US20080051366A1 - Aminosugar, glycosaminoglycan, and s-adenoslymethionine composition for the treatment and repair of connective tissue - Google Patents
Aminosugar, glycosaminoglycan, and s-adenoslymethionine composition for the treatment and repair of connective tissue Download PDFInfo
- Publication number
- US20080051366A1 US20080051366A1 US11/785,915 US78591507A US2008051366A1 US 20080051366 A1 US20080051366 A1 US 20080051366A1 US 78591507 A US78591507 A US 78591507A US 2008051366 A1 US2008051366 A1 US 2008051366A1
- Authority
- US
- United States
- Prior art keywords
- composition
- glucosamine
- connective tissue
- manganese
- sam
- 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
- 239000000203 mixture Substances 0.000 title claims abstract description 117
- 229920002683 Glycosaminoglycan Polymers 0.000 title claims abstract description 71
- 210000002808 connective tissue Anatomy 0.000 title claims abstract description 61
- 150000002337 glycosamines Chemical class 0.000 title claims abstract description 31
- 230000008439 repair process Effects 0.000 title claims abstract description 30
- 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 abstract description 99
- 229960001570 ademetionine Drugs 0.000 claims abstract description 96
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 claims abstract description 91
- 229960002442 glucosamine Drugs 0.000 claims abstract description 88
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 claims abstract description 86
- 206010061218 Inflammation Diseases 0.000 claims abstract description 24
- 230000004054 inflammatory process Effects 0.000 claims abstract description 23
- 230000001603 reducing effect Effects 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000012634 fragment Substances 0.000 claims abstract description 16
- 229920002567 Chondroitin Polymers 0.000 claims abstract description 11
- 241001465754 Metazoa Species 0.000 claims description 89
- 241000282412 Homo Species 0.000 claims description 41
- DLGJWSVWTWEWBJ-HGGSSLSASA-N chondroitin Chemical compound CC(O)=N[C@@H]1[C@H](O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@H](O)C=C(C(O)=O)O1 DLGJWSVWTWEWBJ-HGGSSLSASA-N 0.000 claims description 26
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 claims description 7
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 claims description 7
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 claims description 7
- 229950006780 n-acetylglucosamine Drugs 0.000 claims description 7
- MTDHILKWIRSIHB-UHFFFAOYSA-N (5-azaniumyl-3,4,6-trihydroxyoxan-2-yl)methyl sulfate Chemical compound NC1C(O)OC(COS(O)(=O)=O)C(O)C1O MTDHILKWIRSIHB-UHFFFAOYSA-N 0.000 claims description 5
- 229960002849 glucosamine sulfate Drugs 0.000 claims description 5
- CBOJBBMQJBVCMW-BTVCFUMJSA-N (2r,3r,4s,5r)-2-amino-3,4,5,6-tetrahydroxyhexanal;hydrochloride Chemical compound Cl.O=C[C@H](N)[C@@H](O)[C@H](O)[C@H](O)CO CBOJBBMQJBVCMW-BTVCFUMJSA-N 0.000 claims description 4
- 150000002301 glucosamine derivatives Chemical class 0.000 claims description 4
- 229960001911 glucosamine hydrochloride Drugs 0.000 claims description 4
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 abstract description 65
- 229910052748 manganese Inorganic materials 0.000 abstract description 65
- 239000011572 manganese Substances 0.000 abstract description 65
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 30
- 235000019163 vitamin B12 Nutrition 0.000 abstract description 29
- 239000011715 vitamin B12 Substances 0.000 abstract description 29
- 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 abstract description 22
- 229930003779 Vitamin B12 Natural products 0.000 abstract description 19
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 abstract description 19
- 238000004519 manufacturing process Methods 0.000 abstract description 14
- -1 chondroitin salts Chemical class 0.000 abstract description 13
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 abstract description 11
- 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 abstract description 11
- 108700003601 dimethylglycine Proteins 0.000 abstract description 11
- 235000019152 folic acid Nutrition 0.000 abstract description 11
- 239000011724 folic acid Substances 0.000 abstract description 11
- 229960000304 folic acid Drugs 0.000 abstract description 11
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 abstract description 11
- 235000019158 vitamin B6 Nutrition 0.000 abstract description 11
- 239000011726 vitamin B6 Substances 0.000 abstract description 11
- 239000011159 matrix material Substances 0.000 abstract description 3
- 241000124008 Mammalia Species 0.000 abstract 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 abstract 2
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 abstract 1
- 229940011671 vitamin b6 Drugs 0.000 abstract 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 88
- 229920001287 Chondroitin sulfate Polymers 0.000 description 45
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 43
- 229940059329 chondroitin sulfate Drugs 0.000 description 43
- 235000010323 ascorbic acid Nutrition 0.000 description 41
- 239000011668 ascorbic acid Substances 0.000 description 41
- 229940072107 ascorbate Drugs 0.000 description 39
- 108010067787 Proteoglycans Proteins 0.000 description 32
- 102000016611 Proteoglycans Human genes 0.000 description 32
- 230000015572 biosynthetic process Effects 0.000 description 26
- 238000003786 synthesis reaction Methods 0.000 description 23
- 102000008186 Collagen Human genes 0.000 description 22
- 108010035532 Collagen Proteins 0.000 description 22
- 229920001436 collagen Polymers 0.000 description 22
- 150000002696 manganese Chemical class 0.000 description 17
- 235000000346 sugar Nutrition 0.000 description 16
- 241000283073 Equus caballus Species 0.000 description 15
- 230000009469 supplementation Effects 0.000 description 14
- 230000006870 function Effects 0.000 description 13
- 150000008163 sugars Chemical class 0.000 description 12
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 11
- 210000000845 cartilage Anatomy 0.000 description 11
- 229920002674 hyaluronan Polymers 0.000 description 11
- 229960003160 hyaluronic acid Drugs 0.000 description 11
- 230000007812 deficiency Effects 0.000 description 10
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 9
- 230000003110 anti-inflammatory effect Effects 0.000 description 9
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 8
- 235000015872 dietary supplement Nutrition 0.000 description 8
- 230000037361 pathway Effects 0.000 description 8
- 238000009790 rate-determining step (RDS) Methods 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 241000283086 Equidae Species 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 201000008482 osteoarthritis Diseases 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 230000017423 tissue regeneration Effects 0.000 description 7
- 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 6
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 6
- 230000000202 analgesic effect Effects 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000008103 glucose Substances 0.000 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 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 230000011987 methylation Effects 0.000 description 6
- 238000007069 methylation reaction Methods 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 230000008901 benefit Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 235000005911 diet Nutrition 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 229920000768 polyamine Polymers 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- RSYSVNVHLXTDIR-ZZMNMWMASA-L (2r)-2-[(1s)-1,2-dihydroxyethyl]-3-hydroxy-5-oxo-2h-furan-4-olate;manganese(2+) Chemical compound [Mn+2].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] RSYSVNVHLXTDIR-ZZMNMWMASA-L 0.000 description 4
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 description 4
- 102000003886 Glycoproteins Human genes 0.000 description 4
- 108090000288 Glycoproteins Proteins 0.000 description 4
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 4
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 4
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 4
- 230000001430 anti-depressive effect Effects 0.000 description 4
- 230000002917 arthritic effect Effects 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 230000003413 degradative effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229920002521 macromolecule Polymers 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 229930182817 methionine Natural products 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 229910052711 selenium Inorganic materials 0.000 description 4
- 239000011669 selenium Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 3
- 101710132601 Capsid protein Proteins 0.000 description 3
- 108010024636 Glutathione Proteins 0.000 description 3
- 229920002971 Heparan sulfate Polymers 0.000 description 3
- AEMOLEFTQBMNLQ-HNFCZKTMSA-N L-idopyranuronic acid Chemical compound OC1O[C@@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-HNFCZKTMSA-N 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 229960005305 adenosine Drugs 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 3
- 208000018631 connective tissue disease Diseases 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229960003180 glutathione Drugs 0.000 description 3
- 230000035876 healing Effects 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 239000006186 oral dosage form Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- WUUGFSXJNOTRMR-IOSLPCCCSA-N 5'-S-methyl-5'-thioadenosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CSC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 WUUGFSXJNOTRMR-IOSLPCCCSA-N 0.000 description 2
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 2
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 2
- 208000005623 Carcinogenesis Diseases 0.000 description 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 102000051366 Glycosyltransferases Human genes 0.000 description 2
- 108700023372 Glycosyltransferases Proteins 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 108010050808 Procollagen Proteins 0.000 description 2
- 229930003268 Vitamin C Natural products 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 210000001188 articular cartilage Anatomy 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 230000036952 cancer formation Effects 0.000 description 2
- 239000007894 caplet Substances 0.000 description 2
- 231100000504 carcinogenesis Toxicity 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000009232 chiropractic Methods 0.000 description 2
- 229940107200 chondroitin sulfates Drugs 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- 230000003412 degenerative effect Effects 0.000 description 2
- 229940019765 dermatin Drugs 0.000 description 2
- 230000000378 dietary effect Effects 0.000 description 2
- 150000002016 disaccharides Chemical group 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 description 2
- 229930182830 galactose Natural products 0.000 description 2
- 229940097043 glucuronic acid Drugs 0.000 description 2
- 150000004676 glycans Polymers 0.000 description 2
- 108700014210 glycosyltransferase activity proteins Proteins 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 210000001503 joint Anatomy 0.000 description 2
- 108700041430 link Proteins 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 238000007726 management method Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 150000002772 monosaccharides Chemical group 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000037081 physical activity Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 150000004804 polysaccharides Polymers 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 2
- 239000002516 radical scavenger Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 description 2
- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 description 2
- 230000019635 sulfation Effects 0.000 description 2
- 238000005670 sulfation reaction Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 210000002435 tendon Anatomy 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 235000019154 vitamin C Nutrition 0.000 description 2
- 239000011718 vitamin C Substances 0.000 description 2
- 230000029663 wound healing Effects 0.000 description 2
- 206010065687 Bone loss Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010007733 Catabolic state Diseases 0.000 description 1
- 241000777300 Congiopodidae Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 208000020564 Eye injury Diseases 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 206010023230 Joint stiffness Diseases 0.000 description 1
- 229920000288 Keratan sulfate Polymers 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 235000010582 Pisum sativum Nutrition 0.000 description 1
- 240000004713 Pisum sativum Species 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 239000005700 Putrescine Substances 0.000 description 1
- ZJUKTBDSGOFHSH-WFMPWKQPSA-N S-Adenosylhomocysteine Chemical compound O[C@@H]1[C@H](O)[C@@H](CSCC[C@H](N)C(O)=O)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZJUKTBDSGOFHSH-WFMPWKQPSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 description 1
- 230000001195 anabolic effect Effects 0.000 description 1
- 230000002202 anti-cholestatic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 125000003289 ascorbyl group Chemical group [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000005842 biochemical reaction Methods 0.000 description 1
- 230000008236 biological pathway Effects 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 150000001720 carbohydrates Chemical group 0.000 description 1
- 230000036996 cardiovascular health Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000003011 chondroprotective effect Effects 0.000 description 1
- 239000007931 coated granule Substances 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 230000037319 collagen production Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 210000000399 corneal endothelial cell Anatomy 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000009088 enzymatic function Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 230000002414 glycolytic effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 150000008273 hexosamines Chemical class 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 208000018937 joint inflammation Diseases 0.000 description 1
- 210000005067 joint tissue Anatomy 0.000 description 1
- KXCLCNHUUKTANI-RBIYJLQWSA-N keratan Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@H](COS(O)(=O)=O)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@H](O[C@@H](O[C@H]3[C@H]([C@@H](COS(O)(=O)=O)O[C@@H](O)[C@@H]3O)O)[C@H](NC(C)=O)[C@H]2O)COS(O)(=O)=O)O[C@H](COS(O)(=O)=O)[C@@H]1O KXCLCNHUUKTANI-RBIYJLQWSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-CLQWQSTFSA-N l-iduronic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@@H](O)[C@@H]1O AEMOLEFTQBMNLQ-CLQWQSTFSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 235000014571 nuts Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001855 preneoplastic effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 231100001055 skeletal defect Toxicity 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 229940063673 spermidine Drugs 0.000 description 1
- 229940063675 spermine Drugs 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 150000003464 sulfur compounds Chemical class 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 230000008364 tissue synthesis Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 208000002670 vitamin B12 deficiency Diseases 0.000 description 1
- 235000020985 whole grains Nutrition 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
-
- 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
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
-
- 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
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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]
Definitions
- the present invention relates to compositions for the repair and reduction of inflammation of connective tissue in humans and animals and, in particular, to compositions capable of promoting anti-inflammation, chondroprotection, chondromodulation, chondrostabilization, chondrometabolization and the repair and replacement of human and animal connective tissue.
- connective tissues of humans and animals are constantly subjected to stresses and strains from mechanical forces and from diseases that can result in afflictions, such as arthritis, joint inflammation and stiffness. Indeed, connective tissue afflictions are quite common, presently affecting millions of Americans. Further, such afflictions can be not only painful but, in their extreme, debilitating.
- connective tissue afflictions can be quite problematic. A simple decrease in the stress to which the connective tissue is subjected is often not an option, especially in the case of athletes and animals such as race horses. Consequently, treatment is often directed at controlling the symptoms of the afflictions and not their causes, regardless of the stage of the degenerative process.
- steroids such as corticosteroids and NSAIDs
- corticosteroids such as corticosteroids and NSAIDs
- drugs such as these, which inhibit the body's own natural healing processes, may lead to further deterioration of the connective tissue.
- Connective tissue for example articular cartilage
- Connective tissue is naturally equipped to repair itself by manufacturing and remodeling prodigious amounts of collagen (a chief component of connective tissue such as cartilage) and proteoglycans (PGs) (the other major component of connective tissue such as cartilage).
- collagen a chief component of connective tissue such as cartilage
- proteoglycans the other major component of connective tissue such as cartilage
- the building blocks for collagen are amino acids, especially proline, glycine and lysine.
- PGs are large and complex macromolecules comprised mainly of long chains of modified sugars called glycosaminoglycans (GAGs) or mucopolysaccharides.
- GAGs glycosaminoglycans
- mucopolysaccharides are understood in the art to be interchangeable.
- PGs provide the framework for collagen formation and also hold water to give flexibility, resiliency and resistance to compression.
- the pathways by which both collagen and GAG form single molecule precursors are quite long.
- the pathways by which collagen and GAGs are produced include what is called a rate-limiting step—that is, one highly regulated control point beyond which there is a commitment to finish.
- the presence of such rate-limiting steps permits complicated biosynthetic processes to be more easily and efficiently controlled by permitting the organism to focus on one point. For example, if conditions demand production and all the requisite raw materials are in place, then stimulation of the rate-limiting step will cause the end product to be produced. To stop or slow production, the organism needs simply to regulate the rate-limiting step.
- the rate-limiting step is the conversion of glucose to glucosamine for the production of GAGs.
- Glucosamine an aminosugar, is the key precursor to all the various modified sugars found in GAGs, including glucosamine sulfate, galactosamine, N-acetylglucosamine, etc.
- Glucosamine also makes up to 50% of hyaluronic acid—the backbone of PGs—on which other GAGs, like chondroitin sulfate are added.
- the GAGs are then used to build PGs and, eventually, connective tissue. Once glucosamine is formed, there is no turning away from the synthesis of GAG polymers.
- Glucosamine has been shown to be rapidly absorbed into humans and animals after oral administration. A significant portion of the ingested glucosamine localizes to cartilage and joint tissues, where it remains for long periods. This indicates that oral administration of glucosamine reaches connective tissues, where glucosamine is incorporated into newly-synthesized connective tissue.
- Glycosaminoglycans and collagen are the chief structural elements of all connective tissues. Their synthesis is essential for proper maintenance and repair of connective tissues. In vitro, the introduction of glucosamine has been demonstrated to increase the synthesis of collagen and glycosaminoglycans in fibroblasts, which is the first step in repair of connective tissues. In vivo, topical application of glucosamine has enhanced wound healing. Glucosamine has also exhibited reproducible improvement in symptoms and cartilage integrity in humans with osteoarthritis. [L. Bucci, Nutritional Supplement Advisor , (July 1992)].
- Glucosamine is the main building block of connective tissue and may be provided either through the enzymatic conversion of glucose or through diet or external administration (see FIG. 1 ). Glucosamine may be converted into the other main component of connective tissue, namely PGs, upon incorporation of glucosamine into GAGs (see FIG. 2 ).
- GAGs are large complexes of polysaccharide chains associated with a small amount of protein. These compounds have the ability to bind large amounts of water, thereby producing a gel-like matrix that forms the body's ground substance. GAGs stabilize and support cellular and fibrous components of tissue while maintaining the water and salt balance of the body. The combination of insoluble protein and the ground substance forms connective tissue. For example, cartilage is rich in ground substance while tendon is composed primarily of fibers.
- GAGs are long chains composed of repeating disaccharide units of monosaccharides (aminosugar-acidic sugar repeating units).
- the aminosugar is typically glucosamine or galactosamine.
- the aminosugar may also be sulfated.
- the acidic sugar may be D-glucuronic acid or L-iduronic acid.
- GAGs, with the exception of hyaluronic acid are covalently bound to a protein, forming proteoglycan monomers.
- These PGs consist of a core protein to which linear carbohydrate chains formed of monosaccharides are attached.
- the species of GAGs include chondroitin sulfate and keratin sulfate.
- the proteoglycan monomers then associate with a molecule of hyaluronic acid to form PG aggregates. The association of the core protein to hyaluronic acid is stabilized by link proteins.
- the polysaccharide chains are elongated by the sequential addition of acidic sugars and aminosugars, and the addition is catalyzed by a family of transferases.
- Aminosugars such as glucosamine, are synthesized through a series of enzymatic reactions that convert glucose to glucosamine, or alternatively may be provided through the diet. The glucosamine is then incorporated into the GAGs as described above.
- Acidic sugars may be provided through the diet, may be obtained through degradation of GAGs by degradative enzymes, or produced through the uronic acid pathway.
- All GAGs contain hexosamine or uronic acid derivative products of the glucose pathway and from exogenous glucosamine, for example: Hyaluronic acid Glucosamine + Glucuronic Acid Keretan-Sulfate Glucosamine + Galactose Chondroitin Sulfate Glucuronic Acid + Galactosamine Heparin Sulfate Glucosamine + Glucuronic or Iduronic Acid Heparan Sulfate Glucosamine + Glucuronic or Iduronic Acid Dermatin Sulfate Iduronic Acid + Galactosamine
- Chondroitin sulfate is a GAG that provides a further substrate for the synthesis of the proteoglycans.
- the provision of the chondroitin in its salt (sulfate) form facilitates its delivery and uptake by the humans and animals in the production of connective tissue.
- the sulfate portion of chondroitin sulfate is available for use in catalyzing the conversion of glucosamine to GAGs.
- Fragments of GAGs, including chondroitin sulfate may also be used to provide a substrate for synthesis of proteoglycans since the assembly of PG occurs in the extracellular space.
- glycosaminoglycan has been shown to have cardiovascular health benefits. [Morrison et al., Coronary Heart Disease and the Mucopolysaccharides ( Glycosaminoglycans ), pp. 109-127 (1973)].
- the preferred form of glycosaminoglycan included in the compositions of the present invention is chondroitin sulfate or fragments thereof.
- Chondroitin sulfate also acts to inhibit the degradative enzymes that break down connective tissue. In so doing, chondroitin sulfate promotes the maintenance of healthy connective tissues.
- chondroitin sulfate works in concert with the glucosamine but may work in a different fashion. The ability of chondroitin sulfate to block degradation is one of its important functions.
- SAM S-Adenosylmethionine
- SAM plays a significant role in transmethylation processes with more than 40 anabolic or catabolic reactions involving the transfer of the methyl group of SAM to substrates such as nucleic acids, proteins, and lipids, among others.
- the release of the methyl group from SAM is the start of a “transsulfuration” pathway that produces all endogenous sulfur compounds.
- SAM After donating its methyl group, SAM is converted into.
- S-adenosylhomocysteine which in turn is hydrolyzed to adenosine and homocysteine.
- the amino acid cysteine may then be produced from the homocysteine.
- the cysteine thus produced may exert a reducing effect by itself or as an active part of glutathione, which is a main cell anti-oxidant. [Stramentinoli, cited above].
- SAM has been used to treat various disorders. In various forms of liver disease, SAM acts as an anticholestatic agent. [Adachi et al., Japan Arch. Inter. Med., 33:185-192 (1986).]. SAM has also been administered as an antidepressant for use in the management of psychiatric disorders [Caruso et al., Lancet, 1: 904 (1984)], and as an anti-inflammatory compound in the management of osteoarthritis [Domljan et al., Int. J. Clin. Pharm. Toxicol., 27(7):329-333 (1989)].
- SAM per se is unstable due to its high reactivity.
- the relatively recent synthesis of stable salts has made SAM available for research and therapeutic use. [See, e.g., U.S. Pat. Nos. 4,990,606 and 5,102,791].
- SAM has been used outside of the United States in a number of clinical trials concerning the treatment of osteoarthritis. While used in these trials primarily as an analgesic and replacement for NSAID therapy, SAM is a precursor of polyamines. In addition to their analgesic and anti-inflammatory properties, and their ability to scavenge free radicals, polyamines may stabilize the polyanionic macromolecules of proteoglycans. [Schumacher, Am. J. Med., 83(5A):2 (1987)].
- SAM may also function as a source of endogenous sulfur, which will increase sulfation of GAGs to be incorporated in proteoglycans.
- the inclusion of SAM is particularly beneficial in instances of subclinical deficiencies of SAM, occurring especially in elderly populations with higher risk of osteoarthritis [Frezza et al., Gastroenterol., 99:211-215 (1990)].
- the supplementation of SAM may aid in instances of SAM deficiency where the ability of the body to sulfate GAGs may be compromised.
- a number of metabolites of SAM aid in the repair of connective tissue, including glutathione, polyamines, methylthioadenosine, and adenosine.
- Glutathione works as a scavenger of oxygen-related products [Shumacher, Am. J. Med., 83(Supp 5a) :1-4 (1987); Matthew & Lewis, Pharmacol . ( Life Sci. Adv .), 9:145-152 (1990); Szabo et al., Science, 214:200-202 (1981)] and thus has an anti-inflammatory effect.
- Polyamines including spermine, spermidine, and putrescine, stabilize polyanionic macromolecules of proteoglycans [Schumacher, cited above; Conroy et al., Biochem. J., 162:347-350 (1977)] and thus protect proteolytic and glycolytic enzymes.
- the SAM metabolite methylthioadenosine has a pronounced anti-inflammatory effect [Matthews & Lewis, 1990] while adenosine has a more modest anti-inflammatory effect [Matthews & Lewis, 1990].
- exogenous SAM is stable in digestive juices when given orally.
- the metabolism of exogenous SAM appears to follow known pathways of endogenous SAM metabolism.
- oral SAM was tolerated to the same extent as placebo with very mild nonspecific side effects.
- glycosyltransferases are important in glycosaminoglycan synthesis (hyaluronic acid, chondroitin sulfate, keratan sulfate, heparin sulfate and dermatin sulfate, etc.), collagen synthesis, and in the functions of many other glycoproteins and glycolipids.
- Manganese deficiency leads to abnormal bone growth, swollen and enlarged joints, and slipped tendons in humans and animals. In humans, manganese deficiencies are also associated with bone loss and arthritis. Levels of all glycosaminoglycans are decreased in connective tissues during manganese deficiencies, with chondroitin sulfates being most depleted. Manganese-deficient organisms quickly normalize glycosaminoglycans and collagen synthesis when manganese is replenished.
- methyl donors or methyl donor cofactors such as vitamins B12 and B6, folic acid, dimethylglycine, and trimethylglycine.
- vitamins B12 and B6 folic acid
- dimethylglycine dimethylglycine
- trimethylglycine trimethylglycine
- these compounds augment the function of SAM in that they are cofactors in methylation.
- these compounds are likely to be lacking in patients suffering from connective tissue disorders. For example, it is estimated that 12% of the elderly population in the United States suffers from a vitamin B12 deficiency, a group more likely to suffer from connective tissue disorders.
- vitamin B12 has an important environmental influence on the accumulation of homocysteine that results from the metabolism of SAM.
- methyl donors or methyl donor cofactors such as vitamin B12 and the others listed in the preceding paragraph, can reduce levels of homocysteine when administered either alone or in combination.
- Vitamin B12 is generally known to function as a coenzyme in biochemical reactions such as the synthesis of proprionic acid and of methionine. Recent evidence suggests that the elevated levels of plasma homocysteine increase the risk of occlusive vascular disease. Adequate amounts of vitamin B12 are considered the most important environmental influence on the accumulation of unnecessary homocysteine. [Joosten et al., Am. J. Clin. Nutr., 58(4): 468-76 (1993)]. In addition, it is also understood that vitamin B12 may play a role in the methylation of selenium. [Chen and Whanger, Tox. and Appl. Pharm., 118:65-72 (1993)]. Specifically, increased levels of vitamin B12 significantly contribute to selenium methylation and might decrease overall selenium toxicity by preventing its accumulation in tissues. [Chen and Whanger, cited above].
- glucosamine increases synthesis of collagen and glycosaminoglycans, the first step in repair of connective tissues, in fibroblasts.
- topical application of glucosamine has enhanced wound healing.
- compositions which include analgesic, anti-inflammatory, and antidepressant components, as well as components that provide the building blocks for the production of connective tissue in humans and that also protect against the degradation of that tissue.
- compositions which contain S-Adenosylmethionine and an aminosugar or salts thereof, such as glucosamine, for facilitating the repair and reducing the inflammation of connective tissue in humans and animals.
- compositions which contain S-Adenosylmethionine and GAGs, such as chondroitin salts and fragments thereof, for facilitating the repair and for reducing the inflammation of connective tissue in humans and animals.
- compositions which contain S-Adenosylmethionine, an aminosugar or salts thereof, and GAGs or fragments thereof for facilitating the repair and for reducing the inflammation of connective tissue in humans and animals.
- methyl donors or methyl donor cofactors such as vitamins B12 and B6, folic acid, dimethylglycine, and trimethylglycine, to the compositions of the present invention for humans and animals if desirable.
- FIG. 1 is a sequence for the biosynthesis of hexosamines.
- FIG. 2 is a schematic flowchart illustrating the biological pathway by which the composition of the present invention aids in protection and repair of connective tissue.
- FIG. 3 is an enlarged portion of the flowchart of FIG. 2 .
- a composition selected from the group consisting of SAM and an aminosugar or salts thereof e.g., glucosamine
- SAM and GAGs e.g., chondroitin salts
- SAM, an aminosugar (or salts thereof), and GAGs (or fragments thereof) is provided to humans and animals for stimulating both collagen and PG synthesis and for reducing inflammation.
- Manganese preferably manganese salts, may optionally be included to any of these compositions.
- other optional ingredients include methyl donors or methyl donor cofactors, such as vitamins B12 and B6, folic acid, dimethylglycine, and trimethylglycine.
- compositions may act to accomplish several functions, including bypassing the glucose to glucosamine rate-limiting step in the natural production of proteoglycans in humans and animals, and producing additional quantities of collagen and proteoglycans for use in the repair of damaged connective tissue.
- inflammation of connective tissue may be reduced by the compositions of the invention.
- the compositions of the present invention may achieve these functions directly or through indirect pathways—i.e., through their effect on other components in the living system which in turn can increase connective tissue synthesis or reduce inflammation.
- a composition of the present invention include S-Adenosylmethionine (SAM) and an aminosugar, such as glucosamine, preferably in a salt form.
- SAM S-Adenosylmethionine
- the composition includes SAM and a glycosaminoglycan, such as chondroitin (preferably in a salt form such as chondroitin sulfate).
- the composition of the present invention includes SAM, an aminosugar, such as glucosamine, preferably in a salt form, and a glycosaminoglycan, such as chondroitin (preferably in a salt form, such as chondroitin sulfate).
- fragments of a glycosaminoglycan may be used in a composition of the invention in addition to or in substitution for the glycosaminoglycan.
- Each of these compositions may optionally include manganese.
- a preferred form of manganese in such compositions is a manganese salt, such as manganese ascorbate, because the ascorbate is a soluble form of manganese which further provides ascorbic acid, a substance needed for collagen synthesis.
- Other manganese salts such, as for example, sulfate or gluconate, may be used however.
- Each of these compositions may optionally contain one or more methyl donors or methyl donor cofactors selected from the group consisting of vitamins B12 and B6, folic acid, dimethylglycine, and trimethylglycine.
- the biosynthetic pathway for the production of connective tissue which is affected by the method of the present invention by virtue of the components of the composition of the present invention which aid in connective tissue repair, functions as described in the above background section of this application.
- the aminosugar glucosamine is the base of the composition, providing the primary substrate for both collagen and proteoglycan synthesis.
- Glucosamine is the preferred substrate for proteoglycan synthesis, including chondroitin sulfates and hyaluronic acid.
- the glucosamine preferably is in a salt form so as to facilitate its delivery and uptake by humans and animals.
- the preferred salt forms are glucosamine hydrochloride, glucosamine sulfate and N-acetylglucosamine.
- composition of the present invention provides the human or animal organism with exogenous quantities of SAM, an aminosugar or salts thereof, and a glycosaminoglycan or fragments thereof. If desired, the composition also provides the human or animal organism with exogenous quantities of manganese cofactors. Also if desired, the compositions of the present invention may include methyl donors or methyl donor cofactors, such as vitamins B12 and B6, folic acid, dimethylglycine, and trimethylglycine.
- exogenous glucosamine provided by the composition of present invention is converted to proteoglycans as is seen in FIG. 2 and as described above.
- the glucosamine may be converted with the aid of manganese directly into GAG, including hyaluronic acid (which is 50% glucosamine and which forms the backbone of the proteoglycans).
- This core protein is then linked to the hyaluronic acid via the link protein, as is seen in FIG. 3 .
- the free amino acids are, with the aid of manganese and zinc cofactors (and ascorbic acid or vitamin C), converted to procollagen.
- the procollagen is then converted into collagen with the aid of copper or iron cofactors and vitamin C (ascorbic acid) and sulfate chelates.
- compositions of the present invention containing SAM and glucosamine advantageously stimulate the synthesis of collagen and glycosaminoglycans or mucopolysaccharides (GAGS), including hyaluronic acid, the backbone of proteoglycans (PG's), thereby providing a natural tissue repair function.
- GGS glycosaminoglycans or mucopolysaccharides
- PG's proteoglycans
- These compositions provide the connective tissue repair function of glucosamine, the increased sulfation of GAGs by SAM, the stabilization by SAM metabolites of the polyanionic macromolecules of proteoglycans, and the additional analgesic, anti-inflammatory, and anti-depressant effects of SAM.
- manganese provides a further benefit if a deficiency of the mineral exists or if it is otherwise desired.
- methyl donors or methyl donor cofactors such as vitamins B12 and B6, folic acid, dimethylglycine, and trimethylglycine, helps to promote methylation and thereby convert homocysteine to methionine.
- compositions of the invention comprises SAM and chondroitin salts (such as chondroitin sulfate).
- SAM operates in this composition, in conjunction with endogenous glucosamine, as described above.
- Chondroitin salts operate with SAM and endogenous glucosamine by inhibiting the synovial degradative enzymes.
- Chondroitin salts (such as chondroitin sulfate) also directly contribute to the pool of GAGs of cartilaginous tissue.
- Manganese salts may also be included in this composition in those cases where a deficiency of manganese exists.
- Methyl donors or methyl donor cofactors such as vitamins B12 and B6, folic acid, dimethylglycine, and trimethylglycine, may optionally be included in these compositions to help promote methylation and thereby convert homocysteine to methionine.
- composition of the present invention contains SAM, glucosamine, and chondroitin salts (such as chondroitin sulfate) and mixtures and fragments thereof, and also advantageously stimulates the synthesis of collagen and glycosaminoglycans or mucopolysaccharides (GAGs), including hyaluronic acid, thereby providing a natural tissue repair function.
- This composition provides the superior connective tissue repair function of glucosamine, the above-described benefits of SAM, and the above-described benefits from chondroitin salts (including chondroitin sulfate) and fragments of chondroitin salts.
- Chondroitin salts (including chondroitin sulfate) also operate with SAM and glucosamine by inhibiting the synovial degradative enzymes. Chondroitin salts (including chondroitin sulfate) also directly contribute to the pool of GAGs of cartilaginous tissue. Manganese provides a further benefit if a deficiency of the mineral exists.
- methyl donors or methyl donor cofactors such as vitamins B12 and B6, folic acid, dimethylglycine, and trimethylglycine, may optionally be included in these compositions to help promote methylation and thereby convert homocysteine to methionine. Tissue repair can thus be accomplished, in the context of the treatment and repair of connective tissue and the treatment of arthritic conditions, in almost all areas of the body both human and animal.
- compositions comprising amounts of SAM in combination with glucosamine including salts thereof in combination with chondroitin salts (including chondroitin sulfate) or fragments thereof, or amounts of SAM and chondroitin salts (including chondroitin sulfate) or fragments thereof in combination with glucosamine including salts thereof, may be administered to humans and animals thereof for stimulating both collagen and proteoglycan synthesis.
- An additional preferred composition comprising amounts of SAM and chondroitin salts (including chondroitin sulfate) or fragments thereof may be administered to humans and animals for stimulating proteoglycan synthesis and reducing inflammation.
- Manganese salts may also be optionally included in each composition in cases where a deficiency of manganese exists.
- Methyl donors or methyl donor cofactors such as vitamins B12 and B6, folic acid, dimethylglycine, and trimethylglycine may optionally be included to these compositions as well.
- compositions of the present invention are administered to promote tissue repair, including cartilage repair, and the treatment of arthritic conditions as well as connective tissue damage in humans and animals.
- the anti-depressant effect of SAM may help to alleviate the burden of sickness for some patients, thus enhancing their quality of life.
- This effect, as well as the analgesic and anti-inflammatory effects of SAM which will help alleviate the pain associated with arthritic conditions may help remove impediments to physical activity. Increased levels of physical activity, in turn, can supply the loading and unloading forces necessary for the regeneration of articular cartilage. Supplementation with glucosamine, with its chondroprotective role, thus helps to ensure that the raw materials are available to support the increased regeneration of cartilage.
- the compositions of the present invention are also understood to play a role in chondromodulation, chondrostabilization, and chondrometabolizaton.
- the dosage of SAM in the nutritional supplements of the present invention ranges from about 5 mg to about 5,000 mg in humans and small animals, and from about 2 mg to about 20,000 mg in large animals (e.g., equine).
- the dosage of glucosamine in the nutritional supplements of the present invention ranges from about 50 mg to about 5,000 mg in humans and small animals, and from about 250 mg to about 40,000 mg in large animals (e.g., equine).
- the dosage of chondroitin salts in the nutritional supplements of the present invention ranges from about 15 mg to about 5,000 mg in humans and small animals, and from about 100 mg to about 30,000 mg in large animals.
- manganese When included in the compositions of the present invention, manganese may optionally be present in the range of about 2 to about 75 mg in humans and small animals, and from about 10 mg to about 500 mg in large animals.
- the ascorbate component of the manganese ascorbate may range from about 10 mg to about 500 mg in humans and small animals, and from about 50 mg to about 2,500 mg in large animals.
- the methyl donors or methyl donor cofactors such as vitamins B12 and B6, folic acid, dimethylglycine, and trimethylglycine may be present in the range of about 0.1 mg to about 10 mg in humans and small animals, and from about 1 mg to about 100 mg in large animals.
- a dosage of the nutritional supplement composition of the present invention may consist of one or more capsules or tablets for human oral consumption.
- the preferred weight of the dosage is between about 5 mg to about 5,000 mg, and preferably about 2,500 mg.
- the dosage may be administered in a single daily dosage form in which all components are present, e.g., a capsule or tablet of preferably 2,500 mg.
- the dosage may also be administered in more than one dosage form in which each dosage form contains at least one component.
- the multiple dosage forms may be co-administered as a single dosage.
- a single dosage may be comprised of a SAM dosage form co-administered with a glucosamine and chondroitin salts dosage form.
- the nutritional supplement compositions of the present invention may be administered more than once daily.
- the nutritional supplement compositions of the present invention may be in the form of an oral dosage form of 1250 mg administered twice daily or 833 mg administered three times daily.
- the number of daily administrations will depend upon the needs of the human or animal recipient. Different connective tissue disorders and injuries require different amounts of the compositions of the present invention. In that regard, several dosages may be administered depending on the particular needs of the human or animal.
- compositions of the present invention may for example be administered in scoops.
- Such administration may take the form, for example, of a level scoopful containing about 1,800 mg glucosamine, about 600 mg chondroitin salts, about 16 mg of manganese (when included in the form of manganese ascorbate), and about 104 mg of ascorbate (when included in the form of manganese ascorbate).
- compositions of the invention may be made by conventional methods.
- the above-described ingredients are combined as the active ingredient in intimate admixture with a suitable carrier according to conventional compounding techniques.
- This carrier may take a wide variety of forms depending upon the form of preparation desired for administration, e.g., oral, sublingual, nasal, guttural, rectal, transdermal or parenteral.
- any usual pharmaceutical medium may be employed.
- oral liquid preparations e.g., suspensions, elixirs, and solutions
- media containing for example, water, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used.
- Carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to prepare oral solids (e.g., powders, capsules, pills, caplets, tablets, microencapsulated granules, microtablets, coated granules and lozenges).
- Capsules or tablets are a preferred oral dosage form. Controlled release forms may also be used.
- lozenges, tablets, pills, caplets, and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
- the compositions of the present invention may be in the form of one or more of these oral dosage forms—i.e., a single dosage may be in multiple forms.
- the carrier will usually comprise sterile water, although other ingredients may be included, e.g., to aid solubility or for preservation purposes.
- injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents, and the like may be employed.
- composition of the present invention is made in one or more capsules for oral administration in humans and small animals.
- each dosage contains: Human & Small Animal Range/Dose SAM 5-5,000 mg Glucosamine 50-5,000 mg Chondroitin Sulfate 15-5,000 mg
- a manganese salt is added to the composition of Example 1 so that each dosage contains: Human & Small Animal Range/Dose SAM 5-5,000 mg Glucosamine 50-5,000 mg Chondroitin Sulfate 15-5,000 mg Manganese (as Ascorbate) 2-75 mg Ascorbate (as Manganese 10-500 mg Ascorbate)
- Example 1 For larger animals, such as horses, the composition of Example 1 is administered as filled-scoops.
- manganese salts may be added to the composition of Example 3 so that each dosage contains: Large Animal (Equine) Range/Dose SAM 2-20,000 mg Glucosamine 250-40,000 mg Chondroitin Sulfate 100-30,000 mg Manganese (as Ascorbate) 10-500 mg Ascorbate (as Manganese 50-2,500 mg Ascorbate)
- each dosage contains: Human & Small Animal Range/Dose SAM 5-5,000 mg Glucosamine 50-5,000 mg
- a manganese salt is added to the composition of Example 5 so that each dosage contains: Human & Small Animal Range/Dose SAM 5-5,000 mg Glucosamine 50-5,000 mg Manganese (as Ascorbate) 2-75 mg Ascorbate (as Manganese 10-500 mg Ascorbate)
- Example 5 For larger animals, such as horses, the composition of Example 5 is administered as filled scoops.
- manganese salts may be added to the composition of Example 7 so that each dosage contains: Large Animal (Equine) Range/Dose SAM 2-20,000 mg Glucosamine 250-40,000 mg Manganese (as Ascorbate) 10-500 mg Ascorbate (as Manganese 50-2,500 mg Ascorbate)
- each dosage contains: Human & Small Animal Range/Dose SAM 5-5,000 mg Chondroitin Sulfate 15-5,000 mg
- a manganese salt is added to the composition of Example 9 so that each dosage contains: Human & Small Animal Range e/Dose SAM 5-5,000 mg Chondroitin Sulfate 15-5,000 mg Manganese (as Ascorbate) 2-75 mg Ascorbate (as Manganese 10-500 mg Ascorbate)
- Example 10 For larger animals, such as horses, the composition of Example 10 is administered as filled scoops.
- manganese salts may be added to the composition of Example 11 so that each dosage contains: Large Animal (Equine) Range/Dose SAM 2-20,000 mg Chondroitin Sulfate 100-30,000 mg Manganese (as Ascorbate) 10-500 mg Ascorbate (as Manganese 50-2,500 mg Ascorbate)
- each dosage contains: Human & Small Animal Range/Dose SAM 5-5,000 mg Glucosamine 50-5,000 mg Chondroitin Sulfate 15-5,000 mg vitamin B12 0.1-10 mg
- a manganese salt is added to the composition of Example 13 so that each dosage contains: Human & Small Animal Range/Dose SAM 5-5,000 mg Glucosamine 50-5,000 mg Chondroitin Sulfate 15-5,000 mg Manganese (as Ascorbate) 2-75 mg Ascorbate (as Manganese 10-500 mg Ascorbate) vitamin B12 0.1-10 mg
- Example 13 For larger animals, such as horses, the composition of Example 13 is administered as filled scoops.
- manganese salts may be added to the composition of Example 15 so that each dosage contains: Large Animal (Equine) Range/Dose SAM 2-20,000 mg Glucosamine 250-40,000 mg Chondroitin Sulfate 100-30,000 mg Manganese (as Ascorbate) 10-500 mg Ascorbate (as Manganese 50-2,500 mg Ascorbate) vitamin B12 1-100 mg
- each dosage contains: Human & Small Animal Range/Dose SAM 5-5,000 mg Glucosamine 50-5,000 mg vitamin B12 0.1-10 mg
- a manganese salt is added to the composition of Example 17 so that each dosage contains: Human & Small Animal Range/Dose SAM 5-5,000 mg Glucosamine 50-5,000 mg Manganese (as Ascorbate) 2-75 mg Ascorbate (as Manganese 10-500 mg Ascorbate) vitamin B12 0.1-10 mg
- Example 17 For larger animals, such as horses, the composition of Example 17 is administered as filled scoops.
- manganese salts may be added to the composition of Example 19 so that each dosage contains: Large Animal (Equine) Range/Dose SAM 2-20,000 mg Glucosamine 250-40,000 mg Manganese (as Ascorbate) 10-500 mg Ascorbate (as Manganese 50-2,500 mg Ascorbate) vitamin B12 1-100 mg
- each dosage contains: Human & Small Animal Range/Dose SAM 5-5,000 mg Chondroitin Sulfate 15-5,000 mg vitamin B12 0.1-10 mg
- a manganese salt is added to the composition of Example 21 so that each dosage contains: Human & Small Animal Range e/Dose SAM 5-5,000 mg Chondroitin Sulfate 15-5,000 mg Manganese (as Ascorbate) 2-75 mg Ascorbate (as Manganese 10-500 mg Ascorbate) vitamin B12 0.1-10 mg
- Example 21 For larger animals, such as horses, the composition of Example 21 is administered as filled scoops.
- manganese salts may be added to the composition of Example 23 so that each dosage contains: Large Animal (Equine) Range/Dose SAM 2-20,000 mg Chondroitin Sulfate 100-30,000 mg Manganese (as Ascorbate) 10-500 mg Ascorbate (as Manganese 50-2,500 mg Ascorbate) vitamin B12 1-100 mg
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Dermatology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A composition for the protection, treatment and repair and for reducing the inflammation of connective tissue in mammals and a method for the treatment of connective tissue in mammals by the administration of the composition. The composition includes S-Adenosylmethionine (SAM), and a component selected from an aminosugar or salts thereof (e.g., glucosamine) or glycosaminoglycans (e.g., chondroitin salts) or mixtures or fragments thereof. The composition optionally includes manganese which promotes the production of connective tissue matrix. The composition also optionally includes methyl donors or methyl donor cofactors, such as vitamin B12, vitamin B6, folic acid, dimethylglycine or trimethylglycine.
Description
- The present application is a continuation-in-part of co-pending U.S. patent application Ser. No. 08/779,996, filed Dec. 23, 1996, the disclosure of which is incorporated by reference herein in its entirety.
- 1. Field of the Invention
- The present invention relates to compositions for the repair and reduction of inflammation of connective tissue in humans and animals and, in particular, to compositions capable of promoting anti-inflammation, chondroprotection, chondromodulation, chondrostabilization, chondrometabolization and the repair and replacement of human and animal connective tissue.
- 2. Background of the Invention
- The connective tissues of humans and animals are constantly subjected to stresses and strains from mechanical forces and from diseases that can result in afflictions, such as arthritis, joint inflammation and stiffness. Indeed, connective tissue afflictions are quite common, presently affecting millions of Americans. Further, such afflictions can be not only painful but, in their extreme, debilitating.
- The treatment of connective tissue afflictions can be quite problematic. A simple decrease in the stress to which the connective tissue is subjected is often not an option, especially in the case of athletes and animals such as race horses. Consequently, treatment is often directed at controlling the symptoms of the afflictions and not their causes, regardless of the stage of the degenerative process.
- Presently, steroids, such as corticosteroids and NSAIDs, are widely used for the treatment of these ailments. [Vidal, et al., Pharmocol. Res. Commun., 10:557-569 (1978)]. However, drugs such as these, which inhibit the body's own natural healing processes, may lead to further deterioration of the connective tissue.
- Connective tissue, for example articular cartilage, is naturally equipped to repair itself by manufacturing and remodeling prodigious amounts of collagen (a chief component of connective tissue such as cartilage) and proteoglycans (PGs) (the other major component of connective tissue such as cartilage). This ongoing process is placed under stress when an injury occurs. In such cases, the production of connective tissue matrix (collagen and PGs) can double or triple over normal levels, thereby increasing the demand for the building blocks of both collagens and proteoglycans.
- The building blocks for collagen are amino acids, especially proline, glycine and lysine. PGs are large and complex macromolecules comprised mainly of long chains of modified sugars called glycosaminoglycans (GAGs) or mucopolysaccharides. The terms GAGs and mucopolysaccharides are understood in the art to be interchangeable. PGs provide the framework for collagen formation and also hold water to give flexibility, resiliency and resistance to compression.
- Like almost every biosynthetic pathway in the body, the pathways by which both collagen and GAG form single molecule precursors are quite long. As is also characteristic of other biosynthetic pathways, the pathways by which collagen and GAGs are produced include what is called a rate-limiting step—that is, one highly regulated control point beyond which there is a commitment to finish. The presence of such rate-limiting steps permits complicated biosynthetic processes to be more easily and efficiently controlled by permitting the organism to focus on one point. For example, if conditions demand production and all the requisite raw materials are in place, then stimulation of the rate-limiting step will cause the end product to be produced. To stop or slow production, the organism needs simply to regulate the rate-limiting step.
- In the production of PGs, the rate-limiting step is the conversion of glucose to glucosamine for the production of GAGs. Glucosamine, an aminosugar, is the key precursor to all the various modified sugars found in GAGs, including glucosamine sulfate, galactosamine, N-acetylglucosamine, etc. Glucosamine also makes up to 50% of hyaluronic acid—the backbone of PGs—on which other GAGs, like chondroitin sulfate are added. The GAGs are then used to build PGs and, eventually, connective tissue. Once glucosamine is formed, there is no turning away from the synthesis of GAG polymers.
- Glucosamine has been shown to be rapidly absorbed into humans and animals after oral administration. A significant portion of the ingested glucosamine localizes to cartilage and joint tissues, where it remains for long periods. This indicates that oral administration of glucosamine reaches connective tissues, where glucosamine is incorporated into newly-synthesized connective tissue.
- Glycosaminoglycans and collagen are the chief structural elements of all connective tissues. Their synthesis is essential for proper maintenance and repair of connective tissues. In vitro, the introduction of glucosamine has been demonstrated to increase the synthesis of collagen and glycosaminoglycans in fibroblasts, which is the first step in repair of connective tissues. In vivo, topical application of glucosamine has enhanced wound healing. Glucosamine has also exhibited reproducible improvement in symptoms and cartilage integrity in humans with osteoarthritis. [L. Bucci, Nutritional Supplement Advisor, (July 1992)].
- The pathway for the production of proteoglycans may be briefly described as follows. Glucosamine is the main building block of connective tissue and may be provided either through the enzymatic conversion of glucose or through diet or external administration (see
FIG. 1 ). Glucosamine may be converted into the other main component of connective tissue, namely PGs, upon incorporation of glucosamine into GAGs (seeFIG. 2 ). - More specifically, GAGs are large complexes of polysaccharide chains associated with a small amount of protein. These compounds have the ability to bind large amounts of water, thereby producing a gel-like matrix that forms the body's ground substance. GAGs stabilize and support cellular and fibrous components of tissue while maintaining the water and salt balance of the body. The combination of insoluble protein and the ground substance forms connective tissue. For example, cartilage is rich in ground substance while tendon is composed primarily of fibers.
- GAGs are long chains composed of repeating disaccharide units of monosaccharides (aminosugar-acidic sugar repeating units). The aminosugar is typically glucosamine or galactosamine. The aminosugar may also be sulfated. The acidic sugar may be D-glucuronic acid or L-iduronic acid. GAGs, with the exception of hyaluronic acid, are covalently bound to a protein, forming proteoglycan monomers. These PGs consist of a core protein to which linear carbohydrate chains formed of monosaccharides are attached. In cartilage proteoglycan, the species of GAGs include chondroitin sulfate and keratin sulfate. The proteoglycan monomers then associate with a molecule of hyaluronic acid to form PG aggregates. The association of the core protein to hyaluronic acid is stabilized by link proteins.
- The polysaccharide chains are elongated by the sequential addition of acidic sugars and aminosugars, and the addition is catalyzed by a family of transferases. Aminosugars, such as glucosamine, are synthesized through a series of enzymatic reactions that convert glucose to glucosamine, or alternatively may be provided through the diet. The glucosamine is then incorporated into the GAGs as described above. Acidic sugars may be provided through the diet, may be obtained through degradation of GAGs by degradative enzymes, or produced through the uronic acid pathway.
- Since repeating disaccharide units contain one aminosugar (such as glucosamine), it is clear that the presence of an aminosugar in the production of connective tissue is important. Glucosamine is, by far, the more important ingredient in the production of connective tissue since it is the essential building block of GAGs. See
FIG. 1 . All GAGs contain hexosamine or uronic acid derivative products of the glucose pathway and from exogenous glucosamine, for example:Hyaluronic acid Glucosamine + Glucuronic Acid Keretan-Sulfate Glucosamine + Galactose Chondroitin Sulfate Glucuronic Acid + Galactosamine Heparin Sulfate Glucosamine + Glucuronic or Iduronic Acid Heparan Sulfate Glucosamine + Glucuronic or Iduronic Acid Dermatin Sulfate Iduronic Acid + Galactosamine - Chondroitin sulfate is a GAG that provides a further substrate for the synthesis of the proteoglycans. The provision of the chondroitin in its salt (sulfate) form facilitates its delivery and uptake by the humans and animals in the production of connective tissue. In addition, the sulfate portion of chondroitin sulfate is available for use in catalyzing the conversion of glucosamine to GAGs. Fragments of GAGs, including chondroitin sulfate, may also be used to provide a substrate for synthesis of proteoglycans since the assembly of PG occurs in the extracellular space.
- In addition, chondroitin sulfate has been shown to have cardiovascular health benefits. [Morrison et al., Coronary Heart Disease and the Mucopolysaccharides (Glycosaminoglycans), pp. 109-127 (1973)]. Thus, the preferred form of glycosaminoglycan included in the compositions of the present invention is chondroitin sulfate or fragments thereof.
- Chondroitin may be more efficacious than glucosamine for injury rehabilitation. [Christensen, Chiropractic Products, pp. 100-102 (April 1993)]. An evaluation of glucosamine versus chondroitin for treatment of osteoarthritis has been conducted and concludes, contrary to Christensen, that glucosamine is preferred. [Murray, MPI's Dynamic Chiropractic, pp. 8-10 (Sep. 12, 1993)]. Neither reference teaches or suggests combining the materials. Bucci (Townsend Letter for Doctors, pp. 52-54, January 1994), discloses the combination of glucosamine and chondroitin for treatment of osteoarthritis. Bucci has acknowledged that this combination was personally disclosed to him by one of the present inventors.
- Chondroitin sulfate also acts to inhibit the degradative enzymes that break down connective tissue. In so doing, chondroitin sulfate promotes the maintenance of healthy connective tissues. When combined with glucosamine, which functions primarily as a building block for the synthesis of connective tissue, chondroitin sulfate works in concert with the glucosamine but may work in a different fashion. The ability of chondroitin sulfate to block degradation is one of its important functions.
- S-Adenosylmethionine (SAM) is a significant physiologic compound which is present throughout body tissue and takes part in a number of biologic reactions as a methyl group donor or as an enzymatic activator during the synthesis and metabolism of hormones, neurotransmitters, nucleic acids, phospholipids, and proteins. SAM may be second only to adenosine triphosphate (ATP) in the variety of reactions in which it is a cofactor. SAM is metabolized via three metabolic pathways of transmethylation, transsulfuration, and aminopropylation. [Stramentinoli, Am. J. Med., 83(5A) :35-42 (1987)]. In higher organisms, SAM plays a significant role in transmethylation processes with more than 40 anabolic or catabolic reactions involving the transfer of the methyl group of SAM to substrates such as nucleic acids, proteins, and lipids, among others. Also, the release of the methyl group from SAM is the start of a “transsulfuration” pathway that produces all endogenous sulfur compounds. After donating its methyl group, SAM is converted into. S-adenosylhomocysteine, which in turn is hydrolyzed to adenosine and homocysteine. The amino acid cysteine may then be produced from the homocysteine. The cysteine thus produced may exert a reducing effect by itself or as an active part of glutathione, which is a main cell anti-oxidant. [Stramentinoli, cited above].
- SAM has been used to treat various disorders. In various forms of liver disease, SAM acts as an anticholestatic agent. [Adachi et al., Japan Arch. Inter. Med., 33:185-192 (1986).]. SAM has also been administered as an antidepressant for use in the management of psychiatric disorders [Caruso et al., Lancet, 1: 904 (1984)], and as an anti-inflammatory compound in the management of osteoarthritis [Domljan et al., Int. J. Clin. Pharm. Toxicol., 27(7):329-333 (1989)].
- Low levels of SAM are believed to play a role in reducing the risk of certain cancers. [Feo et al., Carcinogenesis, 6:1713-20 (1985)]. In addition, the administration of SAM has also been associated with a fall in the amount of early reversible nodules and the prevention of the development of late pre-neoplastic. lesions and hepatocellular carcinomas. [Garcea et al., Carcinogenesis, 8:653-58 (1987)].
- Unfortunately, SAM per se is unstable due to its high reactivity. The relatively recent synthesis of stable salts, however, has made SAM available for research and therapeutic use. [See, e.g., U.S. Pat. Nos. 4,990,606 and 5,102,791].
- SAM has been used outside of the United States in a number of clinical trials concerning the treatment of osteoarthritis. While used in these trials primarily as an analgesic and replacement for NSAID therapy, SAM is a precursor of polyamines. In addition to their analgesic and anti-inflammatory properties, and their ability to scavenge free radicals, polyamines may stabilize the polyanionic macromolecules of proteoglycans. [Schumacher, Am. J. Med., 83(5A):2 (1987)].
- SAM may also function as a source of endogenous sulfur, which will increase sulfation of GAGs to be incorporated in proteoglycans. The inclusion of SAM is particularly beneficial in instances of subclinical deficiencies of SAM, occurring especially in elderly populations with higher risk of osteoarthritis [Frezza et al., Gastroenterol., 99:211-215 (1990)]. The supplementation of SAM may aid in instances of SAM deficiency where the ability of the body to sulfate GAGs may be compromised.
- In addition, a number of metabolites of SAM aid in the repair of connective tissue, including glutathione, polyamines, methylthioadenosine, and adenosine. Glutathione works as a scavenger of oxygen-related products [Shumacher, Am. J. Med., 83(Supp 5a) :1-4 (1987); Matthew & Lewis, Pharmacol. (Life Sci. Adv.), 9:145-152 (1990); Szabo et al., Science, 214:200-202 (1981)] and thus has an anti-inflammatory effect. Polyamines, including spermine, spermidine, and putrescine, stabilize polyanionic macromolecules of proteoglycans [Schumacher, cited above; Conroy et al., Biochem. J., 162:347-350 (1977)] and thus protect proteolytic and glycolytic enzymes. These polyamines also have an anti-inflammatory effect [Bird et al., Agents Actions, 13:342-347 (1983); Oyangui, Agents Actions, 14:228-237 (1984)], probably as a scavenger of oxygen-related products (Kafy et al., Agents Actions, 18:555-559 (1986); Matthews & Lewis, cited above], and have an analgesic effect [Bird et al., cited above; Oyangui, cited above]. The SAM metabolite methylthioadenosine has a pronounced anti-inflammatory effect [Matthews & Lewis, 1990] while adenosine has a more modest anti-inflammatory effect [Matthews & Lewis, 1990].
- Studies have shown that some forms of exogenous SAM are stable in digestive juices when given orally. [Stramentinoli et al., cited above; Vendemiale et al., Scand. J. Gastroenterol., 24:407-415 (1989)]. The metabolism of exogenous SAM appears to follow known pathways of endogenous SAM metabolism. (Kaye et al., Drugs, 40(Suppl. 3) :124-138 (1990)]. In humans, oral SAM was tolerated to the same extent as placebo with very mild nonspecific side effects. (Schumacher, cited above; Frezza et al., cited above].
- Manganese plays a role in the synthesis of GAGs, collagen and glycoproteins which are important constituents of cartilage and bone. Manganese is important for enzyme activity of glycosyltransferases. This family of enzymes is responsible for linking sugars together into glycosaminoglycans, adding sugars to other glycoproteins, adding sulfate to aminosugars, converting sugars into other modified sugars, and adding sugars to lipids. The enzymatic functions of glycosyltransferases are important in glycosaminoglycan synthesis (hyaluronic acid, chondroitin sulfate, keratan sulfate, heparin sulfate and dermatin sulfate, etc.), collagen synthesis, and in the functions of many other glycoproteins and glycolipids.
- Manganese also plays a role in the synthesis of glycosaminoglycans and glycoproteins, which are important constituents of cartilage and bone. Many reproductive problems in horses and skeletal abnormalities in foals have been ascribed to manganese deficiency. (Current Therapy in Equine Medicine, 2:402-403 (1987)].
- Manganese deficiency leads to abnormal bone growth, swollen and enlarged joints, and slipped tendons in humans and animals. In humans, manganese deficiencies are also associated with bone loss and arthritis. Levels of all glycosaminoglycans are decreased in connective tissues during manganese deficiencies, with chondroitin sulfates being most depleted. Manganese-deficient organisms quickly normalize glycosaminoglycans and collagen synthesis when manganese is replenished.
- Approximately 40% of dietary manganese is absorbed by the body tissue. Storage of manganese in the body is minimal—a mere 12 to 20 mg is present in the body at any one time. Large amounts of calcium and phosphorus in the intestine are also known to interfere with manganese absorption. The richest dietary sources are the foods least consumed by the general public, such as whole grain cereals and breads, dried peas, beans and nuts. The ascorbate form of manganese is preferred due to the high bioavailability and the need for vitamin C (ascorbic acid) for collagen production. Vitamin C also enhances manganese uptake by the body.
- Other optional ingredients in the compositions of the present invention are methyl donors or methyl donor cofactors, such as vitamins B12 and B6, folic acid, dimethylglycine, and trimethylglycine. These ingredients augment the function of SAM in that they are cofactors in methylation. In addition, these compounds are likely to be lacking in patients suffering from connective tissue disorders. For example, it is estimated that 12% of the elderly population in the United States suffers from a vitamin B12 deficiency, a group more likely to suffer from connective tissue disorders.
- An adequate amount of vitamin B12, for example, has an important environmental influence on the accumulation of homocysteine that results from the metabolism of SAM. In other words, methyl donors or methyl donor cofactors, such as vitamin B12 and the others listed in the preceding paragraph, can reduce levels of homocysteine when administered either alone or in combination.
- Vitamin B12 is generally known to function as a coenzyme in biochemical reactions such as the synthesis of proprionic acid and of methionine. Recent evidence suggests that the elevated levels of plasma homocysteine increase the risk of occlusive vascular disease. Adequate amounts of vitamin B12 are considered the most important environmental influence on the accumulation of unnecessary homocysteine. [Joosten et al., Am. J. Clin. Nutr., 58(4): 468-76 (1993)]. In addition, it is also understood that vitamin B12 may play a role in the methylation of selenium. [Chen and Whanger, Tox. and Appl. Pharm., 118:65-72 (1993)]. Specifically, increased levels of vitamin B12 significantly contribute to selenium methylation and might decrease overall selenium toxicity by preventing its accumulation in tissues. [Chen and Whanger, cited above].
- 3. Description of Background Art
- Several disclosures suggest provide exogenous quantities of glucosamine in order to bypass the rate-limiting step of the conversion of glucose to glucosamine in those pathways that produce PGs. For example, the intravenous administration of glucosamine (a precursor of the GAGs) and derivatives thereof has been disclosed in U.S. Pat. No. 3,232,836, issued to Carlozzi et al., for assisting in the healing of wounds on the surface of the body. In U.S. Pat. No. 3,682,076, issued to Rovati, the use of glucosamine and salts thereof is disclosed for the treatment of arthritic conditions. Finally, the use of glucosamine salts has also been disclosed for the treatment of inflammatory diseases of the gastrointestinal tract in U.S. Pat. No. 4,006,224 issued to Prudden. In vitro, glucosamine increases synthesis of collagen and glycosaminoglycans, the first step in repair of connective tissues, in fibroblasts. In vivo, topical application of glucosamine has enhanced wound healing.
- Several disclosures also suggest going one step further in bypassing the glucose-to-glucosamine rate-limiting step, by providing exogenbus quantities of various of the modified sugars found in the GAGS for producing proteoglycans. For example, in U.S. Pat. No. 3,6797,652 issued to Rovati et al., the use of N-acetylglucosamine is disclosed for treating degenerative afflictions of the joints.
- In still other disclosures of which we are aware, it has been taught to go still one step further in bypassing the glucose-to-glucosamine rate-limiting step by providing exogenous quantities of the GAGs themselves (with and without various of the modified sugars). For example, in U.S. Pat. No. 3,371,012 issued to Furuhashi, a preservative is disclosed for eye graft material that includes galactose, N-acetylglucosamine (a modified sugar found in the GAGS) and chondroitin sulfate (a GAG). Additionally, U.S. Pat. No. 4,486,416 issued to Soll et al., discloses a method of protecting corneal endothelial cells exposed to the trauma of intraocular lens implantation surgery by administering a prophylactically effective amount of chondroitin sulfate. Also, U.S. Pat. No. 5,141,928 issued to Goldman discloses the prevention and treatment of eye injuries using glycosaminoglycan polysulfates.
- U.S. Pat. No. 4,983,580 issued to Gibson, discloses methods for enhancing the healing of corneal incisions. These methods include the application of a corneal motor composition of fibronectin, chondroitin sulfate and collagen to the incision.
- In U.S. Pat. No. 4,801,619 issued to Lindblad, the intraarticular administration of hyaluronic acid is disclosed for the treatment of progressive cartilage degeneration caused by proteoglycan degradation.
- The use of a SAM and selenium composition as a nutritional supplement is disclosed in U.S. patent application Ser. No. 08/725,194 filed by one of the present inventors and is herein incorporated by reference. In addition, one of the inventors of the present invention has taught, in U.S. Pat. No. 5,587,363 the combination of an aminosugar, such as glucosamine, and a glycosaminoglycan, such as chondroitin, for treatment of degenerative joint diseases. One of the present inventors has further taught the optional inclusion of manganese in a composition of an aminosugar and a glycosaminoglycan in U.S. Pat. No. 5,364,845.
- Accordingly, it can be seen that there remains a need for compositions which include analgesic, anti-inflammatory, and antidepressant components, as well as components that provide the building blocks for the production of connective tissue in humans and that also protect against the degradation of that tissue.
- It is therefore an object of the present invention to provide a composition for the protection and repair and for reducing the inflammation of connective tissue in humans and animals.
- It is a further object of the present invention to provide compositions which contain S-Adenosylmethionine and an aminosugar or salts thereof, such as glucosamine, for facilitating the repair and reducing the inflammation of connective tissue in humans and animals.
- It is another object of the present invention to provide compositions which contain S-Adenosylmethionine and GAGs, such as chondroitin salts and fragments thereof, for facilitating the repair and for reducing the inflammation of connective tissue in humans and animals.
- It is yet a further object of the present invention to provide compositions which contain S-Adenosylmethionine, an aminosugar or salts thereof, and GAGs or fragments thereof for facilitating the repair and for reducing the inflammation of connective tissue in humans and animals.
- It is another object to optionally provide manganese to any of these compositions for humans and animals.
- It is still a further object to optionally provide methyl donors or methyl donor cofactors, such as vitamins B12 and B6, folic acid, dimethylglycine, and trimethylglycine, to the compositions of the present invention for humans and animals if desirable.
- It is a further object of the present invention to provide methods of administering these compositions.
- These and other objects of the present invention will become readily apparent from a reading of the following detailed description and examples.
-
FIG. 1 is a sequence for the biosynthesis of hexosamines. -
FIG. 2 is a schematic flowchart illustrating the biological pathway by which the composition of the present invention aids in protection and repair of connective tissue. -
FIG. 3 is an enlarged portion of the flowchart ofFIG. 2 . - According to the present invention, a composition selected from the group consisting of SAM and an aminosugar or salts thereof (e.g., glucosamine); SAM and GAGs (e.g., chondroitin salts) or fragments thereof; and SAM, an aminosugar (or salts thereof), and GAGs (or fragments thereof) is provided to humans and animals for stimulating both collagen and PG synthesis and for reducing inflammation. Manganese, preferably manganese salts, may optionally be included to any of these compositions. In addition, other optional ingredients include methyl donors or methyl donor cofactors, such as vitamins B12 and B6, folic acid, dimethylglycine, and trimethylglycine. These compositions may act to accomplish several functions, including bypassing the glucose to glucosamine rate-limiting step in the natural production of proteoglycans in humans and animals, and producing additional quantities of collagen and proteoglycans for use in the repair of damaged connective tissue. In addition, inflammation of connective tissue may be reduced by the compositions of the invention. The compositions of the present invention may achieve these functions directly or through indirect pathways—i.e., through their effect on other components in the living system which in turn can increase connective tissue synthesis or reduce inflammation.
- In one embodiment, a composition of the present invention include S-Adenosylmethionine (SAM) and an aminosugar, such as glucosamine, preferably in a salt form. In another embodiment of the present invention, the composition includes SAM and a glycosaminoglycan, such as chondroitin (preferably in a salt form such as chondroitin sulfate). In another embodiment, the composition of the present invention includes SAM, an aminosugar, such as glucosamine, preferably in a salt form, and a glycosaminoglycan, such as chondroitin (preferably in a salt form, such as chondroitin sulfate). Alternatively, fragments of a glycosaminoglycan may be used in a composition of the invention in addition to or in substitution for the glycosaminoglycan. Each of these compositions may optionally include manganese. A preferred form of manganese in such compositions is a manganese salt, such as manganese ascorbate, because the ascorbate is a soluble form of manganese which further provides ascorbic acid, a substance needed for collagen synthesis. Other manganese salts such, as for example, sulfate or gluconate, may be used however. Each of these compositions may optionally contain one or more methyl donors or methyl donor cofactors selected from the group consisting of vitamins B12 and B6, folic acid, dimethylglycine, and trimethylglycine.
- Referring to
FIGS. 2 and 3 , the biosynthetic pathway for the production of connective tissue, which is affected by the method of the present invention by virtue of the components of the composition of the present invention which aid in connective tissue repair, functions as described in the above background section of this application. - In a preferred embodiment, the aminosugar glucosamine is the base of the composition, providing the primary substrate for both collagen and proteoglycan synthesis. Glucosamine is the preferred substrate for proteoglycan synthesis, including chondroitin sulfates and hyaluronic acid. The glucosamine preferably is in a salt form so as to facilitate its delivery and uptake by humans and animals. The preferred salt forms are glucosamine hydrochloride, glucosamine sulfate and N-acetylglucosamine.
- Administration of a preferred embodiment of the composition of the present invention provides the human or animal organism with exogenous quantities of SAM, an aminosugar or salts thereof, and a glycosaminoglycan or fragments thereof. If desired, the composition also provides the human or animal organism with exogenous quantities of manganese cofactors. Also if desired, the compositions of the present invention may include methyl donors or methyl donor cofactors, such as vitamins B12 and B6, folic acid, dimethylglycine, and trimethylglycine.
- The exogenous glucosamine provided by the composition of present invention is converted to proteoglycans as is seen in
FIG. 2 and as described above. - In the former case, the glucosamine may be converted with the aid of manganese directly into GAG, including hyaluronic acid (which is 50% glucosamine and which forms the backbone of the proteoglycans). This core protein is then linked to the hyaluronic acid via the link protein, as is seen in
FIG. 3 . - In the latter case, the free amino acids are, with the aid of manganese and zinc cofactors (and ascorbic acid or vitamin C), converted to procollagen. The procollagen is then converted into collagen with the aid of copper or iron cofactors and vitamin C (ascorbic acid) and sulfate chelates.
- Thus, preferred compositions of the present invention containing SAM and glucosamine advantageously stimulate the synthesis of collagen and glycosaminoglycans or mucopolysaccharides (GAGS), including hyaluronic acid, the backbone of proteoglycans (PG's), thereby providing a natural tissue repair function. These compositions provide the connective tissue repair function of glucosamine, the increased sulfation of GAGs by SAM, the stabilization by SAM metabolites of the polyanionic macromolecules of proteoglycans, and the additional analgesic, anti-inflammatory, and anti-depressant effects of SAM. The optional addition of manganese provides a further benefit if a deficiency of the mineral exists or if it is otherwise desired. The optional inclusion of methyl donors or methyl donor cofactors, such as vitamins B12 and B6, folic acid, dimethylglycine, and trimethylglycine, helps to promote methylation and thereby convert homocysteine to methionine.
- Another preferred composition of the invention comprises SAM and chondroitin salts (such as chondroitin sulfate). SAM operates in this composition, in conjunction with endogenous glucosamine, as described above. Chondroitin salts operate with SAM and endogenous glucosamine by inhibiting the synovial degradative enzymes. Chondroitin salts (such as chondroitin sulfate) also directly contribute to the pool of GAGs of cartilaginous tissue. Manganese salts may also be included in this composition in those cases where a deficiency of manganese exists. Methyl donors or methyl donor cofactors, such as vitamins B12 and B6, folic acid, dimethylglycine, and trimethylglycine, may optionally be included in these compositions to help promote methylation and thereby convert homocysteine to methionine.
- Another preferred embodiment of the composition of the present invention contains SAM, glucosamine, and chondroitin salts (such as chondroitin sulfate) and mixtures and fragments thereof, and also advantageously stimulates the synthesis of collagen and glycosaminoglycans or mucopolysaccharides (GAGs), including hyaluronic acid, thereby providing a natural tissue repair function. This composition provides the superior connective tissue repair function of glucosamine, the above-described benefits of SAM, and the above-described benefits from chondroitin salts (including chondroitin sulfate) and fragments of chondroitin salts. Chondroitin salts (including chondroitin sulfate) also operate with SAM and glucosamine by inhibiting the synovial degradative enzymes. Chondroitin salts (including chondroitin sulfate) also directly contribute to the pool of GAGs of cartilaginous tissue. Manganese provides a further benefit if a deficiency of the mineral exists. As with the compositions described above, methyl donors or methyl donor cofactors, such as vitamins B12 and B6, folic acid, dimethylglycine, and trimethylglycine, may optionally be included in these compositions to help promote methylation and thereby convert homocysteine to methionine. Tissue repair can thus be accomplished, in the context of the treatment and repair of connective tissue and the treatment of arthritic conditions, in almost all areas of the body both human and animal.
- In the present method for the treatment and repair and for reducing the inflammation of connective tissue in humans and animals, preferred compositions comprising amounts of SAM in combination with glucosamine including salts thereof in combination with chondroitin salts (including chondroitin sulfate) or fragments thereof, or amounts of SAM and chondroitin salts (including chondroitin sulfate) or fragments thereof in combination with glucosamine including salts thereof, may be administered to humans and animals thereof for stimulating both collagen and proteoglycan synthesis. An additional preferred composition comprising amounts of SAM and chondroitin salts (including chondroitin sulfate) or fragments thereof may be administered to humans and animals for stimulating proteoglycan synthesis and reducing inflammation. Manganese salts may also be optionally included in each composition in cases where a deficiency of manganese exists. Methyl donors or methyl donor cofactors, such as vitamins B12 and B6, folic acid, dimethylglycine, and trimethylglycine may optionally be included to these compositions as well.
- The compositions of the present invention are administered to promote tissue repair, including cartilage repair, and the treatment of arthritic conditions as well as connective tissue damage in humans and animals. The anti-depressant effect of SAM may help to alleviate the burden of sickness for some patients, thus enhancing their quality of life. This effect, as well as the analgesic and anti-inflammatory effects of SAM which will help alleviate the pain associated with arthritic conditions, may help remove impediments to physical activity. Increased levels of physical activity, in turn, can supply the loading and unloading forces necessary for the regeneration of articular cartilage. Supplementation with glucosamine, with its chondroprotective role, thus helps to ensure that the raw materials are available to support the increased regeneration of cartilage. The compositions of the present invention are also understood to play a role in chondromodulation, chondrostabilization, and chondrometabolizaton.
- The dosage of SAM in the nutritional supplements of the present invention ranges from about 5 mg to about 5,000 mg in humans and small animals, and from about 2 mg to about 20,000 mg in large animals (e.g., equine). The dosage of glucosamine in the nutritional supplements of the present invention ranges from about 50 mg to about 5,000 mg in humans and small animals, and from about 250 mg to about 40,000 mg in large animals (e.g., equine). The dosage of chondroitin salts in the nutritional supplements of the present invention ranges from about 15 mg to about 5,000 mg in humans and small animals, and from about 100 mg to about 30,000 mg in large animals. When included in the compositions of the present invention, manganese may optionally be present in the range of about 2 to about 75 mg in humans and small animals, and from about 10 mg to about 500 mg in large animals. The ascorbate component of the manganese ascorbate may range from about 10 mg to about 500 mg in humans and small animals, and from about 50 mg to about 2,500 mg in large animals. When included in the compositions of the present invention, the methyl donors or methyl donor cofactors, such as vitamins B12 and B6, folic acid, dimethylglycine, and trimethylglycine may be present in the range of about 0.1 mg to about 10 mg in humans and small animals, and from about 1 mg to about 100 mg in large animals.
- As a preferred embodiment, a dosage of the nutritional supplement composition of the present invention may consist of one or more capsules or tablets for human oral consumption. In such an embodiment, the preferred weight of the dosage is between about 5 mg to about 5,000 mg, and preferably about 2,500 mg. The dosage may be administered in a single daily dosage form in which all components are present, e.g., a capsule or tablet of preferably 2,500 mg. The dosage may also be administered in more than one dosage form in which each dosage form contains at least one component. When a single dosage is administered in more than one dosage form, the multiple dosage forms may be co-administered as a single dosage. Thus, for example, a single dosage may be comprised of a SAM dosage form co-administered with a glucosamine and chondroitin salts dosage form.
- Alternatively, the nutritional supplement compositions of the present invention may be administered more than once daily. Hence, for example, the nutritional supplement compositions of the present invention may be in the form of an oral dosage form of 1250 mg administered twice daily or 833 mg administered three times daily. The number of daily administrations will depend upon the needs of the human or animal recipient. Different connective tissue disorders and injuries require different amounts of the compositions of the present invention. In that regard, several dosages may be administered depending on the particular needs of the human or animal.
- Alternatively, and of particular use in large animals, the compositions of the present invention may for example be administered in scoops. Such administration may take the form, for example, of a level scoopful containing about 1,800 mg glucosamine, about 600 mg chondroitin salts, about 16 mg of manganese (when included in the form of manganese ascorbate), and about 104 mg of ascorbate (when included in the form of manganese ascorbate).
- These preparations may be made by conventional methods. For example, to prepare the compositions of the invention, the above-described ingredients are combined as the active ingredient in intimate admixture with a suitable carrier according to conventional compounding techniques. This carrier may take a wide variety of forms depending upon the form of preparation desired for administration, e.g., oral, sublingual, nasal, guttural, rectal, transdermal or parenteral.
- In preparing the compositions in oral dosage form, any usual pharmaceutical medium may be employed. For oral liquid preparations (e.g., suspensions, elixirs, and solutions), media containing for example, water, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used. Carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to prepare oral solids (e.g., powders, capsules, pills, caplets, tablets, microencapsulated granules, microtablets, coated granules and lozenges). Capsules or tablets are a preferred oral dosage form. Controlled release forms may also be used. Because of their ease in administration, lozenges, tablets, pills, caplets, and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. The compositions of the present invention may be in the form of one or more of these oral dosage forms—i.e., a single dosage may be in multiple forms.
- For parenteral products, the carrier will usually comprise sterile water, although other ingredients may be included, e.g., to aid solubility or for preservation purposes. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents, and the like may be employed.
- Having discussed the composition of the present invention, it will be more clearly perceived and better understood from the following specific examples which are intended to provide examples of the preferred embodiments and do not limit the present invention.
- The composition of the present invention is made in one or more capsules for oral administration in humans and small animals. In a preferred embodiment, each dosage contains:
Human & Small Animal Range/Dose SAM 5-5,000 mg Glucosamine 50-5,000 mg Chondroitin Sulfate 15-5,000 mg - For those situations in which manganese supplementation is desired, a manganese salt is added to the composition of Example 1 so that each dosage contains:
Human & Small Animal Range/Dose SAM 5-5,000 mg Glucosamine 50-5,000 mg Chondroitin Sulfate 15-5,000 mg Manganese (as Ascorbate) 2-75 mg Ascorbate (as Manganese 10-500 mg Ascorbate) - For larger animals, such as horses, the composition of Example 1 is administered as filled-scoops.
Large Animal (Equine) Range/Dose SAM 2-20,000 mg Glucosamine 250-40,000 mg Chondroitin Sulfate 100-30,000 mg - For those situations in which manganese supplementation is desired, manganese salts may be added to the composition of Example 3 so that each dosage contains:
Large Animal (Equine) Range/Dose SAM 2-20,000 mg Glucosamine 250-40,000 mg Chondroitin Sulfate 100-30,000 mg Manganese (as Ascorbate) 10-500 mg Ascorbate (as Manganese 50-2,500 mg Ascorbate) - For a further preferred composition, each dosage contains:
Human & Small Animal Range/Dose SAM 5-5,000 mg Glucosamine 50-5,000 mg - For those situations in which manganese supplementation is desired, a manganese salt is added to the composition of Example 5 so that each dosage contains:
Human & Small Animal Range/Dose SAM 5-5,000 mg Glucosamine 50-5,000 mg Manganese (as Ascorbate) 2-75 mg Ascorbate (as Manganese 10-500 mg Ascorbate) - For larger animals, such as horses, the composition of Example 5 is administered as filled scoops.
Large Animal (Equine) Range/Dose SAM 2-20,000 mg Glucosamine 250-40,000 mg - For those situations in which manganese supplementation is desired, manganese salts may be added to the composition of Example 7 so that each dosage contains:
Large Animal (Equine) Range/Dose SAM 2-20,000 mg Glucosamine 250-40,000 mg Manganese (as Ascorbate) 10-500 mg Ascorbate (as Manganese 50-2,500 mg Ascorbate) - For a further preferred composition, each dosage contains:
Human & Small Animal Range/Dose SAM 5-5,000 mg Chondroitin Sulfate 15-5,000 mg - For those situations in which manganese supplementation is desired, a manganese salt is added to the composition of Example 9 so that each dosage contains:
Human & Small Animal Range e/Dose SAM 5-5,000 mg Chondroitin Sulfate 15-5,000 mg Manganese (as Ascorbate) 2-75 mg Ascorbate (as Manganese 10-500 mg Ascorbate) - For larger animals, such as horses, the composition of Example 10 is administered as filled scoops.
Large Animal (Equine) Range/Dose SAM 2-20,000 mg Chondroitin Sulfate 100-30,000 mg - For those situations in which manganese supplementation is desired, manganese salts may be added to the composition of Example 11 so that each dosage contains:
Large Animal (Equine) Range/Dose SAM 2-20,000 mg Chondroitin Sulfate 100-30,000 mg Manganese (as Ascorbate) 10-500 mg Ascorbate (as Manganese 50-2,500 mg Ascorbate) - For those situations in which methyl donors or methyl donor cofactors are desired, such compounds may be added to the composition of Example 1 so that each dosage contains:
Human & Small Animal Range/Dose SAM 5-5,000 mg Glucosamine 50-5,000 mg Chondroitin Sulfate 15-5,000 mg vitamin B12 0.1-10 mg - For those situations in which manganese supplementation is desired, a manganese salt is added to the composition of Example 13 so that each dosage contains:
Human & Small Animal Range/Dose SAM 5-5,000 mg Glucosamine 50-5,000 mg Chondroitin Sulfate 15-5,000 mg Manganese (as Ascorbate) 2-75 mg Ascorbate (as Manganese 10-500 mg Ascorbate) vitamin B12 0.1-10 mg - For larger animals, such as horses, the composition of Example 13 is administered as filled scoops.
Large Animal (Equine) Range/Dose SAM 2-20,000 mg Glucosamine 250-40,000 mg Chondroitin Sulfate 100-30,000 mg vitamin B12 1-100 mg - For those situations in which manganese supplementation is desired, manganese salts may be added to the composition of Example 15 so that each dosage contains:
Large Animal (Equine) Range/Dose SAM 2-20,000 mg Glucosamine 250-40,000 mg Chondroitin Sulfate 100-30,000 mg Manganese (as Ascorbate) 10-500 mg Ascorbate (as Manganese 50-2,500 mg Ascorbate) vitamin B12 1-100 mg - For a further preferred composition, each dosage contains:
Human & Small Animal Range/Dose SAM 5-5,000 mg Glucosamine 50-5,000 mg vitamin B12 0.1-10 mg - For those situations in which manganese supplementation is desired, a manganese salt is added to the composition of Example 17 so that each dosage contains:
Human & Small Animal Range/Dose SAM 5-5,000 mg Glucosamine 50-5,000 mg Manganese (as Ascorbate) 2-75 mg Ascorbate (as Manganese 10-500 mg Ascorbate) vitamin B12 0.1-10 mg - For larger animals, such as horses, the composition of Example 17 is administered as filled scoops.
Large Animal (Equine) Range/Dose SAM 2-20,000 mg Glucosamine 250-40,000 mg vitamin B12 1-100 mg - For those situations in which manganese supplementation is desired, manganese salts may be added to the composition of Example 19 so that each dosage contains:
Large Animal (Equine) Range/Dose SAM 2-20,000 mg Glucosamine 250-40,000 mg Manganese (as Ascorbate) 10-500 mg Ascorbate (as Manganese 50-2,500 mg Ascorbate) vitamin B12 1-100 mg - For a further preferred composition, each dosage contains:
Human & Small Animal Range/Dose SAM 5-5,000 mg Chondroitin Sulfate 15-5,000 mg vitamin B12 0.1-10 mg - For those situations in which manganese supplementation is desired, a manganese salt is added to the composition of Example 21 so that each dosage contains:
Human & Small Animal Range e/Dose SAM 5-5,000 mg Chondroitin Sulfate 15-5,000 mg Manganese (as Ascorbate) 2-75 mg Ascorbate (as Manganese 10-500 mg Ascorbate) vitamin B12 0.1-10 mg - For larger animals, such as horses, the composition of Example 21 is administered as filled scoops.
Large Animal (Equine) Range/Dose SAM 2-20,000 mg Chondroitin Sulfate 100-30,000 mg vitamin B12 1-100 mg - For those situations in which manganese supplementation is desired, manganese salts may be added to the composition of Example 23 so that each dosage contains:
Large Animal (Equine) Range/Dose SAM 2-20,000 mg Chondroitin Sulfate 100-30,000 mg Manganese (as Ascorbate) 10-500 mg Ascorbate (as Manganese 50-2,500 mg Ascorbate) vitamin B12 1-100 mg - Many modifications may be made without departing from the basic spirit of the present invention. Accordingly, it will be appreciated by those skilled in the art that within the scope of the appended claims, the invention may be practiced other than has been specifically described herein.
Claims (20)
1. A composition for treatment and repair and for reducing the inflammation of connective tissue in humans and animals comprising:
S-Adenosylmethionine;
a glycosaminoglycan selected from the group consisting of chondroitin, chondroitin salts, fragments, and mixtures thereof; and
an aminosugar selected from the group consisting of glucosamine, glucosamine salts and mixtures thereof.
2. The composition of claim 1 , wherein the salt of glucosamine is selected from the group consisting of glucosamine hydrochloride, glucosamine sulfate, and N-acetylglucosamine.
3. A method for the treatment and repair and for reducing the inflammation of connective tissue in humans and animals comprising the step of administering the S-Adenosylmethionine, the glycosaminoglycan, and the aminosugar of the composition of claim 1 , to a human or an animal.
4. The composition of claim 1 , wherein a dose of the S-Adenosylmethionine ranges from about 2 mg to about 20,000 mg, a dose of the aminosugar ranges from about 50 mg to about 40,000 mg, and a dose of the glycosaminoglycan ranges from about 15 mg to about 30,000 mg.
5. A method for the treatment and repair and for reducing the inflammation of connective tissue in humans and animals comprising the step of administering the composition of claim 1 to a human or an animal.
6. A method for the treatment and repair and for reducing the inflammation of connective tissue in humans and animals comprising the step of administering the S-Adenosylmethionine, the glycosaminoglycan, and the aminosugar of the composition of claim 1 to a human or an animal.
7. The method of claim 6 , wherein each of the S-Adenosylmethionine, the aminosugar, or the glycosaminoglycan are administered orally, sublingually, nasally, gutturally, rectally, transdermally, or parenterally.
8. A composition for treatment and repair and for reducing the inflammation of connective tissue in humans and animals comprising:
S-Adenosylmethionine and an aminosugar selected from the group consisting of glucosamine, glucosamine salts and mixtures thereof.
9. The composition of claim 8 , wherein the salt of glucosamine is selected from the group consisting of glucosamine hydrochloride, glucosamine sulfate, and N-acetylglucosamine.
10. A method for the treatment and repair and for reducing the inflammation of connective tissue in humans and animals comprising the step of administering the S-Adenosylmethionine and the aminosugar of the composition of claim 8 , to a human or an animal.
11. The composition of claim 6 , wherein a dose of the S-Adenosylmethionine ranges from about 2 mg to about 20,000 mg, and a dose of the aminosugar ranges from about 50 mg to about 40,000 mg.
12. A method for the treatment and repair and for reducing the inflammation of connective tissue in humans and animals comprising the step of administering the composition of claim 8 , to a human or an animal.
13. A composition for treatment and repair and for reducing the inflammation of connective tissue in humans and animals comprising:
S-Adenosylmethionine and a glycosaminoglycan selected from the group consisting of chondroitin, chondroitin salts, fragments, and mixtures thereof.
14. A method for the treatment and repair and for reducing the inflammation of connective tissue in humans and animals comprising the step of administering the S-Adenosylmethionine and the glycosaminoglycan of the composition of claim 13 , to a human or an animal.
15. The composition of claim 13 , wherein a dose of the S-Adenosylmethionine ranges from about 2 mg to about 20,000 mg, and a dose of the glycosaminoglycan ranges from about 15 mg to about 30,000 mg.
16. A composition for treatment and repair and for reducing the inflammation of connective tissue in humans and animals comprising:
S-Adenosylmethionine and an aminosugar selected from the group consisting of glucosamine, glucosamine salts and mixtures thereof.
17. The composition of claim 16 , wherein the salt of glucosamine is selected from the group consisting of glucosamine hydrochloride, glucosamine sulfate, and N-acetylglucosamine.
18. A method for the treatment and repair and for reducing the inflammation of connective tissue in humans and animals comprising the step of administering the S-Adenosylmethionine and the aminosugar of the composition of claim 16 , to a human or an animal.
19. The composition of claim 16 , wherein a dose of the S-Adenosylmethionine ranges from about 2 mg to about 20,000 mg, and a dose of the aminosugar ranges from about 50 mg to about 40,000 mg.
20. A method for the treatment and repair and for reducing the inflammation of connective tissue in humans and animals comprising the step of administering the composition of claim 16 to a human or an animal.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/785,915 US20080051366A1 (en) | 1996-12-23 | 2007-04-20 | Aminosugar, glycosaminoglycan, and s-adenoslymethionine composition for the treatment and repair of connective tissue |
US12/473,452 US20090291909A1 (en) | 1996-12-23 | 2009-05-28 | Aminosugar, glycosaminoglycan, and s-adenosylmethionine composition for the treatment and repair of connective tissue |
US12/843,355 US20100330198A1 (en) | 1996-12-23 | 2010-07-26 | Aminosugar, glycosaminoglycan, and s-adenosylmethionine composition for the treatment and repair of connective tissue |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/779,996 US6492349B1 (en) | 1993-03-31 | 1996-12-23 | Aminosugar and glycosaminoglycan composition for the treatment and repair of connective tissue |
US08/797,294 US6271213B1 (en) | 1996-12-23 | 1997-02-07 | Aminosugar, glycosaminoglycan, and S-adenosylmethionine composition for the treatment and repair of connective tissue |
US09/834,726 US6583123B2 (en) | 1996-12-23 | 2001-04-16 | Aminosugar, glycosaminoglycan, and S-adenosylmethionine composition for the treatment and repair of connective tissue |
US10/408,255 US20030216348A1 (en) | 1996-12-23 | 2003-04-08 | Aminosugar, glycosaminoglycan, and S-Adenosylmethionine composition for the treatment and repair of connective tissue |
US11/785,915 US20080051366A1 (en) | 1996-12-23 | 2007-04-20 | Aminosugar, glycosaminoglycan, and s-adenoslymethionine composition for the treatment and repair of connective tissue |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/408,255 Continuation US20030216348A1 (en) | 1996-12-23 | 2003-04-08 | Aminosugar, glycosaminoglycan, and S-Adenosylmethionine composition for the treatment and repair of connective tissue |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/473,452 Continuation US20090291909A1 (en) | 1996-12-23 | 2009-05-28 | Aminosugar, glycosaminoglycan, and s-adenosylmethionine composition for the treatment and repair of connective tissue |
Publications (1)
Publication Number | Publication Date |
---|---|
US20080051366A1 true US20080051366A1 (en) | 2008-02-28 |
Family
ID=25118246
Family Applications (7)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/779,996 Expired - Fee Related US6492349B1 (en) | 1993-03-31 | 1996-12-23 | Aminosugar and glycosaminoglycan composition for the treatment and repair of connective tissue |
US08/797,294 Expired - Lifetime US6271213B1 (en) | 1996-12-23 | 1997-02-07 | Aminosugar, glycosaminoglycan, and S-adenosylmethionine composition for the treatment and repair of connective tissue |
US09/834,726 Expired - Fee Related US6583123B2 (en) | 1996-12-23 | 2001-04-16 | Aminosugar, glycosaminoglycan, and S-adenosylmethionine composition for the treatment and repair of connective tissue |
US10/408,255 Abandoned US20030216348A1 (en) | 1996-12-23 | 2003-04-08 | Aminosugar, glycosaminoglycan, and S-Adenosylmethionine composition for the treatment and repair of connective tissue |
US11/785,915 Abandoned US20080051366A1 (en) | 1996-12-23 | 2007-04-20 | Aminosugar, glycosaminoglycan, and s-adenoslymethionine composition for the treatment and repair of connective tissue |
US12/473,452 Abandoned US20090291909A1 (en) | 1996-12-23 | 2009-05-28 | Aminosugar, glycosaminoglycan, and s-adenosylmethionine composition for the treatment and repair of connective tissue |
US12/843,355 Abandoned US20100330198A1 (en) | 1996-12-23 | 2010-07-26 | Aminosugar, glycosaminoglycan, and s-adenosylmethionine composition for the treatment and repair of connective tissue |
Family Applications Before (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/779,996 Expired - Fee Related US6492349B1 (en) | 1993-03-31 | 1996-12-23 | Aminosugar and glycosaminoglycan composition for the treatment and repair of connective tissue |
US08/797,294 Expired - Lifetime US6271213B1 (en) | 1996-12-23 | 1997-02-07 | Aminosugar, glycosaminoglycan, and S-adenosylmethionine composition for the treatment and repair of connective tissue |
US09/834,726 Expired - Fee Related US6583123B2 (en) | 1996-12-23 | 2001-04-16 | Aminosugar, glycosaminoglycan, and S-adenosylmethionine composition for the treatment and repair of connective tissue |
US10/408,255 Abandoned US20030216348A1 (en) | 1996-12-23 | 2003-04-08 | Aminosugar, glycosaminoglycan, and S-Adenosylmethionine composition for the treatment and repair of connective tissue |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/473,452 Abandoned US20090291909A1 (en) | 1996-12-23 | 2009-05-28 | Aminosugar, glycosaminoglycan, and s-adenosylmethionine composition for the treatment and repair of connective tissue |
US12/843,355 Abandoned US20100330198A1 (en) | 1996-12-23 | 2010-07-26 | Aminosugar, glycosaminoglycan, and s-adenosylmethionine composition for the treatment and repair of connective tissue |
Country Status (3)
Country | Link |
---|---|
US (7) | US6492349B1 (en) |
AU (1) | AU5622198A (en) |
WO (1) | WO1998027988A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20150224069A1 (en) * | 2011-08-01 | 2015-08-13 | Tixupharma | Method of treatment of periodontum and damaged oral tissue by administering oral compositions comprising supramolecular complexes of polyanionic polymers and spermidine |
US20160101067A1 (en) * | 2011-08-01 | 2016-04-14 | Tixupharma | Supramolecular complexes of polyanionic polymers and spermidine in tissue maintenance and repair |
Families Citing this family (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6492349B1 (en) * | 1993-03-31 | 2002-12-10 | Nutramax Laboratories, Inc. | Aminosugar and glycosaminoglycan composition for the treatment and repair of connective tissue |
US20010000472A1 (en) * | 1998-02-27 | 2001-04-26 | Nutramax Laboratories, Inc. | L-ergothioneine, milk thistle, and s-adenosylmethionine for the prevention, treatment and repair of liver damage |
US7906153B2 (en) * | 1998-04-08 | 2011-03-15 | Theta Biomedical Consulting & Development Co., Inc. | Anti-inflammatory compositions for treating multiple sclerosis |
US6524609B1 (en) * | 1999-08-18 | 2003-02-25 | Nutri-Vet, Llc | Treating arthritis in animals with dietary supplements |
US6908630B2 (en) * | 2000-08-01 | 2005-06-21 | Metaproteomics, Llc | Combinations of sesquiterpene lactones and ditepene triepoxide lactones for synergistic inhibition of cyclooxygenase-2 |
US20020182237A1 (en) * | 2001-03-22 | 2002-12-05 | The Procter & Gamble Company | Skin care compositions containing a sugar amine |
BRPI0101486B1 (en) * | 2001-04-17 | 2017-09-19 | Cristália Produtos Químicos Farmacêuticos Ltda. | PHARMACEUTICAL COMPOSITION FOR TOPIC USE CONTAINING HEPARIN FOR TREATMENT OF SKIN OR MUCOSAL INJURIES CAUSED BY BURNS |
WO2002098449A1 (en) * | 2001-06-01 | 2002-12-12 | Nippon Meat Packers, Inc. | Remedies for joint injury and functional foods |
WO2003059924A1 (en) * | 2002-01-18 | 2003-07-24 | Biotie Therapies Corporation | Novel binding epitopes for helicobacter pylori and use thereof |
JP2005519914A (en) * | 2002-01-23 | 2005-07-07 | インスティチュート オブ ニュートラシューティカル リサーチ ピーティーワイ リミテッド | Nutraceuticals for the treatment, protection and recovery of connective tissue |
RU2216332C1 (en) * | 2002-02-18 | 2003-11-20 | Акционерное Курганское общество медицинских препаратов и изделий "Синтез" | Curative preparation for treatment of arthrosis |
US20030181713A1 (en) * | 2002-03-04 | 2003-09-25 | Srirangam Jayaram Kasturi | Processes for the synthesis of chloroadenosine and methylthioadenosine |
US8455458B2 (en) | 2002-10-16 | 2013-06-04 | Arthrodynamic Technologies, Animal Health Division, Inc. | Composition and method for treating connective tissue damage |
US7485629B2 (en) * | 2002-10-16 | 2009-02-03 | Arthrodynamic Technologies, Animal Health Division, Inc. | Composition and method for treatment of joint damage |
US7803787B2 (en) * | 2002-10-16 | 2010-09-28 | Arthrodynamic Technologies, Animal Health Division, Inc. | Composition and method for treating connective tissue damage by transmucosal administration |
US20080003258A1 (en) * | 2002-10-16 | 2008-01-03 | Marcum Frank D | Composition and Method for Treating Rheumatoid Arthritis |
US20040127402A1 (en) * | 2002-12-27 | 2004-07-01 | Vad Vijay B. | Injectible composition and method for treating degenerative animal joints |
US20040161476A1 (en) | 2003-02-19 | 2004-08-19 | Hahn Sungtack Samuel | Cystitis treatment with high dose chondroitin sulfate |
GB2426706A (en) * | 2004-01-16 | 2006-12-06 | Inst Of Nutraceutical Res Pty | Glycosaminoglycan peptides derived from connective tissues and use thereof in the prevention of arthritis and other degenerative medical conditions |
US20050176674A1 (en) * | 2004-02-09 | 2005-08-11 | Friesen Kim G. | Composition and method for use in cartilage affecting conditions |
US8377904B2 (en) * | 2004-02-09 | 2013-02-19 | Hill's Pet Nutrition, Inc. | Composition and method for use in cartilage affecting conditions |
US20050176807A1 (en) * | 2004-02-09 | 2005-08-11 | Friesen Kim G. | Composition and method for use in cartilage affecting conditions |
US20070122473A1 (en) * | 2005-11-12 | 2007-05-31 | Felton Linda A | Aminosugar and/or glycosaminoglycan composition having therapeutic use |
US20080045448A1 (en) * | 2006-08-18 | 2008-02-21 | Alan Robert Vinitsky | Reversing autonomic nervous system dysfunction by potentiating methylation |
JP5175481B2 (en) * | 2006-10-23 | 2013-04-03 | エーザイフード・ケミカル株式会社 | Cartilage regeneration promoter |
WO2008154178A1 (en) * | 2007-06-06 | 2008-12-18 | Novus International Inc. | Dietary supplements for promotion of growth, repair, and maintenance of bone and joints |
US9186375B2 (en) | 2007-06-21 | 2015-11-17 | Arthrodynamic Technologies, Animal Health Division, Inc. | Glycosaminoglycan compositions in combination with stem cells |
US20090286289A1 (en) * | 2008-03-10 | 2009-11-19 | Pang Danny Z | Production of Hyaluronate Unsaturated Disaccharides and its Application |
US7936736B2 (en) | 2008-09-08 | 2011-05-03 | Proctor Jr James Arthur | Enforcing policies in wireless communication using exchanged identities |
JP5689458B2 (en) * | 2009-05-13 | 2015-03-25 | ワイス・エルエルシー | Methods for stabilizing dietary supplements containing glucosamine |
WO2012121140A1 (en) * | 2011-03-04 | 2012-09-13 | ライオン株式会社 | Growth hormone secretion promoter |
WO2014074859A1 (en) * | 2012-11-08 | 2014-05-15 | Ingeneron Inc. | Media for culturing, preserving, and administering regenerative cells |
EP2886104A1 (en) | 2013-12-11 | 2015-06-24 | Patir, Suleyman | An intra-articular gel |
WO2016156354A1 (en) | 2015-03-31 | 2016-10-06 | Sanovel Ilac Sanayi Ve Ticaret A.S. | Pharmaceutical composition comprising loxoprofen, glucosamine, chondroitin, hyaluronic acid for joint and cartilage disorders |
WO2018165574A1 (en) * | 2017-03-10 | 2018-09-13 | The Regents Of The University Of California | Method for diagnosing risk for inflammatory disease through glycan profiling |
EP3873415A1 (en) | 2018-11-02 | 2021-09-08 | Unilever Global Ip Limited | Bioenergetic nicotinic acid glycerol esters, compositions and methods of using same |
RU2751037C1 (en) * | 2020-04-03 | 2021-07-07 | Богдан Иванович Асатуров | Pharmaceutical composition based on human urine autobiocomponents for transdermal application for therapeutic or cosmetic purposes |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5358720A (en) * | 1993-10-22 | 1994-10-25 | Koppel Richard M | Treatment of arthritic conditions |
US5364845A (en) * | 1993-03-31 | 1994-11-15 | Nutramax Laboratories, Inc. | Glucosamine, chondroitin and manganese composition for the protection and repair of connective tissue |
US6271213B1 (en) * | 1996-12-23 | 2001-08-07 | Nutramax Laboratories, Inc. | Aminosugar, glycosaminoglycan, and S-adenosylmethionine composition for the treatment and repair of connective tissue |
Family Cites Families (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3232836A (en) | 1959-08-24 | 1966-02-01 | Pfizer & Co C | Facilitating healing of body surface wounds by intravenous administration of n-acetyl glucosamine, glucosamine, or pharmaceutically acceptable acid salts of glucosamine |
US3371012A (en) | 1964-08-07 | 1968-02-27 | Seikagaku Kogyo Co Ltd | Preservative for eye graft material |
DE1792346C3 (en) | 1968-08-22 | 1980-10-23 | Rotta Research Laboratorium S.P.A., San Fruttuoso Di Monza, Mailand (Italien) | Pharmaceutical preparation for the treatment of degenerative joint diseases |
IT1044707B (en) | 1968-10-26 | 1980-04-21 | Rotta Research Lab | PROCEDURE FOR THE PREPARATION OF GLUCOSANINE SALTS AND PHARMACEUTICAL PREPARATIONS INCLUDING THESE GLUCOSAMINE SALTS AS ACTIVE AGENTS |
US4006224A (en) | 1975-09-29 | 1977-02-01 | Lescarden Ltd. | Method and agent for treating inflammatory disorders of the gastrointestinal tract |
US4486416A (en) | 1981-03-02 | 1984-12-04 | Soll David B | Protection of human and animal cells subject to exposure to trauma |
IT1137640B (en) | 1981-08-24 | 1986-09-10 | Bioresearch Srl | STABLE SALTS OF S-ADENOSYLMETHIONINE, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC COMPOSITIONS THAT INCLUDE THEM AS AN ACTIVE PRINCIPLE |
IT1137892B (en) | 1981-08-24 | 1986-09-10 | Bioresearch Srl | STABLE SALTS OF S-ADENOSYLMETHIONINE, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC COMPOSITIONS THAT INCLUDE THEM AS AN ACTIVE PRINCIPLE |
FR2550823B1 (en) | 1982-01-25 | 1986-01-10 | Thibonnet Bernard | LIQUID FUEL SAVING HEATER |
US4473551A (en) | 1982-08-23 | 1984-09-25 | Faxon Pharmaceuticals, Inc. | Anti-inflammatory composition |
IT1173992B (en) | 1984-05-16 | 1987-06-24 | Bioresearch Spa | STABLE SALTS OF SULPHO-ADENOSYL-METHIONINE (SAME) PARTICULARLY SUITABLE FOR ORAL PHARMACEUTICAL USE |
IT1173990B (en) | 1984-05-16 | 1987-06-24 | Bioresearch Spa | STABLE SALTS OF SULPHO-ADENOSYL-METHIONINE (SAME) PARTICULARLY SUITABLE FOR PARENTERAL USE |
US4647453A (en) | 1984-10-18 | 1987-03-03 | Peritain, Ltd. | Treatment for tissue degenerative inflammatory disease |
SE8501723L (en) | 1985-04-09 | 1986-10-10 | Pharmacia Ab | PREPARATION TO BE USED IN TREATMENT OF LED INFLAMMATION |
US4772591A (en) | 1985-09-25 | 1988-09-20 | Peritain, Ltd. | Method for accelerated wound healing |
DE3602670A1 (en) | 1986-01-29 | 1987-07-30 | Speck Ulrich | USE OF N-ACETYLGLUCOSAMINE FOR THE THERAPY OF DEGENERATIVE JOINT PROCESSES AND RELATED DISEASES |
US4983580A (en) | 1986-04-04 | 1991-01-08 | Allergan, Inc. | Methods and materials for use in corneal wound healing |
FR2609397B1 (en) | 1988-02-23 | 1991-12-13 | Serobiologiques Lab Sa | USE OF A CARBOHYDRATE SUBSTANCE OR COMPOSITION AS AN ACTIVE INGREDIENT OF A DERMATOLOGICAL AND / OR COSMETOLOGICAL AND / OR PHARMACEUTICAL AND / OR CELL STIMULANT COMPOSITION, AND COMPOSITION CONTAINING SUCH A CARBON SUBSTANCE OR COMPOSITION |
US5656286A (en) * | 1988-03-04 | 1997-08-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
US5446070A (en) * | 1991-02-27 | 1995-08-29 | Nover Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
GB8900812D0 (en) | 1989-01-14 | 1989-03-08 | Univ Manchester | Pharmaceutical method and compositions |
US5141928B1 (en) | 1989-12-20 | 1995-11-14 | Brujo Inc | Ophthalmic medication |
US5272135A (en) | 1991-03-01 | 1993-12-21 | Chiron Ophthalmics, Inc. | Method for the stabilization of methionine-containing polypeptides |
ATE173627T1 (en) | 1992-09-04 | 1998-12-15 | Fuji Chem Ind Co Ltd | MEDICAL COMPOSITION |
US6204259B1 (en) * | 1993-01-14 | 2001-03-20 | Monsanto Company | Manganese complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxide |
US5691325A (en) * | 1994-01-14 | 1997-11-25 | Sandyk; Reuven | Method for ameliorating age-related disease conditions |
US5565286A (en) | 1994-11-17 | 1996-10-15 | International Business Machines Corporation | Combined attenuated-alternating phase shifting mask structure and fabrication methods therefor |
CA2224088A1 (en) * | 1995-06-07 | 1996-12-19 | Monsanto Company | Process for preparing substituted polyazamacrocycles |
AU770010B2 (en) * | 1998-06-05 | 2004-02-12 | Nutramax Laboratories, Inc. | Agents and methods for protection, treatment and repair of connective tissue |
-
1996
- 1996-12-23 US US08/779,996 patent/US6492349B1/en not_active Expired - Fee Related
-
1997
- 1997-02-07 US US08/797,294 patent/US6271213B1/en not_active Expired - Lifetime
- 1997-12-12 WO PCT/US1997/023985 patent/WO1998027988A1/en active Application Filing
- 1997-12-12 AU AU56221/98A patent/AU5622198A/en not_active Abandoned
-
2001
- 2001-04-16 US US09/834,726 patent/US6583123B2/en not_active Expired - Fee Related
-
2003
- 2003-04-08 US US10/408,255 patent/US20030216348A1/en not_active Abandoned
-
2007
- 2007-04-20 US US11/785,915 patent/US20080051366A1/en not_active Abandoned
-
2009
- 2009-05-28 US US12/473,452 patent/US20090291909A1/en not_active Abandoned
-
2010
- 2010-07-26 US US12/843,355 patent/US20100330198A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5364845A (en) * | 1993-03-31 | 1994-11-15 | Nutramax Laboratories, Inc. | Glucosamine, chondroitin and manganese composition for the protection and repair of connective tissue |
US5364845C1 (en) * | 1993-03-31 | 2002-09-10 | Nutramax Lab Inc | Glusosamine chondroitin and manganese composition for the protection and repair of connective tissue |
US5358720A (en) * | 1993-10-22 | 1994-10-25 | Koppel Richard M | Treatment of arthritic conditions |
US6271213B1 (en) * | 1996-12-23 | 2001-08-07 | Nutramax Laboratories, Inc. | Aminosugar, glycosaminoglycan, and S-adenosylmethionine composition for the treatment and repair of connective tissue |
US6583123B2 (en) * | 1996-12-23 | 2003-06-24 | Nutramax Laboratories, Inc. | Aminosugar, glycosaminoglycan, and S-adenosylmethionine composition for the treatment and repair of connective tissue |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20150224069A1 (en) * | 2011-08-01 | 2015-08-13 | Tixupharma | Method of treatment of periodontum and damaged oral tissue by administering oral compositions comprising supramolecular complexes of polyanionic polymers and spermidine |
US20160101067A1 (en) * | 2011-08-01 | 2016-04-14 | Tixupharma | Supramolecular complexes of polyanionic polymers and spermidine in tissue maintenance and repair |
Also Published As
Publication number | Publication date |
---|---|
US20100330198A1 (en) | 2010-12-30 |
US20090291909A1 (en) | 2009-11-26 |
WO1998027988A1 (en) | 1998-07-02 |
US6492349B1 (en) | 2002-12-10 |
US6583123B2 (en) | 2003-06-24 |
US20020032169A1 (en) | 2002-03-14 |
US6271213B1 (en) | 2001-08-07 |
US20030216348A1 (en) | 2003-11-20 |
AU5622198A (en) | 1998-07-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6583123B2 (en) | Aminosugar, glycosaminoglycan, and S-adenosylmethionine composition for the treatment and repair of connective tissue | |
EP1849471B1 (en) | Compositions comprising an aminosugar, chondroitin, and S-adenosylmethionine | |
US5587363A (en) | Aminosugar and glycosaminoglycan composition for the treatment and repair of connective tissue | |
US6645948B2 (en) | Nutritional composition for the treatment of connective tissue | |
US6476005B1 (en) | Oral and injectable nutritional composition | |
WO1999062524A1 (en) | Aminosugar, glycosaminoglycan, and s-adenosylmethionine composition for the treatment and repair of connective tissue | |
US20050113287A1 (en) | Composition to enhance joint function and repair | |
CA2446615C (en) | Nutritional composition for the treatment of connective tissue | |
AU5778801A (en) | Improvements in effervescent tablet manufacture | |
US20070298117A1 (en) | Compositions and kits comprising a melatonin component and a chondroprotective component | |
Petito | The Role of hyCURE® and Other Chondroprotective Agents in Oral Dietary Supplements |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |