WO2001056609A1 - Composition pharmaceutique destinee au traitement d'une hyperhomocysteinemie provoquee par un medicament - Google Patents
Composition pharmaceutique destinee au traitement d'une hyperhomocysteinemie provoquee par un medicament Download PDFInfo
- Publication number
- WO2001056609A1 WO2001056609A1 PCT/EP2000/008801 EP0008801W WO0156609A1 WO 2001056609 A1 WO2001056609 A1 WO 2001056609A1 EP 0008801 W EP0008801 W EP 0008801W WO 0156609 A1 WO0156609 A1 WO 0156609A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- pharmaceutical
- pharmaceutical composition
- nicotinic acid
- combination
- Prior art date
Links
- 208000033892 Hyperhomocysteinemia Diseases 0.000 title claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 12
- 239000003814 drug Substances 0.000 title claims abstract description 11
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims abstract description 29
- LXNHXLLTXMVWPM-UHFFFAOYSA-N Vitamin B6 Natural products CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims abstract description 21
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 235000019152 folic acid Nutrition 0.000 claims abstract description 19
- 239000011724 folic acid Substances 0.000 claims abstract description 19
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229960000304 folic acid Drugs 0.000 claims abstract description 17
- -1 cyano- Chemical class 0.000 claims abstract description 13
- 229940011671 vitamin b6 Drugs 0.000 claims abstract description 11
- 229960003512 nicotinic acid Drugs 0.000 claims abstract description 10
- 235000001968 nicotinic acid Nutrition 0.000 claims abstract description 10
- 239000011664 nicotinic acid Substances 0.000 claims abstract description 10
- 235000019158 vitamin B6 Nutrition 0.000 claims abstract description 10
- 239000011726 vitamin B6 Substances 0.000 claims abstract description 10
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims abstract description 9
- 229960004308 acetylcysteine Drugs 0.000 claims abstract description 9
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 claims abstract description 9
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229940123208 Biguanide Drugs 0.000 claims abstract description 8
- 229940035676 analgesics Drugs 0.000 claims abstract description 8
- 239000000730 antalgic agent Substances 0.000 claims abstract description 8
- 239000000935 antidepressant agent Substances 0.000 claims abstract description 8
- 229940005513 antidepressants Drugs 0.000 claims abstract description 8
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000004283 biguanides Chemical class 0.000 claims abstract description 7
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000003637 steroidlike Effects 0.000 claims abstract description 6
- 206010020772 Hypertension Diseases 0.000 claims abstract description 5
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000001450 anions Chemical class 0.000 claims abstract description 5
- 229940125753 fibrate Drugs 0.000 claims abstract description 5
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 5
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229960003105 metformin Drugs 0.000 claims abstract description 5
- 229960000278 theophylline Drugs 0.000 claims abstract description 5
- 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 compound 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 claims abstract description 4
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 claims abstract description 4
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000001961 anticonvulsive agent Substances 0.000 claims abstract description 4
- 235000008191 folinic acid Nutrition 0.000 claims abstract description 4
- 239000011672 folinic acid Substances 0.000 claims abstract description 4
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 claims abstract description 4
- 229960001691 leucovorin Drugs 0.000 claims abstract description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims abstract 5
- PFWLFWPASULGAN-UHFFFAOYSA-N 7-methylxanthine Chemical compound N1C(=O)NC(=O)C2=C1N=CN2C PFWLFWPASULGAN-UHFFFAOYSA-N 0.000 claims abstract 4
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims abstract 3
- 229930105110 Cyclosporin A Natural products 0.000 claims abstract 3
- 108010036949 Cyclosporine Proteins 0.000 claims abstract 3
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims abstract 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims abstract 3
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 claims abstract 3
- 229960000623 carbamazepine Drugs 0.000 claims abstract 3
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 claims abstract 3
- 229960001265 ciclosporin Drugs 0.000 claims abstract 3
- 229930182912 cyclosporin Natural products 0.000 claims abstract 3
- 229960001680 ibuprofen Drugs 0.000 claims abstract 3
- 229960000905 indomethacin Drugs 0.000 claims abstract 3
- 229960000485 methotrexate Drugs 0.000 claims abstract 3
- 229960002036 phenytoin Drugs 0.000 claims abstract 3
- 238000011282 treatment Methods 0.000 claims description 16
- 239000004480 active ingredient Substances 0.000 claims description 14
- 230000003225 hyperhomocysteinemia Effects 0.000 claims description 14
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 claims description 13
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 claims description 8
- 229960003237 betaine Drugs 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 7
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 6
- 239000000945 filler Substances 0.000 claims description 6
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 6
- 239000003018 immunosuppressive agent Substances 0.000 claims description 6
- 239000003826 tablet Substances 0.000 claims description 6
- 230000001939 inductive effect Effects 0.000 claims description 5
- 229940088594 vitamin Drugs 0.000 claims description 5
- 229930003231 vitamin Natural products 0.000 claims description 5
- 235000013343 vitamin Nutrition 0.000 claims description 5
- 239000011782 vitamin Substances 0.000 claims description 5
- 239000003524 antilipemic agent Substances 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 230000003556 anti-epileptic effect Effects 0.000 claims description 3
- 229960003965 antiepileptics Drugs 0.000 claims description 3
- 239000008298 dragée Substances 0.000 claims description 3
- 239000007938 effervescent tablet Substances 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 235000008160 pyridoxine Nutrition 0.000 claims description 2
- 239000011677 pyridoxine Substances 0.000 claims description 2
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 claims 2
- 229960001380 cimetidine Drugs 0.000 claims 2
- 239000002552 dosage form Substances 0.000 claims 2
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 239000007941 film coated tablet Substances 0.000 claims 1
- 239000006186 oral dosage form Substances 0.000 claims 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 abstract description 16
- 239000013543 active substance Substances 0.000 abstract description 8
- 230000036772 blood pressure Effects 0.000 abstract description 5
- 239000005541 ACE inhibitor Substances 0.000 abstract description 4
- 229940127291 Calcium channel antagonist Drugs 0.000 abstract description 4
- 239000002333 angiotensin II receptor antagonist Substances 0.000 abstract description 4
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 abstract description 4
- 239000002934 diuretic Substances 0.000 abstract description 4
- 229940030606 diuretics Drugs 0.000 abstract description 4
- 150000002632 lipids Chemical class 0.000 abstract description 3
- 210000002381 plasma Anatomy 0.000 abstract description 3
- 150000001413 amino acids Chemical class 0.000 abstract description 2
- 239000003638 chemical reducing agent Substances 0.000 abstract 2
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 abstract 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 7
- 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 6
- 235000019163 vitamin B12 Nutrition 0.000 description 6
- 239000011715 vitamin B12 Substances 0.000 description 6
- 229930003779 Vitamin B12 Natural products 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- RTAPDZBZLSXHQQ-UHFFFAOYSA-N 8-methyl-3,7-dihydropurine-2,6-dione Chemical class N1C(=O)NC(=O)C2=C1N=C(C)N2 RTAPDZBZLSXHQQ-UHFFFAOYSA-N 0.000 description 4
- 229960002297 fenofibrate Drugs 0.000 description 4
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 4
- 239000000902 placebo Substances 0.000 description 4
- 229940068196 placebo Drugs 0.000 description 4
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 description 4
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 description 4
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 4
- 239000002220 antihypertensive agent Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 235000000639 cyanocobalamin Nutrition 0.000 description 3
- 239000011666 cyanocobalamin Substances 0.000 description 3
- 229960002104 cyanocobalamin Drugs 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 208000000412 Avitaminosis Diseases 0.000 description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 description 2
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 2
- 206010021135 Hypovitaminosis Diseases 0.000 description 2
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 238000001793 Wilcoxon signed-rank test Methods 0.000 description 2
- 229940127088 antihypertensive drug Drugs 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 229940020832 fenofibrate 200 mg Drugs 0.000 description 2
- 229940014144 folate Drugs 0.000 description 2
- 229960002003 hydrochlorothiazide Drugs 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 208000030401 vitamin deficiency disease Diseases 0.000 description 2
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 1
- 229960002576 amiloride Drugs 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229940082205 hydrochlorothiazide 25 mg Drugs 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229960001327 pyridoxal phosphate Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960004813 trichlormethiazide Drugs 0.000 description 1
- LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical group 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4415—Pyridoxine, i.e. Vitamin B6
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—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
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- composition for the treatment of drug-induced hyperhomocysteinemia is provided.
- the invention relates to a pharmaceutical composition for the therapy of hyperhomocysteinemia, which, for. B. induced by therapy with antihypertensive drugs, analgesics, antidepressants, immunosuppressants, H 2 -receptor blockers, antiepeleptics, methylxanthines, biguanides or lipid-lowering agents.
- hyperhomocysteinemia increased levels of the amino acid homocysteine in the blood plasma
- anti-hypertensive drugs diuretics, calcium antagonists, ACE inhibitors or angiotensin-II receptor antagonists
- non-steroidal analgesics non-steroidal analgesics
- antidepressants lithium
- Immunosuppressants methylxanthines (theophylline)
- biguanides metalformin
- lipid-lowering agents foribrates, anion exchangers, nicotinic acid and nicotinic acid analogues.
- Elevated homocysteine levels represent a risk factor for the development of coronary heart disease, apoplexy and peripheral occlusive disease. Treatment of these elevated homocysteine levels is therefore carried out as part of the prevention of coronary artery disease, apoplexy and peripheral occlusive disease. Congenital and acquired causes of hyperhomocysteinemia are known. Deficiency of the vitamins cobalamin (vitamin B12), folic acid or pyridoxine chloride (vitamin B6) are a common cause of hyperhomocysteinemia. B vitamins and folic acid have important coenzyme functions in the breakdown of homocysteine.
- the therapy consists in the targeted vitamin substitution of folic acid, vitamin B6 or B12 (O. Stanger; metabolism, news about the risk factor homocysteine, medical journal Dr. Med. 06/99). It is therefore an object of the invention to prevent the development of drug-induced hyperhomocysteinemia by means of suitable active ingredient additions.
- a pharmaceutical composition comprising a combination of a pharmaceutical active ingredient inducing hyperhomocysteinemia and at least one or more of the active ingredients cobalamin (cyano-, hydroxo-, methyl-), folic acid (pteroyiglutamic acid, methyltetrahydrofolate, folinic acid), vitamin B6 (pyridoxine chloride) , Betaine or N-acetylcysteine is suitable, can prevent an increase in the homocysteine concentration in the blood plasma, as has been observed with the administration of blood pressure-lowering drugs, analgesics, antidepressants, immunosuppressants, H 2 -receptors, antiepeleptics, methylxanthines, biguanides or lipid-lowering drugs ,
- the following table shows the effect of antihypertensive therapy on parameters of homocysteine metabolism in patients with high blood pressure.
- the median with the smallest and the largest value in brackets or the mean with simple standard deviation is given.
- the probability of error (p-value values) was determined using the Wilcoxon test for connected samples.
- Vitamin B6 (PLP) (ng / mL) 9.0 (5.0-39.4) 10.9 (5.2-39.3) 0.10
- Vitamin B12 (cobalamin) 369 (217-1115) 358 (123-907) 0.75
- Vitamin B6 (PLP) (ng / mL) 9.0 (5.1-36.4) 10.3 (4.7-25.9) 0.53
- homocysteine-lowering active ingredients are used in combination with the pharmaceutical active ingredients inducing hyperhomocysteinemia in the following daily doses for the indicated indications:
- N-acetylcysteine up to 5,000 mg
- the combination of the active pharmaceutical ingredients with the vitamins mentioned can preferably be taken orally, e.g. B. in the form of capsules, dragees, tablets, tablets or film tablets.
- the combination of the active pharmaceutical ingredients with betaine or N-acetylcysteine can preferably be administered orally, e.g. B. in the form of an effervescent tablet.
- the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, which contain the compounds according to the invention, and processes for the preparation of these preparations.
- suitable pharmaceutical preparations are as follows:
- the pharmaceutical preparations listed can also contain other active pharmaceutical ingredients.
- the pharmaceutical preparations listed above are prepared in a customary manner by known methods, e.g. by mixing the active ingredient (s) with the excipient (s).
- diuretics calcium antagonists, ACE inhibitors and angiotensin-II receptor antagonists
- Active substances that belong to the class of diuretics, calcium antagonists, ACE inhibitors or angiotensin-II receptor antagonists are listed in Table 1.
- Other side effects than the newly found hyperhomocysteinemia when taking these antihypertensive agents are already known.
- the patient was given a pharmaceutical preparation according to the invention as
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Abstract
L'invention concerne une composition pharmaceutique destinée à la fabrication de bloqueurs de récepteurs de H2 (cimétidine), d'analgésiques non-stéroïdiques (ibuprofène, indométacine), d'antidépresseurs (lithium), d'antiépiléptiques (phénytoïne, carbamazépine), d'immunosuppresseurs (cyclosporine, méthotrexate), de méthylxanthines (théophylline), de biguanides (métformine), et d'hypolipidémiants (fibrates, échangeurs d'anions, acide nicotinique et analogues d'acide nicotinique), ou d'agents pharmaceutiques destinés au traitement de l'hypertension et contenant une combinaison d'un agent actif provoquant une hyperhomocystéinémie et au moins un des agents actifs suivants ; cobalamine (cyano-, hydroxy-, méthyl-), acide folique (acide ptéroglutaminique, méthyltétrahydrofolate, acide folinique), vitamine B6 (chlorure de pyridoxine), bétaïne ou N-acétylcystéine. Selon une nouvelle observation, une hyperhomocystéinémie (concentration élevée de l'acide aminé homocystéine dans le plasma sanguin) est induite par la prise d'agents pharmaceutiques hypotenseurs (diurétiques, antagonistes de calcium, inhibiteurs de l'enzyme de conversion de l'angiotensine ou antagonistes de récepteurs d'angiotensine II), d'analgésiques non-stéroïdiques, d'antidépresseurs (lithium), de méthylxanthines (théophylline), de biguanides (métformine), ou d'hypolipidémiants (fibrates, échangeurs d'anions, acide nicotinique et analogues d'acide nicotinique).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2000272858A AU2000272858A1 (en) | 2000-02-03 | 2000-09-08 | Pharmaceutical composition for treating hyperhomocysteinaemia caused by medicaments |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10004651.7 | 2000-02-03 | ||
| DE10004651A DE10004651A1 (de) | 2000-02-03 | 2000-02-03 | Kombination von blutdrucksenkenden Wirkstoffen mit Wirkstoffen, die den Homocysteinspiegel zu senken vermögen |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2001056609A1 true WO2001056609A1 (fr) | 2001-08-09 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2000/008801 WO2001056609A1 (fr) | 2000-02-03 | 2000-09-08 | Composition pharmaceutique destinee au traitement d'une hyperhomocysteinemie provoquee par un medicament |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU2000272858A1 (fr) |
| DE (1) | DE10004651A1 (fr) |
| WO (1) | WO2001056609A1 (fr) |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003045359A2 (fr) * | 2001-11-26 | 2003-06-05 | Astion Oncology Aps | Combinaison de derives de cimetidine et de cysteine pour traiter le cancer |
| WO2005011642A1 (fr) * | 2003-08-05 | 2005-02-10 | Galephar M/F | Composition pharmaceutique a unite simple comprenant un melange de fibranne et un agent reducteur d'homocysteine |
| EP1518554A1 (fr) * | 2003-09-26 | 2005-03-30 | Medosan Industrie Biochimiche Riunite S.r.l. | Composition pharmaceutique pour le traitement de l'hyperhomocystéinémie |
| WO2005016228A3 (fr) * | 2003-08-14 | 2005-05-19 | Dpharm Ltd | Compositions et procedes visant a reduire le risque d'epilepsie et/ou traiter des troubles convulsifs |
| WO2006005173A1 (fr) * | 2004-07-09 | 2006-01-19 | Medicure International Inc. | Polytherapies utilisant des derives d'acide nicotinique et un pyridoxal-5'-phosphate ou un compose associe de pyridoxal-5'-phosphate |
| EP1681055A1 (fr) * | 2005-01-13 | 2006-07-19 | PEJO Iserlohn Heilmittel-und Diät-GmbH & Co.KG | Préparation pharmaceutique pour le traitement des taux d'homocysteine elevés |
| WO2006086856A1 (fr) * | 2005-02-15 | 2006-08-24 | Messadek, Jallal | Compositions therapeutiques combinees et leurs procedes d’utilisation |
| WO2008061456A1 (fr) * | 2006-11-20 | 2008-05-29 | Pficker Pharmaceuticals Ltd. | Composé folacine-metformine et sa production |
| US7608640B2 (en) | 1999-03-02 | 2009-10-27 | Jallal Messadek | Glycine betaine and its use |
| US7786077B2 (en) | 2005-04-27 | 2010-08-31 | Jallal Messadek | Insulins combinations |
| US8101599B2 (en) | 2002-05-17 | 2012-01-24 | Novartis Ag | Pharmaceutical composition containing anti-hypertensive agents |
| US8318805B2 (en) | 2004-11-10 | 2012-11-27 | Jallal Messadek | Modulation of nitric oxide synthases by betaines |
| US8343947B2 (en) | 2003-07-15 | 2013-01-01 | Jallal Messadek | Therapeutic treatment |
| CN103386130A (zh) * | 2013-06-27 | 2013-11-13 | 深圳奥萨医药有限公司 | Ace抑制剂/噻嗪类利尿剂/5-甲基四氢叶酸药物组合物及用途 |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10016379B2 (en) | 2015-10-30 | 2018-07-10 | Robin L. Webb | Method of treatment for third spacing |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6008221A (en) * | 1996-11-06 | 1999-12-28 | Bristol-Myers Squibb Company | Method for treating Alzheimer's disease with folic acid |
| WO1999044563A2 (fr) * | 1998-03-06 | 1999-09-10 | Brown Charles L Iii | Composition pour le traitement et la prevention de coronaropathie |
-
2000
- 2000-02-03 DE DE10004651A patent/DE10004651A1/de not_active Ceased
- 2000-09-08 WO PCT/EP2000/008801 patent/WO2001056609A1/fr active Application Filing
- 2000-09-08 AU AU2000272858A patent/AU2000272858A1/en not_active Abandoned
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| A.K.AARSAND, S.M.CARLSEN: "Folate administration reduces circulating homocysteine levels in NIDDM patients on long-term metformin treatment", JOURNAL OF INTERNAL MEDICINE, vol. 244, no. 2, 1998, pages 169 - 174, XP000990675 * |
| A.VAN EDE E.A.: "Effect of folic and folinic acid suppletion on toxicity and efficacy of methotrexate in rheumatoid arthritis: a randomized,doubleblind 48 weel clinical trial", ARTHRITIS & RHEUMATISM ABSTRACT SUPPLEMENT, vol. 42, no. 9 suppl, 1999, pages S380, XP002163899 * |
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| S.L.MORGAN E.A.: "Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoic arthritis: Implications for cardiovascular disease prevention", JOURNAL OF RHEUMATOLOGY, vol. 25, no. 3, 1998, pages 441 - 446, XP000990681 * |
| T.APELAND E.A.: "Plasma homocysteine concentrations in patients with epilepsy on carbamazepine monotherapy", EPILEPSIA, vol. 40, no. suppl 2, 1999, pages 280, XP000990677 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7608640B2 (en) | 1999-03-02 | 2009-10-27 | Jallal Messadek | Glycine betaine and its use |
| WO2003045359A3 (fr) * | 2001-11-26 | 2003-12-18 | Astion Oncology Aps | Combinaison de derives de cimetidine et de cysteine pour traiter le cancer |
| WO2003045359A2 (fr) * | 2001-11-26 | 2003-06-05 | Astion Oncology Aps | Combinaison de derives de cimetidine et de cysteine pour traiter le cancer |
| US8101599B2 (en) | 2002-05-17 | 2012-01-24 | Novartis Ag | Pharmaceutical composition containing anti-hypertensive agents |
| US8343947B2 (en) | 2003-07-15 | 2013-01-01 | Jallal Messadek | Therapeutic treatment |
| WO2005011642A1 (fr) * | 2003-08-05 | 2005-02-10 | Galephar M/F | Composition pharmaceutique a unite simple comprenant un melange de fibranne et un agent reducteur d'homocysteine |
| CN1867550B (zh) * | 2003-08-14 | 2012-08-15 | 迪-药品有限公司 | 用于降低癫痫发生的危险和/或用于治疗癫痫发作疾病的组合物和方法 |
| WO2005016228A3 (fr) * | 2003-08-14 | 2005-05-19 | Dpharm Ltd | Compositions et procedes visant a reduire le risque d'epilepsie et/ou traiter des troubles convulsifs |
| AU2004264744B2 (en) * | 2003-08-14 | 2009-12-10 | Advanced Neuroprotective Systems Ltd. | Compositions and methods for reducing the risk of epileptic occurrence and/or for treatment of seizure disorders |
| US7745426B2 (en) | 2003-08-14 | 2010-06-29 | D-Pharm Ltd. | Compositions and methods for reducing the risk of epileptic occurrence and/or for treatment of seizure disorders |
| EP1518554A1 (fr) * | 2003-09-26 | 2005-03-30 | Medosan Industrie Biochimiche Riunite S.r.l. | Composition pharmaceutique pour le traitement de l'hyperhomocystéinémie |
| WO2006005173A1 (fr) * | 2004-07-09 | 2006-01-19 | Medicure International Inc. | Polytherapies utilisant des derives d'acide nicotinique et un pyridoxal-5'-phosphate ou un compose associe de pyridoxal-5'-phosphate |
| US8318805B2 (en) | 2004-11-10 | 2012-11-27 | Jallal Messadek | Modulation of nitric oxide synthases by betaines |
| EP1681055A1 (fr) * | 2005-01-13 | 2006-07-19 | PEJO Iserlohn Heilmittel-und Diät-GmbH & Co.KG | Préparation pharmaceutique pour le traitement des taux d'homocysteine elevés |
| US7780990B2 (en) | 2005-02-15 | 2010-08-24 | Jallal Messadek | Combination therapeutic compositions and method of use |
| WO2006086856A1 (fr) * | 2005-02-15 | 2006-08-24 | Messadek, Jallal | Compositions therapeutiques combinees et leurs procedes d’utilisation |
| US7786077B2 (en) | 2005-04-27 | 2010-08-31 | Jallal Messadek | Insulins combinations |
| US8329710B2 (en) | 2006-11-20 | 2012-12-11 | Sino-Us Pficker Pharmaceuticals Co. | Metformin folate and preparation of the same |
| WO2008061456A1 (fr) * | 2006-11-20 | 2008-05-29 | Pficker Pharmaceuticals Ltd. | Composé folacine-metformine et sa production |
| CN103386130A (zh) * | 2013-06-27 | 2013-11-13 | 深圳奥萨医药有限公司 | Ace抑制剂/噻嗪类利尿剂/5-甲基四氢叶酸药物组合物及用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2000272858A1 (en) | 2001-08-14 |
| DE10004651A1 (de) | 2001-08-16 |
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