JP4459303B2 - Method of treating disease in mammals resulting from inflammatory reaction and composition thereof - Google Patents
Method of treating disease in mammals resulting from inflammatory reaction and composition thereof Download PDFInfo
- Publication number
- JP4459303B2 JP4459303B2 JP51274197A JP51274197A JP4459303B2 JP 4459303 B2 JP4459303 B2 JP 4459303B2 JP 51274197 A JP51274197 A JP 51274197A JP 51274197 A JP51274197 A JP 51274197A JP 4459303 B2 JP4459303 B2 JP 4459303B2
- Authority
- JP
- Japan
- Prior art keywords
- pyruvate
- inflammatory
- composition
- mediator
- drugs
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000000203 mixture Substances 0.000 title claims description 44
- 201000010099 disease Diseases 0.000 title claims description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 24
- 241000124008 Mammalia Species 0.000 title claims description 19
- 238000000034 method Methods 0.000 title description 35
- 206010061218 Inflammation Diseases 0.000 title description 4
- 230000004054 inflammatory process Effects 0.000 title description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 33
- 239000003814 drug Substances 0.000 claims description 33
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 claims description 30
- 230000028709 inflammatory response Effects 0.000 claims description 29
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 claims description 26
- 229940076788 pyruvate Drugs 0.000 claims description 26
- 210000004962 mammalian cell Anatomy 0.000 claims description 25
- 210000004027 cell Anatomy 0.000 claims description 22
- 229940079593 drug Drugs 0.000 claims description 20
- 210000000265 leukocyte Anatomy 0.000 claims description 20
- 230000002757 inflammatory effect Effects 0.000 claims description 19
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 229940054269 sodium pyruvate Drugs 0.000 claims description 15
- 239000001301 oxygen Substances 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 206010014561 Emphysema Diseases 0.000 claims description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
- 229940124597 therapeutic agent Drugs 0.000 claims description 11
- 239000003963 antioxidant agent Substances 0.000 claims description 10
- 230000001413 cellular effect Effects 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- 230000002829 reductive effect Effects 0.000 claims description 10
- 102000004190 Enzymes Human genes 0.000 claims description 9
- 108090000790 Enzymes Proteins 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 7
- 206010003598 Atelectasis Diseases 0.000 claims description 6
- 102000004127 Cytokines Human genes 0.000 claims description 6
- 108090000695 Cytokines Proteins 0.000 claims description 6
- 208000007123 Pulmonary Atelectasis Diseases 0.000 claims description 6
- 230000001684 chronic effect Effects 0.000 claims description 6
- 208000023504 respiratory system disease Diseases 0.000 claims description 6
- 208000006673 asthma Diseases 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 102000004169 proteins and genes Human genes 0.000 claims description 5
- 108090000623 proteins and genes Proteins 0.000 claims description 5
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims description 4
- 229940121375 antifungal agent Drugs 0.000 claims description 4
- 229940125715 antihistaminic agent Drugs 0.000 claims description 4
- 239000000739 antihistaminic agent Substances 0.000 claims description 4
- 230000003078 antioxidant effect Effects 0.000 claims description 4
- 239000003443 antiviral agent Substances 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 201000009267 bronchiectasis Diseases 0.000 claims description 4
- 206010006451 bronchitis Diseases 0.000 claims description 4
- 229940088598 enzyme Drugs 0.000 claims description 4
- 229940088597 hormone Drugs 0.000 claims description 4
- 239000005556 hormone Substances 0.000 claims description 4
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 4
- 230000002685 pulmonary effect Effects 0.000 claims description 4
- 150000003431 steroids Chemical class 0.000 claims description 4
- 108091005804 Peptidases Proteins 0.000 claims description 3
- 239000004365 Protease Substances 0.000 claims description 3
- 230000000843 anti-fungal effect Effects 0.000 claims description 3
- 229940124350 antibacterial drug Drugs 0.000 claims description 3
- 239000000428 dust Substances 0.000 claims description 3
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 2
- 206010015150 Erythema Diseases 0.000 claims description 2
- 206010020751 Hypersensitivity Diseases 0.000 claims description 2
- 102000035195 Peptidases Human genes 0.000 claims description 2
- 206010035664 Pneumonia Diseases 0.000 claims description 2
- 241000287531 Psittacidae Species 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- 208000026935 allergic disease Diseases 0.000 claims description 2
- 229940018333 calcium pyruvate Drugs 0.000 claims description 2
- UZWMCCLZMHPPKW-UHFFFAOYSA-L calcium;2-oxopropanoate Chemical compound [Ca+2].CC(=O)C([O-])=O.CC(=O)C([O-])=O UZWMCCLZMHPPKW-UHFFFAOYSA-L 0.000 claims description 2
- HUKIJZIDGFUNMG-UHFFFAOYSA-N dimethyl 4-oxocyclohexane-1,2-dicarboxylate Chemical compound COC(=O)C1CCC(=O)CC1C(=O)OC HUKIJZIDGFUNMG-UHFFFAOYSA-N 0.000 claims description 2
- 231100000321 erythema Toxicity 0.000 claims description 2
- 230000003352 fibrogenic effect Effects 0.000 claims description 2
- 239000007789 gas Substances 0.000 claims description 2
- 229960001340 histamine Drugs 0.000 claims description 2
- 230000009610 hypersensitivity Effects 0.000 claims description 2
- 208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 2
- OFJHGWPRBMPXCX-UHFFFAOYSA-M lithium;2-oxopropanoate Chemical compound [Li+].CC(=O)C([O-])=O OFJHGWPRBMPXCX-UHFFFAOYSA-M 0.000 claims description 2
- UNRZVMSDTHBRQJ-UHFFFAOYSA-L manganese(2+);2-oxopropanoate Chemical compound [Mn+2].CC(=O)C([O-])=O.CC(=O)C([O-])=O UNRZVMSDTHBRQJ-UHFFFAOYSA-L 0.000 claims description 2
- 230000000414 obstructive effect Effects 0.000 claims description 2
- 206010035653 pneumoconiosis Diseases 0.000 claims description 2
- JKVUQLWTIZFTMF-UHFFFAOYSA-M potassium;2-oxopropanoate Chemical compound [K+].CC(=O)C([O-])=O JKVUQLWTIZFTMF-UHFFFAOYSA-M 0.000 claims description 2
- 150000003180 prostaglandins Chemical class 0.000 claims description 2
- 208000036273 reactive airway disease Diseases 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 206010043554 thrombocytopenia Diseases 0.000 claims description 2
- UBRKSSSORHJPQI-UHFFFAOYSA-L zinc;2-oxopropanoate Chemical compound [Zn+2].CC(=O)C([O-])=O.CC(=O)C([O-])=O UBRKSSSORHJPQI-UHFFFAOYSA-L 0.000 claims description 2
- 102000015696 Interleukins Human genes 0.000 claims 1
- 108010063738 Interleukins Proteins 0.000 claims 1
- 208000018569 Respiratory Tract disease Diseases 0.000 claims 1
- 239000000443 aerosol Substances 0.000 claims 1
- 230000007794 irritation Effects 0.000 claims 1
- 239000000644 isotonic solution Substances 0.000 claims 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 claims 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 claims 1
- 239000000725 suspension Substances 0.000 claims 1
- 230000006378 damage Effects 0.000 description 18
- 230000019254 respiratory burst Effects 0.000 description 17
- 230000001225 therapeutic effect Effects 0.000 description 12
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 10
- 235000006708 antioxidants Nutrition 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 6
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 6
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- -1 tocopherol ester Chemical class 0.000 description 6
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 5
- 208000014674 injury Diseases 0.000 description 5
- 235000014655 lactic acid Nutrition 0.000 description 5
- 239000004310 lactic acid Substances 0.000 description 5
- 210000004379 membrane Anatomy 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- 239000003642 reactive oxygen metabolite Substances 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 4
- 229940061720 alpha hydroxy acid Drugs 0.000 description 4
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 4
- 150000004716 alpha keto acids Chemical class 0.000 description 4
- 229940121363 anti-inflammatory agent Drugs 0.000 description 4
- 239000002260 anti-inflammatory agent Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 229940113601 irrigation solution Drugs 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- 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 4
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 4
- 208000009304 Acute Kidney Injury Diseases 0.000 description 3
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 3
- 229940123457 Free radical scavenger Drugs 0.000 description 3
- 241000233866 Fungi Species 0.000 description 3
- 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 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 208000033626 Renal failure acute Diseases 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 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 3
- 201000011040 acute kidney failure Diseases 0.000 description 3
- 150000001277 beta hydroxy acids Chemical class 0.000 description 3
- 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 3
- 201000011510 cancer Diseases 0.000 description 3
- 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 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 229940120503 dihydroxyacetone Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 230000002147 killing effect Effects 0.000 description 3
- 230000003859 lipid peroxidation Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 239000006199 nebulizer Substances 0.000 description 3
- 229940107700 pyruvic acid Drugs 0.000 description 3
- 239000002516 radical scavenger Substances 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 229960002477 riboflavin Drugs 0.000 description 3
- 235000019192 riboflavin Nutrition 0.000 description 3
- 239000002151 riboflavin Substances 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 235000010384 tocopherol Nutrition 0.000 description 3
- 229930003799 tocopherol Natural products 0.000 description 3
- 239000011732 tocopherol Substances 0.000 description 3
- 229960001295 tocopherol Drugs 0.000 description 3
- 239000003053 toxin Substances 0.000 description 3
- 231100000765 toxin Toxicity 0.000 description 3
- 108700012359 toxins Proteins 0.000 description 3
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 2
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229920001287 Chondroitin sulfate Polymers 0.000 description 2
- 102000003992 Peroxidases Human genes 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000035508 accumulation Effects 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 210000000577 adipose tissue Anatomy 0.000 description 2
- 150000007824 aliphatic compounds Chemical class 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229940059329 chondroitin sulfate Drugs 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 238000007323 disproportionation reaction Methods 0.000 description 2
- 239000008151 electrolyte solution Substances 0.000 description 2
- 229940021013 electrolyte solution Drugs 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 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 2
- 230000012010 growth Effects 0.000 description 2
- 239000005550 inflammation mediator Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 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 2
- 230000009545 invasion Effects 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- SXQFCVDSOLSHOQ-UHFFFAOYSA-N lactamide Chemical class CC(O)C(N)=O SXQFCVDSOLSHOQ-UHFFFAOYSA-N 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 230000004199 lung function Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 108040007629 peroxidase activity proteins Proteins 0.000 description 2
- 210000001539 phagocyte Anatomy 0.000 description 2
- 230000003711 photoprotective effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 150000004671 saturated fatty acids Chemical class 0.000 description 2
- 235000003441 saturated fatty acids Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 239000000717 tumor promoter Substances 0.000 description 2
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 2
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- IIRJJZHHNGABMQ-HTLJXXAVSA-N (2S)-2-(2-hydroxypropanoylamino)-3-phenylpropanoic acid Chemical compound CC(O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 IIRJJZHHNGABMQ-HTLJXXAVSA-N 0.000 description 1
- IJKKTQLUXOILBQ-GDVGLLTNSA-N (2s)-2-(2-hydroxypropanoylamino)-3-methylbutanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)C(C)O IJKKTQLUXOILBQ-GDVGLLTNSA-N 0.000 description 1
- WOCQGWHMXPRWHW-WUCPZUCCSA-N (2s)-2-(2-hydroxypropanoylamino)propanoic acid Chemical compound CC(O)C(=O)N[C@@H](C)C(O)=O WOCQGWHMXPRWHW-WUCPZUCCSA-N 0.000 description 1
- WSWCOQWTEOXDQX-MQQKCMAXSA-M (E,E)-sorbate Chemical compound C\C=C\C=C\C([O-])=O WSWCOQWTEOXDQX-MQQKCMAXSA-M 0.000 description 1
- WHBMMWSBFZVSSR-GSVOUGTGSA-N (R)-3-hydroxybutyric acid Chemical compound C[C@@H](O)CC(O)=O WHBMMWSBFZVSSR-GSVOUGTGSA-N 0.000 description 1
- ARSRBNBHOADGJU-UHFFFAOYSA-N 7,12-dimethyltetraphene Chemical compound C1=CC2=CC=CC=C2C2=C1C(C)=C(C=CC=C1)C1=C2C ARSRBNBHOADGJU-UHFFFAOYSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- BUMIGZVUJKNXCO-MLWJPKLSSA-N CC(C)C[C@@H](C(O)=O)NC(=O)C(C)O Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)C(C)O BUMIGZVUJKNXCO-MLWJPKLSSA-N 0.000 description 1
- JYNQEELVVSUBGX-LOJRBXKRSA-N CC[C@H](C)[C@@H](C(O)=O)NC(=O)C(C)O Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)C(C)O JYNQEELVVSUBGX-LOJRBXKRSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 102000016938 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 206010011086 Coronary artery occlusion Diseases 0.000 description 1
- 208000001840 Dandruff Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 239000006145 Eagle's minimal essential medium Substances 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010020649 Hyperkeratosis Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 208000001126 Keratosis Diseases 0.000 description 1
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000000185 Localized scleroderma Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- CLNVOWMDSFOIPV-UHFFFAOYSA-N N-lactoyl-Glycine Chemical compound CC(O)C(=O)NCC(O)=O CLNVOWMDSFOIPV-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 206010051246 Photodermatosis Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 208000037656 Respiratory Sounds Diseases 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 102000019197 Superoxide Dismutase Human genes 0.000 description 1
- 108010012715 Superoxide dismutase Proteins 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000009911 Urinary Calculi Diseases 0.000 description 1
- 208000009982 Ventricular Dysfunction Diseases 0.000 description 1
- 206010047924 Wheezing Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 239000002956 ash Substances 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000003855 balanced salt solution Substances 0.000 description 1
- 210000002459 blastocyst Anatomy 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- QXDMQSPYEZFLGF-UHFFFAOYSA-L calcium oxalate Chemical compound [Ca+2].[O-]C(=O)C([O-])=O QXDMQSPYEZFLGF-UHFFFAOYSA-L 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 208000029039 cyanide poisoning Diseases 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 230000000120 cytopathologic effect Effects 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000000249 desinfective effect Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 230000037336 dry skin Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 235000010382 gamma-tocopherol Nutrition 0.000 description 1
- 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 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 208000027096 gram-negative bacterial infections Diseases 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000003434 inspiratory effect Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 230000000622 irritating effect Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 150000004715 keto acids Chemical class 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 229940116871 l-lactate Drugs 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000008816 organ damage Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000036284 oxygen consumption Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 238000007539 photo-oxidation reaction Methods 0.000 description 1
- 230000008845 photoaging Effects 0.000 description 1
- 230000009090 positive inotropic effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229940063566 proventil Drugs 0.000 description 1
- 238000009613 pulmonary function test Methods 0.000 description 1
- 230000010349 pulsation Effects 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 210000002254 renal artery Anatomy 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 230000037380 skin damage Effects 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229940075554 sorbate Drugs 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940071127 thioglycolate Drugs 0.000 description 1
- CWERGRDVMFNCDR-UHFFFAOYSA-M thioglycolate(1-) Chemical compound [O-]C(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-M 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 239000003860 topical agent Substances 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 208000008281 urolithiasis Diseases 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 230000006815 ventricular dysfunction Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000002676 xenobiotic agent Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 239000002478 γ-tocopherol Substances 0.000 description 1
- QUEDXNHFTDJVIY-DQCZWYHMSA-N γ-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-DQCZWYHMSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/16—Central respiratory analeptics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Rheumatology (AREA)
- Obesity (AREA)
- Diabetes (AREA)
- Pain & Pain Management (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明の背景
１．本発明の技術分野
本発明は、哺乳類細胞における所望しない呼吸性バースト、酵素の産生および細胞シグナル伝達物質により引き起こされる炎症反応を伴う哺乳類細胞に起因する哺乳類における損傷およびその結果の疾病を抑制しかつ治療する治療方法に関する。更に、本発明はこの治療方法に用いる組成物に関する。
従来技術
反応性酸素種は、とりわけ好気代謝、薬物、毒物ならびに生体異物の異化、紫外線ならびにＸ線照射および侵入する細菌を殺傷するための（白血球等の）食細胞の呼吸性バースト、ならびに外来の物体に反応して細胞によって産生される。例えば、過酸化水素は、ほとんどの生存する生物の呼吸の過程で特にストレスが与えられかつ生存する細胞により産生される。
これら活性酸素種は、細胞を損傷させ得る。このような損傷の重大な例は、不飽和脂質の酸化的分解を含む脂質の過酸化である。脂質の過酸化は、膜の構造および機能に非常に有害であり、多くの細胞病理学的影響を引き起こし得るものである。細胞は、脂質の過酸化に対してスーパーオキシドジスムターゼ、カタラーゼ、ならびにペルオキシダーゼのような遊離基除去剤を産生することにより防護する。損傷した細胞は、遊離基除去剤を産生能を低下させている。過剰な過酸化水素は、ピリミジンと反応して5、6-二重結合を開環させ得る。Hallaender等（1971年）によると、この反応は、相補的塩基と水素結合するピリミジンの能力を阻害する。このような酸化的生化学的損傷は、細胞膜の完全性の欠損、酵素活性の低下、運搬キネティクスの変化、膜の脂質含量の変化、およびカルシウムイオン、アミノ酸ならびに他の細胞性物質の漏出を引き起こし得る。
反応性酸素中間体の産生は、アテローム硬化症、関節炎、細胞傷害、皮膚炎、光老化、皺、紫外線角化上皮症、腫瘍形成、癌、高血圧、パーキンソン病、肺疾患、ならびに心疾患のような多くの皮膚、組織、ならびに器官の障害の原因となっていると考えられている。腫瘍形成における活性酸素遊離基の役割は、（a）腫瘍プロモータが活性酸素のレベルを上昇させる、（b）多くの遊離基生成系が腫瘍の成長を促進する、（c）特定の抗酸化剤が腫瘍プロモータの生化学的効果を阻害するという知見に基づき提案される。
In Vitroでは、反応性酸素中間体は、細胞培養培地中において培地の成分の自己酸化および光酸化により生成され得る。切除および貯蔵の間、移植組織は酸化的損傷被り、細胞膜の完全性が失われかつ組織の使用し得る寿命が短くなる。
細胞を酸化的損傷させた場合、蘇生処置は細胞の修繕を必要とする。抗酸化剤は、活性酸素種に伴う傷害を阻害することが見出されている。例えば、ピルビン酸塩ならびに他のアルファケト酸は過酸化水素と急速ににかつ化学量論的に反応して、細胞溶解から細胞を保護することが報告されている（O’Donnell-Tormery等、J.Exp.Med., 165，第500〜510頁［1987年］）。
Nathによる米国特許第5,210,098号は、治療を必要としている患者に非毒性ピルビン酸塩を投与することにより急性腎臓障害を阻止ならびに予防する方法を開示している。
Nathの発明は、急性腎臓障害あるいはその危険がある患者にピルビン酸塩の有効量を投与することからなる治療方法を提供するものである。ピルビン酸塩、好ましくはピルビン酸ナトリウムは、診療上許容し得る液体担体に分散あるいは溶解し、前記腎臓障害を阻止あるいは予防する有効量を非経口的に投与するのが好ましく、この結果、正常な腎機能が回復する。ある場合においては、ピルビン酸塩は、腎臓あるいは近位腎動脈循環に直接注入することができる。この方法は、火傷と閉塞症を含む外傷、および虚血、糸球体腎炎ならびに例えばグラム陰性細菌感染による敗血症の直後の再灌流を含むが、これらのみに限定しない様々な原因による急性腎臓障害を予防あるいはその影響を弱めるのに効果的である。
Martin等、1994年、即ち米国特許第5,296,370号は、哺乳類細胞に対する損傷を予防ならびに減少し、かつ損傷した哺乳類細胞の蘇生率を向上させる治療用組成物を開示している。１つの実施様態において、この治療用組成物は、（a）ピルビン酸、治療上許容し得るピルビン酸の塩よりなる群から選択されるピルビン酸塩ならびにこれらの混合物、（b）酸化防止剤、ならびに（c）損傷した哺乳類細胞の蘇生に必要な脂肪酸であることを特徴とする飽和および不飽和脂肪酸からなる。
Miller等による米国特許第5,256,697号は、ピルビン酸前駆体の治療上有効量を哺乳類に経口的に投与して、インスリン耐性を改善し、持続するインスリンレベルを低下させならびに脂肪増加を減少させる方法を開示している。
すべてVan Scott等による米国特許第3,920,835号、第3,984,556号ならびに第3,988,470号は、座瘡、ふけ、および手掌角化症各々の治療方法を開示し、これらの方法は、アルファ-ヒドロキシ酸、アルファ-ケト酸およびこれらのエステル、ならびに3-ヒドロキシブチル酸よりなる群から選択される２〜６個の炭素原子を含む低級脂肪族化合物を治療上許容し得る担体中約１％〜２０％含む局所用組成物を冒された領域に適用することよりなる。この脂肪族化合物は、ピルビン酸および乳酸を含む。
共にYu等による米国特許第4,105,783号および第4、197、316号は、各々、乾燥皮膚を治療する方法および組成物を開示し、その方法および組成物は、アルファ-ヒドロキシ酸、ベータ-ヒドロキシ酸、ならびにアルファ-ケト酸のアミドおよびアンモニウム塩よりなる群から選択される化合物を治療上許容し得る担体中約１％〜２０％含む組成物を冒された領域に適用することよりなる。この化合物は、ピルビン酸および乳酸のアミドならびにアンモニウム塩を含む。
Van Scott等による米国特許第4,234,599号は、光線性ならびに非光線性皮膚硬化症の治療方法を開示し、この方法は、治療上許容し得る担体中にて、アルファ-ヒドロキシ酸、ベータ-ヒドロキシ酸、ならびにアルファ-ケト酸よりなる群から選択される化合物の有効量を含む組成物を冒された領域に適用することよりなる。この酸性化合物は、ピルビン酸ならびに乳酸を含む。
Wildnauer等による米国特許第4,294,852号は、皮膚を治療する組成物を開示し、この組成物は、Ｃ３〜Ｃ８の脂肪族アルコールと共にVan Scott等により開示されたアルファ-ヒドロキシ酸、ベータ-ヒドロキシ酸、ならびにアルファ-ケト酸を含む。
Veechによる米国特許第4,663,166号は、各々20:1〜1:1の比のL-乳酸塩ならびにピルビン酸塩の混合物、あるいは各々6:1〜0.5:1の比のD-ベータ-ヒドロキシブチル酸塩とアセトアセテートの混合物を含む電解質溶液を開示している。
ピルビン酸ナトリウムが、モルモットおよびラットにおいてアセチルサリチル酸が原因の様々なびらん、潰瘍、ならびに胃粘膜における出血を減少させることが報告されている。アセチルサリチル酸の鎮痛および解熱の性質は、ピルビン酸ナトリウムにより損なわれない（Puschmann, Arzneimittelforschung, 33，第410〜415頁および第415〜416頁［1983年］）。
ピルビン酸塩が、不可逆的損傷を引き起こさない短期間の冠状動脈閉塞の直後の持続性心室機能障害を起こした心筋に対して陽性の変力効果を発揮することが報告されている（Mentzer等、Ann.Surg., 209，第629〜633頁［1989年］）。
ピルビン酸塩が、左心室圧力および動作パラメータの相対的安定化を産生し、かつ梗塞のサイズを縮少させることが報告されている。ピルビン酸塩は、心臓の自発的拍動の再開ならびに正常な速度および圧力発生の回復を向上させる（Bunger等、J. Mol. Cell. Cardiol., 18，第423〜438頁［1986年］，Mochizuki等、J. Physiol.（Paris）, 76，第805〜812頁［1980年］，Regitz等、Cardiovasc. Res., 15，第652〜658頁［1981年］，Giannelli等、Ann.Thorac. Surg., 21，第386〜396頁［1976年］）。
ピルビン酸ナトリウムが、シアン化合物中毒に対して（おそらくシアノヒドリンを形成することにより）拮抗剤として作用し、硫化ナトリウムの致死的効果に対して防護し、かつ機能的、形態学的ならびに生化学的程度の軸索のアクリルアミド神経障害の開始およびその進行を妨げることが報告されている（Schwartz等、Toxicol. Appl. Pharmacol., 50，第437〜422頁［1979年］，Sabri等、Brain Res., 483，第1〜11頁［1989年］）。
ピルビン酸ナトリウムを使用して異常な奇形赤血球細胞を正常な赤血球に戻す進行したL1210白血病の化学療法剤治療が報告されている。奇形赤血球は、適する薬剤により腫瘍に移行するのが妨げられた（Cohen、Cancer Chemother,Pharmacol., 5，第175〜179頁［1981年］）。
In vivoにおいて7、12-ジメチルベンザアントラセンにさらした異所性器官移植体の初代培養が、インターロイキン-2刺激した末梢血リンパ球、骨髄腫ならびにハイブリドーマ、ブタ胚、ならびにヒト胚盤胞の培養物と一緒にピルビン酸ナトリウムを追補した増殖培地中いて維持されたことが報告されている（Shacter等、J.Immunol, Methods, 99，第259〜270頁［1987年］，Marchok等、Cancer Res., 37，第1811〜1821頁［1977年］，Davis、J. Report. Fertil, Suppl., 33，第115〜124頁［1985年］，Okamoto等、No To Shinkei, 38，第593〜598頁［1986年］，Cohen等、J. In Vitro Fert. Embryo Transfer., 2，第59〜64頁［1985年］）。
すべてStankoによる米国特許第4,158,057号、第4,351,835号、第4,415,576号および第4,645,764号は、各々、アルコール摂取による哺乳類の肝臓における脂肪の蓄積を予防する方法、哺乳類において体重を制御する方法、哺乳類における蛋白質濃度が上昇する間の体脂肪を阻害する方法ならびに生育中における体脂肪の蓄積を制御する方法を開示している。これらの方法は、ピルビン酸塩とジヒドロキシアセトン、ならびに随意にリボフラビンの治療用混合物を哺乳類に投与することからなる。Stankoによる米国特許第4,548,937号は、哺乳類にピルビン酸塩ならびに随意にリボフラビンの治療的有効量を投与するからなる、哺乳類の重量増加を制御する方法を開示している。Stankoによる米国特許第4,812,479号は、哺乳類にジヒドロキシアセトン、ならびに随意にリボフラビンおよびピルビン酸塩の治療的有効量を投与するからなる、哺乳類の重量増加を制御する方法を開示している。
ピルビン酸ナトリウムを含むカルシウム-オキサレート結石形成餌を与えられたラットはピルビン酸ナトリウムを与えられていない対照のラットより尿結石（石）の形成が少ないことが報告されている（Ogawa等、Hinvokika Kivo, 32，第1341〜1347頁［1986年］）。
Houlsbyによる米国特許第4,521,375号は、生育する組織と接触する表面を殺菌する方法を開示している。この方法は、過酸化水素水を用いて殺菌し次いでピルビン酸を用いて表面を中和することからなる。
Tauda等による米国特許第4,416,982号は、ペルオキシダーゼの存在下で過酸化水素をフェノールまたはアニリン誘導体と反応させることによる過酸化水素を分解する方法を開示している。
Lindstrom等による米国特許第4,696,917号は、Eagleの塩、コンドロイチン硫酸、緩衝液、2-メルカプトエタノール、およびピルビン酸塩を用いたEagleの最小必須培地からなる、灌注溶液を開示している。この灌注溶液は、随意にアスコルビン酸およびアルファ-トコフェロールを含有することができる。Lindstrom等による米国特許第4,725,586号は、平衡塩類溶液、コンドロイチン硫酸、緩衝溶液、2-メルカプトエタノール、重炭酸ナトリウムまたはデキストロース、ピルビン酸塩、リン酸ナトリウム緩衝液系およびシスチンからなる灌注溶液を開示している。この灌注溶液は、随意にアスコルビン酸およびガンマ-トコフェロールを含有することができる。
Bissett等による米国特許第4,847,069号は、（a）ソルボヒドロキサム酸、（b）ステロイド系抗炎症剤および天然の抗炎症剤から選択される抗炎症剤、ならびに（c）局所用担体からなる光防護組成物を開示している。脂肪酸を緩和剤として存在させることもできる。Bissett等による米国特許第4,847,071号は、（a）トコフェロールまたはトコフェロールエステル遊離基除去剤、（b）ステロイド系抗炎症剤および天然の抗炎症剤から選択される抗炎症剤、ならびに（c）局所用担体からなる光防護組成物を開示している。Bissett等による米国特許第4,847,072号は、局所用担体中２５％以下のトコフェロールソルベートを含む局所用組成物を開示している。
細菌系および酵母系へのピルビン酸ナトリウムの添加は過酸化水素の産生を阻害し、増殖を促進し、かつ反応性酸素中間体の毒性に対して系を防護することが報告されている。ニワトリの脂肪に含まれている不飽和脂肪酸と飽和脂肪酸の至適な比は、膜の修復を促進しかつ細胞毒素を減少させた。抗酸化剤のグルタチオンおよびチオグリコール酸塩は活性酸素種により誘発される損傷を減少させる（Martin、Ph.D.学位論文［1987〜89年］）。
上記の治療用組成物および方法が反応性酸素中間体の産生を阻害することが報告されているが、しかし、哺乳類細胞における所望しない呼吸性バースト、酵素の産生ならびに細胞シグナル伝達物質に起因する哺乳類における損傷およびその結果の疾病を治療する組成物および方法は報告されていない。
本発明の要旨
本発明は、炎症反応を伴う哺乳類細胞に起因する哺乳類における疾病の治療方法ならびにこの方法に有用な組成物に関する。炎症反応を伴う哺乳類細胞に起因する哺乳類における疾病の治療方法は、炎症反応に関与している哺乳類細胞を炎症媒介物質と接触させることかならなり、炎症媒介物質を所望しない炎症反応を減少させ得る量を存在させかつ炎症媒介物質が抗酸化剤であることを特徴とする。
所望しない炎症反応を低下させるために添加しかつ抗酸化剤である炎症反応媒介物質は、更に細胞のエネルギー源を提供しかつ他の細胞性成分の生合成の基礎単位となり得るものである。炎症反応媒介物質は、更に細胞性代謝速度を上昇させ得るものである。
更に、本発明は、所望しない炎症反応に起因する哺乳類における疾病状態を減少しかつ治療する、炎症反応媒介物質ならびに担体組成物からなる組成物に関し、炎症反応媒介物質が、抗酸化剤でありかつ哺乳類細胞において所望しない炎症反応を減少させ得ることを特徴とする。
炎症反応媒介物質は、単独で、組み合わせて、ならびに抗細菌薬、抗ウィルス薬、抗真菌薬、抗ヒスタミン薬、蛋白質、酵素、ホルモン、非ステロイド系抗炎症剤、サイトカインおよびステロイドなどのような他の治療薬と組み合わせて使用することができる。
炎症反応媒介物質を投与する方法は、吸入によるのが好ましい。
発明の詳細な説明
炎症反応を伴う哺乳類細胞に起因する哺乳類における疾病を治療する治療用組成物および方法を見出した。炎症反応に対して最初に反応し得る哺乳類細胞は、白血球である。
炎症反応を伴う哺乳類細胞に起因する哺乳類における疾病の治療方法において、哺乳類細胞は炎症媒介物質と接触する。炎症媒介物質は、所望しない炎症反応を減少させ得る量で存在し、かつ抗酸化剤である。
よく呼吸性バーストなどに例えられる炎症反応は、最初の白血球の哺乳類細胞を防護するのための反応である。これらの細胞は、通常は損傷または侵入された部位において様々な活性化合物が放出されることにより、哺乳類の損傷または侵入に対して反応する。とりわけ、放出される化合物は、プロテアーゼのような酵素および過酸化水素のような活性酸素種である。
呼吸性バーストは、白血球球により用いられ得る刺激に対する反応において、白血球に取り込まれたかあるいは近くの外来性細胞、ウィルス、微粒子ならびに数種の毒素を破壊するために、一連の酸化剤を提供することを目的としている。「呼吸性バースト」という用語は、白血球が適当な刺激にさらされた際に開始される統合された一連の代謝現象を指すのである。この群の現象は、白血球による全ての酸素依存性殺傷である。
これらの現象の最初に、白血球の刺激により酸素取込みの急激な増加が起こる。静止した白血球による酸素の消耗は、細胞のタイプにより異なるにもかかわらず、全てが適当な刺激に対して酸素の取込の増加を伴うよう反応する。
白血球の刺激は、更にヘキソースモノホスフェート分路を介したグルコースの酸化を引き起こす。ヘキソースモノホスフェート分路は、電子受容体として供給するNADP+を用いてグルコースを二酸化炭素と五炭糖に酸化する代謝経路である。従って、ヘキソースモノホスフェート分路の活性化は、呼吸性バーストの間、NADPHのNADP+への酸化が増加することを意味している。
この呼吸性バーストは、スーパーオキシドおよび過酸化水素を産生する。呼吸性バーストにより取り込まれた酸素は、スーパーオキシドに変換される。過酸化水素は、呼吸性バーストの間に主にスーパーオキシド陰イオンの不均化から発生する。
Ｏ-2+Ｏ-2+2Ｈ+→Ｈ2Ｏ2+Ｏ2
８０パーセントのスーパーオキシドが過酸化水素に変換され、かつこの不均化反応が呼吸性バーストの間に産生される過酸化水素のただ１つの重要な供給源であることは、RootとMetcalfにより示されならびにJ. Clin. Invest., 60:1266において報告されている。過酸化水素とスーパーオキシドが、白血球による殺傷作用を実施するものであると考えられている。
多くの薬剤が、可溶性ならびに粒子状であっても、呼吸性バーストを活性化することができる。粒子状の活性剤は、身体の内部器官ならびに領域に対しては細菌、ウィルスおよび真菌類が含まれ、外界と接している肺、皮膚ならびに消化および排泄系のような腔ならびに器官に対しては細菌、ウィルス、真菌類、繊維、煙、粉塵、灰、花粉、煙霧などが含まれる。可溶性薬剤は、毒素、医療用化合物、ならびに細菌、真菌類および感染した哺乳類細胞などの排泄物である。
白血球における呼吸性バーストの活性化は、通常１秒未満の刺激にさらされた直後に起こる。呼吸性バーストの刺激において、白血球における酸素の消費は、特にスーパーオキシド、ペルオキシドならびに過酸化水素の産生の結果、１００倍以上まで増加する。本明細書で用いている「白血球」という用語は、リンパ球、食細胞、マクロファージならびに助細胞を含む。
通常、呼吸性バーストの後は、刺激物および／または刺激の機構は、白血球が通常の静止状態に戻ることにより停止する。呼吸性バーストが停止しない場合には、白血球の炎症作用が多くの疾病を引き起こすのを阻止し得ない状態が継続する。化合物が白血球の組織細胞ならびに他の白血球の攻撃、損傷および殺傷により産生されるにつれて、これらの疾病が生じる。この呼吸性バーストを停止の不成功ならびにその結果の周囲の組織細胞、血液細胞、他の白血球および損傷した細胞の損傷が、本発明により治療される疾病を引き起こす。所望しない炎症反応が宿主細胞の損傷を引き起こし、かつこの損傷がこれとは別の脅威を宿主に与える場合に、炎症反応が生じる。
好適な実施様態において、炎症媒介物質を含む治療用組成物を炎症の領域に局部的に投与する。他の好適な実施様態において、治療用組成物を体系的に投与する。更に他の好適な実施様態において、治療用組成物を体系的にと同時に局部的に投与する。
好適な実施様態において、治療用組成物を吸入法により投与する。治療用組成物は、第１に任意の手段により噴霧することができる。治療用組成物は、吸入により肺組織に容易に接触させるのに十分に小さい小滴あるいは粒子サイズを用いることにより液体および個体の形態とすることができる。
他の好適な実施様態において、治療薬の無菌溶液は、噴霧され患者により吸入される。炎症媒介物質の治療上有効な量を吸入させる。これは、１回の吸入においてあるいは典型的には１〜３０分の時間にわたる反復吸入により達成することができる。吸入は２０分未満のうちに完了するのが好ましく、１５分以内に完了するのが最も好ましい。
ここで用いる「損傷した細胞」という用語は、（a）膜を通過する運搬が減少し、細胞内における毒素および正常な細胞の廃棄物の増加および／または栄養物および細胞の内部を修復するのに必要な他の成分の減少の１つ以上のことに起因する膜の損傷、（b）細胞の抗酸化剤および酵素の産生能の低下による細胞内部の活性酸素濃度の増加、ならびに（c）正常な細胞機能の回復に先んじて修復あるいは置換すべきＤＮＡ、ＲＮＡならびにリボゾームの損傷を若干あるいはすべてを有する細胞である。
炎症媒介物質は、哺乳類細胞と接触させる際に、細胞のエネルギー源および他の細胞成分の生合成の基礎単位を提供するものであるのが好ましい。
減少させる炎症反応は、炎症反応として当業者において知られている酸素遊離基の産生、過酸化水素の産生、サイトカインおよび／またはプロテアーゼの産生、プロスタグランジンの産生、紅斑、ヒスタミンおよびインターロイキンの産生などの少なくとも１つある。
炎症媒介物質は、ピルビン酸前駆体、ピルビン酸塩、乳酸前駆体および乳酸塩よりなる群から選択される少なくとも１種類の化合物であるのが好ましい。前駆体は、その物質を形成する物質であり、本明細書ではその物質の塩も含む。
ピルビン酸塩は、ピルビン酸、ピルビン酸リチウム、ピルビン酸ナトリウム、ピルビン酸カリウム、ピルビン酸マグネシウム、ピルビン酸カルシウム、ピルビン酸亜鉛、ピルビン酸マンガンおよびこれらの混合物よりなる群から選択されるのが好ましい。ピルビン酸ナトリウムが最も好ましい。
他の好ましい炎症媒介物質は、ピルビル-グリシン、ピルビル-アラニン、ピルビル-ロイシン、ピルビル-バリン、ピルビル-イソロイシン、ピルビル-フェニルアラニン、ピルビボアミド、ジヒドロキシアセトン、およびプロピレングリコールよりなる群から選択される。
好ましい炎症媒介物質の塩は、炎症媒介物質の塩として用いた際に哺乳類細胞に副作用を与えない塩である。典型的な塩は、リチウム、ナトリウム、カリウム、アルミニウム、マグネシウム、カルシウム、亜鉛、マンガン、アンモニウムなどならびにこれらの混合物である。
乳酸前駆体は、ラクチル-グリシン、ラクチル-アラニン、ラクチル-ロイシン、ラクチル-バリン、ラクチル-イソロイシン、ラクチル-フェニルアラニン、ラクトアミドおよび乳酸の様々な塩よりなる群から選択されるのが好ましい。
所望しない炎症反応により引き起こされる哺乳類における疾病を減少させかつ治療する組成物は、炎症反応媒介物質および担体組成物を含む。
担体組成物は、錠剤、カプセル、液体、電解質液、電解質媒体、腸溶錠剤およびカプセル、経口剤、局部剤、クリーム、ゲル、軟膏、チューインガムおよび菓子などよりなる群から選択される。
炎症媒介物質は、治療上有効な量にて投与し、所望しない炎症反応を減少させる。０．００１〜１０グラムの投与量が好ましく、０．００１〜１グラムの投与量がさらに好ましく、０．００１〜０．２５グラムの投与量が最も好ましい。投与の方法および治療条件は、治療効果を得るのに必要な投与量により大きく影響されると考えらる。
本発明の組成物および方法により治療できる典型的な気道疾病は、気管支喘息、急性気管支炎、肺気腫、慢性閉塞性肺気腫、小葉中心性肺気腫、汎細葉性肺気腫、慢性閉塞性気管支炎、反応性気道疾病、嚢胞性線維症、気管支拡張症、後天性気管支拡張症、カルタグナー症候群、無気肺、急性無気肺、慢性無気肺、肺炎、本態性血小板減少症、在郷軍人病、オウム病、線維形成性塵肺、有機粉塵による疾病、刺激性ガスおよび化学物質による疾病、肺過敏症、肺特発性浸潤性疾患などを含むが、これらに限定はしない。
特に治療すべき疾病は、肺気腫ならびに喘息である。
本発明の炎症媒介物質は、他の治療薬より前、後および／または他の治療薬と一緒に投与することができる。典型的な治療薬は、抗細菌薬、抗ウィルス薬、抗真菌薬、抗ヒスタミン薬、蛋白質、酵素、ホルモン、非ステロイド系抗炎症剤、サイトカイン、ステロイドなどである。
本発明の様々な改良および変型は、上記の教示から想到し得るものであるが、しかし、本発明は下記する実施例により制限されるものではない。従って、添付した請求の範囲内において、特に下記する方法とは別の方法でも本発明を実施することができる。
実施例
被験者：
肺気腫および特定の気道疾病である５９歳の男性を上記のように３ヶ月間治療した。治療する前、被験者は、呼吸する能力が制限され、いずれの他の治療薬にも反応せず、労働できない状態（休職中）であった。３ヶ月の治療後、被験者は、症状が顕著に改善している様であった。事実、劇的な結果が２週間以内に観察された。
治療：
５ミリモルのピルビン酸ナトリウム溶液５ミリリットルを０．２ミクロンのフィルターを通して濾過滅菌した。滅菌したピルビン酸ナトリウムをデビルビス（DeVilbiss Co., Somerset, Pennsylvania 15501-0635）により製造された「プルモ エイド（Pulmo Aid）」噴霧器に移した。滅菌したピルビン酸ナトリウムを使い捨て噴霧器を備えたプルモ エイド装置により噴霧し、患者に吸気させた。患者は、溶液の全てが噴霧されかつ吸気されるまで、プルモ エイド噴霧器より普通に吸気した。この吸気過程は、典型的には約１０〜２０分かかる。
患者を定期的に吸気治療法により治療する。最初、治療は、約６時間の間隔を空けて１日に約４回である。治療を始めて３０日後、治療は約８時間の間隔を空けて１日に約３回までに減らす。治療を始めて６０日後、治療は１日に１回まで更に減らす。９０日後には、治療は１週間に３〜５回にする。
下記するデータは、投与前および治療を始めて２ヶ月後の様々な肺能力ならびに肺機能試験の結果を示している。
最初の治療後２０〜３０分に、１回呼吸量は増加し、喘鳴が止まりならびに運動負荷の増加が観察された。治療開始の最初の２週間以内に、「プロベンテル［Proventil］」（シェアリング［Schering］により製造されたサルブチール）を１日当たり1600mgから400mgまで減らすことができた。酸素の使用は、治療開始後すぐに取り止めた。
結論：
治療の結果は次の通りである。
（１）肺機能が２０％改善した。
（２）若干の医療レベルが低下し、酸素の使用を停止した。
（３）反応性気道疾病状態が、吸入器を必要としないところまで減少した。
（４）運動負荷の増加が試験され、これが肺気腫ならびに特定の気道疾病ではない人の値に近づいていることが証明された。被験者は、前の仕事に完全に復帰することができた。
（５）肺機能の減少は再発しなかった。
（６）精神状態が顕著に改善した。
上述の炎症反応を伴う哺乳類細胞における疾病の治療方法が本発明の好適な実施様態ではあるが、しかし、本発明はこの明確な方法に限定されるものではなく、かつその変型も添付する請求の範囲において規定した本発明の範囲から逸脱し得るものではないということは理解されよう。Background of the invention
1. TECHNICAL FIELD OF THE INVENTION
The present invention relates to a therapeutic method for inhibiting and treating damage and resulting disease in mammals due to mammalian cells with inflammatory responses caused by unwanted respiratory bursts, enzyme production and cell signaling substances in mammalian cells. . The invention further relates to a composition for use in this method of treatment.
Conventional technology
Reactive oxygen species include, among other things, aerobic metabolism, catabolism of drugs, toxicants and xenobiotics, UV and X-ray irradiation and respiratory bursts of phagocytes (such as leukocytes) to kill invading bacteria, and foreign objects Produced by cells in response to. For example, hydrogen peroxide is produced by surviving cells that are particularly stressed during the respiration process of most living organisms.
These reactive oxygen species can damage cells. A serious example of such damage is lipid peroxidation, including oxidative degradation of unsaturated lipids. Lipid peroxidation is very detrimental to membrane structure and function and can cause many cytopathological effects. Cells protect against lipid peroxidation by producing free radical scavengers such as superoxide dismutase, catalase, and peroxidase. Damaged cells have reduced ability to produce free radical scavengers. Excess hydrogen peroxide can react with pyrimidine to open the 5,6-double bond. According to Hallaender et al. (1971), this reaction inhibits the ability of pyrimidines to hydrogen bond with complementary bases. Such oxidative biochemical damage causes loss of cell membrane integrity, reduced enzyme activity, altered transport kinetics, altered membrane lipid content, and leakage of calcium ions, amino acids and other cellular substances. obtain.
The production of reactive oxygen intermediates such as atherosclerosis, arthritis, cytotoxicity, dermatitis, photoaging, epilepsy, UV keratoepitheliosis, tumor formation, cancer, hypertension, Parkinson's disease, lung disease, and heart disease It is believed to cause many skin, tissue, and organ damage. The role of free radicals in tumorigenesis is: (a) tumor promoters increase levels of free radicals, (b) many free radical generating systems promote tumor growth, (c) certain antioxidants Is proposed based on the finding that it inhibits the biochemical effects of tumor promoters.
In Invitro, reactive oxygen intermediates can be generated in cell culture media by autooxidation and photooxidation of the components of the media. During excision and storage, the transplanted tissue undergoes oxidative damage, the integrity of the cell membrane is lost, and the usable life of the tissue is shortened.
When cells are oxidatively damaged, resuscitation procedures require cell repair. Antioxidants have been found to inhibit the injury associated with reactive oxygen species. For example, pyruvate as well as other alpha keto acids have been reported to react rapidly and stoichiometrically with hydrogen peroxide to protect cells from cell lysis (O'Donnell-Tormery et al. J. Exp. Med., 165, pp. 500-510 [1987]).
US Pat. No. 5,210,098 by Nath discloses a method for preventing and preventing acute kidney injury by administering non-toxic pyruvate to patients in need of treatment.
Nath's invention provides a method of treatment comprising administering an effective amount of pyruvate to a patient with or at risk for acute kidney injury. Pyruvate, preferably sodium pyruvate, is preferably administered parenterally in an effective amount to disperse or dissolve in a clinically acceptable liquid carrier and prevent or prevent the kidney damage. Renal function is restored. In some cases, pyruvate can be injected directly into the kidney or proximal renal artery circulation. This method prevents trauma, including burns and obstruction, and acute kidney injury due to a variety of causes including, but not limited to, ischemia, glomerulonephritis and reperfusion immediately following sepsis due to eg Gram-negative bacterial infection. Or it is effective to weaken the influence.
Martin et al., 1994, US Pat. No. 5,296,370, discloses therapeutic compositions that prevent and reduce damage to mammalian cells and increase the resuscitation rate of damaged mammalian cells. In one embodiment, the therapeutic composition comprises (a) pyruvate, a pyruvate selected from the group consisting of therapeutically acceptable salts of pyruvate, and mixtures thereof, (b) an antioxidant, And (c) saturated and unsaturated fatty acids characterized by fatty acids necessary for resuscitation of damaged mammalian cells.
U.S. Pat.No. 5,256,697 by Miller et al. Describes a method for orally administering a therapeutically effective amount of a pyruvate precursor to a mammal to improve insulin resistance, lower sustained insulin levels as well as reduce fat gain. Disclosure.
U.S. Pat.Nos. 3,920,835, 3,984,556, and 3,988,470, all by Van Scott et al., Disclose methods for treating acne, dandruff, and palmar keratosis, which include alpha-hydroxy acids, alpha- Topically containing about 1% to 20% in a therapeutically acceptable carrier of keto acids and their esters and lower aliphatic compounds containing 2 to 6 carbon atoms selected from the group consisting of 3-hydroxybutyric acid Applying the composition to the affected area. This aliphatic compound contains pyruvic acid and lactic acid.
U.S. Pat. Nos. 4,105,783 and 4,197,316, both by Yu et al., Disclose methods and compositions for treating dry skin, respectively, which include alpha-hydroxy acids, beta-hydroxy acids. And applying to the affected area a composition comprising about 1% to 20% in a therapeutically acceptable carrier of a compound selected from the group consisting of amides and ammonium salts of alpha-keto acids. This compound includes pyramide and lactic acid amides and ammonium salts.
U.S. Pat. No. 4,234,599 by Van Scott et al. Discloses a method for treating photo- and non-photo-irradiated dermatosclerosis comprising the steps of alpha-hydroxy acid, beta-hydroxy acid in a therapeutically acceptable carrier. And applying to the affected area a composition comprising an effective amount of a compound selected from the group consisting of alpha-keto acids. This acidic compound includes pyruvic acid as well as lactic acid.
U.S. Pat. No. 4,294,852 to Wildnauer et al. Discloses a composition for treating the skin, which is an alpha-hydroxy acid, beta-hydroxy acid, disclosed by Van Scott et al. With C3-C8 fatty alcohols, As well as alpha-keto acids.
U.S. Pat.No. 4,663,166 to Veech describes a mixture of L-lactate and pyruvate each in a ratio of 20: 1 to 1: 1, or D-beta-hydroxybutyric acid in a ratio of 6: 1 to 0.5: 1 each. An electrolyte solution comprising a mixture of salt and acetoacetate is disclosed.
Sodium pyruvate has been reported to reduce various erosions, ulcers and bleeding in the gastric mucosa caused by acetylsalicylic acid in guinea pigs and rats. The analgesic and antipyretic properties of acetylsalicylic acid are not impaired by sodium pyruvate (Puschmann,Arzneimittelforschung33, pp. 410-415 and 415-416 [1983]).
Pyruvate has been reported to exert a positive inotropic effect on myocardium with persistent ventricular dysfunction immediately following a brief coronary artery occlusion that does not cause irreversible damage (Mentzer et al.,Ann.Surg209, 629-633 [1989]).
Pyruvate has been reported to produce relative stabilization of left ventricular pressure and operating parameters and reduce infarct size. Pyruvate improves the resumption of spontaneous heart pulsation and normal speed and recovery of pressure generation (Bunger et al.,J. Mol. Cell. Cardiol., 18, 423-438 [1986], Mochizuki et al.,J. Physiol. (Paris)76, 805-812 [1980], Regitz et al.,Cardiovasc. Res., 15, 652-658 [1981], Giannelli et al.,Ann.Thorac. Surg., 21, 386-396 [1976]).
Sodium pyruvate acts as an antagonist against cyanide poisoning (possibly by forming cyanohydrin), protects against the lethal effects of sodium sulfide, and has a functional, morphological and biochemical extent Has been reported to interfere with the onset and progression of acrylamide neuropathy in axons (Schwartz et al.,Toxicol. Appl. Pharmacol., 50, 437-422 [1979], Sabri et al.,Brain Res., 483, pp. 1-11 [1989]).
Chemotherapy treatment of advanced L1210 leukemia has been reported that uses sodium pyruvate to return abnormal malformed red blood cells to normal red blood cells. Malformed erythrocytes were prevented from entering the tumor by a suitable drug (Cohen,Cancer Chemother, Pharmacol., 5, pp. 175-179 [1981]).
In vivoPrimary cultures of ectopic organ transplants exposed to 7,12-dimethylbenzanthracene in HCV along with interleukin-2 stimulated peripheral blood lymphocytes, myeloma and hybridoma, porcine embryos, and human blastocyst cultures Have been maintained in growth media supplemented with sodium pyruvate (Shacter et al.,J. Immunol, Methods99, pp. 259-270 [1987], Marchok, etc.Cancer res., 37, 1811-1821 [1977], Davis,J. Report. Fertil, Suppl., 33, 115-124 [1985], Okamoto et al.,No To Shinkei, 38, 593-598 [1986], Cohen et al.,J. In Vitro Fert. Embryo Transfer., 2, 59-64 [1985]).
U.S. Pat.Nos. 4,158,057, 4,351,835, 4,415,576 and 4,645,764, all by Stanko, respectively, describe methods for preventing fat accumulation in the liver of mammals due to alcohol consumption, methods for controlling body weight in mammals, proteins in mammals Disclosed are methods for inhibiting body fat during elevated concentrations and methods for controlling body fat accumulation during growth. These methods consist of administering to a mammal a therapeutic mixture of pyruvate and dihydroxyacetone, and optionally riboflavin. Stanko, US Pat. No. 4,548,937 discloses a method for controlling weight gain in a mammal comprising administering to the mammal a therapeutically effective amount of pyruvate and optionally riboflavin. Stanko, US Pat. No. 4,812,479 discloses a method for controlling weight gain in mammals comprising administering to a mammal a therapeutically effective amount of dihydroxyacetone, and optionally riboflavin and pyruvate.
Rats fed a calcium-oxalate stone-forming diet containing sodium pyruvate have been reported to produce less urinary stones (stones) than control rats not fed sodium pyruvate (Ogawa et al.,Hinvokika Kivo32, pp. 1341-1347 [1986]).
Houlsby U.S. Pat. No. 4,521,375 discloses a method of disinfecting surfaces that come into contact with growing tissue. This method consists of sterilizing with aqueous hydrogen peroxide and then neutralizing the surface with pyruvic acid.
U.S. Pat. No. 4,416,982 by Tauda et al. Discloses a method for decomposing hydrogen peroxide by reacting hydrogen peroxide with a phenol or aniline derivative in the presence of peroxidase.
US Pat. No. 4,696,917 by Lindstrom et al. Discloses an irrigation solution consisting of Eagle's minimum essential medium using Eagle's salt, chondroitin sulfate, buffer, 2-mercaptoethanol, and pyruvate. This irrigation solution can optionally contain ascorbic acid and alpha-tocopherol. U.S. Pat.No. 4,725,586 by Lindstrom et al. Discloses an irrigation solution comprising a balanced salt solution, chondroitin sulfate, buffer solution, 2-mercaptoethanol, sodium bicarbonate or dextrose, pyruvate, sodium phosphate buffer system and cystine. ing. This irrigation solution can optionally contain ascorbic acid and gamma-tocopherol.
U.S. Pat. No. 4,847,069 by Bissett et al. Describes photoprotection comprising (a) solvohydroxamic acid, (b) an anti-inflammatory agent selected from steroidal and natural anti-inflammatory agents, and (c) a topical carrier A composition is disclosed. Fatty acids can also be present as relaxation agents. US Pat. No. 4,847,071 by Bissett et al. Describes (a) a tocopherol or tocopherol ester free radical scavenger, (b) an anti-inflammatory agent selected from steroidal and natural anti-inflammatory agents, and (c) topical use A photoprotective composition comprising a carrier is disclosed. U.S. Pat. No. 4,847,072 to Bissett et al. Discloses a topical composition comprising no more than 25% tocopherol sorbate in a topical carrier.
The addition of sodium pyruvate to bacterial and yeast systems has been reported to inhibit the production of hydrogen peroxide, promote growth and protect the system against the toxicity of reactive oxygen intermediates. The optimal ratio of unsaturated and saturated fatty acids in chicken fat promoted membrane repair and reduced cytotoxins. Antioxidants glutathione and thioglycolate reduce damage induced by reactive oxygen species (Martin, Ph.D. dissertation [1987-89]).
The above therapeutic compositions and methods have been reported to inhibit the production of reactive oxygen intermediates, but mammals due to unwanted respiratory bursts, enzyme production and cell signaling agents in mammalian cells There have been no reports of compositions and methods for treating injuries and resulting diseases.
Summary of the present invention
The present invention relates to a method for treating diseases in mammals caused by mammalian cells with an inflammatory response, as well as compositions useful in this method. A method of treating a disease in a mammal caused by a mammalian cell with an inflammatory response involves contacting the mammalian cell involved in the inflammatory response with an inflammatory mediator, which can reduce an unwanted inflammatory response In an amount and characterized in that the inflammatory mediator is an antioxidant.
Inflammatory response mediators, which are added to reduce unwanted inflammatory responses and are antioxidants, can further provide a source of cellular energy and serve as a building block for the biosynthesis of other cellular components. Inflammatory response mediators can further increase cellular metabolic rates.
The present invention further relates to a composition comprising an inflammatory response mediator and a carrier composition for reducing and treating a disease state in a mammal due to an undesired inflammatory response, wherein the inflammatory response mediator is an antioxidant and It is characterized by being able to reduce unwanted inflammatory responses in mammalian cells.
Inflammatory response mediators alone, in combination and others such as antibacterial drugs, antiviral drugs, antifungal drugs, antihistamines, proteins, enzymes, hormones, non-steroidal anti-inflammatory drugs, cytokines and steroids, etc. Can be used in combination with other therapeutic agents.
The method of administering the inflammatory response mediator is preferably by inhalation.
Detailed Description of the Invention
We have discovered therapeutic compositions and methods for treating diseases in mammals resulting from mammalian cells with an inflammatory response. Mammalian cells that can initially respond to an inflammatory response are leukocytes.
In a method of treating a disease in a mammal caused by a mammalian cell with an inflammatory response, the mammalian cell is contacted with an inflammatory mediator. Inflammatory mediators are present in amounts that can reduce undesired inflammatory responses and are antioxidants.
Inflammatory reactions, often compared to respiratory bursts, are reactions to protect the first leukocyte mammalian cells. These cells respond to mammalian injury or invasion, usually by releasing various active compounds at the site of injury or invasion. In particular, the released compounds are enzymes such as proteases and reactive oxygen species such as hydrogen peroxide.
Respiratory burst provides a series of oxidants to destroy extraneous cells, viruses, microparticles, and some toxins that are taken up by or nearby leukocytes in response to stimuli that can be used by leukocytes. It is an object. The term “respiratory burst” refers to a series of integrated metabolic events that are initiated when leukocytes are exposed to appropriate stimuli. This group of phenomena is all oxygen-dependent killing by leukocytes.
At the beginning of these phenomena, leukocyte stimulation causes a rapid increase in oxygen uptake. Although the depletion of oxygen by quiescent leukocytes varies by cell type, all react to an appropriate stimulus with increased oxygen uptake.
Leukocyte stimulation also causes glucose oxidation through hexose monophosphate shunts. The hexose monophosphate shunt is a metabolic pathway that oxidizes glucose to carbon dioxide and pentose using NADP + supplied as an electron acceptor. Thus, activation of the hexose monophosphate shunt implies an increase in the oxidation of NADPH to NADP + during the respiratory burst.
This respiratory burst produces superoxide and hydrogen peroxide. Oxygen taken up by the respiratory burst is converted to superoxide. Hydrogen peroxide arises mainly from the disproportionation of superoxide anions during the respiratory burst.
O-2+ O-2+ 2H+→ H2O2+ O2
Root and Metcalf show that 80 percent superoxide is converted to hydrogen peroxide and that this disproportionation reaction is the only important source of hydrogen peroxide produced during the respiratory burst. And reported in J. Clin. Invest., 60: 1266. Hydrogen peroxide and superoxide are considered to carry out the killing action by leukocytes.
Many drugs can activate the respiratory burst, whether soluble or particulate. Particulate active agents include bacteria, viruses and fungi for internal organs and areas of the body, and for cavities and organs such as lungs, skin and digestive and excretory systems in contact with the outside world This includes bacteria, viruses, fungi, fiber, smoke, dust, ash, pollen, and haze. Soluble drugs are toxins, medical compounds, and excreta such as bacteria, fungi and infected mammalian cells.
Activation of respiratory burst in leukocytes usually occurs immediately after exposure to stimuli of less than 1 second. In stimulating respiratory bursts, oxygen consumption in leukocytes increases by more than 100 times, particularly as a result of superoxide, peroxide and hydrogen peroxide production. As used herein, the term “leukocytes” includes lymphocytes, phagocytic cells, macrophages as well as auxiliary cells.
Typically, after a respiratory burst, the irritant and / or mechanism of stimulation stops when the white blood cells return to normal resting state. If the respiratory burst does not stop, the state in which the inflammatory action of leukocytes cannot prevent many diseases from continuing continues. These diseases occur as compounds are produced by the attack, damage and killing of leukocyte tissue cells and other leukocytes. The failure to stop this respiratory burst and the resulting damage to surrounding tissue cells, blood cells, other white blood cells and damaged cells cause the disease to be treated by the present invention. An inflammatory response occurs when an undesired inflammatory response causes damage to the host cell and this damage poses another threat to the host.
In a preferred embodiment, a therapeutic composition comprising an inflammatory mediator is administered locally to the area of inflammation. In other preferred embodiments, the therapeutic composition is administered systematically. In yet another preferred embodiment, the therapeutic composition is administered systematically and locally.
In a preferred embodiment, the therapeutic composition is administered by inhalation. The therapeutic composition can be sprayed first by any means. The therapeutic composition can be in liquid and solid form by using droplets or particle sizes that are small enough to be easily contacted with lung tissue by inhalation.
In another preferred embodiment, a sterile solution of the therapeutic agent is nebulized and inhaled by the patient. Inhaling a therapeutically effective amount of an inflammatory mediator. This can be accomplished in a single inhalation or by repeated inhalation typically over a period of 1 to 30 minutes. Inhalation is preferably completed within less than 20 minutes, and most preferably within 15 minutes.
As used herein, the term “damaged cell” refers to (a) reduced transport across the membrane, increased toxin and normal cell waste within the cell, and / or restoration of nutrients and the interior of the cell. Membrane damage due to one or more of the reductions in other components required for the cells, (b) increased intracellular reactive oxygen levels due to reduced production of cellular antioxidants and enzymes, and (c) A cell having some or all damage to DNA, RNA and ribosome to be repaired or replaced prior to restoration of normal cell function.
Inflammatory mediators preferably provide a building block for the biosynthesis of cellular energy sources and other cellular components when contacted with mammalian cells.
Decreasing inflammatory responses include oxygen free radical production, hydrogen peroxide production, cytokine and / or protease production, prostaglandin production, erythema, histamine and interleukin production known to those skilled in the art as inflammatory reactions There is at least one of them.
The inflammation mediator is preferably at least one compound selected from the group consisting of pyruvate precursor, pyruvate, lactic acid precursor and lactate. A precursor is a substance that forms the substance, and also includes salts of the substance herein.
The pyruvate is preferably selected from the group consisting of pyruvate, lithium pyruvate, sodium pyruvate, potassium pyruvate, magnesium pyruvate, calcium pyruvate, zinc pyruvate, manganese pyruvate and mixtures thereof. Most preferred is sodium pyruvate.
Other preferred inflammatory mediators are selected from the group consisting of pyruville-glycine, pyruville-alanine, pyruvir-leucine, pyruvir-valine, pyruvir-isoleucine, pyruvir-phenylalanine, pyrbiboamide, dihydroxyacetone, and propylene glycol.
Preferred salts of inflammatory mediators are salts that do not give side effects to mammalian cells when used as inflammatory mediator salts. Typical salts are lithium, sodium, potassium, aluminum, magnesium, calcium, zinc, manganese, ammonium and the like as well as mixtures thereof.
The lactic acid precursor is preferably selected from the group consisting of lactyl-glycine, lactyl-alanine, lactyl-leucine, lactyl-valine, lactyl-isoleucine, lactyl-phenylalanine, lactamide and various salts of lactic acid.
Compositions for reducing and treating diseases in mammals caused by unwanted inflammatory responses include inflammatory response mediators and carrier compositions.
The carrier composition is selected from the group consisting of tablets, capsules, liquids, electrolyte solutions, electrolyte media, enteric tablets and capsules, oral agents, topical agents, creams, gels, ointments, chewing gums and confectionery.
Inflammatory mediators are administered in a therapeutically effective amount to reduce unwanted inflammatory responses. A dosage of 0.001-10 grams is preferred, a dosage of 0.001-1 grams is more preferred, and a dosage of 0.001-0.25 grams is most preferred. The method of administration and the treatment conditions are thought to be greatly influenced by the dose required to obtain a therapeutic effect.
Typical airway diseases that can be treated by the compositions and methods of the present invention are bronchial asthma, acute bronchitis, emphysema, chronic obstructive emphysema, centrilobular emphysema, panlobular emphysema, chronic obstructive bronchitis, reactivity Airway disease, cystic fibrosis, bronchiectasis, acquired bronchiectasis, Cartagner syndrome, atelectasis, acute atelectasis, chronic atelectasis, pneumonia, essential thrombocytopenia, military illness, parrot disease Including, but not limited to, fibrogenic pneumoconiosis, diseases caused by organic dust, diseases caused by irritating gases and chemicals, pulmonary hypersensitivity, lung idiopathic invasive disease and the like.
The diseases to be treated in particular are emphysema as well as asthma.
The inflammation mediators of the present invention can be administered before, after and / or with other therapeutic agents. Typical therapeutic agents are antibacterial agents, antiviral agents, antifungal agents, antihistamines, proteins, enzymes, hormones, nonsteroidal anti-inflammatory agents, cytokines, steroids and the like.
Various modifications and variations of the present invention can be devised from the above teachings, but the invention is not limited to the following examples. Accordingly, within the scope of the appended claims, the invention may be practiced otherwise than as specifically described below.
Example
subject:
A 59-year-old man with emphysema and certain airway diseases was treated for 3 months as described above. Prior to treatment, subjects had limited ability to breathe, did not respond to any other treatment, and were unable to work (absence of work). After 3 months of treatment, the subject appeared to have a marked improvement in symptoms. In fact, dramatic results were observed within 2 weeks.
Treatment:
Five milliliters of 5 mM sodium pyruvate solution was filter sterilized through a 0.2 micron filter. Sterile sodium pyruvate was transferred to a “Pulmo Aid” nebulizer manufactured by DeVilbiss Co., Somerset, Pennsylvania 15501-0635. Sterile sodium pyruvate was nebulized by a plume device equipped with a disposable nebulizer and inhaled by the patient. The patient inhaled normally from the plume nebulizer until all of the solution was nebulized and inhaled. This inhalation process typically takes about 10-20 minutes.
Patients are regularly treated with inspiratory therapy. Initially, treatment is about 4 times a day with an interval of about 6 hours. After 30 days of treatment, treatment is reduced to about 3 times a day with an interval of about 8 hours. After 60 days of treatment, treatment is further reduced to once a day. After 90 days, treatment is 3-5 times per week.
The data presented below shows the results of various pulmonary performance and pulmonary function tests before administration and 2 months after the start of treatment.
Twenty to thirty minutes after the first treatment, tidal volume increased, wheezing stopped as well as increased exercise load. Within the first two weeks of treatment, “Proventil” (salvutil manufactured by Schering) could be reduced from 1600 mg to 400 mg per day. Oxygen use was withdrawn immediately after treatment began.
Conclusion:
The results of treatment are as follows.
(1) The lung function improved by 20%.
(2) The medical level slightly decreased and the use of oxygen was stopped.
(3) Reactive airway disease status decreased to the point where an inhaler was not required.
(4) Increased exercise load was tested and proved to be close to that of people who are not emphysema as well as specific airway diseases. Subject was able to fully return to previous work.
(5) The decrease in lung function did not recur.
(6) Mental condition improved significantly.
The above-described method for treating diseases in mammalian cells with an inflammatory response is a preferred embodiment of the present invention, however, the present invention is not limited to this specific method, and variants thereof are also appended. It will be understood that departures may be made from the scope of the invention as defined in scope.
Claims (17)
炎症媒介物質が、哺乳類細胞と接触させた場合、細胞のエネルギー源および他の細胞性成分の生合成の基礎単位を提供するものであり、ピルビン酸塩よりなる群から選択される少なくとも１種類の化合物であることを特徴とする吸入薬剤。An inhalation drug for the treatment of mammalian respiratory tract diseases caused by mammalian cells with an inflammatory response, said inhalation drug comprising contacting a mammalian cell with an inflammatory mediator, wherein the inflammatory mediator does not desire an inflammatory mediator. In an inhaled drug, characterized in that it is present in a reduced amount and the inflammatory mediator is an antioxidant,
Inflammatory mediators, at least one when in contact with mammalian cell state, and are intended to provide a basis unit of biosynthesis of energy sources and other cellular components of the cells, which are selected from the group consisting of pyruvate An inhalation drug characterized by being a compound of :
炎症媒介物質が、哺乳類細胞と接触させた場合、細胞のエネルギー源および他の細胞性成分の生合成の基礎単位を提供するものであり、炎症媒介物質が、ピルビン酸塩よりなる群から選択される少なくとも１種類の化合物であることを特徴とする組成物。In a composition comprising an inflammatory response mediator and a carrier composition for reducing and treating airway disease in a mammal due to an undesired inflammatory response,
When the inflammatory mediator is contacted with a mammalian cell, it provides a basic unit of cellular energy source and biosynthesis of other cellular components, and the inflammatory mediator is selected from the group consisting of pyruvate A composition comprising at least one compound.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US396295P | 1995-09-19 | 1995-09-19 | |
| US60/003,962 | 1995-09-19 | ||
| PCT/US1996/014304 WO1997010818A1 (en) | 1995-09-19 | 1996-09-06 | Method and composition for treating mammalian diseases caused by inflammatory response |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH10509463A JPH10509463A (en) | 1998-09-14 |
| JP4459303B2 true JP4459303B2 (en) | 2010-04-28 |
Family
ID=21708422
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP51274197A Expired - Lifetime JP4459303B2 (en) | 1995-09-19 | 1996-09-06 | Method of treating disease in mammals resulting from inflammatory reaction and composition thereof |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0804181A4 (en) |
| JP (1) | JP4459303B2 (en) |
| AU (1) | AU719332B2 (en) |
| CA (1) | CA2205112C (en) |
| IL (1) | IL119225A (en) |
| MX (1) | MX9703653A (en) |
| NZ (1) | NZ306832A (en) |
| TW (1) | TW434012B (en) |
| WO (1) | WO1997010818A1 (en) |
| ZA (1) | ZA967833B (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2373611C (en) * | 1999-05-14 | 2009-06-23 | Cellular Sciences, Inc. | Method and composition for treating mammalian nasal and sinus diseases caused by inflammatory response |
| JP2004528307A (en) * | 2001-03-15 | 2004-09-16 | ユニバーシティ オブ ピッツバーグ オブ ザ コモンウェルス システム オブ ハイヤー エデュケーション | Use of pyruvate and / or derivatives thereof for the treatment of inflammatory conditions mediated by cytokines |
| US6623723B2 (en) * | 2001-08-21 | 2003-09-23 | Cellular Sciences Inc. | Method for treating bronchial constriction and bronchospasm |
| US6689810B2 (en) * | 2001-08-21 | 2004-02-10 | Cellular Sciences, Inc. | Method for treating pulmonary disease states in mammals by altering indigenous in vivo levels of nitric oxide |
| US20030105162A1 (en) * | 2001-08-21 | 2003-06-05 | Celluar Sciences, Inc. | Method for treating bronchial constriction and bronchospasm |
| US8076373B2 (en) * | 2001-09-11 | 2011-12-13 | North Cell Pharmacetical | Method for treating mammalian diseases and injuries caused by the over-expression of peroxynitrite |
| JP5630750B2 (en) * | 2008-03-18 | 2014-11-26 | 国立大学法人 岡山大学 | Excitatory chemical transmission regulator and screening method thereof |
| US11571455B2 (en) | 2013-04-11 | 2023-02-07 | Vanderbilt University | Methods and compositions for treating alcoholic liver disease |
| JP2020524144A (en) | 2017-06-16 | 2020-08-13 | ヴァンダービルト ユニヴァーシティ | Methods and compositions for treating microbial inflammation |
| EP3797766A1 (en) * | 2019-09-24 | 2021-03-31 | Evonik Operations GmbH | Compositions for use in reducing inflammation |
| KR20220097972A (en) * | 2019-11-14 | 2022-07-08 | 메르크 파텐트 게엠베하 | cell culture medium |
Family Cites Families (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1857M (en) * | 1962-03-08 | 1963-06-10 | Roussel Uclaf | New drug in particular for the treatment of diseases of viral origin. |
| US3279997A (en) * | 1963-10-22 | 1966-10-18 | Herbert D Schneyer | Enteric coated calcium lactate tablets containing an antihistamine and thiamine chloride |
| US3879537A (en) * | 1973-09-04 | 1975-04-22 | Scott Eugene J Van | Treatment of ichthyosiform dermatoses |
| US3988470A (en) * | 1974-02-25 | 1976-10-26 | Scott Eugene J Van | Treatment of palmar and plant disturbed keratosis |
| US4158057A (en) * | 1975-03-28 | 1979-06-12 | Stanko Ronald T | Prevention of the accumulation of fatty deposits in the liver |
| US4021572A (en) * | 1975-07-23 | 1977-05-03 | Scott Eugene J Van | Prophylactic and therapeutic treatment of acne vulgaris utilizing lactamides and quaternary ammonium lactates |
| US4197316A (en) * | 1975-07-23 | 1980-04-08 | Scott Eugene J Van | Treatment of dry skin |
| US4234599A (en) * | 1978-10-04 | 1980-11-18 | Scott Eugene J Van | Treatment of skin keratoses with α-hydroxy acids and related compounds |
| US4351835A (en) * | 1981-04-01 | 1982-09-28 | Montefiore Hospital | Method for preventing body fat deposition in mammals |
| US4415576A (en) * | 1981-04-01 | 1983-11-15 | Montefiore Hospital | Method for preventing body fat deposition in mammals |
| US4521375A (en) * | 1982-11-23 | 1985-06-04 | Coopervision, Inc. | Sterilizing treatment with hydrogen peroxide and neutralization of residual amounts thereof |
| DE3302694A1 (en) * | 1983-01-27 | 1984-08-02 | Retheto Filmtechnik Theilemann & Co, 8000 München | ORAL CARE PRODUCTS |
| WO1986000227A1 (en) * | 1984-06-22 | 1986-01-16 | Veech Richard L | Electrolyte solutions and in vivo use thereof |
| US4696917A (en) * | 1985-08-01 | 1987-09-29 | Lindstrom Richard L | Irrigation solution |
| JPS63135370A (en) * | 1986-11-26 | 1988-06-07 | Grelan Pharmaceut Co Ltd | Antiallergic agent |
| IN168530B (en) * | 1987-11-06 | 1991-04-20 | Lyphomed Inc | |
| WO1990000900A1 (en) * | 1988-07-20 | 1990-02-08 | Amgen Inc. | Method of treating inflammatory disorders by reducing phagocyte activation |
| JP2794021B2 (en) * | 1988-11-02 | 1998-09-03 | エーザイ株式会社 | Transdermal preparation containing azelastine or its salts |
| EP0477345A1 (en) * | 1990-03-30 | 1992-04-01 | Amgen Inc. | Respiratory burst suppression factor |
| US5210098A (en) * | 1990-09-21 | 1993-05-11 | Regents Of The University Of Minnesota | Use of pyruvate to treat acute renal failure |
| US5296370A (en) * | 1990-10-04 | 1994-03-22 | Rutgers, The State University | Repair medium for the resuscitation of injured cells |
| US5648380A (en) * | 1991-03-01 | 1997-07-15 | Warner-Lambert Company | Anti-inflammatory wound healing compositions and methods for preparing and using same |
| WO1993016690A1 (en) * | 1992-02-25 | 1993-09-02 | Warner-Lambert Company | Cytoprotective compositions containing pyruvate and antioxidants |
| US5256697A (en) * | 1992-04-16 | 1993-10-26 | Abbott Laboratories | Method of administering pyruvate and methods of synthesizing pyruvate precursors |
| JP3236658B2 (en) * | 1992-04-27 | 2001-12-10 | 花王株式会社 | Bronchodilator |
| US5536751A (en) * | 1994-05-09 | 1996-07-16 | The United States Of America As Represented By The Secretary Of The Army | Pharmaceutical alpha-keto carboxylic acid compositions method of making and use thereof |
-
1996
- 1996-09-06 NZ NZ306832A patent/NZ306832A/en not_active IP Right Cessation
- 1996-09-06 WO PCT/US1996/014304 patent/WO1997010818A1/en active Application Filing
- 1996-09-06 CA CA002205112A patent/CA2205112C/en not_active Expired - Lifetime
- 1996-09-06 AU AU69159/96A patent/AU719332B2/en not_active Ceased
- 1996-09-06 JP JP51274197A patent/JP4459303B2/en not_active Expired - Lifetime
- 1996-09-06 MX MX9703653A patent/MX9703653A/en unknown
- 1996-09-06 EP EP96929932A patent/EP0804181A4/en not_active Withdrawn
- 1996-09-09 IL IL11922596A patent/IL119225A/en not_active IP Right Cessation
- 1996-09-17 ZA ZA967833A patent/ZA967833B/en unknown
- 1996-09-18 TW TW085111379A patent/TW434012B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0804181A1 (en) | 1997-11-05 |
| ZA967833B (en) | 1997-06-02 |
| AU6915996A (en) | 1997-04-09 |
| WO1997010818A1 (en) | 1997-03-27 |
| AU719332B2 (en) | 2000-05-04 |
| IL119225A0 (en) | 1996-12-05 |
| NZ306832A (en) | 2001-04-27 |
| EP0804181A4 (en) | 2005-02-02 |
| JPH10509463A (en) | 1998-09-14 |
| IL119225A (en) | 2000-09-28 |
| CA2205112C (en) | 2008-11-18 |
| TW434012B (en) | 2001-05-16 |
| MX9703653A (en) | 1998-07-31 |
| CA2205112A1 (en) | 1997-03-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20020006961A1 (en) | Method and composition for treating mammalian nasal and sinus diseases caused by inflammatory response | |
| CA2597395C (en) | Method and composition for treating mammalian diseases and injuries caused by the over-expression of peroxynitrite | |
| US5605931A (en) | Protective prostaglandins for use in conjunction with chemotherapeutic agents | |
| US5939459A (en) | Method and composition for treating mammalian disease caused by inflammatory response | |
| JP2005501106A (en) | Methods for treating mammalian lung disease states by altering in vivo native nitric oxide concentrations | |
| JP4459303B2 (en) | Method of treating disease in mammals resulting from inflammatory reaction and composition thereof | |
| EP0614359A1 (en) | Wound healing compositions containing a pyruvate, an antioxidant and a mixture of fatty acids | |
| US7122578B2 (en) | Method and composition for treating mammalian diseases and injuries which cause pain, erythema, swelling, crusting, ischemia scarring and excess white blood cell infiltration | |
| JP2011190274A (en) | Method and composition for treating mammalian nasal and sinus diseases caused by inflammatory response | |
| CZ20021559A3 (en) | Use of dinitrogen dioxide for producing a medicament intended for treating airways constriction | |
| AU674131C (en) | Wound healing compositions containing a pyruvate, an antioxidant and a mixture of fatty acids |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20061031 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20070126 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20070320 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20070616 |
|
| A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20070726 |
|
| A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20071011 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20091229 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20100210 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130219 Year of fee payment: 3 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130219 Year of fee payment: 3 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20140219 Year of fee payment: 4 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| EXPY | Cancellation because of completion of term |