r,5r)-2-(6-aminopurin-9-yl)-5-methanidyloxolane-3,4-diol;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 Chemical compound [Co+3].O[C@H]1[C@@H](O)[C@@H]([CH2-])O[C@@H]1N1C2=NC=NC(N)=C2N=C1.[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 OAJLVMGLJZXSGX-SLAFOUTOSA-L 0.000 description 1
- WELIVEBWRWAGOM-UHFFFAOYSA-N 3-amino-n-[2-[2-(3-aminopropanoylamino)ethyldisulfanyl]ethyl]propanamide Chemical compound NCCC(=O)NCCSSCCNC(=O)CCN WELIVEBWRWAGOM-UHFFFAOYSA-N 0.000 description 1
- JVJFIQYAHPMBBX-UHFFFAOYSA-N 4-hydroxynonenal Chemical compound CCCCCC(O)C=CC=O JVJFIQYAHPMBBX-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000000187 Abnormal Reflex Diseases 0.000 description 1
- 208000006888 Agnosia Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 102000003669 Antiporters Human genes 0.000 description 1
- 108090000084 Antiporters Proteins 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010003062 Apraxia Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000000412 Avitaminosis Diseases 0.000 description 1
- 208000023328 Basedow disease Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- 201000004813 Bronchopneumonia Diseases 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 206010051290 Central nervous system lesion Diseases 0.000 description 1
- 206010008096 Cerebral atrophy Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 102100034976 Cystathionine beta-synthase Human genes 0.000 description 1
- 102000020018 Cystathionine gamma-Lyase Human genes 0.000 description 1
- 108010045283 Cystathionine gamma-lyase Proteins 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 201000010374 Down Syndrome Diseases 0.000 description 1
- 206010013887 Dysarthria Diseases 0.000 description 1
- 206010013976 Dyspraxia Diseases 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 208000004929 Facial Paralysis Diseases 0.000 description 1
- 206010016322 Feeling abnormal Diseases 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 206010019075 Hallucination, visual Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 108010020869 Homocysteine S-Methyltransferase Proteins 0.000 description 1
- 208000025500 Hutchinson-Gilford progeria syndrome Diseases 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010021135 Hypovitaminosis Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- GGLZPLKKBSSKCX-YFKPBYRVSA-N L-ethionine Chemical compound CCSCC[C@H](N)C(O)=O GGLZPLKKBSSKCX-YFKPBYRVSA-N 0.000 description 1
- 206010024264 Lethargy Diseases 0.000 description 1
- 206010024971 Lower respiratory tract infections Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 208000027530 Meniere disease Diseases 0.000 description 1
- 102100024614 Methionine synthase reductase Human genes 0.000 description 1
- 108010030837 Methylenetetrahydrofolate Reductase (NADPH2) Proteins 0.000 description 1
- 102100029684 Methylenetetrahydrofolate reductase Human genes 0.000 description 1
- 102000019010 Methylmalonyl-CoA Mutase Human genes 0.000 description 1
- 108010051862 Methylmalonyl-CoA mutase Proteins 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000011644 Neurologic Gait disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 206010029306 Neurological signs and symptoms Diseases 0.000 description 1
- 206010030216 Oesophagitis Diseases 0.000 description 1
- 206010031009 Oral pain Diseases 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 201000011152 Pemphigus Diseases 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 208000031845 Pernicious anaemia Diseases 0.000 description 1
- 208000005374 Poisoning Diseases 0.000 description 1
- 208000007932 Progeria Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 208000001431 Psychomotor Agitation Diseases 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- 206010037213 Psychomotor retardation Diseases 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010038583 Repetitive speech Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 208000032023 Signs and Symptoms Diseases 0.000 description 1
- 206010043169 Tearfulness Diseases 0.000 description 1
- KLBQZWRITKRQQV-UHFFFAOYSA-N Thioridazine Chemical compound C12=CC(SC)=CC=C2SC2=CC=CC=C2N1CCC1CCCCN1C KLBQZWRITKRQQV-UHFFFAOYSA-N 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 206010044688 Trisomy 21 Diseases 0.000 description 1
- 208000036826 VIIth nerve paralysis Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 206010047513 Vision blurred Diseases 0.000 description 1
- 208000003056 Vitamin B6 deficiency Diseases 0.000 description 1
- 206010047642 Vitiligo Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 230000037354 amino acid metabolism Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 201000003465 angular cheilitis Diseases 0.000 description 1
- 208000005028 anomia Diseases 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 201000003984 candidiasis Diseases 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 208000007287 cheilitis Diseases 0.000 description 1
- 238000000546 chi-square test Methods 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- FDJOLVPMNUYSCM-UVKKECPRSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(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-2,7, Chemical compound [Co+3].N#[C-].C1([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)[N-]\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 FDJOLVPMNUYSCM-UVKKECPRSA-L 0.000 description 1
- 230000003931 cognitive performance Effects 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 230000002542 deteriorative effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000035487 diastolic blood pressure Effects 0.000 description 1
- 230000009699 differential effect Effects 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 208000025688 early-onset autosomal dominant Alzheimer disease Diseases 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 238000005562 fading Methods 0.000 description 1
- 208000015756 familial Alzheimer disease Diseases 0.000 description 1
- 210000001652 frontal lobe Anatomy 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001914 gastric parietal cell Anatomy 0.000 description 1
- 230000002518 glial effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000005022 impaired gait Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000037041 intracellular level Effects 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229940029329 intrinsic factor Drugs 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000008449 language Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 238000007449 liver function test Methods 0.000 description 1
- 238000009593 lumbar puncture Methods 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000031852 maintenance of location in cell Effects 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 230000037345 metabolism of vitamins Effects 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000037230 mobility Effects 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000036473 myasthenia Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 239000001272 nitrous oxide Substances 0.000 description 1
- 208000030212 nutrition disease Diseases 0.000 description 1
- 235000003715 nutritional status Nutrition 0.000 description 1
- 230000010627 oxidative phosphorylation Effects 0.000 description 1
- 230000037324 pain perception Effects 0.000 description 1
- 208000012237 paracetamol poisoning Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 210000001152 parietal lobe Anatomy 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 230000006697 redox regulation Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 208000022925 sleep disturbance Diseases 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000012030 stroop test Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000007944 thiolates Chemical class 0.000 description 1
- 229960002784 thioridazine Drugs 0.000 description 1
- 230000003867 tiredness Effects 0.000 description 1
- 208000016255 tiredness Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003936 working memory Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
-
- 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
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K31/10—Sulfides; Sulfoxides; Sulfones
-
- 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
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
- A61K38/063—Glutathione
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/08—Antiseborrheics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to a method for treating or preventing a functional Vitamin B 12 deficiency in an individual and to medical compositions for use in said method.
- a functional B 12 deficiency may present as dementia, other neuropsychiatric abnormality and/or vascular disease.
- Homocysteine is an intermediary amino acid derived from the breakdown of methionine. Its serum levels increase in individuals having folate, Vitamin B 12 (cobalamin) and pyridoxine deficiencies and genetically defective enzymes involved in its metabolism. Hyperhomocysteinemia, the term given to raised blood concentration of homocysteine, is associated with cardiovascular, peripheral vascular, and cerebrovascular disease. A potential role for hyperhomocysteinernia in the aetiology of Alzheimer's Disease (AD) has been postulated. Support for this comes from several recent investigations (1, 2, 3, 4).
- a tissue deficiency of cobalamin also results in elevated serum methylmalonic acid. Raised levels of methylmalonic acid have also been demonstrated in serum of patients with AD suggesting that they suffer from metabolic cobalamin deficiency (6). Elevated serum homocysteine and methylmalonic acid have also been associated with neurological and psychiatric signs and symptoms (e.g. impaired vibration sense, paraesthesia, impaired position sense, impaired touch or pain perception, “diabetic” neuropathy, ataxia, abnormal gait, decreased reflexes and muscle strength, weakness, fatigue) and various neurological and psychiatric disorders, including chronic fatigue syndrome, depressive illness and multiple sclerosis indicating that cobalamin deficiency is commonly associated with such disorders (7). Interestingly, the usual haematological signs of cobalamin deficiency including anaemia and macrocytosis are commonly absent in these patients.
- AD metabolic evidence of B 12 /folate deficiency arises independently of nutritional status (as determined by body mass index) and is not associated with haematological abnormalities, which would occur with malabsorption of B 12 or folate.
- the deficiency is not associated with low levels of red blood cell folate, again suggesting normal intake/absorption, but is associated with elevated blood levels of cysteine, demonstrating increased transsulfuration of homocysteine.
- This identifies the biochemical locus of the hyperhomocysteinemia as arising from a remethylation defect with a compensatory increased flux via the transsulfuration pathway.
- blood levels of glutathione a key antioxidant, are inversely associated with disease severity.
- Both endothelium and neurons lack an intact transsulfuration pathway, impairing their ability to synthesize the antioxidant gluthathione. Both tissues also lack any alternative means to remethylate homocysteine via betaine, namely betaine:homocysteine methyltransferase (9). Increased cellular export of homocysteine is therefore the only route available to these tissues when the methionine synthase reaction is impaired by oxidative stress.
- the “functional” vitamin B 12 deficiency that wises due to the effects of oxidative stress on B 12 metabolism as recognized by the Inventor may be revealed by elevated blood levels of homocysteine and/or methylmalonic acid, and/or low levels of total serum B 12 and/or low levels of the B 12 carrier protein holo-transcobalamin.
- a functional vitamin B 12 deficiency occurs in the absence of any demonstrable malabsorption of the vitamin and, usually, in the absence of any associated haematological abnormalities. The recognition of this functional deficiency has enabled the inventor to arrive at a method and composition for treating and/or preventing symptoms associated therewith.
- a further object of the present invention is to provide an improved medical composition for use in treating or preventing a functional Vitamin B 12 deficiency in an individual which may eventually present as dementia, other neuropsychiatric abnormality and/or vascular disease.
- a first aspect of the present invention provides a method for treating or preventing a functional Vitamin B 12 deficiency in an individual, the method comprising administering to the individual a therapeutically effective amount of a medical composition that directly or indirectly supplies a cobalt-sulphur bond in the upper ⁇ -axial ligand of an intracellular cobalamin molecule thereby facilitating intracellular processing of cobalamins.
- a second aspect of the present invention provides a medical composition for use in the treatment or prevention of a functional Vitamin B 12 deficiency in an individual, the composition comprising a compound or a combination of compounds that directly or indirectly supplies a cobalt-sulphur bond in the upper ⁇ -axial ligand of an intracellular cobalamin molecule thereby facilitating intracellular processing of cobalamins.
- the cobalt-sulphur bond in the upper ⁇ -axial ligand of the cobalamin molecule may be provided directly by administering a therapeutic amount of a thiolatocobalamin that already contains the cobalt-sulphur bond or indirectly by the co-adminstration of Vitamin B 12 (cyanocobalamin) or a derivative thereof with a sulphur containing molecule, such as glutathione, or a precursor thereof.
- the medical composition may facilitate intracellular processing of cobalamin in tissues that suffer from oxidative stress, in particular neuronal tissue and vascular endothelium.
- any suitable thiolatocobalamin may be provided to supply directly the cobalt-sulphur bond, including the preferred compound glutathionylcobalamin (CAS: 129128-04-7) and related sulphur-containing cobalamins having the generic form Co ⁇ -[ ⁇ -(5,6-Dimethylbenzimidazolyl)]-Co ⁇ -ligandyl)cobamide, in which the upper ⁇ -axial ligand group is co-ordinated to the cobamide by a sulphur-cobalt bond, such as (but not limited to) sulphitocobalamin (syn-sulfitocobalamin; CAS: 15671-27-9), cysteinylcobalamin (CAS: 60659-91-8), cyclohexylthiolatocobalamin and pentafluorophenylthiolatocobalamin.
- glutathionylcobalamin CAS: 129128-04-7
- related sulphur-containing cobalamins having the generic form Co
- a third aspect of the present invention provides a method for treating or preventing a functional Vitamin B 12 deficiency in an individual, the method comprising administering to the individual a therapeutically effective amount of a thiolatocobalamin.
- a fourth aspect provides a medical composition for use in the treatment or prevention of a functional Vitamin B 12 deficiency in an individual, the medical composition comprising a thiolatocobalamin.
- a fifth aspect of the present invention provides a method for treating or preventing a functional Vitamin B 12 deficiency in an individual comprising administering to the individual a therapeutically effective amount of Vitamin B 12 or a derivative thereof selected from the group consisting of hydroxocobalamin, methylcobalamin and adenosyl cobalamin in conjunction with a therapeutically effective amount of glutathione and/or a precursor for the compound glutathione, the precursors being selected from the group consisting of N-acetyl cysteine, glycine, L-glutamine, L-taurine, L-methionine, S-adenosyl methionine, ⁇ -lipoic acid, L- ⁇ oxothiazolidine-4-carboxylate, L- ⁇ -glutamyl-L-cysteinylglycyl ethyl ester, butylated hydroxyanisole, butylated hydroxytoluene, ⁇ -glutamyl cysteine,
- a sixth aspect of the present invention provides a medical composition for use in the treatment or prevention of a functional Vitamin B 12 deficiency in an individual, the composition comprising Vitamin B 12 or a derivative thereof selected from the group consisting of hydroxocobalamin, methylcobalamin and adenosyl cobalamin in combination with glutathione and/or a precursor for the compound glutathione, the precursors being selected from the group consisting of N-acetyl cysteine, glycine, L-glutamine, L-taurine, L-methionine, S-adenosyl methionine, ⁇ -lipoic acid, L- ⁇ oxothiazolidine-4-carboxylate, L- ⁇ -glutamyl-L-cysteinylglycyl ethyl ester, butylated hydroxyanisole, butylated-hydroxytoluene, ⁇ -glutamyl cysteine, cysteinyiglycine and acety
- the medical composition according to this aspect of the present invention preferably comprises Vitamin B 12 , or a derivative thereof, and N-acetyl cysteine or ⁇ -lipoic acid.
- the medical composition is particularly suitable for facilitating processing of cobalamin in neuronal tissues and vascular endothelium that are vulnerable to the effects of oxidative stress.
- a combined treatment of a thiolatocobalamin, glutathione, a glutathione precursor and/or cobalamin may also be administered to the individual.
- the medical composition may be co-administered with additional compounds to assist in their therapeutic action against neuropsychiatric and/or vascular disease.
- the composition may be co-administered with other factors involved in the metabolism of homocysteine, such as folate and/or vitamin B6.
- the compositions may also be co-administered with any methyl-donor, such as, but not limited to, folic acid, methyl-folate, S-adenosylmethionine, betaine, choline and carnitine.
- Any appropriate mode of administration may be used, such as (but not limited to) oral, sublingual, intravenous and parenteral administration.
- Example 1 investigates the relationship between homocysteine, haematolocal indices and dementia duration in patients with clinically diagnosed Alzheimers Disease (AD)
- Example 2 investigates the effects of the co-administration of a glutathione precursor (N-acetyl cysteine or ⁇ -lipoic acid) and hydroxocobalamin (a derivative of Vitamin B 12 ) to patients with a functional Vitamin B 12 deficiency and suffering from a neuropsychiatric abnormality
- Example 3 provides evidence for a functional Vitamin B 12 deficiency in patients with DSM-IV criteria for primary degenerative dementia of Alzheimer type and investigates its relationship with cognitive score
- FIG. 1 illustrates the primary activation cycle of the ethionine synthase reaction
- FIG. 2 illustrates the re-activation of cob(II)-alamin by methionine synthase reductase
- FIG. 3 illustrates the transulfuration pathway wherein homocysteine is metabolized to glutathione (GSH);
- FIG. 4 illustrates the effect of oxidative stress on homocysteine flux and its implication for neuronal and vascular endothelial cobalamin metabolism
- FIG. 5 is a scatter diagram showing the relationship between ADAS-Cog score and plasma glutathione in patients with DSM-TV criteria for primary degeneration dementia of Alzheimer type (filled circles) and controls (open circles).
- the present invention relates to the recognition of the implication of hyperhomocysteinemia in a pathogenic mechanism common to the development of AD, vascular disease and aging.
- this mechanism relates to the influence of ambient redox status on key enzymes of homocysteine metabolism.
- An inevitable implication of this mechanism is aberrant intraneuronal and intra-endothelial processing of cobalamins by the ⁇ -ligand transferase and cobalamin reductase enzymes.
- cobalamin in current use, such as hydroxocobalamin (CAS: 13422-51-0), cyanocobalamin (“Vitamin B 12 ” CAS: 68-19-9), methylcobalamin (CAS: 13422-55-4) and adenosyl cobalamin (“Coenzyme B12” CAS: 13870-904) cannot be utilised by neurones or vascular endothelium due to their lack of a crucial Co—S bond resulting in this particular metabolic block.
- the adminstration of glutathionylcobalamin, or any related cobalamins of the generic form Co ⁇ -[ ⁇ -(5,6-Dimethylbenzimidazolyl)]-Co ⁇ -ligandyl)cobamide, in which the upper ⁇ -axial ligand group is co-ordinated to the cobamide by a sulphur-cobalt bond (i.e. thiolatocobalamins) can overcome this redox-related metabolic block.
- the presence of a cobalt-sulphur bond in the upper ligand of the cobalamin molecule is an essential prerequisite for intracellular processing of cobalamins. Neurones and vascular endothelium are unable to generate this bond under conditions of oxidative stress.
- the method and compositions provided by the present invention ensure the presence of a cobalt-sulphur bond in neuronal or vascular endothelium cobalamin, either directly by administering a thiolatocobalamin or indirectly by co-administering currently available forms of Vitamin.
- B 12 together with the sulphur-containing molecule glutathione or one of its precursors, such as N-acetyl cysteine (NAC) or ⁇ -lipoic acid.
- Homocysteine is a key junction metabolite in methionine metabolism. Homocysteine may be methylated by means of the enzyme methionine synthase (MS) or transsulfurated by the enzyme cystathionine ⁇ -synthase (CBS) leading to cystathionine. The latter is subsequently converted to cysteine, a precursor of reduced glutathione (GSH).
- MS methionine synthase
- CBS cystathionine ⁇ -synthase
- GSH reduced glutathione
- AD oxidative stress in AD
- the brain is especially vulnerable to oxidative stress for several reasons. It has high concentrations of catalytic iron and a relatively low level of antioxidant enzymes compared to other tissues. It is rich in membrane lipids and polyunsaturated fatty acids amenable to peroxidation and has high energy demands met almost exclusively by oxidative phosphorylation. Oxidative damage, although a common finding in the aging brain, is more severe in patients with AD.
- oxidative stress has recently been associated with cognitive decline even in healthy elderly.
- oxidative stress can compromise cobalamin (Vitamin B 12 ) metabolism in dementia or vascular disease.
- the thiolate of homocysteine reacts with the methyl (CH 3 ) group of MS-bound methylcobalamin to produce methionine and four-coordinate cob(I)alamin.
- DMB dimethylbenzimidazole
- Methylcobalamin cycles via a protonation and deprotonation, between enzyme bound Cob(M)alamin and free Cob(I)alamin states, as illustrated in FIG. 1 .
- S-adenosylmethionine (SAM) and an electron source (*) regenerate the active form of MS when cob(I)alamin is abnormally oxidised to cob(II)alamin (see FIG. 2 ).
- SAM S-adenosylmethionine
- * electron source regenerate the active form of MS when cob(I)alamin is abnormally oxidised to cob(II)alamin (see FIG. 2 ).
- MCM methymalonyl-CoA mutase
- the upper axial carbon-cobalt bond splits heterolytically rather than homolytically and the cobalt atom remains in the relatively inert cobapalamin form.
- Oxidative stress impairs MS function whilst relatively sparing mutase activity. Hence, a consequence of oxidative stress is to increase homocysteine levels. Oxidative damage is also associated with the formation of cobalamin analogues which have been demonstrated in vivo (13) and, more recently, have been observed in AD (14).
- oxidative stress can increase homocysteine flux via the transsulfuration pathway as a consequence of its stimulation of cystathionine ⁇ -synthase (CBS) activity (see FIG. 3 ).
- CBS cystathionine ⁇ -synthase
- the redox sensitivity of CBS probably represents an autocorrective response resulting in increased intracellular levels of glutathione (GSH) in cells challenged by oxidative stress (10).
- GSH glutathione
- the absence of cystathionase, and hence low glutathione, in neurones makes these cells particularly prone to such challenges (FIG. 4 , a ) as does the low activity of CBS in vascular endothelial cells (FIG. 4 , b ).
- oxidative stress has a further serious implication for cobalamin metabolism within neurones and vascular endothelial cells.
- the key enzymes involved in the processing of various forms of cobalamin following their delivery to the cell by transcobalamin (TC) have been delineated (15), see. FIG. 4 .
- Different ⁇ -ligand forms of cobalamin bound to TC are internalised and converted to methyl- and adenosyl-forms.
- Methylcobalamin is formed in the reaction catalysed by methionine synthase as an intermediate of the methyl transfer reaction provided that cobalamin is made available in an appropriate redox form (cob(I)alamin or cob(II)alamin).
- Glutathionylcobalamin (GS-Cbl), a naturally occurring intracellular form of cobalamin, is a proximal precursor in the biosynthesis of cobalamin enzymes (15).
- ⁇ -ligand transferase (beta-LT) is a cytosolic enzyme utilizing FAD, NADPH, and reduced glutathione (GSH).
- cob(III)alamin reductase has also been studied (15). This utilises aq-Cbl, GS-Cbl and HSO 3 -Cbl as substrates, but preferentially the latter two. Little or no reductase activity was observed with Me-Cbl, Ado-Cbl or CN-Cbl as substrates.
- the product of this reaction, cob(II)alamin becomes bound to cytosolic MS (or, alternatively, is further reduced to cob(I)alamin in mitochondria, followed by conversion to adenosylcobalamin, a co-factor for methylmalonylCoA mutase), see FIG. 4 .
- GSH glutathione
- GS-Cbl the obligate intracellular intermediate form of cobalamin
- GSH glutathione
- GS-Cbl the obligate intracellular intermediate form of cobalamin
- GSH is a ubiquitous tripeptide consisting of glycine, cysteine and glutamate. It participates in many vital cellular functions, including the synthesis of proteins, enzyme activity, metabolism, and protection against oxidative stress. Neuronal and vascular endothelial GSH synthesis depends on the presence of its precursors. Glutamate and glycine are synthesised via several metabolic pathways, and therefore their influence on GSH synthesis is limited.
- cysteine is rapidly oxidised to cystine, which is extracellularly predominant. Cystine is taken up by glial cells via the cystine/glutamate antiporter and subsequently reduced to cysteine. Neurones are not able to reduce cystine to cysteine nor convert cystathionine to cysteine (see FIG. 4 , a ) and therefore depend upon glial cysteine to preserve their GSH level. Cysteine has been confirmed as a rate limiting precursor for neuronal GSH synthesis. Consequently, glutathione content of neurones is very low. Similarly, vascular endothelium also lacks the ability to synthesize endogenous cysteine from homocysteine (see FIG. 4 , b ).
- a cobalt-sulphur bond in neuronal and endothelial cobalamins will circumvent this block and reduce homocysteine levels in these tissues and that this can be achieved by either the direct administration of a thiolatocobalamin, such as synthetic glutathionyl cobalamin (Method of manufacture described in, for example, GB 945772) or indirectly by the co-administration of Vitamin B 12 and glutathione, or one of the precursors such as, for example, N-acetyl cysteine (CAS: 616-91-1), glycine (CAS: 56-40-6), L-glutamine (CAS: 56-85-9), L-taurine (CAS: 107-35-7), L-methionine (CAS: 63-68-3), ⁇ -lipoic acid (CAS: 62-46-4), cysteinylglycine (CAS:19246-18-5) and S-adenosyl methionine (CAS: 29908-03-0
- Controls were healthy cognitively intact age and sex matched elderly volunteers from a group General Practice in a comparable semi-rural area of predominantly lower socio-economic class. Patients or controls receiving vitamin B 12 or folate supplements, or taking medication known to influence homocysteine were excluded.
- MMSE Mini Metal State Examination
- ADAS-Cog Alzheimer Disease Assessment Scale
- Body mass index was determined from height and weight measured at assessment. Duration of dementia in months was determined from records wherever possible, or alternatively from next of kin or carers.
- Non-fasting blood samples were taken for full blood count, red cell folate (RCF), creatinine, B 12 , folate, and homocysteine assays. Separation and freezing were performed within one hour of venepuncture.
- An automated cell counter was used to measure haemoglobin (Hb) concentration, and MCV (Coulter Gen-S, Beckman Coulter, High Wycombe, Bucks, UK).
- the red cell distribution width (RDW) was mathematically derived from the frequency over red cell volume histogram on the same instrument. A broad curve, resulting from cells with wide range of cell volume, will yield a raised RDW,
- An automated biochemistry analyser was used to analyse creatinine (Synchron LX-20 analyser, Beckman Coulter, High Wycombe, Bucks, UK) and an automated chemiluminescence analyser was used to measure folate, vitamin B 12 and RCF (ACS:180 SE, Bayer plc, Newbury, Berks UK) using the manufacturers' recommended protocols.
- homocysteine was assayed with an automated HPLC system (DS30 Hey Analyser, Drew Scientific Group plc, Barrow in Furness, Cumbria, UK). All forms of homocysteine were assayed including protein bound, non-protein bound, free forms both oxidized (dimer and mixed disulphides) and reduced. Values presented therefore always refer to “total” plasma levels.
- a generalized linear model was used to determine the relationship between haematological variables and disease duration in the patient group. Gender was included as an additional variable.
- AD patients therefore exhibit a “functional” B 12 /folate deficiency, but in the absence of “classical” haematological indicators.
- Low serum folate, but normal red cell folate, in AD suggests that these patients are in negative folate balance, i.e. more folate has been catabolized than absorbed.
- Oxidative stress augments the oxidation of an intermediate form of vitamin B 12 generated in the methionine synthase reaction, thereby impairing the metabolism of homocysteine. Furthermore, oxidative stress compromises the intraneuronal reduction of vitamin B 12 to its metabolically active state. Since this stress is confined to brain tissue, haematopoietic methionine synthase activity is relatively unaffected, thus explaining the absence of anaemia and macrocytosis in these patients.
- the present data also shows that the relationship between AD and folate status reflects excess folate catabolism.
- Methionine synthase inactivation results in folate being trapped in the methyltetrahydrofolate form. It is unavailable for polyglutamation, a necessary prerequisite for cellular retention, and is released from cells. It is subsequently excreted in the urine, eventually resulting in folate depletion. Haematopoietic tissue is spared in this process, explaining the normal red cell folate values and absent anaemia.
- Vitamin B 12 (cyanocobalamin), adenosylcobalamin and methylcobalamin have a cobalt-carbon bond at the ⁇ -axial position and hydroxocobalamin has a cobalt-oxygen bond.
- these commonly used pharmaceutical derivatives cannot be used by neuronal tissues under conditions of oxidative stress due to reduced supplies of intracellular glutathione necessary to convert these cobalt bonds to cobalt-sulphur bonds and hence, to a metabolically active form.
- Glutathionylcobalamin or related thiolatocobalamins, in which the upper ⁇ -axial ligand of the cobalamin molecule already possess a sulphur-cobalt bond, can overcome this redox-related metabolic block and thereby reduce the symptoms of oxidative stress on neuronal tissues.
- the co-administration of Vitamin B 12 with glutathione, or a precursor thereof, can also overcome this metabolic block by providing the requisite cobalt-sulphur bond.
- a cobalt-sulphur bond at the upper ⁇ -axial ligand should be of particular utility in the treatment and/or prevention of neuropsychiatric and/or vascular disorders associated with metabolic or other evidence of B 12 deficiency, especially those in which the classical haematological sips of anaemia and macrocytosis are absent or non-significant, as demonstrated by the Example given above.
- Anaemia is absent in such situations due to the bone-marrow being able to metabolize homocysteine and thus, unlike neuronal tissues, has sufficient levels of glutathione to protect against oxidative stress and generate the cobalt-sulphur bond of the obligate intracellular cobalamin intermediate, glutathionylcobalamin.
- Her memory impairment was characterised by short-term memory problems with a very gradual deterioration. There were no significant behavioural problems but the patient did have difficulty with remembering names and putting names to faces.
- Her cognitive function was formally reviewed again 18 months later. Her husband reported that her memory seemed to have deteriorated further, she asked inappropriate questions at times. Her general ability to perform activities of daily living had declined. Her mini-mental state score had declined to 22/30, and it was concluded that she continued to suffer from a slow, age-related cognitive decline. She was commenced on a trial of an acetylcholinesterase inhibitor, but unfortunately had to discontinue this due to troublesome side effects, and there appeared to be no obvious benefit in the first few weeks of treatment anyway.
- Her frontal lobe function was generally good. It was felt that she had a dementing illness of probable Alzheimer-type. She was admitted to a nursing home, but her general condition continued to deteriorate. At a further cognitive review in 1997 she scored only 13/30 on MMSE.
- This lady had a dementing illness of probable Alzheimer-type and co-existing vitamin B 12 deficiency. However it is unlikely that the deficiency was due to malnutrition (she was folate replete) or malabsorption (there was no evidence of a macrocytic anaemia or haematological involvement). It is probable that she had a “functional” vitamin B 12 deficiency as a consequence of cerebral oxidative stress related to her Alzheimer Disease. An attempt to correct this deficiency with hydroxocobalamin did not prevent her cognitive decline.
- her mental condition improved when N-acetylcysteine was co-administered with hydroxocobalamin to provide a cobalt sulphur bond in the upper axial ligand of neuronal cobalamin.
- This patient has probable Alzheimer-type dementia with a co-existing functional vitamin B 12 deficiency revealed by markedly elevated levels of serum homocysteine.
- treatment with monthly hydroxocobalamin injections and oral folate supplements corrected the levels of serum homocysteine, this did not result in a halting of the dementia process.
- glutathione Since this is a necessary precursor for the intracellular processing of vitamin B 12 an attempt was made to increase his glutathione levels by the co-administration of N-acetylcysteine.
- Her vitamin B 12 injections were withdrawn in September 1994. Two weeks later she was very sensitive to light and sounds, had concentration difficulties and could not complete reading any articles in the daily newspaper. She developed a tingling feeling in her lips, tongue and pharynx, “ . . . as when an anaesthesia is fading away”. In October of 1994 she was tested by a neuropsychologist (STROOP test) and performed significantly worse than during her treatment period.
- STROOP test neuropsychologist
- This patient had clinical features of a Chronic Fatigue Syndrome, and also displayed an error of vitamin B 12 metabolism in the central nervous system. This was revealed by increased levels of homocysteine in her cerebrospinal fluid suggesting a functional vitamin B 12 deficiency.
- the addition of the glutathione precursor N-acetylcysteine to her vitamin B 12 therapy resulted in a marked further improvement in her clinical condition, and she was also able to significantly reduce the frequency of these injections.
- her-urinary homocysteine was assayed. This was elevated and she was therefore commenced on regular injections of vitamin B 12 . She soon noticed a very apparent improvement in her symptoms; all her visual and proprioceptive complaints improved, as did her orientation.
- This physician had a presumed diagnosis of multiple sclerosis. She was found to have evidence of a functional B 12 deficiency, revealed by elevated urinary homocysteine levels. Although her symptoms improved with vitamin B 12 supplementation, the co-administration of N-acetylcysteine, to provide a cobalt-suphur bond in the upper axial ligand of cobalamin, resulted in a further marked improvement in her symptoms.
- Plasma homocysteine levels are elevated in Alzheimer Disease, but little is known regarding the levels of other aminothiols in the disease. Evaluating the levels of these associated metabolites will assist in determining the biochemical locus for the elevated homocysteine. Therefore, total plasma homocysteine, cysteine, glutathione and cysteinylglycine levels were determined in patients and controls and their relationship with cognitive scores was investigated.
- Prior education of the subjects was also determined (“none, primary, intermediate, secondary and further”) since this relates to cognitive decline in normal aging (19).
- Smoking (“current, ex, and never”) and hypertensive status were also documented, these being associated with modest elevation of homocysteine (20).
- Prior education and smoking were treated as ordinal variables and hypertensive status as a categorical variable. Height and weight were measured at assessment to calculate body mass index (BMI). Ethical approval was granted, and informed consent obtained.
- BMI body mass index
- Non-fasting blood samples were taken for full blood count, red cell folate (RCF), creatinine, B 12 , folate, and aminothiol assays. Separation and freezing were performed within one hour of venepuncture until aminothiol analysis (21).
- Hb haemoglobin
- MCV mean corpuscular volume
- An automated biochemistry analyser was used to analyse creatinine (Synchron LX-20 analyser, Beckman Coulter, High Wycombe, Bucks, UK) and an automated chemiluminescence analyser was used to measure folate, vitamin B 12 and RCF (ACS:180 SE, Bayer plc, Newbury, Berks UK) using the manufacturers' recommended protocols.
- Aminothiols were assayed with an automated HPLC system (DS30 Hcy Analyser, Drew Scientific Group plc, Barrow in Furness, Cumbria, UK) For each aminothiol, all forms including protein bound, non-protein bound, free forms both oxidized (dimer and mixed disulphides) and reduced were measured. Values presented always refer to “total” plasma levels.
- AD patients There were 50 AD patients (17 male and 33 female) and 57 controls (23 male and 34 female). The median age of both groups was 79 years (75-83 for AD and 72-85 for controls). AD patients had a median duration of disease of 24 (13-36) months and a median age of onset of 77 (74-82) years.
- AD patients were found to have significantly decreased folate, and significantly increased plasma homocysteine and cysteine.
- Hb, platelets, MCV, creatinine, B 12 , RCF, cysteinylglycine and glutathione did not differ between groups, as shown in Table 3 below.
- ADAS-Cog 54.9 ⁇ 8.39 ⁇ glutathione
- Plasma homocysteine and cysteine are elevated in Alzheimer Disease implying intact and increased transsulphuration but aberrant re-methylation of homocysteine in patients.
- Glutathionylcobalamin and related thiolatocobalamins may also be used to prevent a functional Vitamin B 12 deficiency in all diseases and disorders associated with low intracellular glutathione, including aging. It is to be appreciated that such patients would,:eventually, develop a functional B 12 deficiency anyway but in the early stages of disease might not have clear metabolic evidence of such deficiency.
- Reduced glutatione levels in mammalian cells are associated with a wide range of pathophysiologic states, including hepatic dysfunction, malignancies, HIV infection, pulmonary disease, Parkinson's disease, related immunologic illnesses and physiological conditions.
- pathophysiologic states including hepatic dysfunction, malignancies, HIV infection, pulmonary disease, Parkinson's disease, related immunologic illnesses and physiological conditions. The following list is for example purposes only and is not exhaustive:
- Gravis neurodegenerative diseases, nutritional disorders, Parkinson's disease, Pemphigus Vulgaris, Primary Hillary Cirrhosis, progeria, psoriasis, Rheumatic Fever, Sarcoidosis, scleroderma, shingles, stroke, toxic poisoning, vasculitis, vitiligo, and Wegener's Granulomatosis.
Abstract
A method and medical composition for the treatment and/or prevention of a functional Vitamin B12 deficiency in an individual that is brought about as a consequence of oxidative stress on biochemical pathways. The functional Vitamin B12 deficiency may eventually present as dementia, other neuropsychiatric abnormality and/or vascular disease. The method involves the administration of a medical composition that supplies a cobalt-sulphur bond in the upper β-ligand of an intracellular cobalamin molecule thereby facilitating intracellular processing of cobalamin. The cobalt-sulphur bond may he provided directly by administration of a thiolatocohalamin, such as glutathianyl-cobalamin or indirectly by the co-administration of Vitamin B12 (or a derivative thereof) with a sulphur-containing molecule, such as glutathione or a precursor thereof.
Description
- The present invention relates to a method for treating or preventing a functional Vitamin B12 deficiency in an individual and to medical compositions for use in said method. Such a functional B12 deficiency may present as dementia, other neuropsychiatric abnormality and/or vascular disease.
- Homocysteine is an intermediary amino acid derived from the breakdown of methionine. Its serum levels increase in individuals having folate, Vitamin B12 (cobalamin) and pyridoxine deficiencies and genetically defective enzymes involved in its metabolism. Hyperhomocysteinemia, the term given to raised blood concentration of homocysteine, is associated with cardiovascular, peripheral vascular, and cerebrovascular disease. A potential role for hyperhomocysteinernia in the aetiology of Alzheimer's Disease (AD) has been postulated. Support for this comes from several recent investigations (1, 2, 3, 4). Perhaps the most compelling of these is the case control study of histologically confirmed AD patients and age-matched controls which demonstrated a 4.6-fold increased risk of having AD in individuals with serum homocysteine >14 micromol/L compared to those with serum homocysteine of less than 11 micromol/L (2). Recently, an important prospective observational study of a cohort of 1092 elderly subjects in the. Framingham Study has greatly strengthened the evidence for an association between plasma homocysteine level and dementia (4). In this study, an elevated plasma total homocysteine level at base line was an independent predictor of the development of clinical dementia, most cases of which were caused by AD. After a median of eight years of follow-up, dementia had developed in 111 subjects. The risk of AD was almost doubled for those with the highest plasma homocysteine levels; a 5 μmol increment in plasma homocysteine increased the risk of AD by 40%, The aforementioned investigations demonstrate that homocysteine also correlates with cognitive scores in AD and vascular dementia. Furthermore, it appears to be an independent predictor of cognitive decline in healthy elderly (5).
- A tissue deficiency of cobalamin also results in elevated serum methylmalonic acid. Raised levels of methylmalonic acid have also been demonstrated in serum of patients with AD suggesting that they suffer from metabolic cobalamin deficiency (6). Elevated serum homocysteine and methylmalonic acid have also been associated with neurological and psychiatric signs and symptoms (e.g. impaired vibration sense, paraesthesia, impaired position sense, impaired touch or pain perception, “diabetic” neuropathy, ataxia, abnormal gait, decreased reflexes and muscle strength, weakness, fatigue) and various neurological and psychiatric disorders, including chronic fatigue syndrome, depressive illness and multiple sclerosis indicating that cobalamin deficiency is commonly associated with such disorders (7). Interestingly, the usual haematological signs of cobalamin deficiency including anaemia and macrocytosis are commonly absent in these patients.
- Previously, individuals with occlusive vascular disease or AD have been treated with folic acid, a folate or a derivative thereof and, optionally, vitamin B12 (U.S. Pat. No. 6,127 370. Smith et al.,). However, the administration of such compounds to patients suffering from hyperhomocysteinemia is not always found to fully alleviate the symptoms associated with such raised levels of homocysteine. The evidence referred to above (1, 2, 3, 4, 5) clearly shows that there is metabolic evidence for B12 deficiency in association with AD vascular disease, age-related cognitive decline and various neuropsychiatric disorders, although the exact mechanism underlying these associations has been unclear until now.
- The Inventor herein demonstrates that in patients with. AD metabolic evidence of B12/folate deficiency, reflected by hyperhomocysteinemia, arises independently of nutritional status (as determined by body mass index) and is not associated with haematological abnormalities, which would occur with malabsorption of B12 or folate. Furthermore, the deficiency is not associated with low levels of red blood cell folate, again suggesting normal intake/absorption, but is associated with elevated blood levels of cysteine, demonstrating increased transsulfuration of homocysteine. This identifies the biochemical locus of the hyperhomocysteinemia as arising from a remethylation defect with a compensatory increased flux via the transsulfuration pathway. Additionally, blood levels of glutathione, a key antioxidant, are inversely associated with disease severity.
- Taken together, the aforementioned findings show that patients with AD have a “functional” vitamin B12 deficiency, rather than a “classical” deficiency arising from impaired absorption of the vitamin (e.g. pernicious anaemia). Recently, further supporting evidence for a functional vitamin B12 deficiency in AD patients has been published (8). This clearly shows a relationship between oxidative stress and elevated concentration of homocysteine in plasma and cerebrospinal fluid of patients with AD. Vascular endothelium and neuronal tissue are particularly sensitive to oxidative stress. The effects of such stress on the intracellular metabolism of vitamin B12 result in the functional deficiency. Both endothelium and neurons lack an intact transsulfuration pathway, impairing their ability to synthesize the antioxidant gluthathione. Both tissues also lack any alternative means to remethylate homocysteine via betaine, namely betaine:homocysteine methyltransferase (9). Increased cellular export of homocysteine is therefore the only route available to these tissues when the methionine synthase reaction is impaired by oxidative stress.
- The “functional” vitamin B12 deficiency that wises due to the effects of oxidative stress on B12 metabolism as recognized by the Inventor may be revealed by elevated blood levels of homocysteine and/or methylmalonic acid, and/or low levels of total serum B12 and/or low levels of the B12 carrier protein holo-transcobalamin. A functional vitamin B12 deficiency occurs in the absence of any demonstrable malabsorption of the vitamin and, usually, in the absence of any associated haematological abnormalities. The recognition of this functional deficiency has enabled the inventor to arrive at a method and composition for treating and/or preventing symptoms associated therewith.
- It is an object of the present invention to provide an improved method of treating or preventing a functional Vitamin B12 deficiency in an individual which may eventually present as dementia, other neuropsychiatric abnormality and/or vascular disease. Such symptoms are brought about as a consequence of oxidative stress on biochemical pathways.
- A further object of the present invention is to provide an improved medical composition for use in treating or preventing a functional Vitamin B12 deficiency in an individual which may eventually present as dementia, other neuropsychiatric abnormality and/or vascular disease.
- Accordingly, a first aspect of the present invention provides a method for treating or preventing a functional Vitamin B12 deficiency in an individual, the method comprising administering to the individual a therapeutically effective amount of a medical composition that directly or indirectly supplies a cobalt-sulphur bond in the upper β-axial ligand of an intracellular cobalamin molecule thereby facilitating intracellular processing of cobalamins.
- A second aspect of the present invention provides a medical composition for use in the treatment or prevention of a functional Vitamin B12 deficiency in an individual, the composition comprising a compound or a combination of compounds that directly or indirectly supplies a cobalt-sulphur bond in the upper β-axial ligand of an intracellular cobalamin molecule thereby facilitating intracellular processing of cobalamins.
- The cobalt-sulphur bond in the upper β-axial ligand of the cobalamin molecule may be provided directly by administering a therapeutic amount of a thiolatocobalamin that already contains the cobalt-sulphur bond or indirectly by the co-adminstration of Vitamin B12 (cyanocobalamin) or a derivative thereof with a sulphur containing molecule, such as glutathione, or a precursor thereof.
- The medical composition may facilitate intracellular processing of cobalamin in tissues that suffer from oxidative stress, in particular neuronal tissue and vascular endothelium.
- Any suitable thiolatocobalamin may be provided to supply directly the cobalt-sulphur bond, including the preferred compound glutathionylcobalamin (CAS: 129128-04-7) and related sulphur-containing cobalamins having the generic form Coα-[α-(5,6-Dimethylbenzimidazolyl)]-Coβ-ligandyl)cobamide, in which the upper β-axial ligand group is co-ordinated to the cobamide by a sulphur-cobalt bond, such as (but not limited to) sulphitocobalamin (syn-sulfitocobalamin; CAS: 15671-27-9), cysteinylcobalamin (CAS: 60659-91-8), cyclohexylthiolatocobalamin and pentafluorophenylthiolatocobalamin.
- To this end, a third aspect of the present invention provides a method for treating or preventing a functional Vitamin B12 deficiency in an individual, the method comprising administering to the individual a therapeutically effective amount of a thiolatocobalamin.
- A fourth aspect provides a medical composition for use in the treatment or prevention of a functional Vitamin B12 deficiency in an individual, the medical composition comprising a thiolatocobalamin.
- A fifth aspect of the present invention provides a method for treating or preventing a functional Vitamin B12 deficiency in an individual comprising administering to the individual a therapeutically effective amount of Vitamin B 12 or a derivative thereof selected from the group consisting of hydroxocobalamin, methylcobalamin and adenosyl cobalamin in conjunction with a therapeutically effective amount of glutathione and/or a precursor for the compound glutathione, the precursors being selected from the group consisting of N-acetyl cysteine, glycine, L-glutamine, L-taurine, L-methionine, S-adenosyl methionine, α-lipoic acid, L-α oxothiazolidine-4-carboxylate, L-γ-glutamyl-L-cysteinylglycyl ethyl ester, butylated hydroxyanisole, butylated hydroxytoluene, γ-glutamyl cysteine, cysteinylglycine and acetyl-carnitine to facilitate intracellular processing of cobalamin.
- A sixth aspect of the present invention provides a medical composition for use in the treatment or prevention of a functional Vitamin B12 deficiency in an individual, the composition comprising Vitamin B12 or a derivative thereof selected from the group consisting of hydroxocobalamin, methylcobalamin and adenosyl cobalamin in combination with glutathione and/or a precursor for the compound glutathione, the precursors being selected from the group consisting of N-acetyl cysteine, glycine, L-glutamine, L-taurine, L-methionine, S-adenosyl methionine, α-lipoic acid, L-α oxothiazolidine-4-carboxylate, L-γ-glutamyl-L-cysteinylglycyl ethyl ester, butylated hydroxyanisole, butylated-hydroxytoluene, γ-glutamyl cysteine, cysteinyiglycine and acetyl-carnitine to faciliate intracellular processing of cobalamin.
- The medical composition according to this aspect of the present invention preferably comprises Vitamin B12, or a derivative thereof, and N-acetyl cysteine or α-lipoic acid.
- The medical composition is particularly suitable for facilitating processing of cobalamin in neuronal tissues and vascular endothelium that are vulnerable to the effects of oxidative stress.
- It is to be appreciated that a combined treatment of a thiolatocobalamin, glutathione, a glutathione precursor and/or cobalamin may also be administered to the individual.
- Additionally, the medical composition may be co-administered with additional compounds to assist in their therapeutic action against neuropsychiatric and/or vascular disease. For example, the composition may be co-administered with other factors involved in the metabolism of homocysteine, such as folate and/or vitamin B6. The compositions may also be co-administered with any methyl-donor, such as, but not limited to, folic acid, methyl-folate, S-adenosylmethionine, betaine, choline and carnitine.
- Any appropriate mode of administration may be used, such as (but not limited to) oral, sublingual, intravenous and parenteral administration.
- For a better understanding of the present invention and to show more clearly how it may be carried into effect reference will now be made to the following Examples in which Example 1 investigates the relationship between homocysteine, haematolocal indices and dementia duration in patients with clinically diagnosed Alzheimers Disease (AD), Example 2 investigates the effects of the co-administration of a glutathione precursor (N-acetyl cysteine or α-lipoic acid) and hydroxocobalamin (a derivative of Vitamin B12) to patients with a functional Vitamin B12 deficiency and suffering from a neuropsychiatric abnormality, and Example 3 provides evidence for a functional Vitamin B12 deficiency in patients with DSM-IV criteria for primary degenerative dementia of Alzheimer type and investigates its relationship with cognitive score, and with reference to the accompanying drawings, in which:
-
FIG. 1 illustrates the primary activation cycle of the ethionine synthase reaction; -
FIG. 2 illustrates the re-activation of cob(II)-alamin by methionine synthase reductase; -
FIG. 3 illustrates the transulfuration pathway wherein homocysteine is metabolized to glutathione (GSH); -
FIG. 4 illustrates the effect of oxidative stress on homocysteine flux and its implication for neuronal and vascular endothelial cobalamin metabolism; and -
FIG. 5 is a scatter diagram showing the relationship between ADAS-Cog score and plasma glutathione in patients with DSM-TV criteria for primary degeneration dementia of Alzheimer type (filled circles) and controls (open circles). - The present invention relates to the recognition of the implication of hyperhomocysteinemia in a pathogenic mechanism common to the development of AD, vascular disease and aging. In particular, it has been found that this mechanism relates to the influence of ambient redox status on key enzymes of homocysteine metabolism. An inevitable implication of this mechanism is aberrant intraneuronal and intra-endothelial processing of cobalamins by the β-ligand transferase and cobalamin reductase enzymes. Pharmaceutical preparations of cobalamin in current use, such as hydroxocobalamin (CAS: 13422-51-0), cyanocobalamin (“Vitamin B12” CAS: 68-19-9), methylcobalamin (CAS: 13422-55-4) and adenosyl cobalamin (“Coenzyme B12” CAS: 13870-904) cannot be utilised by neurones or vascular endothelium due to their lack of a crucial Co—S bond resulting in this particular metabolic block. However, the adminstration of glutathionylcobalamin, or any related cobalamins of the generic form Coα-[α-(5,6-Dimethylbenzimidazolyl)]-Coβ-ligandyl)cobamide, in which the upper β-axial ligand group is co-ordinated to the cobamide by a sulphur-cobalt bond (i.e. thiolatocobalamins) can overcome this redox-related metabolic block. The presence of a cobalt-sulphur bond in the upper ligand of the cobalamin molecule is an essential prerequisite for intracellular processing of cobalamins. Neurones and vascular endothelium are unable to generate this bond under conditions of oxidative stress. Accordingly, the method and compositions provided by the present invention ensure the presence of a cobalt-sulphur bond in neuronal or vascular endothelium cobalamin, either directly by administering a thiolatocobalamin or indirectly by co-administering currently available forms of Vitamin. B12 together with the sulphur-containing molecule glutathione or one of its precursors, such as N-acetyl cysteine (NAC) or α-lipoic acid.
- In order to be able to determine the effects of high levels of homocysteine in the body and to understand the effects of oxidative stress on homocysteine levels and cobalamin metabolism, it is important to understand the roles of these substances in the body. Homocysteine is a key junction metabolite in methionine metabolism. Homocysteine may be methylated by means of the enzyme methionine synthase (MS) or transsulfurated by the enzyme cystathionine β-synthase (CBS) leading to cystathionine. The latter is subsequently converted to cysteine, a precursor of reduced glutathione (GSH).
- Studies with purified mammalian MS and CBS have revealed that these junction enzymes are sensitive to oxidation, suggesting that the redox regulation of these pathways may be physiologically significant (10). Approximately one half of the intracellular GSH pool in human liver cells is derived from homocysteine via the transsulfuration pathway. The redox sensitivity of these pathways can be rationalized as an autocorrective response resulting in increased GSH synthesis in cells challenged by oxidative stress. The transsulfuration pathway is therefore important for the maintenance of the intracellular GSH pool, and the regulation of this pathway is altered under conditions of oxidative stress.
- There is already considerable evidence implicating oxidative stress in AD (11). The brain is especially vulnerable to oxidative stress for several reasons. It has high concentrations of catalytic iron and a relatively low level of antioxidant enzymes compared to other tissues. It is rich in membrane lipids and polyunsaturated fatty acids amenable to peroxidation and has high energy demands met almost exclusively by oxidative phosphorylation. Oxidative damage, although a common finding in the aging brain, is more severe in patients with AD.
- Furthermore, oxidative stress has recently been associated with cognitive decline even in healthy elderly. A study of 1166 high cognitive functioning subjects aged 60 to 70 demonstrated that increased oxidative stress, or antioxidant deficiency, are risk factors for cognitive decline with increasing age (12).
- There are three ways in which oxidative stress can compromise cobalamin (Vitamin B12) metabolism in dementia or vascular disease. Firstly, in the normal methylation cycle (as illustrated in
FIG. 1 of the accompanying drawings) the thiolate of homocysteine reacts with the methyl (CH3) group of MS-bound methylcobalamin to produce methionine and four-coordinate cob(I)alamin. Histidine (His759 from MS) forms the lower axial cobalt ligand, replacing dimethylbenzimidazole (DMB) that is now in a hydrophobic methionine synthase pocket (*=electron). Cob(I)alamin, a highly reactive cobalamin species, then reacts with an activated form of methylTHF to generate free THF and regenerate methylcobalamin. - Methylcobalamin cycles, via a protonation and deprotonation, between enzyme bound Cob(M)alamin and free Cob(I)alamin states, as illustrated in
FIG. 1 . S-adenosylmethionine (SAM) and an electron source (*) regenerate the active form of MS when cob(I)alamin is abnormally oxidised to cob(II)alamin (seeFIG. 2 ). In the other human cobalamin dependent enzyme system involving methymalonyl-CoA mutase (MCM), the upper axial carbon-cobalt bond splits heterolytically rather than homolytically and the cobalt atom remains in the relatively inert cobapalamin form. Oxidative stress impairs MS function whilst relatively sparing mutase activity. Hence, a consequence of oxidative stress is to increase homocysteine levels. Oxidative damage is also associated with the formation of cobalamin analogues which have been demonstrated in vivo (13) and, more recently, have been observed in AD (14). - Secondly, oxidative stress can increase homocysteine flux via the transsulfuration pathway as a consequence of its stimulation of cystathionine β-synthase (CBS) activity (see
FIG. 3 ). The redox sensitivity of CBS probably represents an autocorrective response resulting in increased intracellular levels of glutathione (GSH) in cells challenged by oxidative stress (10). However, the absence of cystathionase, and hence low glutathione, in neurones makes these cells particularly prone to such challenges (FIG. 4,a) as does the low activity of CBS in vascular endothelial cells (FIG. 4,b). - Thirdly, oxidative stress has a further serious implication for cobalamin metabolism within neurones and vascular endothelial cells. The key enzymes involved in the processing of various forms of cobalamin following their delivery to the cell by transcobalamin (TC) have been delineated (15), see.
FIG. 4 . Different β-ligand forms of cobalamin bound to TC are internalised and converted to methyl- and adenosyl-forms. Methylcobalamin is formed in the reaction catalysed by methionine synthase as an intermediate of the methyl transfer reaction provided that cobalamin is made available in an appropriate redox form (cob(I)alamin or cob(II)alamin). - Glutathionylcobalamin (GS-Cbl), a naturally occurring intracellular form of cobalamin, is a proximal precursor in the biosynthesis of cobalamin enzymes (15). β-ligand transferase (beta-LT) is a cytosolic enzyme utilizing FAD, NADPH, and reduced glutathione (GSH). Although this study utilised CN-cobalamin, it is highly probable that CN-Cbl beta-ligand transferase catalyses a general beta-ligand elimination reaction of newly internalized cobalamins with GS-Cbl being the obligate intracellular intermediate.
- The role of the enzyme cob(III)alamin reductase (CR) has also been studied (15). This utilises aq-Cbl, GS-Cbl and HSO3-Cbl as substrates, but preferentially the latter two. Little or no reductase activity was observed with Me-Cbl, Ado-Cbl or CN-Cbl as substrates. The product of this reaction, cob(II)alamin, becomes bound to cytosolic MS (or, alternatively, is further reduced to cob(I)alamin in mitochondria, followed by conversion to adenosylcobalamin, a co-factor for methylmalonylCoA mutase), see
FIG. 4 . - Hence, intracellular processing of cobalamin requires reduced glutathione (GSH) for the formation of the obligate intracellular intermediate form of cobalamin (GS-Cbl) which possesses an essential cobalt-sulphur bond. GSH is a ubiquitous tripeptide consisting of glycine, cysteine and glutamate. It participates in many vital cellular functions, including the synthesis of proteins, enzyme activity, metabolism, and protection against oxidative stress. Neuronal and vascular endothelial GSH synthesis depends on the presence of its precursors. Glutamate and glycine are synthesised via several metabolic pathways, and therefore their influence on GSH synthesis is limited. However, neuronal and endothelial GSH levels are strongly affected by the supply of cysteine or its oxidised form cystine. Cysteine is rapidly oxidised to cystine, which is extracellularly predominant. Cystine is taken up by glial cells via the cystine/glutamate antiporter and subsequently reduced to cysteine. Neurones are not able to reduce cystine to cysteine nor convert cystathionine to cysteine (see FIG. 4,a) and therefore depend upon glial cysteine to preserve their GSH level. Cysteine has been confirmed as a rate limiting precursor for neuronal GSH synthesis. Consequently, glutathione content of neurones is very low. Similarly, vascular endothelium also lacks the ability to synthesize endogenous cysteine from homocysteine (see FIG. 4,b).
- The absence of an increase in production of reduced glutathione by means of the transsulfuration pathway in neurones and vascular endothelium under conditions of oxidative stress results in reduced glutathione being rapidly depleted in these tissues. Since this is an essential precursor of the obligate intracellular cobalamin intermediate glutathionylcobalamin (GS-Cbl), neuronal and vascular endothelial cobalamin metabolism is compromised. Homocysteine levels will therefore increase even further in a harmful “feed forward” cascade. The Inventor has realized that only the presence of a cobalt-sulphur bond in neuronal and endothelial cobalamins will circumvent this block and reduce homocysteine levels in these tissues and that this can be achieved by either the direct administration of a thiolatocobalamin, such as synthetic glutathionyl cobalamin (Method of manufacture described in, for example, GB 945772) or indirectly by the co-administration of Vitamin B12 and glutathione, or one of the precursors such as, for example, N-acetyl cysteine (CAS: 616-91-1), glycine (CAS: 56-40-6), L-glutamine (CAS: 56-85-9), L-taurine (CAS: 107-35-7), L-methionine (CAS: 63-68-3), α-lipoic acid (CAS: 62-46-4), cysteinylglycine (CAS:19246-18-5) and S-adenosyl methionine (CAS: 29908-03-0).
- The relationship between homocysteine, haematological indices, and dementia duration in patients with clinically diagnosed AD was investigated. It was hypothesized that if metabolic evidence of vitamin B12 deficiency arose by “classical” B12 malabsorption then increasing duration of dementia should be associated with the development of haematological abnormalities.
- Patients were recruited from the Wrexham Maelor Psychogeriatric Assessment Service with features compatible with DSM-IV criteria for primary degenerative dementia of Alzheimer-type. Controls were healthy cognitively intact age and sex matched elderly volunteers from a group General Practice in a comparable semi-rural area of predominantly lower socio-economic class. Patients or controls receiving vitamin B12 or folate supplements, or taking medication known to influence homocysteine were excluded.
- Cognitive scores (Mini Metal State Examination (MMSE) and the cognitive component of the Alzheimer Disease Assessment Scale (ADAS-Cog)) were recorded for cases and controls (16, 17).
- Body mass index (BMI) was determined from height and weight measured at assessment. Duration of dementia in months was determined from records wherever possible, or alternatively from next of kin or carers.
- Non-fasting blood samples were taken for full blood count, red cell folate (RCF), creatinine, B12, folate, and homocysteine assays. Separation and freezing were performed within one hour of venepuncture.
- An automated cell counter was used to measure haemoglobin (Hb) concentration, and MCV (Coulter Gen-S, Beckman Coulter, High Wycombe, Bucks, UK). The red cell distribution width (RDW) was mathematically derived from the frequency over red cell volume histogram on the same instrument. A broad curve, resulting from cells with wide range of cell volume, will yield a raised RDW, An automated biochemistry analyser was used to analyse creatinine (Synchron LX-20 analyser, Beckman Coulter, High Wycombe, Bucks, UK) and an automated chemiluminescence analyser was used to measure folate, vitamin B12 and RCF (ACS:180 SE, Bayer plc, Newbury, Berks UK) using the manufacturers' recommended protocols. Homocysteine was assayed with an automated HPLC system (DS30 Hey Analyser, Drew Scientific Group plc, Barrow in Furness, Cumbria, UK). All forms of homocysteine were assayed including protein bound, non-protein bound, free forms both oxidized (dimer and mixed disulphides) and reduced. Values presented therefore always refer to “total” plasma levels.
- Comparisons between groups were performed using the Mann-Whitney U test. (Statistics for Windows v5.5, StatSoft, Inc., Tulsa, Okla.). Median values are presented with interquartile ranges. A generalized linear model, using a linear link function, was used to assess relationships between variables. Regression parameters are presented with their 95% confidence intervals.
- Forty-four patients and fifty-five control subjects were recruited to the study. There were no significant differences between the two groups regarding age, sex, BMI, and creatinine. Patients scored significantly worse on scores of cognitive function (p<0.0001), see Table 1 below.
-
TABLE 1 Creat- ADAS- Age Sex BMI inine MMSE Cog Controls 79 22 M 24.1 84 28 9 (n = 55) (72-86) 33 F (22.1-28.4) (72-102) (27-29) (7-12) Patients 79 14 M 24.5 85 17 32 (n = 44) (75-84) 30 F (21.8-27.6) (72-115) (13-21) (24-40) - There were no significant differences for Hb, WBC, platelets, MCV, RDW, B12, or RCF between groups. Patients had significantly higher serum homocysteine (p=0.0008) and lower serum folate (p=0.02) than controls, see Table 2 below.
-
TABLE 2 Controls Patients Hb (g/dl) 13.4 (12.5-14.4) 12.8 (12-14.0) WBC (×109/l) 6.9 (6.1-8.0) 6.9 (6.0-8.2) Platelets (×109/l) 219 (184-277) 219 (181-271) MCV (fl) 90.6 (87.8-94.0) 90.0 (87.7-93.5) RDW 13.4 (12.9-14.0) 13.6 (12.9-14.4) B12 (ng/l) 324 (291-445) 328 (268-421) Folate (μg/l) 11.1 (8.2-14.5) 9.1 (6.4-11.7) RCF (μg/l) 332 (272-429) 282 (243-399) Homocysteine (μmol/l) 9.8 (8.5-12.5) 12.2 (9.4-15.7) - A generalized linear model was used to determine the relationship between haematological variables and disease duration in the patient group. Gender was included as an additional variable.
- Increasing duration of dementia was associated with a slight decline in haemoglobin (Hb=13.67−0.023 (−0.003 to −0.04)×duration+0.20 (−0.2 to 0.61)×gender; p=0.02), and platelet count (Platelets=246.6−0.96 (−1.79 to −0.13)×duration−5.3 (−22.2 to 11.7)×gender; p=0.03).
- There was no relationship between disease duration and WBC, MCV, or RDW, Homocysteine, but not B vitamins, declined with increasing dementia duration (Homocysteine=16.4−0.085 (−0.17 to −0.002)×duration+1.95 (0.25 to 3.65)×gender; p=0.048).
- This study confirms earlier observations of increased plasma homocysteine and reduced serum folate levels in patients with clinically diagnosed AD (3;4). Haemoglobin and platelet counts fell only slightly with increasing dementia duration, and there were no other changes in haematological indices; macrocytosis and RDW in particular were not related to disease duration, and no patients were anaemic.
- AD patients therefore exhibit a “functional” B12/folate deficiency, but in the absence of “classical” haematological indicators. Low serum folate, but normal red cell folate, in AD suggests that these patients are in negative folate balance, i.e. more folate has been catabolized than absorbed.
- Lindenbaum et al. (7) suggested that neuropsychiatric features of B vitamin deficiency precede haematological changes. However, the current data clearly shows that this is not the case in patients with AD. It demonstrates that the association between B vitamin deficiency and AD is due to an entirely different pathogenic mechanism from that associated with classical malnutrition or malabsorption-related syndromes and their related haematological sequelae. A “functional” cerebral B12/folate deficiency exists in AD with relative sparing of haematopoietic tissue.
- It is submitted that the effects of AD-related cerebral oxidative stress on vitamin B12 metabolism account for this “functional” deficiency. Oxidative stress augments the oxidation of an intermediate form of vitamin B12 generated in the methionine synthase reaction, thereby impairing the metabolism of homocysteine. Furthermore, oxidative stress compromises the intraneuronal reduction of vitamin B12 to its metabolically active state. Since this stress is confined to brain tissue, haematopoietic methionine synthase activity is relatively unaffected, thus explaining the absence of anaemia and macrocytosis in these patients.
- The present data also shows that the relationship between AD and folate status reflects excess folate catabolism. Methionine synthase inactivation results in folate being trapped in the methyltetrahydrofolate form. It is unavailable for polyglutamation, a necessary prerequisite for cellular retention, and is released from cells. It is subsequently excreted in the urine, eventually resulting in folate depletion. Haematopoietic tissue is spared in this process, explaining the normal red cell folate values and absent anaemia.
- Vitamin B12 (cyanocobalamin), adenosylcobalamin and methylcobalamin have a cobalt-carbon bond at the β-axial position and hydroxocobalamin has a cobalt-oxygen bond. Hence, these commonly used pharmaceutical derivatives cannot be used by neuronal tissues under conditions of oxidative stress due to reduced supplies of intracellular glutathione necessary to convert these cobalt bonds to cobalt-sulphur bonds and hence, to a metabolically active form. Glutathionylcobalamin, or related thiolatocobalamins, in which the upper β-axial ligand of the cobalamin molecule already possess a sulphur-cobalt bond, can overcome this redox-related metabolic block and thereby reduce the symptoms of oxidative stress on neuronal tissues. The co-administration of Vitamin B12 with glutathione, or a precursor thereof, can also overcome this metabolic block by providing the requisite cobalt-sulphur bond. The provision of a cobalt-sulphur bond at the upper β-axial ligand should be of particular utility in the treatment and/or prevention of neuropsychiatric and/or vascular disorders associated with metabolic or other evidence of B12 deficiency, especially those in which the classical haematological sips of anaemia and macrocytosis are absent or non-significant, as demonstrated by the Example given above. Anaemia is absent in such situations due to the bone-marrow being able to metabolize homocysteine and thus, unlike neuronal tissues, has sufficient levels of glutathione to protect against oxidative stress and generate the cobalt-sulphur bond of the obligate intracellular cobalamin intermediate, glutathionylcobalamin.
- The effect of generating a cobalt-sulphur bond by the co-administration of hydroxocobalamin and a glutathione precursor (N-acetyl cysteine or α-lipoic acid) on the symptoms of seven patients suffering from neuropsychiatric abnormalities was investigated.
- Patient 1:
- In 1994, a 78 year old woman visited her General Practitioner (GP) with a several month history of tiredness, lethargy, shakiness, a disturbed sleep pattern, depression and malaise. A Physician had assessed her in 1991 with regard to her malaise when she also complained of feeling miserable, tearful and breathless, with the occasional sensation of a lump in her throat. However, no significant features were found on clinical examination and it was felt that her conditions were anxiety-related. The patient's biochemical and haematological investigations were entirely normal and the patient was discharged. Vitamin B12 and folate levels were-not measured at that time.
- On examination in 1994, there were still no obvious clinical abnormalities, other than slight angular cheilosis. In view of the persistence of her symptoms over the years, further routine blood investigations were carried out. She was not anaemic (Hb 11.9) and had no macrocytosis (MCV 90.0) but she was found to have a profoundly low level of serum Vitamin B12 (11 ng/l) (laboratory range>190 ng/l). This was checked a month later and still found to be very low at only 29 ng/l. Her serum and red cell folate levels were normal (12 μg/l and 299 μg/l respectively). Further investigations were arranged and the patient was found to have gastric parietal cell antibodies but no intrinsic factor antibodies. Her Schilling test was entirely normal. Monthly injections of hydroxocobalamin were commenced and the patient felt much better. She also found that when she occasionally missed her injections her sore mouth returned. She remained mildly anxious but her neuropsychiatric symptoms were initially much improved.
- However, the patient slowly developed memory impairment commencing from around 1998 and her tearfulness recurred. Her memory impairment was characterised by short-term memory problems with a very gradual deterioration. There were no significant behavioural problems but the patient did have difficulty with remembering names and putting names to faces.
- On mental examination in March 2000 the patient was pleasant, co-operative, chatty and cheerful. There were no signs of psychomotor agitation or retardation and there were no functional psychotic features. She was not unduly tearful or pessimistic and her talk was rational in form and content. However, there were clear deficits with regard to cognitive function. Although orientated to time, she had demonstrable short-term memory deficits. On the Mini-Mental State Examination (MMSE) she scored 21/30 (16) and it was felt that she had an early dementing illness, perhaps with associated depressive features. She was commenced on antidepressant medication and offered social support.
- Although the depressive features slowly resolved over a six month treatment with antidepressants, her cognitive decline continued inexorably. Throughout this time she continued to have regular monthly injections of hydroxocobalamin. One year later, her cognitive skills had declined further. At this time (February 2001) she scored 18/30 on MMSE and had an ADAS-Cog score of 28/70 (17). In view of the persistence of her neuropsychiatric abnormality despite regular hydroxocobalamin, N-acetyl cysteine (600 mg) daily was added to her medication, with informed consent, with the aim of ensuring the presence of a cobalt-sulphur bond in neuronal cobalamin and thereby improve neuronal cobalamin metabolism.
- At repeat assessment two weeks later, her husband reported some noticeable improvement in her memory. She was able to remember names and faces that she would otherwise have struggled to recall. She generally felt quite well in herself. Repeat cognitive assessment showed an improvement in her MMSE score to 21/30 and an improvement of eight points on the ADAS-Cog score to 20/70. A seven-point change in the ADAS-Cog score is regarded as clinically significant (18). The main areas of improvement were in scores of orientation, registration, copying skills, word-recall, naming and commands These significant improvements remained at the patient's four-week assessment when the patient gained an additional point on the ADAS-Cog score and demonstrated a dramatic improvement in constructional praxis.
- Thus, this study demonstrates that the co-administration of Vitamin B12 with compounds that ensure the presence of a cobalt-sulphur bond in neuronal cobalamin (i.e. N-acetyl cysteine) can assist in alleviating the symptoms associated with oxidative stress, such as cognitive decline.
- Patient 2:
- In 1995 a 70 year old lady presented to her GP with a 1 year history of short term memory loss. She had no significant past medical history. At her initial assessment her cognitive deficits were relatively mild; she scored 27/30 on mini-mental state examination. Nevertheless, she was seen by a psychogeriatrician who felt that, at this time, her cognitive deficits did not warrant a diagnosis of dementia However, over the following 18 months her memory problems worsened. At a repeat assessment she scored 26/30 on mental state examination, and it was felt that she was probably suffering from “age-associated memory impairment.”
- Her cognitive function was formally reviewed again 18 months later. Her husband reported that her memory seemed to have deteriorated further, she asked inappropriate questions at times. Her general ability to perform activities of daily living had declined. Her mini-mental state score had declined to 22/30, and it was concluded that she continued to suffer from a slow, age-related cognitive decline. She was commenced on a trial of an acetylcholinesterase inhibitor, but unfortunately had to discontinue this due to troublesome side effects, and there appeared to be no obvious benefit in the first few weeks of treatment anyway.
- In 1999 a further formal cognitive assessment was undertaken, and she scored 22/30.on MMSE and 19/70 on an ADAS-Cog assessment. Her most marked areas of deficit were once again related to her short term memory. She had been commenced on folic acid supplements some months previously, but this had resulted in no significant change in her symptoms. She was now found to have a borderline low serum vitamin B12 (195 ng/l) and a low plasma glutathione (2.1 pmol/l). She was therefore commenced on monthly injections of hydroxocobalamin. Her husband felt that this resulted in no significant change in her condition. A further 6 months later, her cognitive function remained generally unchanged; she scored 21/30 on MMSE. In view of her low glutathione, oral N-acetylcysteine (600 mg) was added to her treatment regime. One month later, her husband reported that she had seemed much more lively in herself, happier, and chattier. Indeed, for the first time in many months her practice nurse noted that she could hold a sensible conversation with her, and that there was a marked improvement in her general behaviour. At formal cognitive assessment her MMSE score had improved dramatically to 25/30—the most striking difference being due to her regaining the ability to remember three objects after several minutes.
- This lady suffered from age-associated memory impairment, rather than a dementing illness. Although there was some minor improvement in her symptoms with monthly intramuscular injections of hydroxocobalamin, the addition of oral N-acetylcysteine resulted in a marked improvement in her cognitive scores, particularly with regard to her short-term memory. This example demonstrates the effectiveness of ensuring a cobalt-sulphur bond not only in patients with Alzheimer Disease, but also in cognitive deficits associated with aging in general.
- Patient 3:
- In 1994 a 77 year old lady presented to her GP with a several month history of increasing confusion and memory loss. An aunt had suffered from early-onset Alzheimer's Disease. On examination she was disorientated to time, but not place or person. She had a demonstrable impairment of her short term memory. Routine investigations revealed that she was B12 deficient (172 ng/l (lab reference range >190 ng/l)), but had normal values of serum folate (10.1 μg/l) and RCF (321 μg/l). In particular, she had no evidence of a macrocytic anaemia (Hb 13.4, MCV 89.2).
- She was commenced on monthly injections of hydroxocobalamin (1000 mcg/ml). However, her mental condition continued to deteriorate over the ensuing 2 years, and she began to complain of fatigue and general debilitation. She later developed visual hallucinations, and persecutory ideas secondary to the hallucinations. Cognitive testing at this time (1996) showed that she was poorly orientated in time, although she knew her address, and had a normal working memory. Her anterograde memory was very poor, although her retrograde memory for personal detail was good. Her use of language was generally good, but she had some naming difficulty for low frequency words and her repetition was poor. Her writing was also affected. She showed signs of parietal lobe dysfunction in the form of constructional dyspraxia. Her frontal lobe function was generally good. It was felt that she had a dementing illness of probable Alzheimer-type. She was admitted to a nursing home, but her general condition continued to deteriorate. At a further cognitive review in 1997 she scored only 13/30 on MMSE.
- She was commenced on an acetylcholinesterase inhibitor, and her family felt there was some slight improvement in her condition. At repeat assessment she scored 15/30 on MMSE; she remained disorientated in time, but there was no nominal dysphasia and her attention and concentration were reasonable. The drug treatment, together with regular hydroxocobalamin, was therefore continued.
- Her physical as well as mental condition continued to deteriorate however, and she developed dysphagia and weight loss in 1998. At: this time she scored only 3/10 on an abbreviated mental test. She was admitted to hospital and found to have a grade III oesophagitis. She was treated with a proton-pump inhibitor, and her symptoms of dyspliagia slowly resolved.
- Nevertheless her general physical and mental condition continued to deteriorate. In June 2001 oral N-acetyl cysteine 600 mg daily was added to her treatment, although she was at this time suffering from a severe degree of dementia. However, her family and the nursing staff noticed and commented upon a significant improvement in her condition in response to this treatment. She became generally more alert and brighter than usual, and seemed to recognise her close family; a formal cognitive assessment was not performed in view of the severity alter dementia and associated physical condition. Her general physical condition deteriorated and she died from a bronchopneumonia several weeks later.
- This lady had a dementing illness of probable Alzheimer-type and co-existing vitamin B12 deficiency. However it is unlikely that the deficiency was due to malnutrition (she was folate replete) or malabsorption (there was no evidence of a macrocytic anaemia or haematological involvement). It is probable that she had a “functional” vitamin B12 deficiency as a consequence of cerebral oxidative stress related to her Alzheimer Disease. An attempt to correct this deficiency with hydroxocobalamin did not prevent her cognitive decline. However, even in the terminal stages of her illness, with its associated physical deterioration, her mental condition improved when N-acetylcysteine was co-administered with hydroxocobalamin to provide a cobalt sulphur bond in the upper axial ligand of neuronal cobalamin.
- Patient 4:
- In 1994 a 65 year-old male presented to his GP with a three-year history of gradual memory impairment. His wife reported that he would often forget to close doors or would forget to secure his car. There was no history of wandering, or of any features suggestive of a depressive illness. His appetite had been fine, and there was no history of weight loss. He had recently started to have difficulty with washing and dressing himself He had no significant past medical history, and there was no family history of psychiatric illness or dementia.
- Physical examination was unremarkable, and there were no neurological deficits. On mental state examination he was orientated to place and person but not time. He had difficulty copying figures and had a moderate to severe degree of impairment of both recent and remote memory. He lacked insight into his memory loss and denied having any particular worries or problems. He scored 17/30 on Mini-Mental State Examination, and had a CAMDEX score of 54.
- Routine blood investigations including full blood count, urea and electrolytes, glucose, liver and thyroid function tests were all within normal limits. His serum vitamin B12 and folate levels were also within normal limits at 274 ng/l and 3.9 (ig/l respectively (normal ranges>190 ng/l and >2.2 u.g/l). His red cell folate was also normal at 396 μg/l (normal range>170 μg/l). However, he was found to have a significantly elevated fasting serum homocysteine of 23.7 μmol/l (normal range<13.0 μmol/l). A CT brain scan revealed moderate cerebral atrophy with no other abnormality.
- He was reviewed by several psychogeriatricians, and he was diagnosed as having a probable Alzheimer-type dementia. In view of the abnormal homocysteine result he was commenced on monthly injections of hydroxocobalamin (1,000 mg/ml) as well as folic acid supplementation (5 mg daily). However, his cognitive function continued to slowly deteriorate. By 1997 his wife was finding it increasingly difficult to care for him at home. At this time it was felt that he was not a candidate for an acetylcholinesterase inhibitor because of the severity of his dementia. He was admitted to a specialist nursing home for full time care. Throughout this time he continued with his monthly B12 injections and oral folate supplements.
- A formal re-assessment of his cognitive function was performed in 1999. At this time he scored only 5/30 on Mini-Mental State Examination and 70 on an ADAS-Cog assessment, confirming a severe degree of dementia. His serum homocysteine level was now well within normal limits at 5.7 μmol/l, but he was found to have a low plasma level of glutathione at 2.5 μmol/l (normal range 3-5 μmol/l). N-acetylcysteine 600 mg daily was therefore added to his B-vitamin supplementation as an oral glutathione precursor. Although there was no improvement in his cognitive score, he became significantly less agitated, generally more compliant with his nursing care, and his carers noted that his word finding abilities were much improved. In general his behaviour was considerably improved. His wife was particularly impressed by the addition of N-acetylcysteine to his medication; he had even tried to communicate with her for the first time in many years. She was also struck by the fact that he now once again seemed to recognise her when she visited. His clinical improvement was maintained one year later, after his treatment had been changed from N-acetylcysteine to α-
lipoic acid 50 mg twice daily as an alternative glutathione precursor. - This patient has probable Alzheimer-type dementia with a co-existing functional vitamin B12 deficiency revealed by markedly elevated levels of serum homocysteine. Although treatment with monthly hydroxocobalamin injections and oral folate supplements corrected the levels of serum homocysteine, this did not result in a halting of the dementia process. However, at a late stage of his illness he was found to have low plasma levels of glutathione. Since this is a necessary precursor for the intracellular processing of vitamin B12 an attempt was made to increase his glutathione levels by the co-administration of N-acetylcysteine. This resulted in a marked improvement in his general well-being and behavioural symptoms and this clinical improvement continued with the change to an alternative gluthathione precursor, α-lipoic acid. This demonstrates that, even in the advanced stages of a denaenting illness, ensuring the provision of a cobalt-sulphur bond in the upper axial ligand of vitamin B12 results in clinical improvement.
- Patient 5:
- A 46-year-old nurse was referred to a specialist Chronic Fatigue Clinic with a history of profound fatigue over many years. She described this as an “incredible-fatigue” commencing in her youth.
- As part of her investigations, lumbar puncture was performed on two occasions; in April and in September of 1994. Her CSF-homocysteine level was raised on both occasions; 0.42 and 1.00 μmol/L, respectively (ref.<0.25). Serum homocysteine was normal at 13.2 μmol/L, as was serum MMA at 0.10 μmol/L (ref<0.37). Vitamin B12 levels in CSF were relatively low at 8.8 (normal values 10-15 pmol/L).
- In May 1994 she was commenced on treatment with subcutaneous injections of vitamin B12 in the form of methylcobalamin (Methycobal® 0.5 mg/ml) twice weekly. She experienced a clear improvement after only her third injection. She described this as if “ . . . my head had been enclosed within a bag, and I was now released.” Moreover, a sensation of anaesthesia in the right parts oilier jaw and tongue disappeared. After 4 months she reported that her concentration and memory had improved, as had her functions at work, and her sense of general well-being. Gradually her speech improved and she became more fluent and less erroneous (which others had called attention to).
- Her vitamin B12 injections were withdrawn in September 1994. Two weeks later she was very sensitive to light and sounds, had concentration difficulties and could not complete reading any articles in the daily newspaper. She developed a tingling feeling in her lips, tongue and pharynx, “ . . . as when an anaesthesia is fading away”. In October of 1994 she was tested by a neuropsychologist (STROOP test) and performed significantly worse than during her treatment period.
- She was recommenced on B12 injections, and once again felt well until January 1995 when she started clearing another tooth from amalgam. At this time she experienced “a paralysing fatigue” and a recurrence of her sensation of facial anaesthesia. Although this slowly recovered she still required her vitamin B12 injections very frequently (three times weekly). She was genotyped at this time for the thermolabile variant of the methylene tetrahydrofolate reductase gene (MTHFR) and was found to be normal (homozygous for 677 C).
- She continued to improve slowly over the next few years. By December 1998 although she felt better, she still required sleep of more than 10 hours per night to feel well. In addition to her job, she was also now more actively engaged in the care of her home and two children. She continued to attend the Chronic Fatigue clinic. In April 2001 oral N-Acetylcysteine 400 mg daily was added to her vitamin B12 regime. After only a month she felt “more lively and with less headaches.” She felt very positive about this addition to her treatment and was adamant that she continue it, in spite of some gastroenteric side effects. She continued to improve, and alter three months did not require as much sleep as previously. Most significantly she was now able to reduce the frequency of her vitamin B12 injections to once weekly. Also, she now reported that her headaches had almost completely disappeared.
- This patient had clinical features of a Chronic Fatigue Syndrome, and also displayed an error of vitamin B12 metabolism in the central nervous system. This was revealed by increased levels of homocysteine in her cerebrospinal fluid suggesting a functional vitamin B12 deficiency. Her clinical condition stabilised very slowly but dramatically over the years. She is probably hypersensitive to metals, including nickel, and clearance of the tooth amalgam might have contributed to the improvement. However, she clearly improved in relation to the commencement of her methylcobalamin injections; its effects were confirmed by the marked deterioration in relation to the withdrawal of these injections in 1994. The addition of the glutathione precursor N-acetylcysteine to her vitamin B12 therapy resulted in a marked further improvement in her clinical condition, and she was also able to significantly reduce the frequency of these injections.
- Patient 6:
- A 54-year-old female physician had first become acutely ill when she was 39. The symptoms and signs suggested a brain stem affectation, and she was diagnosed as suffering from multiple sclerosis. She exhibited “slow cerebration” and felt fatigued and hypersomnic. Although she improved slowly over the next 3-4 years, she also developed some new symptoms including a feeling of ‘heaviness’ in her legs, a slightly impaired gait, difficulty in raising herself from a sitting to a standing position, blurred vision in one eye, proprioceptive difficulties, and impaired orientation in time and space.
- At the age of 44 her-urinary homocysteine was assayed. This was elevated and she was therefore commenced on regular injections of vitamin B12. She soon noticed a very apparent improvement in her symptoms; all her visual and proprioceptive complaints improved, as did her orientation.
- However, she still retained some signs of a ‘brain lesion syndrome’; one neurologist best described this as an astheno-emotional syndrome, including discrete signs of right-sided facial paralysis, dysarthria and an auditive aphasia. The auditive aphasia was compensated for by head-phones and an electronic apparatus which synchronizes sound better. Although slowly improving, her persistent chronic fatigue and stress intolerance have made it impossible for her to return to work as a physician.
- At the age of 54, her medication comprised 1 mg of oral cobalamin and 5 mg of folic acid daily. NAC was then added to this regime. After 4 months she reported that she had only been able to take 100 mg daily because of gastro intestinal side effects. Nevertheless, she felt ‘definitely improved’. She found that she had fewer headaches. Her concentration had improved which now enabled her to read and understand even complex matters. Her fatigue was less severe, and she was able to sleep for longer periods at night.
- This physician had a presumed diagnosis of multiple sclerosis. She was found to have evidence of a functional B12 deficiency, revealed by elevated urinary homocysteine levels. Although her symptoms improved with vitamin B12 supplementation, the co-administration of N-acetylcysteine, to provide a cobalt-suphur bond in the upper axial ligand of cobalamin, resulted in a further marked improvement in her symptoms.
- Patient 7:
- In 1996 an 81-year old gentleman was brought to the attention of his GP with regard to deterioration in his short-term memory over the previous five years. He had no significant relevant past medical history. There was a family history of Parkinsonism and cerebrovascular accident in two of his siblings.
- On examination, he had a slightly irregular pulse, borderline hypertension (150/90) and was noted to have cold extremities, but no other obvious abnormalities. He was unable to remember three words after a few minutes. Routine investigations revealed no abnormalities; in particular he was not anaemic (Hb 14.7), had a normal MCV, normal levels of total serum B12 (324 ng/l) and folate (13.3 μg/l), and normal thyroid function tests.
- It was felt that he was suffering from a senile dementia. His condition continued to deteriorate gradually, but then became dramatically worse in a matter of a few weeks in 1997. At this time, he had frequent falls, and had become increasingly confused. It was noted that he tended to fall towards the right, and he had right-sided weakness, and an equivocal right plantar reflex. It was felt that he had sustained a probable TIA, and he was admitted to hospital. CT scan showed a lacunar infarct. He also developed a chest infection. This was treated with antibiotics, and his confusion and mobility improved slightly. He was commended on aspirin and discharged home.
- However, he continued to deteriorate over the ensuing months, became verbally aggressive at times, exhibited repetitive speech, and became increasingly agitated. On cognitive assessment in 1998 he was disorientated to year, unable to name the prime minister, or US president, could not recall the examiners name after a few minutes, and had difficulty with visuo-spatial awareness, manifested by the inability to draw numbers correctly on a clock-face, and inability to copy a 3-dimensional cube figure. He had no depressive features, no delusional thought, no communication problems, or sleep disturbance. It was noted that he had an unsteady gait, and was beginning to need assistance with most activities of daily living. However, there was some improvement in his condition over the ensuing few weeks, and he was therefore discharged from the care of the Psychogeriatric assessment services at this time.
- In 1999, he developed a disturbed sleep pattern and increasing cognitive deficits. His agitation worsened, but was controlled with thioridazine. He sustained a further few falls, and required hospital admission for these by the end of the year. Overall, his general condition had worsened and his wife now found it difficult to cope and care for him at home. He now had word finding difficulties and frequently confabulated, had deterioration of his self-care, frequently wandered, was unsteady on his feet, lacked insight, and had developed an irritable, resentful and suspicious mood, very much unlike his pleasant pre-morbid character.
- He was admitted for full-time care, initially in a residential home, but was shortly transferred to a nursing:home, as they were unable to cope with his increasingly demanding behaviour.
- In 2001 he was found to have raised plasma homocysteine level of 19.8 μmol/l (normal level<16 μmol/l), a lower B12 and folate than previously (297 ng/l and 4.7 μg/l respectively), although he still had a normal red cell folate of 204 μg/l, and no evidence of macrocytic anaemia (Hb13.4, MCV 91). He therefore had evidence of a functional vitamin B12 deficiency, and was commenced on weekly hydroxocobalamin injections together with an oral folate supplement. However, there was no significant improvement in his cognitive function. At this time, he scored 68 on an ADAS-Cog assessment demonstrating a significant degree of dementia. 600 mg NAC daily was added to his treatment regime to indirectly provide a cobalt-sulphur bond in the upper axial ligand of cobalamin. After one month's treatment, he had gained 6 points on his ADAS-Cog score. The staff at the home commented that he was less agitated, and more contented. In particular his wife felt that he was a lot better in himself, more settled, and generally more alert.
- The “stepwise” deteriorating course in this gentleman's condition, patchy distribution of deficits, borderline hypertension, cold extremities, family history of cerebrovascular accident, focal neurological signs and symptoms, and sudden deterioration in symptomatology in association with a lacunar infarct on. CT scan, strongly support a diagnosis of vascular dementia in this gentleman. Furthermore, he had biochemical evidence for a functional vitamin B12 deficiency, in the absence of anaemia. This example demonstrates that in patients with vascular dementia, there is a significant clinical improvement with the co-administration of hydroxocobalamin and N-acetylcysteine to indirectly generate a cobalt-sulphur bond in the upper axial ligand of cobalamin.
- Plasma homocysteine levels are elevated in Alzheimer Disease, but little is known regarding the levels of other aminothiols in the disease. Evaluating the levels of these associated metabolites will assist in determining the biochemical locus for the elevated homocysteine. Therefore, total plasma homocysteine, cysteine, glutathione and cysteinylglycine levels were determined in patients and controls and their relationship with cognitive scores was investigated.
- Fifty patients with features compatible with DSM-IV criteria for primary degenerative dementia of Alzheimer-type, and fifty-seven cognitively intact age-sex matched control subjects had their MMSE and ADAS-Cog scores determined. Aminothiols were assayed with the Drew Scientific DS30 Hcy Analyser. Subjects using homocysteine disruptive medication including vitamin B12, folic acid and hormone replacement therapy were excluded from data analysis. MMSE and ADAS-Cog scores were recorded for cases and controls (16, 17). The latter instrument addresses several cognitive domains and is well validated. It is sensitive to cognitive changes over time and so provides a useful baseline for future studies.
- Prior education of the subjects was also determined (“none, primary, intermediate, secondary and further”) since this relates to cognitive decline in normal aging (19). Smoking (“current, ex, and never”) and hypertensive status were also documented, these being associated with modest elevation of homocysteine (20). For the purpose of statistical analysis, prior education and smoking were treated as ordinal variables and hypertensive status as a categorical variable. Height and weight were measured at assessment to calculate body mass index (BMI). Ethical approval was granted, and informed consent obtained.
- Non-fasting blood samples were taken for full blood count, red cell folate (RCF), creatinine, B12, folate, and aminothiol assays. Separation and freezing were performed within one hour of venepuncture until aminothiol analysis (21).
- An automated cell counter was used to measure haemoglobin (Hb) concentration, and mean corpuscular volume (MCV) (Coulter Gen-S, Beckman Coulter, High Wycombe, Bucks; UK). An automated biochemistry analyser was used to analyse creatinine (Synchron LX-20 analyser, Beckman Coulter, High Wycombe, Bucks, UK) and an automated chemiluminescence analyser was used to measure folate, vitamin B12 and RCF (ACS:180 SE, Bayer plc, Newbury, Berks UK) using the manufacturers' recommended protocols. Aminothiols were assayed with an automated HPLC system (DS30 Hcy Analyser, Drew Scientific Group plc, Barrow in Furness, Cumbria, UK) For each aminothiol, all forms including protein bound, non-protein bound, free forms both oxidized (dimer and mixed disulphides) and reduced were measured. Values presented always refer to “total” plasma levels.
- Comparisons between groups (Wilcoxon-Mann-Whitney test), 95% confidence intervals for differences between medians (Hodges-Lehmann estimates) and measures of association (Spearman rank-order correlation coefficient) were performed using exact, non-parametric methods (StatXact 4 for Windows, Cytel Software Corporation, Cambridge, Mass.). Conventional techniques were used for regression analysis and generalised linear modelling (Statistica for Windows v.5.5, StatSoft, Inc., Tulsa, Okla.). Ridge regression, an extension to conventional regression analysis, was used to correct for possible correlations among the independent variables. For the purpose of generalised linear modelling, continuous variables were specified as the dependent variables, a linear link function was used and mixtures of categorical, ordinal and continuous variables specified as the independent variables. The significance of the model parameters were assessed using a χ2 test. Median results are presented with interquartile ranges and simple regression coefficients are presented with their 95% confidence intervals (95% CI).
- Results:
- There were 50 AD patients (17 male and 33 female) and 57 controls (23 male and 34 female). The median age of both groups was 79 years (75-83 for AD and 72-85 for controls). AD patients had a median duration of disease of 24 (13-36) months and a median age of onset of 77 (74-82) years.
- There was no difference in BMI, prior education or smoking status between patients and controls. Patients had lower median systolic blood pressure than controls (patients: 130 (120-140) mmHg, controls: 145 (130-160) mmHg, 95% CI for difference: 0 to 20, p=0.01) and lower median diastolic blood pressure (patients: 80 (70-82) mmHg, controls: 85 (79-95) mmHg, 95% CI for difference: 5 to 10, p=0.0005).
- Plasma samples were stored for a median of 12 months prior to aminothiol assay (range 1 to 23 months). Regression analysis was used to assess the effect of storage time on these assays. Within the aggregated data (patients plus controls), storage time had no effect upon homocysteine or glutathione levels. There was a small decrease in cysteine and cysteinylglycine levels with storage time: cysteine=142.3−2.33×storage time in months (p=0.0002, 95% CI: −3.52 to −1.14), cysteinylglycine=20.9−0.26×storage time in months (p=0.007, 95% CI: −0.43 to −0.09). The addition of diagnosis as an additional categorical independent variable demonstrated no difference in the effect of storage between patients and controls.
- AD patients were found to have significantly decreased folate, and significantly increased plasma homocysteine and cysteine. Hb, platelets, MCV, creatinine, B12, RCF, cysteinylglycine and glutathione did not differ between groups, as shown in Table 3 below.
-
TABLE 3 p-value (95% CI of difference Controls Patients between medians) BMI 24.1 (22.1-28.4) 24.6 (22.5-27.4) MMSE 28 (27-29) 18 (14-21) p < 0.0001 (8-12) ADAS-Cog 9 (7-12) 32 (24-39) p < 0.0001 (19-26) Hb, g/dl 13.4 (12.5-14.4) 12.9 (12.0-14.2) Platelets, ×109/l 218 (184-277) 216 (182-273) MCV, fl 90.4 (87.8-94.0) 90.4 (88.4-93.6) Creatinine, μmol/l 84 (72-102) 87 (72-115) B12, ng/l 324 (276-445) 334 (268-421) Folate, μg/l 10.5 (8.1-14.5) 9.0 (6.3-11.6) p = 0.018 (0.4-3.8) RCF, μg/l 330 (272-425) 282 (243-399) Homocysteine, (μmol/l) 9.6 (8.2-12.5) 12.6 (9.6-15.8) p = 0.0006 (1.2-4.3) Cysteine, (μmol/l) 107.2 (94.7-129.4) 120.1 (102.0-142.4) p = 0.007 (3.6-23.7) Cysteinylglycine, (μmol/l) 17.7 (15.5-20.3) 17.5 (15.4-21.1) Glutathione, (μmol/l) 2.5 (2.2-2.9) 2.7 (2.2-3.3) - Among the patients, a decrease in MMSE score was associated with a decrease in plasma glutathione: MMSE=8.27+3.56×glutathione (p=0.002, 95% CI: 0.29 to 6.82). Similarly, an increase in ADAS-Cog score was associated with a decrease in plasma glutathione: ADAS-Cog=54.9−8.39×glutathione (p=0.002, 95% CI: −13.6 to −3.22), see
FIG. 5 . To protect against the possibility that these relationships were artefacts caused by a correlation between plasma glutathione and homocysteine, itself known to affect cognitive function (1), (3), a ridge regression analysis was performed with plasma bomocysteine, cysteine and cysteinylglycine as additional independent variables. This analysis confirmed that plasma glutathione was the only aminothiol to be an independent statistically significant predictor of MMSE and ADAS-Cog scores. - Among the controls, there was no relationship between MMSE and glutathione, homocysteine, cysteine and cysteinylglycine. There was an increase in ADAS-Cog with decreasing plasma glutathione: ADAS-Cog=29.6−0.61×glutathione (p=0.04, 95% Cl: −1.21 to −0.002), but this relationship was abolished with the addition of homocysteine, cysteine and cysteinylglycine in a ridge regression model.
- Other possible confounding factors that might influence the relationship between plasma glutathione and cognitive score are age, smoking status, presence of hypertension, and years of education. A generalised linear modelling technique was used to assess the effect of these factors plus plasma glutathione on ADAS-Cog and MMSE scores. The results confirmed that glutathione is an independent predictor of cognitive performance in this study, see Table 4 below.
-
TABLE 4 Scoring Independent Log- system variable likelihood χ2 (1 d.f.) p-value ADAS-Cog Age −72.33 0.35 0.55 Education −76.55 8.78 0.003 Smoking −72.42 0.52 0.47 Glutathione −75.15 5.98 0.014 Hypertension −76.83 9.34 0.002 MMSE Age −56.98 0.0001 0.99 Education −58.26 2.56 0.11 Smoking −57.33 0.69 0.40 Glutathione −60.57 7.18 0.007 Hypertension −58.59 3.22 0.07 - Thus, glutathione was found to be a highly significant and independent predictor of cognitive scores in patients (p=0.002); lower plasma levels were associated with more severe cognitive impairment. Plasma homocysteine and cysteine are elevated in Alzheimer Disease implying intact and increased transsulphuration but aberrant re-methylation of homocysteine in patients. These findings reflect the differential effects of oxidative stress on key enzymes of sulphur amino acid metabolism.
- Glutathionylcobalamin and related thiolatocobalamins may also be used to prevent a functional Vitamin B12 deficiency in all diseases and disorders associated with low intracellular glutathione, including aging. It is to be appreciated that such patients would,:eventually, develop a functional B12 deficiency anyway but in the early stages of disease might not have clear metabolic evidence of such deficiency.
- Reduced glutatione levels in mammalian cells are associated with a wide range of pathophysiologic states, including hepatic dysfunction, malignancies, HIV infection, pulmonary disease, Parkinson's disease, related immunologic illnesses and physiological conditions. The following list is for example purposes only and is not exhaustive:
- Acetaminophen poisoning, ADD, Addision's Disease, aging, AIDS, Alopecia Areata, ALS, Alzheimers' Disease, anemia (hemolytic), Ankylosing Spondylitis, Arteriosclerosis (hardening of the arteries), arthritis (rheumatoid), asthma, autism, autoimmune disease, Behcet's Disease, burns, cachexia, cancer, candida infection, cardiomyopathy (idiopathic), Chronic Fatigue Syndrome, colitis, coronary artery disease, cystic fibrosis, diabetes, Crohn's disease, Down's syndrome, eczema, emphysema, Epstein Barr Viral (EBV) syndrome, fibromyalgia, free radical overload, Goodpasture Syndrome, Graves' Disease, hepatic dysfunction (liver disease), hepatitis B, hepatitis C, hypercholesterolemia (high blood cholesterol), herpes, infections (viral, bacterial and fungal), inflammatory bowel disease (IBD), lupus, macular degeneration (senile and diabetic macular degeneration), malnutrition, Meniere's disease, multiple sclerosis, Myasthenia. Gravis, neurodegenerative diseases, nutritional disorders, Parkinson's disease, Pemphigus Vulgaris, Primary Hillary Cirrhosis, progeria, psoriasis, Rheumatic Fever, Sarcoidosis, scleroderma, shingles, stroke, toxic poisoning, vasculitis, vitiligo, and Wegener's Granulomatosis.
-
- 1. McCaddon et al., [1998] Total Serum Homocysteine in Senile Dementia of Alzheimer Type. Int. J. Psych. 13 235-239.
- 2. Clarke et al., [1998] Folate, Vitamin B12 and Serum Total Homocysteine levels in confirmed Alzheimers Disease. Arch. Neurol. 55 1449-55.
- 3. Lehmann et al., [1999] Identification of cognitive impairment in the elderly; Homocysteine is an early marker. Dement. Geriatr. Cogn. Disord. 10. 12-20.
- 4. Seshadri et al., [2002]. Plasma homocysteine as a risk factor for dementia and Alzheimer's Disease. N. Engl. J. Med. 346(7), 476-483.
- 5. McCaddon et al; [2001] Homocysteine and cognitive decline in healthy elderly. Dement. Geriatr, Cogn. Disord 12 309-313.
- 6. Kristensen et al., [1993] Serum cobalamin and methylmalonic acid in Alzheimer dementia. Acta. Neurol. Scand. 87, 475-481.
- 7. Lindenbaurn et al., [1998] Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anaemia or macrocytosis. N. Engl. J. Med. 318, 1720-1728.
- 8. Selley M L et al [2002] The effect of increased concentrations of homocysteine on the concentration of (E)-4-hydroxy-2-nonenal in the plasma and cerebrospinal fluid of patients with Alzheimer's disease. Neurobiol Aging May-June; 23(3), 383-8.
- 9. Chen et al., [1999]. Homocysteine metabolism in cardiovascular cells and tissues: implications for hyperhomocysteinemia and cardiovascular disease. Adv. Enzyme Regul. 39, 93-109.
- 10. Mosharov, E. et al. [2000]. The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the traussulfuration pathway and its regulation by redox changes. Biochemistry 39, 13005-13011.
- 11. Christen, Y. [2000]. Oxidative stress and Alzheimers disease. Am. J. Clin. Nutr. 71 (suppl), 621S-629S.
- 12. Ben et al., [2000]. Cognitive decline associated with systemic oxidative stress: The EVA. Study. JAGS 48, 1285-1291.
- 13. Kondo et al. [1981] “Nitrous oxide has multiple deleterious effects on cobalamin metabolism and causes decreases in activities of both mammalian cobalamin dependent enzymes in rats.” J. Clin. Invest. 67, 1270-1283.
- 14. McCaddon et al. [2001] “Analogues, ageing and aberrant assimilation of vitamin B12 in Alzheimer's Disease.” Dement: Geriatr. Cogn. Disord 12(2) 133-137.
- 15. Pezacka [1993]. Identification and characterization of two enzymes involved in the intracellular metabolism of cobalainin. Biochim. Biophys. Acta. 1157, 167-177.
- 16. Folstein M et al., [1975] Mini-Mental State: A practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res 12, 189-98.
- 17. Rosen W G et al., [1984] A new rating scale for Alzheimers Disease. Am J. Psychaitr. 141, 1356-64
- 18. Warner J et al., [1999] Alzheimers Disease. Clinical Evidence 2, 341-346.
- 19. Jacqmin-Gadda et al., [1997]. A 5 Year longitudinal study of the Mini-Mental State Examination in. Normal Aging. Am. J. Epidemiol. 145(6): 498-506.
- 20. Nygard et al., [1995]. Total Plasma Homocysteine and Cardiovascular Risk, Profile. The Hordaland Homocysteine Study. JAMA. 274 (19), 1526-33.
- 21. Andersson et al., [1992]. Homocysteine Export from. Erythrocytes and its implication for plasma sampling. Clin. Chem. 38(7), 1311-5.
Claims (27)
1. A medical composition for treating or preventing a functional Vitamin B12 deficiency, the composition comprising a thiolatocobalamin compound that directly supplies a cobalt-sulphur bond in the upper, β-axial ligand of an intracellular cobalamin molecule.
2. (canceled)
3. A medical composition as claimed in claim 1 wherein the thiolatocobalamin compound is glutathionylcobalamin.
4-15. (canceled)
16. A medical composition as claimed in claim 1 wherein the thiolatocobalamin compound is selected from the group consisting of cysteinylcobalamin, cyclohexylthiolatocobalamin and pentafluorophenylthiolatocobalamin.
17-20. (canceled)
21. A method for treating or preventing a functional Vitamin B12 deficiency in an individual that arises due to the effects of oxidative stress on B12 metabolism, the method comprising administering to the individual a therapeutically effective amount of a thiolatocobalamin compound that directly supplies a cobalt-sulphur bond in the upper β-ligand of an intracellular cobalamin.
22. (canceled)
23. A method as claimed in claim 21 wherein the thiolatocobalamin is glutathionylcobalamin.
24-27. (canceled)
28. A method as claimed in claim 21 further comprising co-administering one or more additional compounds from the group consisting of cobalamin, glutathione, a glutathione precursor, folate, a folate derivative, vitamin B6, methyl-folate, S-adenosylmethionine, betaine, choline and carnitine.
29-32. (canceled)
33. A medical composition as claimed in claim 1 further comprising one or more additional compounds from the group consisting of cobalamin, glutathione, a glutathione precursor, Vitamin B6, folate, folic acid, methyl-folate, S-adenosylmethionine, betaine, choline and carnitine.
34. A method as claimed in claim 21 wherein the thiolatocobalamin is selected from the group consisting of cysteinylcobalamin, cyclohexylthiolatocobalamin, and pentafluorophenylthiolatocobalamin.
35. A method for treating an individual having a disease selected from the group consisting of Alzheimer's disease, age-related cognitive decline, mild cognitive impairment, senile dementia, chronic fatigue syndrome, multiple sclerosis, vascular dementia, depression, and vascular disease; wherein the disease has symptoms associated with a functional Vitamin B12 deficiency; said method comprising administering to the individual a therapeutically effective amount of a thiolatocobalamin compound wherein the individual's intracellular processing of cobalamin increases after administering the composition or compositions, and the symptoms associated with the functional Vitamin B12 deficiency improve.
36. A method as claimed in claim 35 wherein the thiolatocobalamin compound is selected from the group consisting of cysteinylcobalamin, glutathionylcobalamin, cyclohexylthiolatocobalamin, and pentafluorophenylthiolatocobalamin.
37. A method as claimed in claim 35 wherein the thiolatocobalamin compound is glutathionylcobalamin.
38. A method as claimed in claim 35 further comprising co-administering one or more additional compounds from the group consisting of cobalamin, glutathione, a glutathione precursor, Vitamin B6, folate, folic acid, methyl-folate, S-adenosylmethionine, betaine, choline and carnitine.
39. A method as in claim 35 , wherein the disease is age-related cognitive decline.
40. A method as in claim 35 , wherein the disease is senile dementia
41. A method as in claim 35 , wherein the disease is Alzheimer's disease.
42. A method as in claim 35 , wherein the disease is vascular dementia.
43. A method as in claim 35 , wherein the disease is mild cognitive impairment.
44. A method as in claim 35 , wherein the disease is chronic fatigue syndrome.
45. A method as in claim 35 , wherein the disease is multiple sclerosis.
46. A method as in claim 35 , wherein the disease is depression.
47. A method as in claim 35 , wherein the disease is vascular disease.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/706,411 US20110077194A1 (en) | 2001-04-25 | 2010-02-16 | Method for Treating or Preventing a Functional Vitamin B12 Deficiency in an Individual and to Medical Compositions for Use in Said Method |
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0110336A GB0110336D0 (en) | 2001-04-25 | 2001-04-25 | A method for treating an individual with metabolic evidence of Vitamid 12 deficiency and co-existing dementia or other neuropsychiatric abnormality |
GB0110336 | 2001-04-25 | ||
GB0120363 | 2001-08-22 | ||
GB0120363A GB0120363D0 (en) | 2001-08-22 | 2001-08-22 | A method for treating an individual with low intracellular glutathione and/or metabolic evidence of vitamin B12 deficiency and co-existing dementia or other |
PCT/GB2002/001843 WO2002087593A1 (en) | 2001-04-25 | 2002-04-22 | A method for treating or preventing a functional vitamin b12 deficiency in an individual and to medical compositions for use in said method |
US10/475,898 US7709460B2 (en) | 2001-04-25 | 2002-04-22 | Method for treating or preventing a functional vitamin B12 deficiency in an individual and medical compositions for use in said method |
US12/706,411 US20110077194A1 (en) | 2001-04-25 | 2010-02-16 | Method for Treating or Preventing a Functional Vitamin B12 Deficiency in an Individual and to Medical Compositions for Use in Said Method |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/475,898 Continuation US7709460B2 (en) | 2001-04-25 | 2002-04-22 | Method for treating or preventing a functional vitamin B12 deficiency in an individual and medical compositions for use in said method |
PCT/GB2002/001843 Continuation WO2002087593A1 (en) | 2001-04-25 | 2002-04-22 | A method for treating or preventing a functional vitamin b12 deficiency in an individual and to medical compositions for use in said method |
Publications (1)
Publication Number | Publication Date |
---|---|
US20110077194A1 true US20110077194A1 (en) | 2011-03-31 |
Family
ID=26246012
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/475,898 Active 2024-09-03 US7709460B2 (en) | 2001-04-25 | 2002-04-22 | Method for treating or preventing a functional vitamin B12 deficiency in an individual and medical compositions for use in said method |
US12/706,411 Abandoned US20110077194A1 (en) | 2001-04-25 | 2010-02-16 | Method for Treating or Preventing a Functional Vitamin B12 Deficiency in an Individual and to Medical Compositions for Use in Said Method |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/475,898 Active 2024-09-03 US7709460B2 (en) | 2001-04-25 | 2002-04-22 | Method for treating or preventing a functional vitamin B12 deficiency in an individual and medical compositions for use in said method |
Country Status (9)
Country | Link |
---|---|
US (2) | US7709460B2 (en) |
EP (1) | EP1381373B1 (en) |
JP (1) | JP2004526793A (en) |
CN (1) | CN1537009A (en) |
AT (1) | ATE329601T1 (en) |
CA (1) | CA2445512C (en) |
DE (1) | DE60212365T2 (en) |
ES (1) | ES2269671T3 (en) |
WO (1) | WO2002087593A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9040082B2 (en) | 2011-06-24 | 2015-05-26 | K-Pax Pharmaceuticals, Inc. | Compositions and methods for treatment of chronic fatigue |
US9901611B2 (en) | 2015-06-19 | 2018-02-27 | Molecular Defenses Corporation | Glutathione formulation and method of use |
US11216742B2 (en) | 2019-03-04 | 2022-01-04 | Iocurrents, Inc. | Data compression and communication using machine learning |
Families Citing this family (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10311089A1 (en) * | 2003-03-13 | 2004-09-23 | Roche Diagnostics Gmbh | Determining disorders, specifically deficiency, of Vitamin B12 and/or folic acid, by measuring levels of holotranscobalamin II, homocysteine, methylmalonic acid and optionally cystathionine |
WO2006053010A2 (en) * | 2004-11-09 | 2006-05-18 | Hill's Pet Nutrition, Inc. | Use of antioxidants for gene modulation |
AR057623A1 (en) * | 2005-11-28 | 2007-12-05 | Omega Bio Pharma H K Ltd | MATERIALS AND METHODS FOR THE TREATMENT OF VIRAL INFECTIONS |
PL1800675T4 (en) | 2005-12-23 | 2012-02-29 | Nutricia Nv | Composition comprising polyunsaturated fatty acids, proteins, manganese and/or molybden and nucleosides/nucleotides for treating dementia |
US7754700B2 (en) * | 2006-04-24 | 2010-07-13 | Trager Seymour F | Composition and methods for alleviating symptoms of neurotoxicity |
CN101460159B (en) * | 2006-06-07 | 2011-11-23 | 协和发酵生化株式会社 | Fatigue-reducing agent |
US7812042B2 (en) * | 2006-09-22 | 2010-10-12 | Kent State University | Pharmaceutical compositions and therapeutic applications for the use of a novel vitamin B12 derivative, N-acetyl-L-cysteinylcobalamin |
US7972633B2 (en) * | 2007-02-07 | 2011-07-05 | Applied Cognitive Sciences, LLC | Nutritional supplements for healthy memory and mental function |
GB0723972D0 (en) * | 2007-12-07 | 2008-01-23 | Queen Mary & Westfield College | Use of vitamin B12 |
WO2009158430A1 (en) | 2008-06-25 | 2009-12-30 | Iskandar Bermans S | (6s)-5-methyltetrahydrofolic acid for therapy of tissue injury |
US8372451B2 (en) * | 2010-02-12 | 2013-02-12 | Alexander Vuckovic, M.D., Llc | Compositions and methods for treating depression |
NZ602032A (en) * | 2010-02-24 | 2014-11-28 | Emisphere Tech Inc | Oral b12 therapy |
WO2012001336A1 (en) * | 2010-07-01 | 2012-01-05 | Isis Innovation Limited | Treatment of cognitive disorders |
JP6015158B2 (en) * | 2012-06-22 | 2016-10-26 | 大正製薬株式会社 | Transcobalamin II gene product regulator |
JP7074663B6 (en) * | 2015-05-28 | 2022-08-01 | ベイラー カレッジ オブ メディスン | Effects of N-Acetylcysteine and Glycine Supplementation to Improve Glutathione Levels |
WO2018144088A1 (en) | 2016-11-03 | 2018-08-09 | Alexander Vuckovic, M.D., Llc | Compositions and methods for treating depression |
EP3406622A1 (en) * | 2017-05-24 | 2018-11-28 | Albert-Ludwigs-Universität Freiburg | Cobalamin derivatives and their use for the treatment of diseases caused by lack of vitamin b12 supply |
FR3068603B1 (en) * | 2017-07-10 | 2020-01-03 | Nuribiol | FOOD SUPPLEMENT TO PROTECT FEMALE AND MALE FERTILITY |
KR20200101948A (en) * | 2017-12-21 | 2020-08-28 | 오사카 유니버시티 | Neurological disease treatment |
US11478503B2 (en) | 2019-11-21 | 2022-10-25 | Lupin, Inc. | Vitamin B12 compound supplementation methods and compositions |
FR3119093B3 (en) * | 2021-01-27 | 2023-02-10 | Nestle Sa | COMPOSITIONS AND METHODS FOR USE IN MOTIVATIONAL PERFORMANCE AUGMENT |
US20220387474A1 (en) * | 2021-06-07 | 2022-12-08 | Peter Nagele | Supplement compositions for nitrous oxide patients |
Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US945772A (en) * | 1909-03-17 | 1910-01-11 | Hoard E | Mop. |
US4940658A (en) * | 1986-11-20 | 1990-07-10 | University Patents, Inc. | Assay for sulfhydryl amino acids and methods for detecting and distinguishing cobalamin and folic acid deficency |
US5668117A (en) * | 1991-02-22 | 1997-09-16 | Shapiro; Howard K. | Methods of treating neurological diseases and etiologically related symptomology using carbonyl trapping agents in combination with previously known medicaments |
US5807832A (en) * | 1987-06-09 | 1998-09-15 | Biotech Australia Pty Limited | Oral delivery of biologically active substances bound to vitamin B12 |
US6008190A (en) * | 1994-12-15 | 1999-12-28 | California Institute Of Technology | Cobalt Schiff base compounds |
US6013632A (en) * | 1997-01-13 | 2000-01-11 | Emory University | Compounds and their combinations for the treatment of influenza infection |
US6127370A (en) * | 1996-11-06 | 2000-10-03 | Bristol-Myers Squibb Company | Method for treating alzheimer's disease |
US6207190B1 (en) * | 1998-08-13 | 2001-03-27 | Chronorx, Llc | Dosage forms for the treatment of the chronic glaucomas |
US6562869B1 (en) * | 1999-09-23 | 2003-05-13 | Juvenon, Inc. | Nutritional supplement for increased energy and stamina |
US6649193B1 (en) * | 1999-06-11 | 2003-11-18 | Henceforth Hibernia Inc. | Prophylactic therapeutic and industrial antioxidant compositions enhanced with stabilized atomic hydrogen/free electrons and methods to prepare and use such compositions |
US6787527B1 (en) * | 1994-11-10 | 2004-09-07 | Duke University | Methods of preventing and treating HIV infection |
US6812248B2 (en) * | 2000-07-05 | 2004-11-02 | John Hopkins University School Of Medicine | Prevention and treatment of degenerative diseases by glutathione and phase II detoxification enzymes |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3130189A (en) | 1959-04-06 | 1964-04-21 | Merck & Co Inc | Hydroxocobalamin-glutathione |
AU4484997A (en) | 1996-09-18 | 1998-04-14 | Thomas F. Brennan | Compositions containing cobalamin and amino acids |
EP0891719A1 (en) | 1997-07-14 | 1999-01-20 | N.V. Nutricia | Nutritional composition containing methionine |
PT951842E (en) | 1999-01-20 | 2003-04-30 | Nutricia Nv | ADAPTED BABY FOOD FORMULA |
GB9906740D0 (en) | 1999-03-23 | 1999-05-19 | Kilgowan Limited | Oral combinations of hydroxocobalamin and folic acid |
AU8003800A (en) | 1999-10-08 | 2001-04-23 | Joyce Corinne Bechthold | Methods and compositions for treating neurobehavioral disorders |
DE10027968A1 (en) | 2000-06-08 | 2001-12-13 | Asta Medica Ag | Adjuvant therapy of dementia using alpha-lipoic acid or derivative, is effective in combination with antidementia or neurotransmission improving agents in improving cognitive function in e.g. Alzheimer's disease patients |
-
2002
- 2002-04-22 JP JP2002584938A patent/JP2004526793A/en active Pending
- 2002-04-22 EP EP02720247A patent/EP1381373B1/en not_active Expired - Lifetime
- 2002-04-22 DE DE60212365T patent/DE60212365T2/en not_active Expired - Lifetime
- 2002-04-22 AT AT02720247T patent/ATE329601T1/en active
- 2002-04-22 US US10/475,898 patent/US7709460B2/en active Active
- 2002-04-22 CN CNA028107241A patent/CN1537009A/en active Pending
- 2002-04-22 CA CA2445512A patent/CA2445512C/en not_active Expired - Fee Related
- 2002-04-22 WO PCT/GB2002/001843 patent/WO2002087593A1/en active IP Right Grant
- 2002-04-22 ES ES02720247T patent/ES2269671T3/en not_active Expired - Lifetime
-
2010
- 2010-02-16 US US12/706,411 patent/US20110077194A1/en not_active Abandoned
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US945772A (en) * | 1909-03-17 | 1910-01-11 | Hoard E | Mop. |
US4940658A (en) * | 1986-11-20 | 1990-07-10 | University Patents, Inc. | Assay for sulfhydryl amino acids and methods for detecting and distinguishing cobalamin and folic acid deficency |
US5807832A (en) * | 1987-06-09 | 1998-09-15 | Biotech Australia Pty Limited | Oral delivery of biologically active substances bound to vitamin B12 |
US5668117A (en) * | 1991-02-22 | 1997-09-16 | Shapiro; Howard K. | Methods of treating neurological diseases and etiologically related symptomology using carbonyl trapping agents in combination with previously known medicaments |
US6787527B1 (en) * | 1994-11-10 | 2004-09-07 | Duke University | Methods of preventing and treating HIV infection |
US6008190A (en) * | 1994-12-15 | 1999-12-28 | California Institute Of Technology | Cobalt Schiff base compounds |
US6127370A (en) * | 1996-11-06 | 2000-10-03 | Bristol-Myers Squibb Company | Method for treating alzheimer's disease |
US6013632A (en) * | 1997-01-13 | 2000-01-11 | Emory University | Compounds and their combinations for the treatment of influenza infection |
US6207190B1 (en) * | 1998-08-13 | 2001-03-27 | Chronorx, Llc | Dosage forms for the treatment of the chronic glaucomas |
US6649193B1 (en) * | 1999-06-11 | 2003-11-18 | Henceforth Hibernia Inc. | Prophylactic therapeutic and industrial antioxidant compositions enhanced with stabilized atomic hydrogen/free electrons and methods to prepare and use such compositions |
US6562869B1 (en) * | 1999-09-23 | 2003-05-13 | Juvenon, Inc. | Nutritional supplement for increased energy and stamina |
US6812248B2 (en) * | 2000-07-05 | 2004-11-02 | John Hopkins University School Of Medicine | Prevention and treatment of degenerative diseases by glutathione and phase II detoxification enzymes |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9040082B2 (en) | 2011-06-24 | 2015-05-26 | K-Pax Pharmaceuticals, Inc. | Compositions and methods for treatment of chronic fatigue |
US9901611B2 (en) | 2015-06-19 | 2018-02-27 | Molecular Defenses Corporation | Glutathione formulation and method of use |
US11216742B2 (en) | 2019-03-04 | 2022-01-04 | Iocurrents, Inc. | Data compression and communication using machine learning |
US11468355B2 (en) | 2019-03-04 | 2022-10-11 | Iocurrents, Inc. | Data compression and communication using machine learning |
Also Published As
Publication number | Publication date |
---|---|
WO2002087593A1 (en) | 2002-11-07 |
US7709460B2 (en) | 2010-05-04 |
CA2445512C (en) | 2010-10-12 |
CN1537009A (en) | 2004-10-13 |
EP1381373B1 (en) | 2006-06-14 |
US20040157783A1 (en) | 2004-08-12 |
ATE329601T1 (en) | 2006-07-15 |
ES2269671T3 (en) | 2007-04-01 |
CA2445512A1 (en) | 2002-11-07 |
DE60212365T2 (en) | 2007-05-31 |
EP1381373A1 (en) | 2004-01-21 |
DE60212365D1 (en) | 2006-07-27 |
JP2004526793A (en) | 2004-09-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20110077194A1 (en) | Method for Treating or Preventing a Functional Vitamin B12 Deficiency in an Individual and to Medical Compositions for Use in Said Method | |
US5795873A (en) | Method for treatment and prevention of deficiencies of vitamins B12, folic acid and B6 | |
US6207651B1 (en) | Method for treatment and prevention of deficiencies of vitamins B12, folic acid, and B6 | |
Wilcken et al. | Homocysteinemia, ischemic heart disease, and the carrier state for homocystinuria | |
US5563126A (en) | Method for treatment and prevention of deficiencies of vitamins B12, folic acid, and B6 | |
Murphy-Chutorian et al. | Methionine intolerance: a possible risk factor for coronary artery disease | |
Ubbink et al. | The effect of a subnormal vitamin B-6 status on homocysteine metabolism. | |
Aisen et al. | A pilot study of vitamins to lower plasma homocysteine levels in Alzheimer disease | |
Seshadri et al. | Homocysteine, B vitamins, and coronary artery disease | |
Stacy et al. | Methionine in the treatment of nitrous-oxide-induced neuropathy and myeloneuropathy | |
US9364497B2 (en) | Treatment of cognitive disorders | |
Stabler et al. | Cerebrospinal fluid methylmalonic acid levels in normal subjects and patients with cobalamin deficiency | |
Martin | B12 and folate deficiency dementia | |
Anderson et al. | No effect of the novel antidiabetic agent nateglinide on the pharmacokinetics and anticoagulant properties of warfarin in healthy volunteers | |
EP1324761B1 (en) | Uridine therapy for patients with elevated purine levels | |
AU2002251315B2 (en) | A method for treating or preventing a functional vitamin B12 deficiency in an individual and to medical compositions for use in said method | |
Peeters et al. | In vivo folic acid supplementation partially corrects in vitro methotrexate toxicity in patients with Down syndrome | |
AU2002251315A1 (en) | A method for treating or preventing a functional vitamin B12 deficiency in an individual and to medical compositions for use in said method | |
King et al. | Cystinuria with hyperuricemia and methioninuria: Biochemical study of a case | |
Foulds et al. | The biochemical basis of the toxic amblyopias | |
ASO et al. | Population Pharmacokinetics, protein Binding and Antiarrhythmic Effects of Disopyramide Enantiomers in Arrhythmic Patients | |
US20030203873A1 (en) | Method for treatment of neuropsychiatric disorders | |
Krishnaswamy | Methionine metabolism in pyridoxine deficiency | |
EP1645276A1 (en) | Treatment of neurodegenerative disorders | |
Virdis et al. | Impact of Hyperhomocyst (e) inemia on Endothelial Function |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |