ITRM20120295A1 - COMPOSITION BASED ON INOSITOL IN SYNERGIC ASSOCIATION WITH ANTIOXIDANT COMPOUNDS SPECIALLY FORMULATED FOR SUPPORT IN THE TROFIC AND FUNCTIONAL ALTERATIONS OF THE NERVOUS SYSTEM FOR THE CONTROL OF ALTERATIONS INDUCED BY RADI ACCUMULATION - Google Patents
COMPOSITION BASED ON INOSITOL IN SYNERGIC ASSOCIATION WITH ANTIOXIDANT COMPOUNDS SPECIALLY FORMULATED FOR SUPPORT IN THE TROFIC AND FUNCTIONAL ALTERATIONS OF THE NERVOUS SYSTEM FOR THE CONTROL OF ALTERATIONS INDUCED BY RADI ACCUMULATION Download PDFInfo
- Publication number
- ITRM20120295A1 ITRM20120295A1 IT000295A ITRM20120295A ITRM20120295A1 IT RM20120295 A1 ITRM20120295 A1 IT RM20120295A1 IT 000295 A IT000295 A IT 000295A IT RM20120295 A ITRM20120295 A IT RM20120295A IT RM20120295 A1 ITRM20120295 A1 IT RM20120295A1
- Authority
- IT
- Italy
- Prior art keywords
- alterations
- inositol
- vitamin
- insulin
- acetyl
- Prior art date
Links
- 230000004075 alteration Effects 0.000 title claims description 37
- 239000003963 antioxidant agent Substances 0.000 title claims description 33
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 title claims description 28
- 229960000367 inositol Drugs 0.000 title claims description 28
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 title claims description 28
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 title claims description 28
- 239000000203 mixture Substances 0.000 title claims description 21
- 210000000653 nervous system Anatomy 0.000 title claims description 16
- 238000009825 accumulation Methods 0.000 title claims description 11
- 230000002195 synergetic effect Effects 0.000 title claims description 10
- 230000003078 antioxidant effect Effects 0.000 title description 42
- 150000001875 compounds Chemical class 0.000 title description 10
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims description 36
- 229960004308 acetylcysteine Drugs 0.000 claims description 33
- 235000006708 antioxidants Nutrition 0.000 claims description 32
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 22
- 238000009472 formulation Methods 0.000 claims description 20
- 229960002663 thioctic acid Drugs 0.000 claims description 20
- AGBQKNBQESQNJD-UHFFFAOYSA-M lipoate Chemical compound [O-]C(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-M 0.000 claims description 18
- 230000004060 metabolic process Effects 0.000 claims description 18
- 235000019136 lipoic acid Nutrition 0.000 claims description 17
- 230000001228 trophic effect Effects 0.000 claims description 17
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims description 16
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 14
- RDHQFKQIGNGIED-MRVPVSSYSA-N O-acetyl-L-carnitine Chemical compound CC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C RDHQFKQIGNGIED-MRVPVSSYSA-N 0.000 claims description 12
- 229960001009 acetylcarnitine Drugs 0.000 claims description 12
- 230000002829 reductive effect Effects 0.000 claims description 12
- 235000000346 sugar Nutrition 0.000 claims description 12
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 claims description 12
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 10
- 229930003268 Vitamin C Natural products 0.000 claims description 10
- 235000001014 amino acid Nutrition 0.000 claims description 10
- 150000001413 amino acids Chemical class 0.000 claims description 10
- 235000019154 vitamin C Nutrition 0.000 claims description 10
- 239000011718 vitamin C Substances 0.000 claims description 10
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 claims description 9
- 229960003495 thiamine Drugs 0.000 claims description 9
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 claims description 8
- 229960002477 riboflavin Drugs 0.000 claims description 8
- 229940088594 vitamin Drugs 0.000 claims description 8
- 229930003231 vitamin Natural products 0.000 claims description 8
- 235000013343 vitamin Nutrition 0.000 claims description 8
- 239000011782 vitamin Substances 0.000 claims description 8
- 235000010374 vitamin B1 Nutrition 0.000 claims description 8
- 239000011691 vitamin B1 Substances 0.000 claims description 8
- 235000019158 vitamin B6 Nutrition 0.000 claims description 8
- 239000011726 vitamin B6 Substances 0.000 claims description 8
- 229940011671 vitamin b6 Drugs 0.000 claims description 8
- KPGXRSRHYNQIFN-UHFFFAOYSA-L 2-oxoglutarate(2-) Chemical compound [O-]C(=O)CCC(=O)C([O-])=O KPGXRSRHYNQIFN-UHFFFAOYSA-L 0.000 claims description 7
- 102000010445 Lactoferrin Human genes 0.000 claims description 7
- 108010063045 Lactoferrin Proteins 0.000 claims description 7
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 7
- 229930003451 Vitamin B1 Natural products 0.000 claims description 7
- 229930003471 Vitamin B2 Natural products 0.000 claims description 7
- 229960000304 folic acid Drugs 0.000 claims description 7
- 235000019152 folic acid Nutrition 0.000 claims description 7
- 239000011724 folic acid Substances 0.000 claims description 7
- CSSYQJWUGATIHM-IKGCZBKSSA-N l-phenylalanyl-l-lysyl-l-cysteinyl-l-arginyl-l-arginyl-l-tryptophyl-l-glutaminyl-l-tryptophyl-l-arginyl-l-methionyl-l-lysyl-l-lysyl-l-leucylglycyl-l-alanyl-l-prolyl-l-seryl-l-isoleucyl-l-threonyl-l-cysteinyl-l-valyl-l-arginyl-l-arginyl-l-alanyl-l-phenylal Chemical compound C([C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CSSYQJWUGATIHM-IKGCZBKSSA-N 0.000 claims description 7
- 229940078795 lactoferrin Drugs 0.000 claims description 7
- 235000021242 lactoferrin Nutrition 0.000 claims description 7
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 claims description 7
- 150000008163 sugars Chemical class 0.000 claims description 7
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 claims description 7
- 235000019164 vitamin B2 Nutrition 0.000 claims description 7
- 239000011716 vitamin B2 Substances 0.000 claims description 7
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 6
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 6
- 230000009467 reduction Effects 0.000 claims description 6
- 229960003080 taurine Drugs 0.000 claims description 6
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 5
- 235000018417 cysteine Nutrition 0.000 claims description 5
- 235000015872 dietary supplement Nutrition 0.000 claims description 5
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 4
- 239000004472 Lysine Substances 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 230000004064 dysfunction Effects 0.000 claims description 4
- 229930182817 methionine Natural products 0.000 claims description 4
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 2
- 229960004203 carnitine Drugs 0.000 claims description 2
- 230000002596 correlated effect Effects 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- PHIQHXFUZVPYII-ZCFIWIBFSA-O (R)-carnitinium Chemical compound C[N+](C)(C)C[C@H](O)CC(O)=O PHIQHXFUZVPYII-ZCFIWIBFSA-O 0.000 claims 1
- 229960002433 cysteine Drugs 0.000 claims 1
- 229960004452 methionine Drugs 0.000 claims 1
- 239000003826 tablet Substances 0.000 claims 1
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 70
- 150000003254 radicals Chemical class 0.000 description 40
- 229940125396 insulin Drugs 0.000 description 36
- 102000004877 Insulin Human genes 0.000 description 34
- 108090001061 Insulin Proteins 0.000 description 34
- 210000004027 cell Anatomy 0.000 description 31
- 230000009471 action Effects 0.000 description 25
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 21
- 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 19
- 230000036542 oxidative stress Effects 0.000 description 19
- 239000000126 substance Substances 0.000 description 19
- 206010022489 Insulin Resistance Diseases 0.000 description 18
- 210000000170 cell membrane Anatomy 0.000 description 18
- 230000001413 cellular effect Effects 0.000 description 18
- 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 16
- 239000008103 glucose Substances 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 15
- 238000004519 manufacturing process Methods 0.000 description 15
- 230000006378 damage Effects 0.000 description 13
- 206010012601 diabetes mellitus Diseases 0.000 description 13
- 230000003834 intracellular effect Effects 0.000 description 12
- 238000011282 treatment Methods 0.000 description 12
- 108010024636 Glutathione Proteins 0.000 description 10
- 230000002255 enzymatic effect Effects 0.000 description 10
- 230000006870 function Effects 0.000 description 10
- 201000001421 hyperglycemia Diseases 0.000 description 10
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 9
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 9
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 9
- 108010076181 Proinsulin Proteins 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 235000003969 glutathione Nutrition 0.000 description 9
- 229960003180 glutathione Drugs 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 239000000600 sorbitol Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 230000001965 increasing effect Effects 0.000 description 8
- 201000001119 neuropathy Diseases 0.000 description 8
- 230000007823 neuropathy Effects 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000001684 chronic effect Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 230000007246 mechanism Effects 0.000 description 7
- 210000003205 muscle Anatomy 0.000 description 7
- 230000007170 pathology Effects 0.000 description 7
- 230000002265 prevention Effects 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 230000001603 reducing effect Effects 0.000 description 7
- 208000011580 syndromic disease Diseases 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 125000003396 thiol group Chemical group [H]S* 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- 206010063837 Reperfusion injury Diseases 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 230000006851 antioxidant defense Effects 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 230000007547 defect Effects 0.000 description 6
- 230000003412 degenerative effect Effects 0.000 description 6
- 229940088597 hormone Drugs 0.000 description 6
- 239000005556 hormone Substances 0.000 description 6
- 150000002632 lipids Chemical class 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 229930091371 Fructose Natural products 0.000 description 5
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 5
- 239000005715 Fructose Substances 0.000 description 5
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 5
- 210000003169 central nervous system Anatomy 0.000 description 5
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 5
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 5
- 201000008980 hyperinsulinism Diseases 0.000 description 5
- 230000002503 metabolic effect Effects 0.000 description 5
- 230000002969 morbid Effects 0.000 description 5
- 230000001590 oxidative effect Effects 0.000 description 5
- 230000001717 pathogenic effect Effects 0.000 description 5
- 150000003904 phospholipids Chemical class 0.000 description 5
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 5
- 229920005862 polyol Polymers 0.000 description 5
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate 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-N 0.000 description 4
- 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 4
- 108010005094 Advanced Glycation End Products Proteins 0.000 description 4
- 102000003746 Insulin Receptor Human genes 0.000 description 4
- 108010001127 Insulin Receptor Proteins 0.000 description 4
- 229960001456 adenosine triphosphate Drugs 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 230000005779 cell damage Effects 0.000 description 4
- 239000005515 coenzyme Substances 0.000 description 4
- 230000006735 deficit Effects 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 230000009931 harmful effect Effects 0.000 description 4
- 230000003902 lesion Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000002858 neurotransmitter agent Substances 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 208000033808 peripheral neuropathy Diseases 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000001243 protein synthesis Methods 0.000 description 4
- 239000003642 reactive oxygen metabolite Substances 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 4
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 239000013626 chemical specie Substances 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 210000000805 cytoplasm Anatomy 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 230000037149 energy metabolism Effects 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 230000002218 hypoglycaemic effect Effects 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 230000002608 insulinlike Effects 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- 208000028867 ischemia Diseases 0.000 description 3
- 229940067606 lecithin Drugs 0.000 description 3
- 239000000787 lecithin Substances 0.000 description 3
- 235000010445 lecithin Nutrition 0.000 description 3
- 230000035800 maturation Effects 0.000 description 3
- 230000006680 metabolic alteration Effects 0.000 description 3
- 230000002107 myocardial effect Effects 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 230000002085 persistent effect Effects 0.000 description 3
- 150000003905 phosphatidylinositols Chemical class 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 230000014616 translation Effects 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 206010053547 Congenital generalised lipodystrophy Diseases 0.000 description 2
- 201000006705 Congenital generalized lipodystrophy Diseases 0.000 description 2
- 102000051325 Glucagon Human genes 0.000 description 2
- 108060003199 Glucagon Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- 102000057248 Lipoprotein(a) Human genes 0.000 description 2
- 108010033266 Lipoprotein(a) Proteins 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 2
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 2
- 229930003756 Vitamin B7 Natural products 0.000 description 2
- 229930003427 Vitamin E Natural products 0.000 description 2
- 108010093894 Xanthine oxidase Proteins 0.000 description 2
- INAPMGSXUVUWAF-GCVPSNMTSA-N [(2r,3s,5r,6r)-2,3,4,5,6-pentahydroxycyclohexyl] dihydrogen phosphate Chemical compound OC1[C@H](O)[C@@H](O)C(OP(O)(O)=O)[C@H](O)[C@@H]1O INAPMGSXUVUWAF-GCVPSNMTSA-N 0.000 description 2
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 230000001195 anabolic effect Effects 0.000 description 2
- 230000002225 anti-radical effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 235000017471 coenzyme Q10 Nutrition 0.000 description 2
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000007123 defense Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 235000020776 essential amino acid Nutrition 0.000 description 2
- 239000003797 essential amino acid Substances 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 2
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 2
- 229960004666 glucagon Drugs 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 230000002641 glycemic effect Effects 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000037041 intracellular level Effects 0.000 description 2
- 230000003859 lipid peroxidation Effects 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000007257 malfunction Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 210000003470 mitochondria Anatomy 0.000 description 2
- 210000001700 mitochondrial membrane Anatomy 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 210000004126 nerve fiber Anatomy 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
- 235000020824 obesity Nutrition 0.000 description 2
- 210000003463 organelle Anatomy 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 230000001991 pathophysiological effect Effects 0.000 description 2
- 210000001428 peripheral nervous system Anatomy 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 108010066381 preproinsulin Proteins 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 230000002797 proteolythic effect Effects 0.000 description 2
- 230000008707 rearrangement Effects 0.000 description 2
- 238000006479 redox reaction Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 210000001082 somatic cell Anatomy 0.000 description 2
- 230000000392 somatic effect Effects 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 230000008093 supporting effect Effects 0.000 description 2
- 235000019157 thiamine Nutrition 0.000 description 2
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 2
- 239000011721 thiamine Substances 0.000 description 2
- 238000010361 transduction Methods 0.000 description 2
- 230000026683 transduction Effects 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- 235000011912 vitamin B7 Nutrition 0.000 description 2
- 239000011735 vitamin B7 Substances 0.000 description 2
- 235000019165 vitamin E Nutrition 0.000 description 2
- 239000011709 vitamin E Substances 0.000 description 2
- 229940046009 vitamin E Drugs 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000001889 Acid-Base Imbalance Diseases 0.000 description 1
- 206010000599 Acromegaly Diseases 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010003594 Ataxia telangiectasia Diseases 0.000 description 1
- 208000037157 Azotemia Diseases 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 206010053582 Bronchopneumopathy Diseases 0.000 description 1
- 108010075254 C-Peptide Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000016938 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- 208000018152 Cerebral disease Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 108091052347 Glucose transporter family Proteins 0.000 description 1
- 102000042092 Glucose transporter family Human genes 0.000 description 1
- 102000006587 Glutathione peroxidase Human genes 0.000 description 1
- 108700016172 Glutathione peroxidases Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 230000010740 Hormone Receptor Interactions Effects 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 102000006386 Myelin Proteins Human genes 0.000 description 1
- 108010083674 Myelin Proteins Proteins 0.000 description 1
- 206010061533 Myotonia Diseases 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 102000015731 Peptide Hormones Human genes 0.000 description 1
- 108010038988 Peptide Hormones Proteins 0.000 description 1
- 206010036049 Polycystic ovaries Diseases 0.000 description 1
- 206010063493 Premature ageing Diseases 0.000 description 1
- 208000032038 Premature aging Diseases 0.000 description 1
- 108091006296 SLC2A1 Proteins 0.000 description 1
- 108091006300 SLC2A4 Proteins 0.000 description 1
- 102100023536 Solute carrier family 2, facilitated glucose transporter member 1 Human genes 0.000 description 1
- 102100033939 Solute carrier family 2, facilitated glucose transporter member 4 Human genes 0.000 description 1
- 102100038803 Somatotropin Human genes 0.000 description 1
- 102000019197 Superoxide Dismutase Human genes 0.000 description 1
- 108010012715 Superoxide dismutase Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 206010047486 Virilism Diseases 0.000 description 1
- 102100033220 Xanthine oxidase Human genes 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 201000010272 acanthosis nigricans Diseases 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 150000001323 aldoses Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000002058 anti-hyperglycaemic effect Effects 0.000 description 1
- 230000003035 anti-peroxidant effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 208000037849 arterial hypertension Diseases 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000005842 biochemical reaction Methods 0.000 description 1
- 230000004791 biological behavior Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 230000007177 brain activity Effects 0.000 description 1
- 230000004094 calcium homeostasis Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000001925 catabolic effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000001765 catechin Chemical class 0.000 description 1
- ADRVNXBAWSRFAJ-UHFFFAOYSA-N catechin Natural products OC1Cc2cc(O)cc(O)c2OC1c3ccc(O)c(O)c3 ADRVNXBAWSRFAJ-UHFFFAOYSA-N 0.000 description 1
- 235000005487 catechin Nutrition 0.000 description 1
- 230000001364 causal effect Effects 0.000 description 1
- 230000032677 cell aging Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000006567 cellular energy metabolism Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 210000003850 cellular structure Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 230000002079 cooperative effect Effects 0.000 description 1
- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical class NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 description 1
- -1 cyclic polyol Chemical class 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 230000003210 demyelinating effect Effects 0.000 description 1
- 201000002342 diabetic polyneuropathy Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000027721 electron transport chain Effects 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 238000012239 gene modification Methods 0.000 description 1
- 208000027892 generalized lipodystrophy Diseases 0.000 description 1
- 230000005017 genetic modification Effects 0.000 description 1
- 235000013617 genetically modified food Nutrition 0.000 description 1
- 230000006377 glucose transport Effects 0.000 description 1
- 230000036252 glycation Effects 0.000 description 1
- 230000034659 glycolysis Effects 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-N hydroperoxyl Chemical compound O[O] OUUQCZGPVNCOIJ-UHFFFAOYSA-N 0.000 description 1
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 description 1
- 201000010066 hyperandrogenism Diseases 0.000 description 1
- 230000003345 hyperglycaemic effect Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000019948 ion homeostasis Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 208000022215 lipoatrophic diabetes Diseases 0.000 description 1
- 201000009099 lipoatrophic diabetes mellitus Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 235000021073 macronutrients Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 238000006241 metabolic reaction Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 210000005012 myelin Anatomy 0.000 description 1
- 230000019261 negative regulation of glycolysis Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000001722 neurochemical effect Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000000626 neurodegenerative effect Effects 0.000 description 1
- 230000002644 neurohormonal effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100001143 noxa Toxicity 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 230000036284 oxygen consumption Effects 0.000 description 1
- 206010053857 partial lipodystrophy Diseases 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 210000002824 peroxisome Anatomy 0.000 description 1
- 229940097156 peroxyl Drugs 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 230000008288 physiological mechanism Effects 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 210000003935 rough endoplasmic reticulum Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 210000004739 secretory vesicle Anatomy 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000000287 tissue oxygenation Effects 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000032895 transmembrane transport Effects 0.000 description 1
- 230000018405 transmission of nerve impulse Effects 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 0.000 description 1
- 125000002264 triphosphate group Chemical group [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/175—Amino acids
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
- A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Anti-Oxidant Or Stabilizer Compositions (AREA)
- Food Preservation Except Freezing, Refrigeration, And Drying (AREA)
Description
Allegato B) Annex B)
DESCRIZIONE DESCRIPTION
Campo dell'Invenzione Field of the Invention
La presente invenzione si riferisce al settore sanitario per il sostegno nelle alterazioni trofiche e funzionali del sistema nervoso; per il controllo delle alterazioni indotte dall’accumulo di radicali liberi e/o dalla riduzione della concentrazione di antiossidanti endogeni e per facilitare il metabolismo degli zuccheri e, più specificamente, ha come oggetto il formulato di un integratore alimentare e/o alimento a fini medici speciali contenente in associazione ed in rapporto di peso sinergico: The present invention refers to the health sector for support in trophic and functional alterations of the nervous system; for the control of the alterations induced by the accumulation of free radicals and / or by the reduction of the concentration of endogenous antioxidants and to facilitate the metabolism of sugars and, more specifically, has as its object the formulation of a food supplement and / or food for special doctors containing in combination and in synergistic weight ratio:
a) Inositolo (a) a) Inositol (a)
b) L-Acetil-Carnitina (b) b) L-Acetyl-Carnitine (b)
c) N-Acetil-L-Cisteina (NAC), (c) c) N-Acetyl-L-Cysteine (NAC), (c)
d) Acido α Lipoico (d) d) Î ± Lipoic Acid (d)
correlati da un rapporto ponderale (a):(b):(c):(d), compreso nell’intervallo da 100:1:1:1 a 1:100:100:100 e da un rapporto ponderale (c):(d) compreso nell’intervallo da 100:1 a 1:100. correlated by a weight ratio (a) :( b) :( c) :( d), included in the range from 100: 1: 1: 1 to 1: 100: 100: 100 and by a weight ratio (c) : (d) in the range from 100: 1 to 1: 100.
Detto formulato può essere fornito in compresse, capsule, capsule gastroresistenti e ridotto in polvere da inserire in bustine. Said formulation can be supplied in tablets, capsules, gastro-resistant capsules and reduced to powder to be inserted in sachets.
Background dell'Invenzione e Scopi dell’invenzione Background of the Invention and Aims of the Invention
E’ noto che i radicali liberi (RL) sono molecole instabili ed estremamente reattive, spesso responsabili, quando in eccesso, di gravi alterazioni alle cellule dell’organismo. Il loro comportamento à ̈ dovuto alla presenza di almeno un elettrone spaiato sull'orbitale più esterno e questa configurazione elettronica li rende altamente instabili e particolarmente reattivi; l’elettrone spaiato, infatti, ha la tendenza ad attirarne a sé un altro dalle molecole con cui viene in contatto. Grazie a questo meccanismo i radicali liberi hanno la capacità di autopropagarsi trasformando i loro bersagli in radicali liberi e scatenando così reazioni a catena che possono provocare estesi danni nella cellula. It is known that free radicals (RL) are unstable and extremely reactive molecules, often responsible, when in excess, of serious alterations to the cells of the organism. Their behavior is due to the presence of at least one unpaired electron on the outermost orbital and this electronic configuration makes them highly unstable and particularly reactive; the unpaired electron, in fact, has the tendency to attract another electron to itself from the molecules with which it comes into contact. Thanks to this mechanism, free radicals have the ability to self-propagate, transforming their targets into free radicals and thus triggering chain reactions that can cause extensive damage to the cell.
La produzione cellulare di radicali liberi à ̈ un evento fisiologico, in particolare à ̈ possibile individuare almeno 5 fonti metaboliche primarie di radicali liberi, in rapporto al sito cellulare interessato alla loro produzione: la membrana plasmatica, i mitocondri, i perossisomi, il reticolo endoplasmatico liscio (microsomi) e il citoplasma; inoltre radicali liberi possono essere prodotti anche a causa di fattori esterni (radiazioni, farmaci, smog). The cellular production of free radicals is a physiological event, in particular it is possible to identify at least 5 primary metabolic sources of free radicals, in relation to the cellular site involved in their production: the plasma membrane, mitochondria, peroxisomes, the endoplasmic reticulum smooth (microsomes) and cytoplasm; moreover, free radicals can also be produced due to external factors (radiation, drugs, smog).
I radicali liberi più conosciuti sono quelli a contenuto d'ossigeno come l'anione superossido, il radicale idrossilico, il radicale perossilico o perossido, l’ossido nitrico. The best known free radicals are those with oxygen content such as superoxide anion, hydroxyl radical, peroxyl radical or peroxide, nitric oxide.
Allegato B) Annex B)
Esistono inoltre alcune specie reattive dell’ossigeno che, pur non essendo veri e propri radicali liberi (non hanno in altre parole elettroni spaiati sull’orbitale esterno), hanno un comportamento biologico similare ed altrettanto nocivo: ad es. il perossido di idrogeno (o acqua ossigenataH2O2). Tutte le specie chimiche reattive dell’ossigeno, di natura non necessariamente radicalica, ma accomunate dalla tendenza più o meno spiccata ad ossidare vari substrati organici, vengono raggruppate sotto il nome di ROS (Reacting Oxygen Species); sebbene queste siano le specie a maggior diffusione esistono specie reattive e radicaliche anche su altri elementi, quali l’azoto, il cloro e lo zolfo. There are also some reactive oxygen species which, although not real free radicals (in other words they do not have unpaired electrons on the external orbital), have a similar and equally harmful biological behavior: eg. hydrogen peroxide (or hydrogen peroxide H2O2). All the reactive chemical species of oxygen, not necessarily of a radical nature, but united by the more or less marked tendency to oxidize various organic substrates, are grouped under the name of ROS (Reacting Oxygen Species); although these are the most widespread species, reactive and radical species exist also on other elements, such as nitrogen, chlorine and sulfur.
Tutti i RL esplicano la loro attività tossica solo quando sono prodotti con una velocità o in una quantità tale da non poter essere inattivati dai sistemi di difesa della cellula; piccole quantità di radicali liberi, infatti, vengono inattivate da sistemi enzimatici endocellulari o da altri antiossidanti. Ma quando la produzione di radicali liberi à ̈ eccessiva si genera una condizione definita stress ossidativo: i sistemi enzimatici e gli antiossidanti intracellulari non riescono più a far fronte alla sovraproduzione e i radicali liberi generano danno cellulare. All RLs carry out their toxic activity only when they are produced with a speed or in such a quantity that they cannot be inactivated by the cell's defense systems; small quantities of free radicals, in fact, are inactivated by endocellular enzymatic systems or by other antioxidants. But when the production of free radicals is excessive, a condition called oxidative stress is generated: the enzymatic systems and intracellular antioxidants are no longer able to cope with the overproduction and free radicals generate cellular damage.
Il principale bersaglio dei radicali liberi à ̈ rappresentato dai fosfolipidi delle membrane cellulari la cui struttura a doppio strato regolare viene così deformata. Le modifiche strutturali e funzionali delle membrane cellulari conseguenti al danno da radicali liberi, comportano alterazioni negli scambi tra comparti intra- ed extra-cellulari fino a compromettere la sopravvivenza stessa della cellula. The main target of free radicals is represented by the phospholipids of the cell membranes whose regular bilayer structure is thus deformed. The structural and functional changes of cell membranes resulting from damage from free radicals involve alterations in the exchanges between intra- and extra-cellular compartments to the point of compromising the very survival of the cell.
Tra i lipidi oggetto preferenziale degli attacchi dei RL figurano anche le lipoproteine LDL o lipoproteine a bassa densità , deputate principalmente al trasporto nel plasma del colesterolo. A contatto con i RL vengono ossidate, con alterazione delle proprietà fisico-strutturali e delle attività biologiche, e trasformate in fattori causali del processo arteriosclerotico. Among the lipids that are the preferred object of RL attacks are also LDL lipoproteins or low density lipoproteins, mainly responsible for transporting cholesterol into the plasma. In contact with RL they are oxidized, with alteration of the physical-structural properties and biological activities, and transformed into causal factors of the arteriosclerotic process.
Il fenomeno dell’ossidazione non à ̈ esclusivo dei lipidi, ma può interessare qualsiasi substrato organico, dagli amminoacidi alle proteine, dai carboidrati agli acidi nucleici. The phenomenon of oxidation is not exclusive to lipids, but can affect any organic substrate, from amino acids to proteins, from carbohydrates to nucleic acids.
L’alterazione delle strutture proteiche porta al malfunzionamento di molti sistemi enzimatici e il danneggiamento del DNA e dell’RNA può condurre a modificazioni genetiche che sarebbero alla base dei meccanismi di insorgenza del cancro e dell’invecchiamento cellulare. The alteration of protein structures leads to the malfunction of many enzymatic systems and damage to DNA and RNA can lead to genetic modifications that are at the basis of the mechanisms of cancer and cellular aging.
I radicali liberi sono coinvolti direttamente nel danno cellulare e tissutale che si riscontra nel diabete mellito, nelle neuropatie, nelle patologie associate ad ischemia-riperfusione, nelle malattie su base infiammatoria, in corso di tumori e in alcune epato-e broncopneumopatie. In generale, tuttavia, non vi à ̈ patologia umana nella quale non sia documentabile un qualche ruolo patogeno delle specie reattive dell’ossigeno. Free radicals are directly involved in the cell and tissue damage that is found in diabetes mellitus, neuropathies, diseases associated with ischemia-reperfusion, inflammatory diseases, in the course of tumors and in some hepato- and bronchopneumopathies. In general, however, there is no human pathology in which some pathogenic role of reactive oxygen species cannot be documented.
Lo stress ossidativo Oxidative stress
Allegato B) Annex B)
Lo stress ossidativo à ̈ la condizione patologica causata dalla rottura dell'equilibrio fisiologico fra la produzione e l'eliminazione, da parte dei sistemi di difesa antiossidanti, di specie chimiche ossidanti. Oxidative stress is the pathological condition caused by the disruption of the physiological balance between the production and elimination, by the antioxidant defense systems, of oxidizing chemical species.
Lo stress ossidativo costituisce uno dei fattori di rischio emergenti per la salute; ad esso, infatti, risultano associati una serie di quadri morbosi, spesso di natura degenerativa e ad andamento cronico. Oxidative stress constitutes one of the emerging health risk factors; in fact, it is associated with a series of morbid pictures, often of a degenerative nature and with a chronic course.
Trasferendo il discorso all’intero organismo, possiamo definire lo stress ossidativo come una particolare forma di stress chimico indotto dalla presenza di una quantità eccessiva di specie reattive per un’aumentata produzione delle stesse e/o per una ridotta capacità di smaltirne le quantità comunque prodotte. By transferring the discussion to the whole organism, we can define oxidative stress as a particular form of chemical stress induced by the presence of an excessive amount of reactive species due to an increased production of the same and / or a reduced ability to dispose of their quantities however produced.
Comunque determinatosi lo stress ossidativo à ̈ alla base di una serie di alterazioni funzionali e strutturali della cellula tra cui: However, once oxidative stress has occurred, it is at the basis of a series of functional and structural alterations of the cell including:
ï‚· Deplezione di NAD+ e di ATP ï ‚· Depletion of NAD + and ATP
ï‚· Caduta del potenziale di membrana mitocondriale ï ‚· Fall of the mitochondrial membrane potential
ï‚· Aumento della permeabilità della membrana plasmatica ï ‚· Increased permeability of the plasma membrane
ï‚· Perossidazione delle biomolecole (glicidi, lipidi, proteine, acidi nucleici…) ï ‚Peroxidation of biomolecules (glycides, lipids, proteins, nucleic acids ...)
ï‚· Ossidazione e deplezione di Glutatione e dei gruppi tiolici proteici ï ‚· Oxidation and depletion of Glutathione and protein thiol groups
ï‚· Ossidazione dei nucleotidi piridinici ï ‚· Oxidation of pyridine nucleotides
ï‚· Alterazioni dei meccanismi di trasduzione del segnale, dell’omeostasi ionica, del citoscheletro ï ‚· Alterations of the mechanisms of signal transduction, of ionic homeostasis, of the cytoskeleton
ï‚· Inibizione della glicolisi ï ‚· Inhibition of glycolysis
Sul piano generale, queste lesioni – dapprima cellulari e poi tissutali – saranno responsabili, infine, di patologie d’organo, quali ad esempio il morbo di Crohn o la pancreatite, oppure di condizioni sistemiche, quali l’invecchiamento precoce, la neuropatia, il danno da ischemia-riperfusione d’organo e così via. Generally speaking, these lesions - first cellular and then tissue - will eventually be responsible for organ pathologies, such as Crohn's disease or pancreatitis, or for systemic conditions, such as aging early, neuropathy, organ ischemia-reperfusion damage and so on.
I sistemi antiossidanti The antioxidant systems
Tutte le forme di vita mantengono un ambiente riducente entro le proprie cellule; quest’ambiente cellulare redox à ̈ preservato da complessi sistemi antiossidanti in equilibrio tra loro. I sistemi antiossidanti possono essere classificati secondo diversi criteri: sulla base dell’origine, in endogeni ed esogeni, sulla base della natura chimica, in enzimatici e non enzimatici, e sulla base della solubilità , in liposolubili e idrosolubili. All life forms maintain a reducing environment within their cells; this redox cellular environment is preserved by complex antioxidant systems in equilibrium with each other. Antioxidant systems can be classified according to different criteria: on the basis of origin, in endogenous and exogenous, on the basis of chemical nature, in enzymatic and non-enzymatic, and on the basis of solubility, in fat-soluble and water-soluble.
Il sistema di difesa antiossidante à ̈ regolarmente distribuito nell’organismo, sia a livello extracellulare che a livello intracellulare. The antioxidant defense system is regularly distributed in the body, both at an extracellular and intracellular level.
Allegato B) Annex B)
A livello dei liquidi extracellulari e, in particolare, nel plasma, l’insieme delle sostanze potenzialmente in grado di cedere equivalenti riducenti costituisce la cosiddetta barriera antiossidante. Ne fanno parte tutte le proteine plasmatiche e, in particolar modo, l’albumina, la bilirubina, l’acido urico, il colesterolo, e i vari antiossidanti esogeni introdotti con l’alimentazione (ascorbato, tocoferolo, polifenoli ecc.). Un ruolo di particolare importanza à ̈ svolto, nel contesto di questa barriera, dai gruppi tiolici (-SH) delle proteine e dei peptidi. At the level of extracellular liquids and, in particular, in the plasma, the set of substances potentially able to release reducing equivalents constitutes the so-called antioxidant barrier. It includes all plasma proteins and, in particular, albumin, bilirubin, uric acid, cholesterol, and various exogenous antioxidants introduced with the diet (ascorbate, tocopherol, polyphenols, etc.). A particularly important role is played, in the context of this barrier, by the thiol groups (-SH) of proteins and peptides.
All’interno delle cellule il sistema di difesa antiossidante comprende alcuni enzimi (superossidodismutasi, catalasi, perossidasi, glutatione perossidasi) ed una serie di sostanze assunte dall’esterno (vitamine e sostanze ad attività antiossidante). Alcuni di questi agenti sono liposolubili e, entrando nella compagine delle membrane cellulari, costituiscono la prima linea di difesa contro l’attacco dei radicali liberi. Altri, invece, sono idrosolubili ed intervengono soprattutto nel contesto della matrice solubile del citoplasma e degli organuli cellulari. Inside the cells, the antioxidant defense system includes some enzymes (superoxide dismutase, catalase, peroxidase, glutathione peroxidase) and a series of substances taken from the outside (vitamins and substances with antioxidant activity). Some of these agents are fat-soluble and, entering the structure of cell membranes, constitute the first line of defense against the attack of free radicals. Others, on the other hand, are water-soluble and mainly intervene in the context of the soluble matrix of the cytoplasm and cellular organelles.
Radicali liberi nel diabete mellito e nella neuropatia ad esso correlata Free radicals in diabetes mellitus and related neuropathy
Il diabete mellito à ̈ lo stadio finale di una sindrome cronica e progressiva a causa multifattoriale e che conduce a fenomeni di insulino-resistenza e/o riduzione della funzione delle ï ¢ cellule pancreatiche. Diabetes mellitus is the final stage of a chronic and progressive syndrome due to multifactorial causes and which leads to phenomena of insulin resistance and / or reduction in the function of pancreatic cells.
In questa condizione morbosa accanto all’aumentata produzione di specie reattive dell’ossigeno secondaria all’iperglicemia e/o all’aumentata resistenza insulinica, si osserva contemporaneamente una riduzione delle difese antiossidanti, fino a configurare il classico quadro fisiopatologico dello stress ossidativo. Si ritiene che l’iperglicemia e l’insulino-resistenza possano favorire lo stress ossidativo e che le specie radicaliche siano in grado di compromettere l’azione dell’insulina, contribuendo a far aumentare ulteriormente la glicemia. In this morbid condition, alongside the increased production of reactive oxygen species secondary to hyperglycemia and / or increased insulin resistance, a reduction of antioxidant defenses is simultaneously observed, up to the classic pathophysiological picture of stress oxidative. It is believed that hyperglycemia and insulin resistance can promote oxidative stress and that radical species are able to compromise the action of insulin, helping to further increase blood sugar.
L’insulino-resistenza, in modelli animali, si associa ad un aumentato livello di perossidazione lipidica, contemporaneamente l’iperglicemia à ̈ ritenuta una delle principali cause responsabili dell’aumento della concentrazione plasmatica di radicali liberi nel diabete mellito. Insulin resistance, in animal models, is associated with an increased level of lipid peroxidation, at the same time hyperglycemia is considered one of the main causes responsible for the increase in the plasma concentration of free radicals in diabetes mellitus.
Recenti studi clinici dimostrano la capacità di sostanze anti-ossidanti (Oner G. & Muderris I.I., 2011) di correggere l’iperglicemia in individui affetti da diabete mellito di tipo II. Recent clinical studies demonstrate the ability of antioxidant substances (Oner G. & Muderris I.I., 2011) to correct hyperglycemia in individuals with type II diabetes mellitus.
Occorre sottolineare che i radicali liberi possono assumere un ruolo determinante nella patogenesi non solo della malattia diabetica in sà ̈ ma anche delle complicanze ad essa legate quali le cardiovasculopatie, la neuropatia, la embriofetopatia eccetera. It should be emphasized that free radicals can play a decisive role in the pathogenesis not only of the diabetic disease itself but also of the related complications such as cardiovascular disease, neuropathy, embryofetopathy, etc.
La neuropatia diabetica à ̈ caratterizzata da un danno a carico del sistema nervoso periferico somatico o vegetativo. È correlata ai disordini biochimici causati dal diabete e negli ultimi anni à ̈ emersa sempre più l’importanza dello stress ossidativo nel collegare l’iperglicemia persistente al danno delle fibre nervose. Diabetic neuropathy is characterized by damage to the somatic or vegetative peripheral nervous system. It is related to the biochemical disorders caused by diabetes and in recent years the importance of oxidative stress in linking persistent hyperglycemia to nerve fiber damage has increasingly emerged.
Allegato B) Annex B)
La patogenesi della neuropatia diabetica risulta multifattoriale, in accordo con la molteplicità delle alterazioni metaboliche che caratterizzano la malattia diabetica; à ̈ però possibile formulare almeno due ipotesi biochimiche responsabili delle manifestazioni cliniche accomunate dalla proprietà di indurre stress ossidativo: The pathogenesis of diabetic neuropathy is multifactorial, in accordance with the multiplicity of metabolic alterations that characterize diabetic disease; However, it is possible to formulate at least two biochemical hypotheses responsible for the clinical manifestations united by the property of inducing oxidative stress:
1. L’attivazione della via dei polioli 1. Activation of the polyol pathway
2. La formazione di Advanced Glycation End Products (AGE) 2. The formation of Advanced Glycation End Products (AGE)
L’attivazione della via dei polioli: Activation of the polyol pathway:
Il glucosio può essere convertito in sorbitolo, un poliolo, nella maggioranza delle cellule, attraverso la via metabolica dei polioli. In presenza di iperglicemia l’attivazione di questa via porta alla trasformazione del glucosio in sorbitolo ed alla seguente conversione del sorbitolo in fruttosio. Il sorbitolo ed il fruttosio hanno la tendenza ad accumularsi all'interno delle cellule e ad uscirne con difficoltà poiché non diffondono attraverso le membrane: ciò determina, come meccanismo di compenso, una deplezione di altre molecole ad attività osmotica tra cui l’inositolo e la taurina. Inoltre gli enzimi che convertono il glucosio in sorbitolo ed il sorbitolo in fruttosio utilizzano come cofattore il NADPH, che viene ossidato a NADP<+>e pertanto non à ̈ più disponibile come cofattore dell’enzima glutatione redattasi, con conseguente deplezione del glutatione ridotto e riduzione delle capacità antiossidanti intracellulari. Glucose can be converted into sorbitol, a polyol, in most cells through the polyol pathway. In the presence of hyperglycemia, the activation of this pathway leads to the transformation of glucose into sorbitol and the subsequent conversion of sorbitol into fructose. Sorbitol and fructose have a tendency to accumulate inside the cells and to exit with difficulty because they do not diffuse through the membranes: this determines, as a compensation mechanism, a depletion of other molecules with osmotic activity including inositol and taurine. Furthermore, the enzymes that convert glucose into sorbitol and sorbitol into fructose use NADPH as a cofactor, which is oxidized to NADP <+> and therefore is no longer available as a cofactor of the enzyme glutathione redactase, with consequent depletion of reduced glutathione and reduction of intracellular antioxidant capacities.
La formazione di Advanced Glycation End Products (AGE): The formation of Advanced Glycation End Products (AGE):
La formazione di prodotti avanzati della glicosilazione prende origine dalla reazione non enzimatica di glicazione delle proteine e cioà ̈ la reazione di interazione tra gruppo aldeidico di uno zucchero riducente o di un metabolita e un aminogruppo di una proteina (Baynes et al., 2000; Vlassara et al., 2003). Inizialmente si formano legami reversibili tra molecole che a loro volta, in seguito ad un riarrangiamento chimico, si trasformano nei cosiddetti AGE. The formation of advanced glycosylation products originates from the non-enzymatic glycation reaction of proteins, i.e. the interaction reaction between the aldehyde group of a reducing sugar or metabolite and an amino group of a protein (Baynes et al., 2000; Vlassara et al., 2003). Initially, reversible bonds are formed between molecules which in turn, following a chemical rearrangement, are transformed into the so-called AGEs.
Gli AGE si formano spontaneamente e fisiologicamente nel nostro organismo, ma in corso di diabete, in presenza di alterazioni del metabolismo intermedio o di iperglicemia cronica, questi fenomeni si accentuano; la loro concentrazione aumenta nei tessuti e nelle cellule dove esplicano il loro effetto nocivo. Gli AGE possono esercitare effetti dannosi in modo diretto, modificando la struttura e la funzione delle macromolecole coinvolte o in modo indiretto, inducendo una risposta cellulare a seconda del distretto colpito dal loro accumulo. AGEs are formed spontaneously and physiologically in our organism, but in the course of diabetes, in the presence of alterations in the intermediate metabolism or chronic hyperglycemia, these phenomena are accentuated; their concentration increases in the tissues and cells where they exert their harmful effect. AGEs can exert harmful effects directly, modifying the structure and function of the macromolecules involved or indirectly, inducing a cellular response depending on the area affected by their accumulation.
Radicali liberi nelle patologie involutive degenerative Free radicals in degenerative involutionary pathologies
Nel processo di invecchiamento cellulare e fisiologico assume grande importanza la continua e cronica esposizione ai radicali liberi dell'ossigeno (Johnson Jr J.E. et al., 1986). Ad essi, infatti, risultano associati non solo l'invecchiamento precoce, ma anche una serie di quadri morbosi, spesso di natura degenerativa e ad andamento cronico. In particolare, il Sistema Nervoso Centrale Allegato B) In the process of cellular and physiological aging, the continuous and chronic exposure to oxygen free radicals assumes great importance (Johnson Jr J.E. et al., 1986). In fact, not only premature aging is associated with them, but also a series of morbid conditions, often of a degenerative nature and with a chronic course. In particular, the Central Nervous System Annex B)
rappresenta, per diverse ragioni (elevato consumo di ossigeno, alti livelli di ferro, concentrazione significativa di acidi grassi polinsaturi) uno dei principali bersagli dei ROS e, quindi, dello stress ossidativo che, a ragione, viene oggi considerato uno dei principali cofattori di malattie neurodegenerative (malattia di Parkinson, malattia di Alzheimer, sclerosi laterale amiotrofica, etc.). Quando i radicali liberi danneggiano la membrana cellulare, la capacità delle cellule di regolare il passaggio di sostanze fra l’interno e l’esterno della cellula può essere alterata. Come conseguenza, la cellula può essere danneggiata da un’esposizione eccessiva ad una normale sostanza nutrizionale come ad esempio il calcio. represents, for various reasons (high oxygen consumption, high iron levels, significant concentration of polyunsaturated fatty acids) one of the main targets of ROS and, therefore, of oxidative stress which, with good reason, is today considered one of the main cofactors of diseases neurodegenerative (Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, etc.). When free radicals damage the cell membrane, the ability of cells to regulate the passage of substances between the inside and outside of the cell can be impaired. As a consequence, the cell can be damaged by excessive exposure to a normal nutritional substance such as calcium.
Per questo motivo, negli ultimi anni il tradizionale approccio terapeutico a queste patologie si sta sempre più aprendo al contributo, talvolta determinante, degli antiossidanti che hanno la capacità di migliorare il trofismo neuronale, più o meno gravemente compromesso dallo squilibrio del bilancio ossidativo nel corso di malattie croniche e degenerative. For this reason, in recent years the traditional therapeutic approach to these pathologies is increasingly opening up to the contribution, sometimes decisive, of antioxidants that have the ability to improve neuronal trophism, more or less severely compromised by the imbalance of the oxidative balance in the course of chronic and degenerative diseases.
Numerosi studi clinici condotti su gruppi di persone in età avanzata evidenziano come l’uso di antiossidanti sia associato ad un miglioramento della memoria e dell’apprendimento (Markesbery WR. 1997; Perrig WJ et al., 1997). Numerous clinical studies conducted on groups of elderly people show that the use of antioxidants is associated with an improvement in memory and learning (Markesbery WR. 1997; Perrig WJ et al., 1997).
Il metabolismo degli zuccheri The metabolism of sugars
La glicemia à ̈ definita come la concentrazione di glucosio nel sangue. È di fondamentale importanza che la glicemia rimanga entro i limiti dell'intervallo di normalità per assicurare il normale apporto energetico al cervello. A differenza di altri organi e dei muscoli, infatti, il cervello non à ̈ in grado di immagazzinare riserve di glucosio dalla cui disponibilità dipende direttamente. Il sistema di regolazione della glicemia à ̈ mediato principalmente da due ormoni fra loro antagonisti che sono secreti dal pancreas: l'insulina e il glucagone. L'azione dell'insulina à ̈ ipoglicemizzante mentre quella del glucagone à ̈, al contrario, iperglicemizzante. Blood sugar is defined as the concentration of glucose in the blood. It is critically important that blood glucose remains within the normal range to ensure normal energy supply to the brain. Unlike other organs and muscles, in fact, the brain is not able to store glucose reserves on whose availability it directly depends. The blood glucose regulation system is mainly mediated by two antagonistic hormones that are secreted by the pancreas: insulin and glucagon. The action of insulin is hypoglycemic while that of glucagon is, on the contrary, hyperglycemic.
L'insulina à ̈ un ormone polipeptidico sintetizzato nelle cellule beta delle isole di Langerhans all'interno del pancreas, ed à ̈ formata da due catene, A e B, unite da due ponti disolfuro. Insulin is a polypeptide hormone synthesized in the beta cells of the islets of Langerhans inside the pancreas, and is made up of two chains, A and B, joined by two disulfide bridges.
L’insulina inizialmente non viene prodotta come tale, bensì in una forma immatura chiamata preproinsulina; una volta sintetizzata nel reticolo endoplasmatico rugoso delle cellule beta pancreatiche, la pre-proinsulina subisce alcune reazioni enzimatiche che la trasformano in proinsulina. Sempre per intervento di alcuni enzimi, all'interno dei granuli secretori, la proinsulina si trasforma in insulina matura tramite allontanamento del peptide di coniugazione o peptide C (Figura 2); quando il livello di glucosio ematico à ̈ alto l’insulina viene secreta ed ha la funzione di ridurre la glicemia mediante l'attivazione di diversi processi metabolici e cellulari. Insulin is initially not produced as such, but in an immature form called preproinsulin; once synthesized in the rough endoplasmic reticulum of pancreatic beta cells, pre-proinsulin undergoes certain enzymatic reactions that transform it into proinsulin. Again by the intervention of some enzymes, inside the secretory granules, proinsulin is transformed into mature insulin by removing the conjugation peptide or C peptide (Figure 2); when the blood glucose level is high, insulin is secreted and has the function of reducing blood sugar by activating various metabolic and cellular processes.
Il legame dell’insulina al suo recettore cellulare costituisce la prima cruciale tappa nell’espressione dell’azione metabolica dell’ormone. The binding of insulin to its cellular receptor constitutes the first crucial step in the expression of the metabolic action of the hormone.
Allegato B) Annex B)
I recettori dell’insulina sono delle glicoproteine situate sulla membrana citoplasmatica delle cellule sensibili all’insulina; l’interazione ormone-recettore determina l'avvicinamento delle due subunità intracellulari del recettore e ne permette l'autofosforilazione e l’attivazione. Il segnale à ̈ poi propagato ed amplificato all’interno della cellula da un insieme di secondi messaggeri. Insulin receptors are glycoproteins located on the cytoplasmic membrane of insulin-sensitive cells; the hormone-receptor interaction determines the approach of the two intracellular subunits of the receptor and allows their autophosphorylation and activation. The signal is then propagated and amplified inside the cell by a set of second messengers.
Il segnale ormonale viene trasmesso al sistema effettore e da questo a un mediatore che, a sua volta, innesca l’attivazione o l’inattivazione di sistemi enzimatici che catalizzano numerosi processi metabolici, in particolare il trasporto transmembrana di glucosio, di aminoacidi e di ioni, la sintesi di proteine e di acidi nucleici, la glicogenosintesi, la glicolisi e la sintesi lipidica (Figura 3). The hormonal signal is transmitted to the effector system and from this to a mediator which, in turn, triggers the activation or inactivation of enzymatic systems that catalyze numerous metabolic processes, in particular the transmembrane transport of glucose, amino acids and of ions, protein and nucleic acid synthesis, glycogenosynthesis, glycolysis and lipid synthesis (Figure 3).
Uno degli effetti più immediati che conseguono al legame insulina-recettore à ̈ la stimolazione dei sistemi di trasporto localizzati sulla membrana cellulare, il più noto dei quali à ̈ il sistema di trasporto del glucosio. One of the most immediate effects resulting from the insulin-receptor binding is the stimulation of the transport systems located on the cell membrane, the best known of which is the glucose transport system.
Si parla di insulino-resistenza quando le cellule dell'organismo sono in una condizione metabolica in cui diminuiscono la propria sensibilità all'azione dell'insulina; ne consegue che il rilascio dell'ormone, in dosi fisiologiche, produce un effetto biologico inferiore rispetto a quanto previsto. Alla base dell’insulino-resistenza possono esserci diversi meccanismi: We talk about insulin resistance when the body's cells are in a metabolic condition in which their sensitivity to the action of insulin decreases; it follows that the release of the hormone, in physiological doses, produces a lower biological effect than expected. There may be several mechanisms at the basis of insulin resistance:
1. MECCANISMI PRE-RECETTORIALI 1. PRE-RECEPTORY MECHANISMS
- insulina strutturalmente anomala - structurally abnormal insulin
- aumento del rapporto proinsulina/insulina - increase in the proinsulin / insulin ratio
- anticorpi anti-insulina - anti-insulin antibodies
2. MECCANISMI RECETTORIALI 2. RECEPTORY MECHANISMS
- ridotta concentrazione dei recettori - reduced concentration of receptors
- ridotta affinità dei recettori - reduced affinity of receptors
3. MECCANISMI POST RECETTORIALI 3. POST RECEPTORY MECHANISMS
- difetto di trasmissione del messaggio - failure of message transmission
- difetti enzimatici intracellulari - intracellular enzymatic defects
Questa distinzione non ha solo un’importanza teorica, ma anche pratica e terapeutica. Infatti nell’insulino-resistenza da cause pre-recettoriali il problema terapeutico consisterà nel far arrivare alla periferia adeguate quantità di insulina biologicamente attiva; nell’insulino-resistenza da cause recettoriali e post-recettoriali il problema consisterà essenzialmente nel modificare la sensibilità periferica dell’organismo all’insulina. This distinction has not only theoretical but also practical and therapeutic importance. In fact, in insulin resistance from pre-receptor causes the therapeutic problem will consist in getting adequate quantities of biologically active insulin to the periphery; in insulin resistance caused by receptor and post-receptor causes the problem will essentially consist in modifying the peripheral sensitivity of the organism to insulin.
Il sistema insulina-recettore-effettore à ̈ regolato in modo che alla perturbazione di uno dei suoi componenti fa seguito l’adattamento degli altri due. In altri termini, un difetto primitivo del recettore insulinico avrà come conseguenza un difetto della capacità di legame e quindi una ridotta Allegato B) The insulin-receptor-effector system is regulated in such a way that the perturbation of one of its components is followed by the adaptation of the other two. In other words, a primary defect of the insulin receptor will result in a defect in the binding capacity and therefore a reduced Annex B)
capacità di utilizzare il glucosio. L’organismo si adatterà a questo difetto accentuando la secrezione di insulina (iperinsulinemia). ability to use glucose. The body will adapt to this defect by accentuating the secretion of insulin (hyperinsulinemia).
Razionale Rational
La presente invenzione, avente come oggetto un formulato a base di Inositolo (a), L-Acetil-Carnitina (b), N-Acetil-Cisteina (NAC) (c) e Acidoï ¡ Lipoico (d), in rapporto ponderale sinergico (a):(b):(c):(d) compreso nell’intervallo da 100:1:1:1 a 1:100:100:100 e da un rapporto ponderale (c):(d) compreso nell’intervallo da 100:1 a 1:100 e con altre sostanze a spiccata attività antiossidante, quali la Lattoferrina e/o l’Epigallocatechinagallato (ECGC) e potenziata con una o più delle seguenti vitamine: Vitamina C, Acido Folico, Vitamina B1, Vitamina B2, Vitamina B6 in sinergismo d’azione per il sostegno del sistema nervoso nelle alterazioni trofiche e funzionali, ha lo scopo di controllare le alterazioni indotte dall’accumulo di radicali liberi e facilitare il metabolismo degli zuccheri. The present invention, having as its object a formulation based on Inositol (a), L-Acetyl-Carnitine (b), N-Acetyl-Cysteine (NAC) (c) and Lipoic Acid (d), in synergistic weight ratio ( a) :( b) :( c) :( d) included in the range from 100: 1: 1: 1 to 1: 100: 100: 100 and a weight ratio (c) :( d) included in ™ range from 100: 1 to 1: 100 and with other substances with strong antioxidant activity, such as Lactoferrin and / or Epigallocatechinagallate (ECGC) and enhanced with one or more of the following vitamins: Vitamin C, Folic Acid, Vitamin B1 , Vitamin B2, Vitamin B6 in synergy of action to support the nervous system in trophic and functional alterations, aims to control the alterations induced by the accumulation of free radicals and facilitate the metabolism of sugars.
Tale formulato, avendo una finalità anaplerotica sul piano della fisiologia di ogni componente funzionale delle cellule somatiche sensibili all’azione dell’insulina, per l’azione simultanea dei suoi componenti, à ̈ in grado anche di ripristinare la funzione totale o parziale di un organo o di un apparato nelle alterazioni metaboliche e nelle neuropatie associate ad insulinoresistenza. This formulation, having an anaplerotic purpose on the physiology level of each functional component of the somatic cells sensitive to the action of insulin, due to the simultaneous action of its components, is also able to restore the total or partial function of an organ or apparatus in metabolic alterations and neuropathies associated with insulin resistance.
L'Inositolo à ̈ un poliolo ciclico comunemente classificato come una vitamina del complesso B (riferendosi ad esso come vitamina B7). Nell’organismo umano à ̈ presente nei fosfolipidi delle membrane cellulari dove gioca un ruolo fondamentale nei messaggeri secondari come inositolo fosfato, come fosfatidilinositolo (PI) e fosfatidilinositolofosfato (PIP). La stragrande maggioranza dell'Inositolo presente nell'organismo umano si trova nelle membrane delle cellule del sistema nervoso centrale e del midollo spinale per regolare la funzionalità della membrana cellulare e delle strutture recettoriali associate e quindi la conseguente responsività della cellula agli stimoli (Figura 1). Inositol is a cyclic polyol commonly classified as a B-complex vitamin (referring to it as vitamin B7). In the human organism it is present in the phospholipids of cell membranes where it plays a fundamental role in secondary messengers such as inositol phosphate, as phosphatidylinositol (PI) and phosphatidylinositolophosphate (PIP). The vast majority of the inositol present in the human body is found in the cell membranes of the central nervous system and spinal cord to regulate the functionality of the cell membrane and associated receptor structures and therefore the consequent responsiveness of the cell to stimuli (Figure 1) .
L’Inositolo à ̈ risultato efficace nel trattamento del disturbo ossessivo-compulsivo in studi a doppio cieco (Fux M et al., 1996). Inositol was found to be effective in the treatment of obsessive-compulsive disorder in double-blind studies (Fux M et al., 1996).
L’Inositolo à ̈ anche efficace nello stimolare la produzione di lecitina nell’organismo. I grassi vengono spostati dal fegato alle cellule con l’aiuto della lecitina; l’Inositolo, quindi, contribuisce al metabolismo dei grassi e aiuta a ridurre il tasso di colesterolo nel sangue (Burgess J.W et al., 2003). Inoltre l’Inositolo, nella forma trifosfato, à ̈ direttamente coinvolto nell’omeostasi del calcio (Fauconnier J et al., 2005). La deplezione intracellulare di Inositolo, quale quella osservata in condizioni di iperinsulinemia persistente, à ̈ alla base di diversi possibili danni cellulari (Brownlee M. 2001; Ho H.T. et al., 2000; Cheung A.K. et al., 2005). Inositol is also effective in stimulating the production of lecithin in the body. Fats are moved from the liver to the cells with the help of lecithin; Inositol, therefore, contributes to the metabolism of fats and helps to reduce the level of cholesterol in the blood (Burgess J.W et al., 2003). Furthermore, inositol, in the triphosphate form, is directly involved in calcium homeostasis (Fauconnier J et al., 2005). Intracellular depletion of Inositol, such as that observed in conditions of persistent hyperinsulinemia, is at the basis of various possible cellular damage (Brownlee M. 2001; Ho H.T. et al., 2000; Cheung A.K. et al., 2005).
Allegato B) Annex B)
Numericamente consistenti sono anche gli studi che dimostrano l'utilità dell’Inositolo nel trattamento della sindrome dell'ovaio policistico (PCOS) e delle manifestazioni cliniche connesse a questa tra cui l'insulino-resistenza, l’iperandrogenismo e l’oligoamenorrea (Papaleo E et al., 2007; Costantino D et al., 2009). Questi studi hanno inoltre dimostrato che esistono difetti nel metabolismo dell’Inositolo nella PCOS riconducibile ad insulino-resistenza, chiarendo così il ruolo dell’Inositolo nella trasduzione del segnale dell'insulina (Nestler, JE 2000). Numerically consistent are also the studies that demonstrate the usefulness of Inositol in the treatment of polycystic ovary syndrome (PCOS) and of the clinical manifestations connected to this including insulin resistance, hyperandrogenism and oligoamenorrhea. (Papaleo E et al., 2007; Costantino D et al., 2009). These studies have also shown that there are defects in the metabolism of inositol in PCOS due to insulin resistance, thus clarifying the role of inositol in the transduction of insulin signal (Nestler, JE 2000).
In presenza di elevati livelli glicemici, infatti, il glucosio entra in eccesso nelle cellule dei tessuti non insulino-dipendenti e viene ridotto dall’aldoso in sorbitolo, successivamente metabolizzato a fruttosio. In the presence of high glycemic levels, in fact, glucose enters the cells of non-insulin-dependent tissues in excess and is reduced by aldose to sorbitol, which is subsequently metabolized to fructose.
Una volta formatisi, il sorbitolo ed il fruttosio non si diffondono liberamente attraverso le membrane e di conseguenza si elevano i livelli intracellulari: le cellule, così, possono subire un danno osmotico. Inoltre gli elevati livelli di glucosio e sorbitolo competono con la captazione di inositolo nei tessuti e il conseguente abbassamento dei livelli del pool cellulare di Inositolo può determinare danno cellulare per: Once formed, sorbitol and fructose do not diffuse freely through the membranes and consequently the intracellular levels are raised: the cells, thus, can suffer osmotic damage. Furthermore, the high levels of glucose and sorbitol compete with the uptake of inositol in the tissues and the consequent lowering of the levels of the cellular pool of Inositol can cause cell damage for:
ï‚· alterazione dei segnali intracellulari ï ‚· alteration of intracellular signals
ï‚· ridotta velocità di sintesi di fosfatidilinositolo ï ‚· reduced speed of synthesis of phosphatidylinositol
ï‚· alterazione del metabolismo fosfolipidico di membrana, con ridotta concentrazione del calcio intracellulare e danno della pompa Na+/K+ ATP-dipendente (Xia P. et al., 1995). La L-Acetil-Carnitina à ̈ un intermedio metabolico acetilato della L-Carnitina dotato di maggiore biodisponibilità aminoacido, e nell’organismo umano, ha la funzione principale di facilitare l'ingresso degli acidi grassi a lunga catena all'interno dei mitocondri dove vengono ossidati per la produzione di adenosin-tri-fosfato (ATP). In tal senso la L-Acetil-Carnitina svolge un ruolo indispensabile per il corretto metabolismo energetico cellulare e trasmettitoriale, esercitando un'azione trofica sul sistema nervoso, sul tessuto muscolare e sul tessuto miocardico attraverso l’incremento della produzione di energia. ï ‚· alteration of membrane phospholipid metabolism, with reduced concentration of intracellular calcium and damage to the ATP-dependent Na + / K + pump (Xia P. et al., 1995). L-Acetyl-Carnitine is an acetylated metabolic intermediate of L-Carnitine with greater amino acid bioavailability, and in the human body, has the main function of facilitating the entry of long-chain fatty acids into the mitochondria where they are oxidized for the production of adenosine tri-phosphate (ATP). In this sense, L-Acetyl-Carnitine plays an indispensable role for the correct cellular and transmitting energy metabolism, exerting a trophic action on the nervous system, muscle tissue and myocardial tissue by increasing energy production.
Nel Brevetto US5973004 si descrive e rivendica una formulazione a base di L-Acetil-Carnitina ed Acido ï ¡ Lipoico per il trattamento delle disfunzioni del metabolismo energetico a livello cerebrale. Nel Brevetto US6565876 la Carnitina, in associazione con l’Inositolo Fosfato, à ̈ stata proposta per il trattamento di disordini cardiovascolari e neuro-cerebrali; di forme di ipossia tissutale; di deficit energetici a livello muscolare; di anomalie di tipo infiammatorio; di alterazioni della coagulazione ematica come la trombosi e di forme di proliferazione tissutale. Patent US5973004 describes and claims a formulation based on L-Acetyl-Carnitine and Lipoic Acid for the treatment of dysfunctions of energy metabolism in the brain. In US patent 6565876, Carnitine, in association with Inositol Phosphate, has been proposed for the treatment of cardiovascular and neuro-cerebral disorders; of forms of tissue hypoxia; energy deficits in the muscles; of inflammatory anomalies; alterations in blood coagulation such as thrombosis and forms of tissue proliferation.
La N-Acetil-Cisteina (NAC) à ̈ il derivato N-acetilato dell’aminoacido solforato L-Cisteina, e può essere considerato il più potente composto antiossidante dell’organismo, in grado di agire sia in maniera diretta che indiretta. N-Acetyl-Cysteine (NAC) is the N-acetylated derivative of the sulfur amino acid L-Cysteine, and can be considered the most powerful antioxidant compound in the body, capable of acting both directly and indirectly.
Allegato B) Annex B)
Grazie alla presenza di un gruppo sulfidrilico (SH) libero la NAC opera in ambiente extracellulare attraverso una reazione non enzimatica, dose-dipendente, diretta contro tutte le specie reattive dell'ossigeno (ROS) (azione diretta). Thanks to the presence of a free sulfhydryl group (SH), NAC operates in an extracellular environment through a non-enzymatic, dose-dependent reaction, directed against all reactive oxygen species (ROS) (direct action).
Inoltre la NAC all’interno delle cellule viene deacetilata a L-Cisteina, che à ̈ uno dei tre aminoacidi essenziali per la sintesi del glutatione, che à ̈ un potente antiossidante fisiologico. In tal senso la NAC può essere considerata un integratore indiretto delle riserve endogene di glutatione (azione indiretta). Furthermore, the NAC inside the cells is deacetylated to L-Cysteine, which is one of the three essential amino acids for the synthesis of glutathione, which is a powerful physiological antioxidant. In this sense, NAC can be considered an indirect supplement of the endogenous reserves of glutathione (indirect action).
In condizioni di stress ossidativo i sistemi di difesa antiossidanti non riescono a contrastare l’eccesso di radicali liberi che sono alla base di una serie di alterazioni funzionali e strutturali della cellula e che determinano lesioni dapprima cellulari, poi tissutali e che saranno responsabili, infine, di patologie d’organo, quali ad esempio la neuropatia diabetica, il danno da riperfusione e la neurodegenerazione. In conditions of oxidative stress the antioxidant defense systems are unable to counteract the excess of free radicals which are the basis of a series of functional and structural alterations of the cell and which determine cellular and then tissue lesions which will be responsible, finally , organ pathologies, such as diabetic neuropathy, reperfusion injury and neurodegeneration.
La NAC, precursore del Glutatione, composto ad elevato potere antiossidante, determina la riduzione delle specie ossidanti e la loro definitiva neutralizzazione. L’azione antiossidante esercitata à ̈ prevalentemente sistemica e a livello delle cellule a funzionalità metabolico-endocrina e secretiva, come quelle dell’epitelio tracheale (Figura 1). Attraverso questo meccanismo la NAC esercita un’azione specifica di prevenzione e di miglioramento del quadro sintomatologico delle patologie associate a stress ossidativo, quali la neuropatia diabetica (Lei S. et al., 2012) e il danno da riperfusione (Wang t. et al., 2011). NAC, precursor of Glutathione, a compound with a high antioxidant power, determines the reduction of oxidizing species and their definitive neutralization. The antioxidant action exerted is mainly systemic and at the level of metabolic-endocrine and secretory function cells, such as those of the tracheal epithelium (Figure 1). Through this mechanism, NAC exerts a specific action of prevention and improvement of the symptomatological picture of pathologies associated with oxidative stress, such as diabetic neuropathy (Lei S. et al., 2012) and reperfusion injury (Wang t. Et al., 2011).
Nel Brevetto WO2011144777-A1 si rivendica l’azione della NAC in associazione con l’acido ï ¡-Lipoico per il trattamento dei disordini neuro-metabolici e delle conseguenti alterazioni demielinizzanti di tipo infiammatorio. Patent WO2011144777-A1 claims the action of NAC in association with ï ¡-Lipoic acid for the treatment of neuro-metabolic disorders and the consequent inflammatory demyelinating alterations.
Inoltre recenti studi clinici (Oner G. & Muderris I.I., 2011) hanno messo in evidenza l’azione ipoglicemizzante svolta dalla NAC nell’iperinsulinemia presente in donne con sindrome dell’ovaio policistico, azione paragonabile al trattamento con metformina, farmaco ipoglicemizzante orale di prima scelta. Furthermore, recent clinical studies (Oner G. & Muderris I.I., 2011) have highlighted the hypoglycemic action performed by NAC in the hyperinsulinemia present in women with polycystic ovary syndrome, an action comparable to treatment with metformin, a hypoglycemic drug first choice oral.
Infatti, la NAC, oltre alla sua azione antiossidante, agisce a livello delle cellule β-pancreatiche regolando e mantenendo una corretta insulinopoiesi, e quindi la secrezione di insulina, ormone necessario alla corretta energizzazione di ogni cellula per l’apporto glico-lipidico. In particolare, la NAC, attraverso i suoi gruppi sulfidrilici (-SH), esercita una azione proteolitica sulla struttura elicoidale della proinsulina permettendo l’esternalizzazione dei ponti disolfuro (S-S) e il riarrangiamento strutturale di questa a insulina, l’ormone fisiologicamente attivo (Figura 2). Grazie a questo meccanismo d’azione, la NAC à ̈ determinante per il trattamento della insulinoresistenza e delle alterazioni metaboliche che ne conseguono. Nel V Convegno dell’Istituto Allegato B) In fact, NAC, in addition to its antioxidant action, acts at the level of β-pancreatic cells by regulating and maintaining correct insulinopoiesis, and therefore the secretion of insulin, a hormone necessary for the correct energization of each cell for the glyco-lipid supply. In particular, NAC, through its sulfhydryl groups (-SH), exerts a proteolytic action on the helical structure of proinsulin allowing the externalization of the disulfide bridges (S-S) and the structural rearrangement of this to insulin, the physiologically active (Figure 2). Thanks to this mechanism of action, NAC is crucial for the treatment of insulin resistance and the resulting metabolic alterations. In the V Conference of the Institute Annex B)
Superiore di Sanità dal titolo “Prevenire le complicanze del diabete: dalla ricerca di base all’assistenza†à ̈ stato messo in luce il legame fisiopatologico tra la insulinoresistenza e la neuropatia. Superior of Health entitled â € œPreventing the complications of diabetes: from basic research to assistanceâ € The pathophysiological link between insulin resistance and neuropathy was highlighted.
Inoltre, proprio la azione coadiuvante della NAC nel trattamento della insulinoresistenza à ̈ stata evidenziata nel Congresso Annuale SID -Sezione Piemonte e Valle d’Aosta -, tenutosi a Torino a Marzo 2010 dal titolo “Dalla ricerca di base all’organizzazione dell’assistenza per migliorare la qualità delle cure†. Furthermore, the adjuvant action of NAC in the treatment of insulin resistance was highlighted in the Annual SID Congress - Piedmont and Valle d'Aosta Section -, held in Turin in March 2010 entitled â € œFrom basic research to the organization of the Assistance to improve the quality of careâ €.
L’Acido ï ¡ Lipoico à ̈ una molecola relativamente piccola formata da una catena di otto atomi di carbonio e due di zolfo in posizione terminale, a formare i due gruppi tiolici (-SH) liberi nella forma ridotta o uniti in un ponte disolfuro (-S-S-) nella forma ossidata. In virtù di queste caratteristiche strutturali, l’acido lipoico à ̈ coinvolto sia in reazioni di ossido-riduzione, che in reazioni di trasporto di gruppi acetilici ed acilici (Figura 1). L’Acido ï ¡ Lipoico ha infatti due principali funzioni: interviene come coenzima nel metabolismo cellulare e protegge il corpo dallo stress ossidativo. In particolare il ruolo biochimico dell’Acidoï ¡ Lipoico à ̈ di coofattore presente in numerosi sistemi enzimatici ad azione catabolica; interviene cioà ̈ in quelle vie metaboliche che portano alla produzione di energia dall’ossidazione dei substrati organici del carbonio (ad esempio il ciclo degli acidi tricarbossilici); (Figura 1). Ï ¡Lipoic Acid is a relatively small molecule formed by a chain of eight carbon atoms and two sulfur atoms in terminal position, forming the two thiol groups (-SH) free in the reduced form or united in a disulfide bridge (-S-S-) in the oxidized form. By virtue of these structural characteristics, lipoic acid is involved both in redox reactions and in transport reactions of acetyl and acyl groups (Figure 1). In fact, Lipoic Acid has two main functions: it acts as a coenzyme in cellular metabolism and protects the body from oxidative stress. In particular, the biochemical role of Lipoic Acid is a coofactor present in numerous enzymatic systems with catabolic action; that is, it intervenes in those metabolic pathways that lead to the production of energy from the oxidation of the organic substrates of carbon (for example the cycle of tricarboxylic acids); (Figure 1).
L’Acido ï ¡ Lipoico possiede inoltre particolari caratteristiche che lo rendono un potente antiossidante perché possiede: The ï ¡Lipoic Acid also has particular characteristics that make it a powerful antioxidant because it has:
1) Elevata biodisponibiltà essendo velocemente assorbito e trasportato attraverso le membrane cellulari. 1) High bioavailability as it is rapidly absorbed and transported across cell membranes.
2) Elevato potere antiossidante manifestando una spiccata attività antiossidante sia nei compartimenti cellulari acquosi (citoplasma), che in quelli lipidici (membrane cellulari), e con azione ad ampio spettro nei confronti di diverse specie radicaliche (anione superossido, idroperossido, perossilico) e chelante degli ioni metallici. 2) High antioxidant power showing a marked antioxidant activity both in the aqueous cellular compartments (cytoplasm), and in the lipid (cell membranes), and with a broad spectrum action against different radical species (superoxide anion, hydroperoxide, peroxyl) and chelating of metal ions.
3) Capacità di rigenerare gli altri antiossidanti: vitamina C, vitamina E, coenzima Q. E’ inoltre un potente promotore del glutatione, di cui incrementa la disponibilità . 3) Ability to regenerate other antioxidants: vitamin C, vitamin E, coenzyme Q. It is also a powerful promoter of glutathione, of which it increases its availability.
Sono inoltre note da tempo le proprietà ipoglicemizzanti dell’Acidoï ¡ Lipoico, proprietà talmente spiccate che gli hanno valso la definizione di composto ad attività insulino-simile (Bilska A. & Wlodek L.2005; Konrad T et al., 1999; Evans LJ et al., 2001; Golbidi S et al., 2011; Kamenova P, 2006). The hypoglycemic properties of Lipoic Acid have also been known for some time, properties so strong that they have earned it the definition of a compound with insulin-like activity (Bilska A. & Wlodek L.2005; Konrad T et al., 1999; Evans LJ et al., 2001; Golbidi S et al., 2011; Kamenova P, 2006).
Nel Brevetto WO2005039539 (A1) si rivendica un formulato a base di Vitamina B1, Acido ï ¡ Lipoico, un derivato della Creatina, L-Arginina ed -ï ¡ cheto-glutarato per il controllo dei livelli Allegato B) Patent WO2005039539 (A1) claims a formulation based on Vitamin B1, ï ¡Lipoic Acid, a derivative of Creatine, L-Arginine and -ï ¡keto-glutarate for the control of levels Annex B)
serici di glucosio, finalizzato al miglioramento della perfusione muscolare, alla base del trattamento della polineuropatia diabetica. glucose serum, aimed at improving muscle perfusion, at the basis of the treatment of diabetic polyneuropathy.
Nel formulato della presente invenzione la NAC e l’Acidoï ¡ Lipoico sono dosati in combinazione con l’Inositolo che, agendo a livello della trasduzione del segnale mediato dall’insulina, potenzia l’azione della NAC. In the formulation of the present invention, NAC and Lipoic Acid are dosed in combination with Inositol which, acting at the level of transduction of the signal mediated by insulin, enhances the action of NAC.
L’efficacia antiossidante del formulato della presente invenzione à ̈ anche potenziata dalla combinazione con L-Acetil-Carnitina e altre sostanze a spiccata attività antiossidante quali la Lattoferrina e/o l’Epigallocatechinagallato (ECGC). The antioxidant efficacy of the formulation of the present invention is also enhanced by the combination with L-Acetyl-Carnitine and other substances with strong antioxidant activity such as Lactoferrin and / or Epigallocatechinagallate (ECGC).
Infatti la Lattoferrina manifesta spiccate proprietà antiossidanti: grazie all’elevata affinità per il ferro la Lattoferrina à ̈ in grado di sequestrare il ferro circolante, di prevenire la formazione dei radicali liberi e di inibire direttamente il processo di ossidazione. Grazie allo spiccato potere antiossidante la Lattoferrina à ̈ utile per il controllo delle alterazioni indotte dall’accumulo di radicali liberi. In fact, Lactoferrin shows strong antioxidant properties: thanks to its high affinity for iron, Lactoferrin is able to sequester circulating iron, prevent the formation of free radicals and directly inhibit the oxidation process. Thanks to its strong antioxidant power, Lactoferrin is useful for controlling the alterations induced by the accumulation of free radicals.
L’Epigallocatechinagallato (ECGC) fa parte delle catechine, un gruppo di sostanze antiossidanti appartenenti alla categoria dei flavonoidi. Epigallocatechinagallate (ECGC) is part of the catechins, a group of antioxidant substances belonging to the category of flavonoids.
Oltre a possedere un'azione antiossidante diretta, l’Epigallocatechinagallato potenzia altri sistemi antiossidanti, riveste un ruolo importante nella prevenzione delle malattie cardiovascolari e contribuisce a diminuire la pressione arteriosa. Grazie allo spiccato potere antiossidante l’Epigallocatechinagallato à ̈ utile per il controllo delle alterazioni indotte dall’accumulo di radicali liberi. In addition to having a direct antioxidant action, Epigallocatechinagallate enhances other antioxidant systems, plays an important role in the prevention of cardiovascular diseases and contributes to lowering blood pressure. Thanks to its strong antioxidant power, Epigallocatechinagallate is useful for controlling the alterations induced by the accumulation of free radicals.
Il formulato della presente invenzione, nei rapporti ponderali proposti, può essere potenziato dalla combinazione con una o più delle seguenti vitamine: Vitamina C, Acido Folico, Vitamina B1, Vitamina B2, Vitamina B6 ed à ̈ sinergico sia ad un integratore che ad una terapia specifica delle neuropatie. The formulation of the present invention, in the proposed weight ratios, can be enhanced by combining it with one or more of the following vitamins: Vitamin C, Folic Acid, Vitamin B1, Vitamin B2, Vitamin B6 and is synergistic to both a supplement and a therapy specific to neuropathies.
Nel primo caso, ripristinando l’energia depauperata (anaplerosi) della cellula, consente il corretto utilizzo delle vitamine somministrate (Vitamina C, Acido Folico, Vitamina B1, Vitamina B2, Vitamina B6) e ne permette una maggior loro permanenza nell’organismo. In the first case, by restoring the depleted energy (anaplerosis) of the cell, it allows the correct use of the vitamins administered (Vitamin C, Folic Acid, Vitamin B1, Vitamin B2, Vitamin B6) and allows them to stay longer in the body .
La vitamina C possiede una forte azione riducente ed à ̈ coinvolta in numerose reazioni di ossidoriduzione. Questa funzione si esplica quando la vitamina C si autoossida e rigenera le sostanze ossidate riportandole alla loro forma originale. Nel corso di questo processo, l’agente ossidante dannoso viene rimosso. Grazie allo spiccato potere antiossidante la Vitamina C à ̈ utile nella prevenzione delle alterazioni indotte dall’accumulo di radicali liberi. Vitamin C has a strong reducing action and is involved in numerous redox reactions. This function occurs when vitamin C self-oxidizes and regenerates the oxidized substances, returning them to their original form. During this process, the harmful oxidizing agent is removed. Thanks to its strong antioxidant power, Vitamin C is useful in the prevention of alterations induced by the accumulation of free radicals.
L'acido folico à ̈ una vitamina idrosolubile del gruppo B necessaria per tutte le reazioni di sintesi, riparazione e metilazione del DNA; per il metabolismo dell'omocisteina (rimetilazione) e di Allegato B) Folic acid is a water-soluble vitamin of group B necessary for all reactions of synthesis, repair and methylation of DNA; for homocysteine metabolism (remethylation) and Annex B)
numerose altre reazioni biochimiche. Grazie a queste proprietà l’acido folico à ̈ un utile sostegno nelle alterazioni trofiche e funzionali del sistema nervoso; in particolare à ̈ necessario per la profilassi antitrombotica, per migliorare l’ossigenazione tissutale ed aumentare la sintesi proteica. La vitamina B1 (tiamina) à ̈ una sostanza idrosolubile, coinvolta come coenzima nel catabolismo dei carboidrati e degli aminoacidi. La tiamina gioca inoltre un ruolo importante nei fenomeni neurochimici e nella sintesi dei precursori del DNA. Essendo un catalizzatore del metabolismo intermedio dei glicidi, à ̈ utile nel sostegno delle alterazioni trofiche e funzionali del sistema nervoso e per facilitare il metabolismo degli zuccheri. numerous other biochemical reactions. Thanks to these properties, folic acid is a useful support in trophic and functional alterations of the nervous system; in particular it is necessary for antithrombotic prophylaxis, to improve tissue oxygenation and increase protein synthesis. Vitamin B1 (thiamine) is a water-soluble substance, involved as a coenzyme in the catabolism of carbohydrates and amino acids. Thiamine also plays an important role in neurochemical phenomena and in the synthesis of DNA precursors. Being a catalyst of the intermediate metabolism of glycides, it is useful in supporting the trophic and functional alterations of the nervous system and to facilitate the metabolism of sugars.
La Vitamina B2 (o Riboflavina) à ̈ essenziale per innumerevoli reazioni metaboliche. In particolare favorisce l'utilizzazione energetica dei macronutrienti assunti con l'alimentazione e la conservazione dell'integrità del sistema nervoso. Vitamin B2 (or Riboflavin) is essential for countless metabolic reactions. In particular, it favors the energetic use of macronutrients taken with food and the preservation of the integrity of the nervous system.
Grazie a queste attività importanti per l’ossidazione intraorganica la Vitamina B2 à ̈ indicata per facilitare il metabolismo degli zuccheri e come sostegno nelle alterazioni trofiche e funzionali del sistema nervoso. Thanks to these important activities for intraorganic oxidation, Vitamin B2 is indicated to facilitate the metabolism of sugars and as a support in trophic and functional alterations of the nervous system.
La Vitamina B6 (Piridossina), coenzima delle decarbossilasi, à ̈ necessaria per la sintesi di alcuni neurotrasmettitori e per la formazione della mielina. Grazie a queste proprietà la Vitamina B6 à ̈ indicata per il sostegno delle alterazioni trofiche e funzionali del sistema nervoso. Vitamin B6 (Pyridoxine), a decarboxylase coenzyme, is necessary for the synthesis of some neurotransmitters and for the formation of myelin. Thanks to these properties, Vitamin B6 is indicated for supporting trophic and functional alterations of the nervous system.
Inoltre il formulato della presente invenzione può essere ancora potenziato dalla combinazione con alcuni aminoacidi o loro derivati scelti tra: Metionina, Cisteina, Taurina, Glutamina, Lisina e Ornitina-ï ¡ cheto-glutarato. Furthermore, the formulation of the present invention can be further enhanced by the combination with some amino acids or their derivatives selected from: Methionine, Cysteine, Taurine, Glutamine, Lysine and Ornithine-ï ¡keto-glutarate.
La Metionina à ̈ un aminoacido essenziale coinvolto nella sintesi della cisteina, della carnicina, della taurina, della lecitina, della fosfatidilcolina e di altri fosfolipidi. In tal senso la Metionina à ̈ utile come sostegno nelle alterazioni trofiche e funzionali del sistema nervoso. Methionine is an essential amino acid involved in the synthesis of cysteine, carnicine, taurine, lecithin, phosphatidylcholine and other phospholipids. In this sense, Methionine is useful as a support in trophic and functional alterations of the nervous system.
La Cisteina oltre a manifestare attività antiossidante diretta à ̈, insieme al glutammato ed alla glicina, un precursore per la biosintesi del glutatione, composto ad elevato potere antiossidante. Grazie allo spiccato potere antiossidante la Cisteina à ̈ utile nella prevenzione delle alterazioni indotte dall’accumulo di radicali liberi. Cysteine in addition to manifesting direct antioxidant activity is, together with glutamate and glycine, a precursor for the biosynthesis of glutathione, a compound with a high antioxidant power. Thanks to its strong antioxidant power, Cysteine is useful in the prevention of alterations induced by the accumulation of free radicals.
La Taurina à ̈ un costituente essenziale dell’organismo umano ed agisce sia come antiossidante che come tonico muscolare; à ̈ particolarmente concentrata a livello dei globuli bianchi, dei muscoli scheletrici, del cuore e del sistema nervoso centrale (regolarizza la trasmissione degli impulsi nervosi e stabilizza le membrane cellulari). Grazie a queste proprietà la Taurina à ̈ indicata come valido sostegno nelle alterazioni trofiche e funzionali del sistema nervoso. Taurine is an essential constituent of the human organism and acts both as an antioxidant and as a muscle tonic; It is particularly concentrated at the level of white blood cells, skeletal muscles, heart and central nervous system (it regulates the transmission of nerve impulses and stabilizes cell membranes). Thanks to these properties, Taurine is indicated as a valid support in trophic and functional alterations of the nervous system.
La Glutammina partecipa all'attività cerebrale, dove svolge un'attività stimolante; à ̈ in grado di penetrare la barriera emato-encefalica ed entrare nel cervello dove viene convertita in glutammato, Allegato B) Glutamine participates in brain activity, where it performs a stimulating activity; It is able to penetrate the blood-brain barrier and enter the brain where it is converted into glutamate, Annex B)
il più importante e diffuso neurotrasmettitore eccitatorio del sistema nervoso centrale. La glutammina à ̈ altresì precorritrice del GABA, un neurotrasmettitore che ha effetti inibitori sulla trasmissione nervosa. Inoltre la Glutammina ha attività antiossidante indiretta intervenendo nella sintesi del glutatione. Grazie a queste caratteristiche la Glutammina à ̈ utile nella prevenzione delle alterazioni indotte dall’accumulo di radicali liberi ed à ̈ indicata come valido sostegno nelle alterazioni trofiche e funzionali del sistema nervoso. the most important and widespread excitatory neurotransmitter of the central nervous system. Glutamine is also a precursor of GABA, a neurotransmitter that has inhibitory effects on nerve transmission. Furthermore, Glutamine has indirect antioxidant activity by intervening in the synthesis of glutathione. Thanks to these characteristics, Glutamine is useful in the prevention of alterations induced by the accumulation of free radicals and is indicated as a valid support in trophic and functional alterations of the nervous system.
La Lisina ha un ruolo fondamentale per la crescita, la riparazione dei tessuti, la sintesi proteica e la produzione di enzimi ed anticorpi. Lysine plays a key role in growth, tissue repair, protein synthesis and the production of enzymes and antibodies.
Grazie a queste caratteristiche la Lisina à ̈ utile come valido sostegno nelle alterazioni trofiche e funzionali del sistema nervoso. Thanks to these characteristics, Lysine is useful as a valid support in trophic and functional alterations of the nervous system.
L'Ornitina-ï ¡ cheto-glutarato à ̈ un sale derivante dalla combinazione di due unità di ornitina e di una molecola di ï ¡ cheto-glutarato. A questa sostanza sono ascritte notevoli proprietà anaboliche ed immunostimolanti. In particolare l'Ornitina-ï ¡ cheto-glutarato diminuisce il catabolismo muscolare, promuovendo la sintesi proteica. Tali caratteristiche sembrano essere legate alla sua capacità di influenzare positivamente la sintesi di ormoni anabolici ed il metabolismo degli amminoacidi. Grazie a queste caratteristiche l'Ornitina- ï ¡ cheto-glutarato à ̈ utile per contrastare le alterazioni trofiche e funzionali del sistema nervoso. Ornithine-ï ¡keto-glutarate is a salt resulting from the combination of two units of ornithine and a molecule of ï ¡keto-glutarate. Notable anabolic and immunostimulating properties are ascribed to this substance. In particular, Ornithine-ï ¡keto-glutarate decreases muscle catabolism, promoting protein synthesis. These characteristics seem to be linked to its ability to positively influence the synthesis of anabolic hormones and the metabolism of amino acids. Thanks to these characteristics, Ornithine-ï ¡keto-glutarate is useful for counteracting trophic and functional alterations of the nervous system.
Ulteriori caratteristiche e vantaggi del trovato risulteranno maggiormente dalla descrizione che à ̈ illustrata nelle unità di disegno allegate ed avanti citate. Further characteristics and advantages of the invention will become clearer from the description which is illustrated in the attached drawing units cited hereinafter.
Descrizione dell’invenzione Description of the invention
Oggetto della presente invenzione à ̈ un formulato a base di Inositolo (a), L-Acetil-Carnitina (b), N-Acetil-Cisteina (NAC) (c) e Acido ï ¡ Lipoico (d), in rapporto ponderale sinergico (a):(b):(c):(d), compreso nell’intervallo da 100:1:1:1 a 1:100:100:100 e da un rapporto ponderale (c):(d) compreso nell’intervallo da 100:1 a 1:100 e con altre sostanze a spiccata attività antiossidante, quali la Lattoferrina e/o l’Epigallocatechinagallato (ECGC) e potenziata con una o più delle seguenti vitamine: Vitamina C, Acido Folico, Vitamina B1, Vitamina B2, Vitamina B6, in sinergismo d’azione per il sostegno del sistema nervoso nelle alterazioni trofiche e funzionali, per il controllo delle alterazioni indotte dall’accumulo di radicali liberi e per facilitare il metabolismo degli zuccheri. The subject of the present invention is a formulation based on Inositol (a), L-Acetyl-Carnitine (b), N-Acetyl-Cysteine (NAC) (c) and ï ¡Lipoic acid (d), in synergistic weight ratio ( a) :( b) :( c) :( d), included in the range from 100: 1: 1: 1 to 1: 100: 100: 100 and by a weight ratio (c) :( d) included in € ™ range from 100: 1 to 1: 100 and with other substances with strong antioxidant activity, such as Lactoferrin and / or Epigallocatechinagallate (ECGC) and enhanced with one or more of the following vitamins: Vitamin C, Folic Acid, Vitamin B1, Vitamin B2, Vitamin B6, in synergy of action to support the nervous system in trophic and functional alterations, to control the alterations induced by the accumulation of free radicals and to facilitate the metabolism of sugars.
Il formulato della presente invenzione, nei rapporti ponderali proposti, può essere considerato, in senso anaplerotico, consensuale alla terapia specifica della lesione patologica d’organo o cellulare, nel senso di essere profilattico per migliorare od esaltare la funzione terapeutica di farmaci specifici o di accelerare il recupero funzionale fisiologico nei limiti dell’entità della lesione indotta dalla Allegato B) The formulation of the present invention, in the proposed weight ratios, can be considered, in an anaplerotic sense, consensual to the specific therapy of the pathological organ or cellular lesion, in the sense of being prophylactic to improve or enhance the therapeutic function of specific drugs or accelerate the physiological functional recovery within the limits of the extent of the lesion induced by Annex B)
noxa patogena. Questa azione di cooperazione con meccanismi fisiologici garantisce il ripristino e/o il recupero morfo-funzionale permanente, indipendentemente dalla durata della somministrazione. Alla base dell’insulino-resistenza, come precedentemente evidenziato, può esservi un’inadeguata maturazione dell’insulina, un malfunzionamento del recettore insulinico, un difetto nella trasmissione intracellulare del segnale o la combinazione di questi fattori. pathogenic noxa. This cooperative action with physiological mechanisms guarantees permanent morpho-functional restoration and / or recovery, regardless of the duration of administration. At the basis of insulin resistance, as previously highlighted, there may be inadequate insulin maturation, a malfunction of the insulin receptor, a defect in intracellular signal transmission or a combination of these factors.
Il meccanismo d’azione dei componenti del formulato della presente invenzione, nei rapporti ponderali proposti, à ̈ sinergico. L’Inositolo à ̈ un costituente delle membrane cellulari ed uno dei secondi messaggeri attivati dall’insulina, inoltre in condizioni di iperinsulinemia si verifica l’abbassamento dei livelli del pool intracellulare di Inositolo, con caduta nella trasmissione intracellulare del segnale dell’insulina. Gli antiossidanti, grazie all’elevato potere riducente, favoriscono la maturazione della proinsulina ed il ripristino della funzionalità sia extra- che intracellulare del recettore. The action mechanism of the components of the formulation of the present invention, in the proposed weight ratios, is synergistic. Inositol is a constituent of cell membranes and one of the second messengers activated by insulin, furthermore in conditions of hyperinsulinemia there is a lowering of the levels of the intracellular pool of Inositol, with a fall in the intracellular transmission of the signal of the ™ insulin. The antioxidants, thanks to their high reducing power, favor the maturation of proinsulin and the restoration of both extra- and intracellular function of the receptor.
La presenza della NAC, oltre alla semplice attività antiperossidativa descritta in altri brevetti, fornisce una quota di importanza terapeutica patogenetica in molte patologie sistemiche metaboliche di cui la più importante per diffusione statistica à ̈ il Diabete Mellito di Tipo II e I. Grazie ai suoi gruppi sulfidrilici (-SH) la NAC esercita una azione proteolitica sulla struttura elicoidale della proinsulina permettendo l’esternalizzazione dei ponti disolfuro (S-S) e quindi il ripristino morfo-funzionale dell’insulina, l’ormone fisiologicamente attivo (Figura 2), riducendo così i livelli di proinsulina e le conseguenti alterazioni dovute alla attivazione di fattori di crescita locali (IGF, Insulin Growth Factor) prodotti dalle cellule epatiche e dai fibroblasti per azione della Somatomedina C, a sua volta regolata dalla Somatotropina. Questi hanno una azione insulino-simile sul tessuto adiposo e sul muscolo e mitogena con conseguente ipertrofia e deficit energetico cellulari (Minuti F., Barreca A., Cordera R., 1997). The presence of NAC, in addition to the simple anti-peroxidative activity described in other patents, provides a share of pathogenetic therapeutic importance in many systemic metabolic diseases of which the most important for statistical diffusion is Type II and I Diabetes Mellitus. Thanks to its groups sulfhydryl (-SH) NAC exerts a proteolytic action on the helical structure of proinsulin allowing the externalization of the disulfide bridges (S-S) and therefore the morpho-functional restoration of insulin, the physiologically active hormone (Figure 2), thus reducing the levels of proinsulin and the consequent alterations due to the activation of local growth factors (IGF, Insulin Growth Factor) produced by hepatic cells and fibroblasts by the action of Somatomedin C, in turn regulated by Somatotropin. These have an insulin-like action on adipose tissue and muscle and mitogen with consequent cellular hypertrophy and energy deficit (Minuti F., Barreca A., Cordera R., 1997).
Studi sulla Lipoproteina a (LP-a), una lipoproteina fortemente eterogena con un ponte disolfuro nella sua struttura, hanno evidenziato l’effetto eulipemizzante esercitato dalla NAC e hanno portato ad intuirne l’utilità nella terapia patogenetica della Sindrome X di Reaven, una sindrome plurimetabolica legata ad ipertensione arteriosa, dislipidemia, obesità ed iperinsulinemia. Studies on Lipoprotein a (LP-a), a highly heterogeneous lipoprotein with a disulfide bridge in its structure, have highlighted the eulipidemic effect exerted by NAC and have led to understand its usefulness in the pathogenetic therapy of Reaven's Syndrome X, a multimetabolic syndrome linked to arterial hypertension, dyslipidemia, obesity and hyperinsulinemia.
Studi successivi hanno messo in evidenza il fatto che nel dosaggio radioimmunologico dell’insulina risultava preponderante una quota di proinsulina. La sperimentazione laboristica eseguita nella V Clinica Medica dell’Università di Roma “La Sapienza†mediante migrazione elettroforetica di molecole di insulina pretrattate con NAC ha messo in luce una variazione della costante di migrazione di queste in seguito a scissione dovuta probabilmente alla rottura dei ponti disolfuro intramolecolari. Subsequent studies have highlighted the fact that a proportion of proinsulin was predominant in the radioimmunoassay of insulin. The laboratory experimentation carried out in the 5th Medical Clinic of the University of Rome â € œLa Sapienzaâ € by means of electrophoretic migration of insulin molecules pretreated with NAC has highlighted a change in the migration constant of these following cleavage probably due to the rupture of the intramolecular disulfide bridges.
Allegato B) Annex B)
Questo ha trovato conferma nella sperimentazione clinica su 30 pazienti affetti da Sindrome X di 1200 mg/die di NAC che hanno ridotto la curva insulinimica senza modificare la curva glicemica in maniera clinicamente significativa. Ciò dimostra che il complesso denominato Sindrome X à ̈ dovuto a iperproinsulinismo di cui la NAC à ̈ un fisiologico trattamento con acquisizione di grande importanza anche negli squilibri lipidici, degli squilibri acido-base e dell’attività antiossidante. Da queste esperienze e da studi precedenti à ̈ possibile quindi definire la NAC come un aminoacido ad attività terapeutica eulipemizzante, pro energetica ed antiossidativa (Savioli e Silvestroni, 1993). L’Acido ï ¡ Lipoico aumenta l’assorbimento cellulare del glucosio ematico, sia nei tessuti insulinodipendenti che in quelli insulino-indipendenti, grazie al potenziamento dei trasportatori cellulari del glucosio (GLUT4 e GLUT1) (Konrad D et al., 2001; Singh U. & Jialal I. 2008; Shay K.P. et al., 2009). This was confirmed in the clinical trial on 30 patients with Syndrome X of 1200 mg / day of NAC who reduced the insulin curve without modifying the glycemic curve in a clinically significant way. This shows that the complex called Syndrome X is due to hyperproinsulinism of which NAC is a physiological treatment with the acquisition of great importance also in lipid imbalances, acid-base imbalances and antioxidant activity. From these experiences and from previous studies it is therefore possible to define NAC as an amino acid with a therapeutic eulipidemic, pro energetic and antioxidative activity (Savioli and Silvestroni, 1993). Ï ¡Lipoic Acid increases the cellular absorption of blood glucose, both in insulin-dependent and insulin-independent tissues, thanks to the enhancement of cellular glucose transporters (GLUT4 and GLUT1) (Konrad D et al., 2001; Singh U. & Jialal I. 2008; Shay K.P. et al., 2009).
L’Acido ï ¡ Lipoico à ̈ un composto ad elevata attività antiossidante/antiradicalica sia in fase acquosa (nel citosol) che in fase lipofila (a livello della membrana). L’effetto ottenuto à ̈ la completa sinergia d’azione del potere antiossidante. Favorisce inoltre la rigenerazione di sostanze antiradicaliche come la Vitamina C, la Vitamina E, il Glutatione ed il Coenzima Q. Come coenzima trasforma il piruvato (metabolita del glucosio) in acetato rendendolo disponibile per la produzione energetica nel Ciclo di Krebs. Tale acido facilita quindi il metabolismo energetico. La sua azione à ̈ favorita e potenziata dalle Vitamine B1 e B6 e dal piruvato stesso. Queste azioni sono alla base della attività insulino-simile di tale acido. Ï ¡Lipoic Acid is a compound with high antioxidant / anti-radical activity both in the aqueous phase (in the cytosol) and in the lipophilic phase (at the membrane level). The effect obtained is the complete synergy of action of the antioxidant power. It also promotes the regeneration of anti-radical substances such as Vitamin C, Vitamin E, Glutathione and Coenzyme Q. As a coenzyme it transforms pyruvate (glucose metabolite) into acetate making it available for energy production in the Krebs cycle. This acid therefore facilitates energy metabolism. Its action is favored and enhanced by Vitamins B1 and B6 and by pyruvate itself. These actions underlie the insulin-like activity of this acid.
La L-Acetil-Carnitina (derivato dell’aminoacido L-Carnitina) svolge molteplici azioni biologiche: partecipazione al metabolismo degli acidi grassi, promozione del trofismo e della crescita cellulare. E’ un importante cofattore del metabolismo energetico cellulare in toto e quindi trasmettitoriale a livello del Sistema Nervoso Centrale. L-Acetyl-Carnitine (derivative of the amino acid L-Carnitine) carries out multiple biological actions: participation in the metabolism of fatty acids, promotion of trophism and cell growth. It is an important cofactor of cellular energy metabolism in its entirety and therefore transmitting at the level of the Central Nervous System.
L’Inositolo, classificabile come vitamina B7, à ̈ un costituente fondamentale di tutte le membrane cellulari ed à ̈ particolarmente abbondante nelle membrane dei nervi. Inositol, classifiable as vitamin B7, is a fundamental constituent of all cell membranes and is particularly abundant in the nerve membranes.
La supplementazione con Inositolo à ̈ necessaria per mantenere o ripristinare la corretta permeabilità e robustezza delle membrane cellulari sottoposte a stress ossidativo. In situazioni di patologia riconducibile a stress ossidativo l’Inositolo si à ̈ dimostrato attivo sia come fattore di protezione per la cellula e i suoi organelli, sia come fattore trofico per il ripristino dell'integrità cellulare e per la capacità di incrementare la neosintesi di fosfolipidi di membrana, modulando l’integrità e la fluidità delle membrane cellulari. Inositol supplementation is necessary to maintain or restore the correct permeability and strength of cell membranes subjected to oxidative stress. In situations of pathology attributable to oxidative stress, Inositol has been shown to be active both as a protective factor for the cell and its organelles, and as a trophic factor for the restoration of cellular integrity and for the ability to increase the neosynthesis of phospholipids membrane, modulating the integrity and fluidity of cell membranes.
L’Inositolo, inoltre, agisce in sinergia d’azione con composti ad attività antiossidante quali ad esempio NAC potenziandone l’azione profisiologica a livello della maturazione della proinsulina in insulina e/o Acidoï ¡ Lipoico. Furthermore, Inositol acts in synergy of action with compounds with antioxidant activity such as for example NAC, enhancing their profisiological action at the level of the maturation of proinsulin into insulin and / or Lipoic Acid.
Allegato B) Annex B)
Lo stress ossidativo à ̈ una condizione morbosa causata dalla rottura dell'equilibrio fisiologico fra la produzione e l'eliminazione, da parte dei sistemi di difesa antiossidanti, di specie chimiche ossidanti. Oxidative stress is a morbid condition caused by the disruption of the physiological balance between the production and elimination, by the antioxidant defense systems, of oxidizing chemical species.
Allo stress ossidativo risultano associati una serie di quadri morbosi, spesso di natura degenerativa e ad andamento cronico, tra cui la neuropatia diabetica, il danno da riperfusione e la genesi delle patologie involutive degenerative. Anche l’insulino-resistenza si associa ad un aumentato livello di perossidazione lipidica, contemporaneamente l’iperglicemia à ̈ ritenuta una delle principali cause responsabili dell’aumento della concentrazione plasmatica di radicali liberi nel diabete mellito. Recenti studi clinici dimostrano la capacità di sostanze anti-ossidanti (Oner G. & Muderris I.I., 2011) di correggere l’iperglicemia in individui affetti da diabete mellito di tipo II. A series of morbid conditions are associated with oxidative stress, often of a degenerative nature and with a chronic course, including diabetic neuropathy, reperfusion damage and the genesis of degenerative involutionary diseases. Insulin resistance is also associated with an increased level of lipid peroxidation, at the same time hyperglycemia is considered one of the main causes responsible for the increase in the plasma concentration of free radicals in diabetes mellitus. Recent clinical studies demonstrate the ability of antioxidant substances (Oner G. & Muderris I.I., 2011) to correct hyperglycemia in individuals with type II diabetes mellitus.
Composti ad azione trofica in associazione a composti ad elevata azione antiossidante trovano sicuramente applicazione nella prevenzione e nella cura delle disfunzioni del metabolismo degli zuccheri. Compounds with trophic action in association with compounds with high antioxidant action certainly find application in the prevention and treatment of sugar metabolism dysfunctions.
La neuropatia diabetica à ̈ caratterizzata da un danno a carico del sistema nervoso periferico somatico o vegetativo. La neuropatia diabetica à ̈ correlata ai disordini biochimici causati dal diabete e negli ultimi anni à ̈ emersa sempre più l’importanza dello stress ossidativo nel collegare l’iperglicemia persistente al danno delle fibre nervose. Anche il danno da riperfusione del miocardio à ̈ riconducibile ad un danno da stress ossidativo in quanto nella fase di riperfusione dopo un'ischemia, il contatto dell'ossigeno molecolare con ipoxantina e xantina ossidasi stimola l'attività dell'enzima con eccessiva produzione di radicali liberi. Inoltre eventuali danni alla membrana mitocondriale portano ad una serie di disfunzioni della catena di trasporto degli elettroni, con aumento della produzione di ROS. Diabetic neuropathy is characterized by damage to the somatic or vegetative peripheral nervous system. Diabetic neuropathy is related to the biochemical disorders caused by diabetes and in recent years the importance of oxidative stress in linking persistent hyperglycemia to nerve fiber damage has increasingly emerged. The myocardial reperfusion damage is also attributable to oxidative stress damage as in the reperfusion phase after ischemia, the contact of molecular oxygen with hypoxanthine and xanthine oxidase stimulates the activity of the enzyme with excessive radical production free. Furthermore, any damage to the mitochondrial membrane leads to a series of dysfunctions of the electron transport chain, with an increase in the production of ROS.
Composti ad elevata azione antiossidante in associazione a fattori trofici e depurativi per le cellule trovano sicuramente applicazione nella cura e nella prevenzione delle neuropatie diabetiche e del danno da riperfusione del miocardio. Compounds with a high antioxidant action in association with trophic and purifying factors for cells certainly find application in the treatment and prevention of diabetic neuropathies and myocardial reperfusion damage.
A differenza di quanto risulta allo stato dell’arte, in cui l’attività antiossidante dei componenti consente la rimozione dei cataboliti endogeni intracellulari con conseguente miglioramento della fisiologia cellulare, il formulato oggetto della presente invenzione nei rapporti ponderali proposti si basa sulla azione pro fisiologica della NAC a livello della insulinopoiesi, in sinergismo d’azione con l’attività antiossidante dell’acido α-Lipoico, della L-Acetil-Carnitina e dell’Inositolo. Unlike what appears to the state of the art, in which the antioxidant activity of the components allows the removal of endogenous intracellular catabolites with consequent improvement of cellular physiology, the formulation object of the present invention in the proposed weight ratios is based on the pro physiological NAC at the level of insulinopoiesis, in synergy of action with the antioxidant activity of Î ± -Lipoic acid, L-Acetyl-Carnitine and Inositol.
La NAC ripristina il quadro neuro-ormonale delle cellule insulino-sensibili risultando un coadiuvante di una terapia intiiperglicemica e di una terapia energetica cellulare. NAC restores the neuro-hormonal picture of insulin-sensitive cells, resulting in an adjuvant of antihyperglycemic therapy and cellular energy therapy.
Alla luce dell’azione fisiologica delle sostanze che costituiscono il formulato oggetto della presente invenzione nei loro rapporti ponderali proposti, esso trova una applicazione clinica eminentemente Allegato B) In light of the physiological action of the substances that make up the formulation object of the present invention in their proposed weight ratios, it finds a clinical application eminently Annex B)
nelle neuropatie degenerative da danno metabolico, post-traumatico, involutivo su base vascolare, su deficit neurotrasmettitoriale e su base post-infiammatoria. in degenerative neuropathies caused by metabolic damage, post-traumatic, involutional on a vascular basis, on neurotransmitter deficit and on a post-inflammatory basis.
I rapporti ponderali proposti di Inositolo (a), L-Acetil-Carnitina (b), N-Acetil-Cisteina (NAC) (c) e Acido ï ¡ Lipoico (d), in rapporto ponderale sinergico (a):(b):(c):(d), compreso nell’intervallo da 100:1:1:1 a 1:100:100:100 e da un rapporto ponderale (c):(d) compreso nell’intervallo da 100:1 a 1:100, prevedono per ogni componente dei dosaggi inferiori rispetto a quelli riportati in letteratura (Papaleo E et al., 2007; Costantino D et al., 2009; Wang T et al., 2011; Oner G & Muderris I I, 2011; Bilska A & Wlodek L, 2005; Konrad T et al., 1999; Evans LJ et al., 2001; Golbidi S et al., 2011). In particolare, questi dosaggi proprio perché inferiori si sono rilevati funzionali ed efficaci per il ripristino dei deficits delle strutture cellulari bersaglio, evitando in tal modo gli effetti collaterali negativi o da superdosaggio, come la saturazione dei processi fisiologici coinvolti. Inoltre, grazie alla formulazione sinergica qui presentata à ̈ possibile utilizzare le minime concentrazioni efficaci di ogni componente al fine di ottenere un effetto risultante di recupero morfo-funzionale in termini fisiologici delle cellule somatiche sensibili all’azione dell’insulina. Il formulato oggetto della presente invenzione, trova applicazione nel trattamento patogenetico o sintomatico della insulino-resistenza e delle principali malattie e sindromi correlate quali: Obesità , Ridotta tolleranza glucidica (con normale o aumentata secrezione insulinica), Diabete Mellito di tipo II, Diabete Mellito di tipo I, Sindrome dell’insulino-resistenza ed acanthosis nigricans tipo A (virilizzazione ed ovaio policistico) e tipo B (anticorpi antirecettore insulinico), Atassia telangectasia, Lipodistrofia parziale o generalizzata (Diabete Lipoatrofico), Uremia, Cirrosi epatica, Acromegalia, Ipercortisolismo endogeno ed esogeno, Miotonia distrofica, Lepreconismo e non deve essere considerato come un apporto terapeutico specifico, ma di “cooperazione†alla terapia del quadro patologico, ancor più in senso profilattico e di recupero quanto meno parziale. The proposed weight ratios of Inositol (a), L-Acetyl-Carnitine (b), N-Acetyl-Cysteine (NAC) (c) and ï ¡Lipoic acid (d), in synergistic weight ratio (a) :( b) : (c) :( d), included in the range from 100: 1: 1: 1 to 1: 100: 100: 100 and by a weight ratio (c) :( d) included in the range from 100: 1 to 1: 100, provide for each component lower dosages than those reported in the literature (Papaleo E et al., 2007; Costantino D et al., 2009; Wang T et al., 2011; Oner G & Muderris I I, 2011; Bilska A & Wlodek L, 2005; Konrad T et al., 1999; Evans LJ et al., 2001; Golbidi S et al., 2011). In particular, these dosages, precisely because they were lower, were found to be functional and effective for restoring the deficits of the target cellular structures, thus avoiding negative or overdosing side effects, such as saturation of the physiological processes involved. Moreover, thanks to the synergistic formulation presented here, it is possible to use the minimum effective concentrations of each component in order to obtain a resulting effect of morpho-functional recovery in physiological terms of the somatic cells sensitive to the action of insulin. The formulation object of the present invention finds application in the pathogenetic or symptomatic treatment of insulin resistance and of the main related diseases and syndromes such as: Obesity, Reduced glucose tolerance (with normal or increased insulin secretion), Type II Diabetes Mellitus, Diabetes Mellitus type I, syndrome of insulin resistance and acanthosis nigricans type A (virilization and polycystic ovary) and type B (anti-insulin receptor antibodies), Ataxia telangiectasia, partial or generalized lipodystrophy (Lipoatrophic diabetes), Uremia, Cirrhosis of the liver, Acromegaly, Hypercortion endogenous and exogenous, dystrophic myotonia, lepreconism and should not be considered as a specific therapeutic contribution, but as a â € œcooperativeâ € to the therapy of the pathological picture, even more in a prophylactic sense and at least partial recovery.
Claims (4)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT000295A ITRM20120295A1 (en) | 2012-06-26 | 2012-06-26 | COMPOSITION BASED ON INOSITOL IN SYNERGIC ASSOCIATION WITH ANTIOXIDANT COMPOUNDS SPECIALLY FORMULATED FOR SUPPORT IN THE TROFIC AND FUNCTIONAL ALTERATIONS OF THE NERVOUS SYSTEM FOR THE CONTROL OF ALTERATIONS INDUCED BY RADI ACCUMULATION |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT000295A ITRM20120295A1 (en) | 2012-06-26 | 2012-06-26 | COMPOSITION BASED ON INOSITOL IN SYNERGIC ASSOCIATION WITH ANTIOXIDANT COMPOUNDS SPECIALLY FORMULATED FOR SUPPORT IN THE TROFIC AND FUNCTIONAL ALTERATIONS OF THE NERVOUS SYSTEM FOR THE CONTROL OF ALTERATIONS INDUCED BY RADI ACCUMULATION |
Publications (1)
Publication Number | Publication Date |
---|---|
ITRM20120295A1 true ITRM20120295A1 (en) | 2013-12-27 |
Family
ID=46833043
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IT000295A ITRM20120295A1 (en) | 2012-06-26 | 2012-06-26 | COMPOSITION BASED ON INOSITOL IN SYNERGIC ASSOCIATION WITH ANTIOXIDANT COMPOUNDS SPECIALLY FORMULATED FOR SUPPORT IN THE TROFIC AND FUNCTIONAL ALTERATIONS OF THE NERVOUS SYSTEM FOR THE CONTROL OF ALTERATIONS INDUCED BY RADI ACCUMULATION |
Country Status (1)
Country | Link |
---|---|
IT (1) | ITRM20120295A1 (en) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994002036A1 (en) * | 1992-07-22 | 1994-02-03 | Metagenics, Inc. | Improved sustained energy and anabolic composition |
US20020182196A1 (en) * | 2001-04-19 | 2002-12-05 | Mccleary Edward Larry | Composition and method for normalizing impaired or deteriorating neurological function |
US20030068391A1 (en) * | 2001-10-04 | 2003-04-10 | Harris Dennis H. | Ingestible nerve and circulatory nutritional formulation |
US20040001817A1 (en) * | 2002-05-14 | 2004-01-01 | Giampapa Vincent C. | Anti-aging nutritional supplement |
WO2005067972A1 (en) * | 2003-12-31 | 2005-07-28 | Integrative Health Consulting, Inc. | Nutrient compositions and methods for enhanced effectiveness of the immune system |
US20080114065A1 (en) * | 2002-11-22 | 2008-05-15 | Pacioretty Linda M | Methods for the treatment of HIV-1 related fat maldistribution, fasting hyperlipidemia and modification of adipocyte physiology |
-
2012
- 2012-06-26 IT IT000295A patent/ITRM20120295A1/en unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994002036A1 (en) * | 1992-07-22 | 1994-02-03 | Metagenics, Inc. | Improved sustained energy and anabolic composition |
US20020182196A1 (en) * | 2001-04-19 | 2002-12-05 | Mccleary Edward Larry | Composition and method for normalizing impaired or deteriorating neurological function |
US20030068391A1 (en) * | 2001-10-04 | 2003-04-10 | Harris Dennis H. | Ingestible nerve and circulatory nutritional formulation |
US20040001817A1 (en) * | 2002-05-14 | 2004-01-01 | Giampapa Vincent C. | Anti-aging nutritional supplement |
US20080114065A1 (en) * | 2002-11-22 | 2008-05-15 | Pacioretty Linda M | Methods for the treatment of HIV-1 related fat maldistribution, fasting hyperlipidemia and modification of adipocyte physiology |
WO2005067972A1 (en) * | 2003-12-31 | 2005-07-28 | Integrative Health Consulting, Inc. | Nutrient compositions and methods for enhanced effectiveness of the immune system |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Singh et al. | Retracted: alpha-lipoic acid supplementation and diabetes | |
US6689385B2 (en) | Formulations for the treatment of insulin resistance and type 2 diabetes mellitus | |
US9278109B2 (en) | Compositions and methods for the prevention of cardiovascular disease | |
US20030078269A1 (en) | Biguanide and sulfonylurea formulations for the prevention and treatment of insulin resistance and type 2 diabetes mellitus | |
EP0969744B1 (en) | Nutritional composition for improvements in cell energetics | |
US20060257502A1 (en) | A combination of mitochondrial nutrients for relieving stress, preventing and improving stress-related disorders | |
US20020182196A1 (en) | Composition and method for normalizing impaired or deteriorating neurological function | |
US20080102137A1 (en) | Composition and method for etiological treatment and prevention of diseases and/or complications associated with chronic glucose metabolism destabilization | |
KR20070057826A (en) | Compositions and methods for nutrition supplementation | |
Di Leo et al. | Long-term taurine supplementation reduces mortality rate in streptozotocin-induced diabetic rats | |
CZ18013U1 (en) | Combined preparation for enhancement of sperm quality | |
WO2015065621A1 (en) | Compounds, compositions, and methods for decreasing intestinal glucose uptake and inducing incretin release | |
Sheikhpour | Diabetes and oxidative stress: The mechanism and action | |
US20100087546A1 (en) | Use of dimethyl sulfone (msm) to reduce homocysteine levels | |
EP1680093A1 (en) | Oral formulation of lipid soluble thiamine, lipoic acid, creatine derivative, and l-arginine alpha-ketoglutarate | |
Erbayraktar et al. | Effects of selenium supplementation on antioxidant defense and glucose homeostasis in experimental diabetes mellitus | |
CA2788865A1 (en) | Composition comprising as active ingredient l-carnitine in combination with hydroxykynurenine-0-beta-dl-glucoside, for the prevention and/or treatment of pathologies of the eye due to ultraviolet radiation | |
El-Awdan et al. | Grape seed extract attenuates hyperglycaemia-induced in rats by streptozotocin | |
Seybolt | Is it time to reassess alpha lipoic acid and niacinamide therapy in schizophrenia? | |
ITRM20120295A1 (en) | COMPOSITION BASED ON INOSITOL IN SYNERGIC ASSOCIATION WITH ANTIOXIDANT COMPOUNDS SPECIALLY FORMULATED FOR SUPPORT IN THE TROFIC AND FUNCTIONAL ALTERATIONS OF THE NERVOUS SYSTEM FOR THE CONTROL OF ALTERATIONS INDUCED BY RADI ACCUMULATION | |
CA3145853A1 (en) | Compositions and methods using trigonelline to produce intracellular nicotinamide adenine dinucleotide (nad+) for treating or preventing physiological disorders or states | |
US20150320096A1 (en) | Dietary Supplement | |
Burd | Lysulin™, a new supplement for Nutritional Support for People with Diabetes and Pre-diabetes (those at risk of developing diabetes) | |
DE102004038155A1 (en) | Physiologically acceptable composition containing alpha lipoic acid, creatine and a phospholipid | |
US20200338153A1 (en) | Anaerobic antioxidant composition |