OA19913A - Compositions and methods for the treatment of metabolic conditions. - Google Patents
Compositions and methods for the treatment of metabolic conditions. Download PDFInfo
- Publication number
- OA19913A OA19913A OA1202000192 OA19913A OA 19913 A OA19913 A OA 19913A OA 1202000192 OA1202000192 OA 1202000192 OA 19913 A OA19913 A OA 19913A
- Authority
- OA
- OAPI
- Prior art keywords
- pharmaceutical grade
- buffer solution
- acid
- buffering agent
- subject
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 292
- 230000002503 metabolic Effects 0.000 title claims abstract description 26
- 239000002253 acid Substances 0.000 claims abstract description 249
- 239000006179 pH buffering agent Substances 0.000 claims abstract description 145
- 230000001225 therapeutic Effects 0.000 claims abstract description 68
- 150000007513 acids Chemical class 0.000 claims abstract description 16
- 208000003269 Mitochondrial Disease Diseases 0.000 claims abstract description 9
- 230000000271 cardiovascular Effects 0.000 claims abstract description 9
- 239000007853 buffer solution Substances 0.000 claims description 175
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 87
- 238000001990 intravenous administration Methods 0.000 claims description 72
- 210000004369 Blood Anatomy 0.000 claims description 67
- 239000008280 blood Substances 0.000 claims description 67
- 239000011575 calcium Substances 0.000 claims description 67
- 239000007864 aqueous solution Substances 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 38
- 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 claims description 36
- 201000010099 disease Diseases 0.000 claims description 35
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 30
- 235000013343 vitamin Nutrition 0.000 claims description 29
- 239000011782 vitamin Substances 0.000 claims description 29
- 229930003231 vitamins Natural products 0.000 claims description 29
- 239000011780 sodium chloride Substances 0.000 claims description 25
- 230000001684 chronic Effects 0.000 claims description 23
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 22
- 229910052791 calcium Inorganic materials 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 239000011734 sodium Substances 0.000 claims description 20
- 150000002500 ions Chemical class 0.000 claims description 19
- 206010020772 Hypertension Diseases 0.000 claims description 18
- 102000004877 Insulin Human genes 0.000 claims description 18
- 108090001061 Insulin Proteins 0.000 claims description 18
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Vitamin C Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 18
- 239000003963 antioxidant agent Substances 0.000 claims description 18
- 229960005070 ascorbic acid Drugs 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 18
- 238000001802 infusion Methods 0.000 claims description 18
- 206010021143 Hypoxia Diseases 0.000 claims description 17
- 235000006708 antioxidants Nutrition 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 17
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 17
- 229940029983 VITAMINS Drugs 0.000 claims description 16
- 229940021016 Vitamin IV solution additives Drugs 0.000 claims description 16
- 201000009910 diseases by infectious agent Diseases 0.000 claims description 16
- 230000004060 metabolic process Effects 0.000 claims description 16
- 230000036740 Metabolism Effects 0.000 claims description 15
- 230000002730 additional Effects 0.000 claims description 15
- 239000011668 ascorbic acid Substances 0.000 claims description 15
- 235000010323 ascorbic acid Nutrition 0.000 claims description 15
- 230000035786 metabolism Effects 0.000 claims description 15
- 230000002792 vascular Effects 0.000 claims description 15
- RWSXRVCMGQZWBV-WDSKDSINSA-N Glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims description 14
- 229960003180 Glutathione Drugs 0.000 claims description 14
- 230000003078 antioxidant Effects 0.000 claims description 14
- 239000008103 glucose Substances 0.000 claims description 14
- 241000894007 species Species 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 208000010444 Acidosis Diseases 0.000 claims description 13
- 208000008787 Cardiovascular Disease Diseases 0.000 claims description 13
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 13
- SBJKKFFYIZUCET-JLAZNSOCSA-N Dehydro-L-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(=O)C1=O SBJKKFFYIZUCET-JLAZNSOCSA-N 0.000 claims description 13
- 235000020960 dehydroascorbic acid Nutrition 0.000 claims description 13
- 239000011615 dehydroascorbic acid Substances 0.000 claims description 13
- 239000001301 oxygen Substances 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 13
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims description 13
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 12
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 claims description 12
- 200000000019 wound Diseases 0.000 claims description 12
- 210000001367 Arteries Anatomy 0.000 claims description 11
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 11
- 229910001424 calcium ion Inorganic materials 0.000 claims description 11
- 230000002708 enhancing Effects 0.000 claims description 11
- 108010033024 EC 1.11.1.12 Proteins 0.000 claims description 10
- 102100016553 GPX4 Human genes 0.000 claims description 10
- 102100013241 GSR Human genes 0.000 claims description 10
- 102000017278 Glutaredoxin Human genes 0.000 claims description 10
- 108050005205 Glutaredoxin Proteins 0.000 claims description 10
- 102000006587 Glutathione Peroxidase Human genes 0.000 claims description 10
- 108020004973 Glutathione Peroxidase Proteins 0.000 claims description 10
- 108010063907 Glutathione Reductase Proteins 0.000 claims description 10
- 206010062060 Hyperlipidaemia Diseases 0.000 claims description 10
- 229940094937 Thioredoxin Drugs 0.000 claims description 10
- 108010079911 Thioredoxin-Disulfide Reductase Proteins 0.000 claims description 10
- 102000013090 Thioredoxin-Disulfide Reductase Human genes 0.000 claims description 10
- 229930003448 Vitamin K Natural products 0.000 claims description 10
- 229940046010 Vitamin K Drugs 0.000 claims description 10
- 229940019697 Vitamin K containing hemostatics Drugs 0.000 claims description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 10
- 102000002933 thioredoxin family Human genes 0.000 claims description 10
- 108060008226 thioredoxin family Proteins 0.000 claims description 10
- 235000019168 vitamin K Nutrition 0.000 claims description 10
- 239000011712 vitamin K Substances 0.000 claims description 10
- 150000003721 vitamin K derivatives Chemical class 0.000 claims description 10
- 108010024636 Glutathione Proteins 0.000 claims description 9
- 210000002216 Heart Anatomy 0.000 claims description 9
- DFPAKSUCGFBDDF-UHFFFAOYSA-N nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 229940105657 CATALASE Drugs 0.000 claims description 8
- 206010007554 Cardiac failure Diseases 0.000 claims description 8
- 108010053835 EC 1.11.1.6 Proteins 0.000 claims description 8
- 102000016938 EC 1.11.1.6 Human genes 0.000 claims description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 8
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 7
- 206010056340 Diabetic ulcer Diseases 0.000 claims description 7
- 208000008466 Metabolic Disease Diseases 0.000 claims description 7
- 208000001089 Multiple System Atrophy Diseases 0.000 claims description 7
- 208000005764 Peripheral Arterial Disease Diseases 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 7
- 201000010238 heart disease Diseases 0.000 claims description 7
- PWHULOQIROXLJO-UHFFFAOYSA-N manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims description 7
- 229960003966 nicotinamide Drugs 0.000 claims description 7
- 235000005152 nicotinamide Nutrition 0.000 claims description 7
- 239000011570 nicotinamide Substances 0.000 claims description 7
- 229960002862 pyridoxine Drugs 0.000 claims description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 229960003495 thiamine Drugs 0.000 claims description 7
- 206010019280 Heart failure Diseases 0.000 claims description 6
- 208000009025 Nervous System Disease Diseases 0.000 claims description 6
- 208000008589 Obesity Diseases 0.000 claims description 6
- 201000001320 atherosclerosis Diseases 0.000 claims description 6
- 201000008739 coronary artery disease Diseases 0.000 claims description 6
- 229960002104 cyanocobalamin Drugs 0.000 claims description 6
- 235000000639 cyanocobalamin Nutrition 0.000 claims description 6
- 239000011666 cyanocobalamin Substances 0.000 claims description 6
- 230000002255 enzymatic Effects 0.000 claims description 6
- FVTCRASFADXXNN-SCRDCRAPSA-N flavin mononucleotide Chemical compound OP(=O)(O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O FVTCRASFADXXNN-SCRDCRAPSA-N 0.000 claims description 6
- 235000020824 obesity Nutrition 0.000 claims description 6
- 201000002911 peripheral artery disease Diseases 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 6
- 239000011591 potassium Substances 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- 230000000699 topical Effects 0.000 claims description 6
- 235000019156 vitamin B Nutrition 0.000 claims description 6
- 239000011720 vitamin B Substances 0.000 claims description 6
- 206010003816 Autoimmune disease Diseases 0.000 claims description 5
- ACTIUHUUMQJHFO-UPTCCGCDSA-N Coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 claims description 5
- 208000004981 Coronary Disease Diseases 0.000 claims description 5
- 108010075031 Cytochromes c Proteins 0.000 claims description 5
- 208000002173 Dizziness Diseases 0.000 claims description 5
- 208000001953 Hypotension Diseases 0.000 claims description 5
- 229940053487 Niacinamide Drugs 0.000 claims description 5
- 229960001295 Tocopherol Drugs 0.000 claims description 5
- 239000006172 buffering agent Substances 0.000 claims description 5
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 claims description 5
- 235000017471 coenzyme Q10 Nutrition 0.000 claims description 5
- 229940110767 coenzyme Q10 Drugs 0.000 claims description 5
- 230000003028 elevating Effects 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 230000001590 oxidative Effects 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 5
- 239000000829 suppository Substances 0.000 claims description 5
- 201000010874 syndrome Diseases 0.000 claims description 5
- 235000010384 tocopherol Nutrition 0.000 claims description 5
- 239000011732 tocopherol Substances 0.000 claims description 5
- 229930003799 tocopherols Natural products 0.000 claims description 5
- 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 claims description 5
- 206010002383 Angina pectoris Diseases 0.000 claims description 4
- 108030002458 EC 1.11.1.15 Proteins 0.000 claims description 4
- 102000007456 EC 1.11.1.15 Human genes 0.000 claims description 4
- 208000001083 Kidney Disease Diseases 0.000 claims description 4
- 206010029149 Nephropathy Diseases 0.000 claims description 4
- 206010029151 Nephropathy Diseases 0.000 claims description 4
- 206010029331 Neuropathy peripheral Diseases 0.000 claims description 4
- 206010038932 Retinopathy Diseases 0.000 claims description 4
- 206010038923 Retinopathy Diseases 0.000 claims description 4
- 208000004124 Rheumatic Heart Disease Diseases 0.000 claims description 4
- 102000019197 Superoxide Dismutase Human genes 0.000 claims description 4
- 108010012715 Superoxide Dismutase Proteins 0.000 claims description 4
- 229930003268 Vitamin C Natural products 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 230000004706 cardiovascular dysfunction Effects 0.000 claims description 4
- 201000001084 cerebrovascular disease Diseases 0.000 claims description 4
- 201000009846 fatty liver disease Diseases 0.000 claims description 4
- 230000036997 mental performance Effects 0.000 claims description 4
- 201000001119 neuropathy Diseases 0.000 claims description 4
- 230000036314 physical performance Effects 0.000 claims description 4
- 235000019154 vitamin C Nutrition 0.000 claims description 4
- 239000011718 vitamin C Substances 0.000 claims description 4
- 150000003700 vitamin C derivatives Chemical class 0.000 claims description 4
- CIWBSHSKHKDKBQ-DUZGATOHSA-N (+)-Ascorbic acid Natural products OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-DUZGATOHSA-N 0.000 claims description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 3
- 208000000103 Anorexia Nervosa Diseases 0.000 claims description 3
- 206010060963 Arterial disease Diseases 0.000 claims description 3
- 206010006895 Cachexia Diseases 0.000 claims description 3
- 206010061592 Cardiac fibrillation Diseases 0.000 claims description 3
- 206010062746 Carditis Diseases 0.000 claims description 3
- 206010014665 Endocarditis Diseases 0.000 claims description 3
- 229940012356 Eye Drops Drugs 0.000 claims description 3
- 206010016256 Fatigue Diseases 0.000 claims description 3
- 208000008665 Gastrointestinal Disease Diseases 0.000 claims description 3
- 206010060378 Hyperinsulinaemia Diseases 0.000 claims description 3
- 208000001252 Hyperlipoproteinemias Diseases 0.000 claims description 3
- 206010022562 Intermittent claudication Diseases 0.000 claims description 3
- 239000002211 L-ascorbic acid Substances 0.000 claims description 3
- 235000000069 L-ascorbic acid Nutrition 0.000 claims description 3
- 108090001030 Lipoproteins Proteins 0.000 claims description 3
- 102000004895 Lipoproteins Human genes 0.000 claims description 3
- 206010027599 Migraine Diseases 0.000 claims description 3
- 208000008085 Migraine Disorders Diseases 0.000 claims description 3
- 206010048592 Musculoskeletal disease Diseases 0.000 claims description 3
- 206010053643 Neurodegenerative disease Diseases 0.000 claims description 3
- 206010033557 Palpitations Diseases 0.000 claims description 3
- 208000003782 Raynaud Disease Diseases 0.000 claims description 3
- 206010037912 Raynaud's phenomenon Diseases 0.000 claims description 3
- 208000003734 Supraventricular Tachycardia Diseases 0.000 claims description 3
- 200000000007 arterial disease Diseases 0.000 claims description 3
- 239000007979 citrate buffer Substances 0.000 claims description 3
- 230000002500 effect on skin Effects 0.000 claims description 3
- 239000003889 eye drop Substances 0.000 claims description 3
- 230000002600 fibrillogenic Effects 0.000 claims description 3
- 230000003451 hyperinsulinaemic Effects 0.000 claims description 3
- 201000008980 hyperinsulinism Diseases 0.000 claims description 3
- 230000003188 neurobehavioral Effects 0.000 claims description 3
- 230000002093 peripheral Effects 0.000 claims description 3
- 229910001414 potassium ion Inorganic materials 0.000 claims description 3
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 claims description 3
- 239000011764 pyridoxine hydrochloride Substances 0.000 claims description 3
- 201000005060 thrombophlebitis Diseases 0.000 claims description 3
- 208000002177 Cataract Diseases 0.000 claims description 2
- 229940037179 Potassium Ion Drugs 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 2
- 201000009596 autoimmune hypersensitivity disease Diseases 0.000 claims description 2
- 201000002146 gastrointestinal system disease Diseases 0.000 claims description 2
- 201000001421 hyperglycemia Diseases 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 239000008363 phosphate buffer Substances 0.000 claims description 2
- NPYPAHLBTDXSSS-UHFFFAOYSA-N potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- 241001520820 Joinvillea ascendens Species 0.000 claims 2
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 claims 1
- 206010012601 Diabetes mellitus Diseases 0.000 abstract description 6
- 230000035492 administration Effects 0.000 description 67
- 206010061218 Inflammation Diseases 0.000 description 62
- 230000004054 inflammatory process Effects 0.000 description 62
- 230000004044 response Effects 0.000 description 41
- 210000004027 cells Anatomy 0.000 description 34
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 34
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 27
- 230000001965 increased Effects 0.000 description 27
- 239000003642 reactive oxygen metabolite Substances 0.000 description 27
- 230000003834 intracellular Effects 0.000 description 24
- DKHGMERMDICWDU-GHDNBGIDSA-N menaquinone-4 Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)=C(C)C(=O)C2=C1 DKHGMERMDICWDU-GHDNBGIDSA-N 0.000 description 24
- 235000002639 sodium chloride Nutrition 0.000 description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- 235000019143 vitamin K2 Nutrition 0.000 description 21
- 239000011728 vitamin K2 Substances 0.000 description 21
- 230000002829 reduced Effects 0.000 description 20
- 230000002378 acidificating Effects 0.000 description 19
- 102000004965 antibodies Human genes 0.000 description 18
- 108090001123 antibodies Proteins 0.000 description 18
- 230000000694 effects Effects 0.000 description 18
- -1 hydrogen ions Chemical class 0.000 description 16
- 239000012528 membrane Substances 0.000 description 16
- 229960001456 Adenosine Triphosphate Drugs 0.000 description 15
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 15
- 210000004379 Membranes Anatomy 0.000 description 15
- 210000002381 Plasma Anatomy 0.000 description 13
- 229940088594 Vitamin Drugs 0.000 description 13
- 230000001413 cellular Effects 0.000 description 13
- 239000007924 injection Substances 0.000 description 13
- 238000002347 injection Methods 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- 150000003722 vitamin derivatives Chemical class 0.000 description 13
- 150000002632 lipids Chemical class 0.000 description 12
- 230000024883 vasodilation Effects 0.000 description 12
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-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 12
- 241000124008 Mammalia Species 0.000 description 11
- 239000003792 electrolyte Substances 0.000 description 11
- 230000013632 homeostatic process Effects 0.000 description 11
- 210000003470 Mitochondria Anatomy 0.000 description 10
- 210000003205 Muscles Anatomy 0.000 description 10
- 210000001519 tissues Anatomy 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 9
- 241000283073 Equus caballus Species 0.000 description 8
- 206010022114 Injury Diseases 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000010586 diagram Methods 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 230000002438 mitochondrial Effects 0.000 description 8
- 239000008194 pharmaceutical composition Substances 0.000 description 8
- 230000001737 promoting Effects 0.000 description 8
- 229940035620 ACTH and synthetic analog preparations Drugs 0.000 description 7
- 102000034451 ATPases Human genes 0.000 description 7
- 108091006096 ATPases Proteins 0.000 description 7
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 7
- 210000003722 Extracellular Fluid Anatomy 0.000 description 7
- 241000282412 Homo Species 0.000 description 7
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 230000001146 hypoxic Effects 0.000 description 7
- 206010001897 Alzheimer's disease Diseases 0.000 description 6
- 208000010125 Myocardial Infarction Diseases 0.000 description 6
- 206010035109 Pituitary-dependent Cushing's syndrome Diseases 0.000 description 6
- 206010052428 Wound Diseases 0.000 description 6
- 239000000427 antigen Substances 0.000 description 6
- 102000038129 antigens Human genes 0.000 description 6
- 108091007172 antigens Proteins 0.000 description 6
- 239000000090 biomarker Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000000875 corresponding Effects 0.000 description 6
- 235000005911 diet Nutrition 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- 239000006196 drop Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229940079593 drugs Drugs 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 230000035876 healing Effects 0.000 description 6
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 6
- 230000037361 pathway Effects 0.000 description 6
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 6
- 210000000172 Cytosol Anatomy 0.000 description 5
- 241000283086 Equidae Species 0.000 description 5
- 206010061255 Ischaemia Diseases 0.000 description 5
- 210000004185 Liver Anatomy 0.000 description 5
- 229960005481 Menatetrenone Drugs 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
- 230000001154 acute Effects 0.000 description 5
- 230000033115 angiogenesis Effects 0.000 description 5
- 239000003125 aqueous solvent Substances 0.000 description 5
- 230000017531 blood circulation Effects 0.000 description 5
- 230000002308 calcification Effects 0.000 description 5
- 239000011768 flavin mononucleotide Substances 0.000 description 5
- 230000001976 improved Effects 0.000 description 5
- 239000011159 matrix material Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 235000009491 menaquinone-4 Nutrition 0.000 description 5
- 239000011676 menaquinone-4 Substances 0.000 description 5
- 238000002496 oximetry Methods 0.000 description 5
- 230000001575 pathological Effects 0.000 description 5
- 239000010452 phosphate Substances 0.000 description 5
- 235000019231 riboflavin-5'-phosphate Nutrition 0.000 description 5
- 229910001415 sodium ion Inorganic materials 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000002194 synthesizing Effects 0.000 description 5
- 230000029663 wound healing Effects 0.000 description 5
- 210000000709 Aorta Anatomy 0.000 description 4
- 210000000988 Bone and Bones Anatomy 0.000 description 4
- 210000004556 Brain Anatomy 0.000 description 4
- 108010035532 Collagen Proteins 0.000 description 4
- 102000008186 Collagen Human genes 0.000 description 4
- 229940012952 Fibrinogen Drugs 0.000 description 4
- 108010049003 Fibrinogen Proteins 0.000 description 4
- 102000008946 Fibrinogen Human genes 0.000 description 4
- 229940019698 Fibrinogen containing hemostatics Drugs 0.000 description 4
- 210000002464 Muscle, Smooth, Vascular Anatomy 0.000 description 4
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 4
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 4
- 208000001132 Osteoporosis Diseases 0.000 description 4
- 108009000578 Oxidative Stress Proteins 0.000 description 4
- 210000002824 Peroxisome Anatomy 0.000 description 4
- 239000004228 Riboflavin-5'-Phosphate Substances 0.000 description 4
- 206010047139 Vasoconstriction Diseases 0.000 description 4
- 230000001058 adult Effects 0.000 description 4
- 230000032683 aging Effects 0.000 description 4
- 230000003139 buffering Effects 0.000 description 4
- 159000000007 calcium salts Chemical class 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 description 4
- 230000001925 catabolic Effects 0.000 description 4
- 230000015271 coagulation Effects 0.000 description 4
- 229920001436 collagen Polymers 0.000 description 4
- 229960005188 collagen Drugs 0.000 description 4
- 230000002354 daily Effects 0.000 description 4
- 230000001771 impaired Effects 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 210000004962 mammalian cells Anatomy 0.000 description 4
- 230000036542 oxidative stress Effects 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 235000008160 pyridoxine Nutrition 0.000 description 4
- 239000011677 pyridoxine Substances 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000001629 suppression Effects 0.000 description 4
- 230000000451 tissue damage Effects 0.000 description 4
- 231100000827 tissue damage Toxicity 0.000 description 4
- 230000025033 vasoconstriction Effects 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- 208000006673 Asthma Diseases 0.000 description 3
- 210000004204 Blood Vessels Anatomy 0.000 description 3
- 102100008428 CCL2 Human genes 0.000 description 3
- 102000009193 Caveolins Human genes 0.000 description 3
- 108050000084 Caveolins Proteins 0.000 description 3
- 108010055292 Chemokine CCL2 Proteins 0.000 description 3
- 102000004420 EC 2.7.3.2 Human genes 0.000 description 3
- 108010042126 EC 2.7.3.2 Proteins 0.000 description 3
- 102100010813 EGF Human genes 0.000 description 3
- 101700033006 EGF Proteins 0.000 description 3
- 102000002045 Endothelin Human genes 0.000 description 3
- 108050009340 Endothelin Proteins 0.000 description 3
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N Endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 3
- 229940116977 Epidermal Growth Factor Drugs 0.000 description 3
- KAQKFAOMNZTLHT-VVUHWYTRSA-N Epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 3
- 210000000497 Foam Cells Anatomy 0.000 description 3
- 208000010412 Glaucoma Diseases 0.000 description 3
- 108090000174 Interleukin-10 Proteins 0.000 description 3
- 102000003814 Interleukin-10 Human genes 0.000 description 3
- 108010002350 Interleukin-2 Proteins 0.000 description 3
- 102000000588 Interleukin-2 Human genes 0.000 description 3
- 108090000978 Interleukin-4 Proteins 0.000 description 3
- 102000004388 Interleukin-4 Human genes 0.000 description 3
- 229940028885 Interleukin-4 Drugs 0.000 description 3
- 229940100601 Interleukin-6 Drugs 0.000 description 3
- 102000004889 Interleukin-6 Human genes 0.000 description 3
- 108090001005 Interleukin-6 Proteins 0.000 description 3
- 210000000265 Leukocytes Anatomy 0.000 description 3
- 206010025169 Lyme disease Diseases 0.000 description 3
- 210000002460 Muscle, Smooth Anatomy 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 102000004067 Osteocalcin Human genes 0.000 description 3
- 108090000573 Osteocalcin Proteins 0.000 description 3
- 102100002607 TIMP1 Human genes 0.000 description 3
- 210000001685 Thyroid Gland Anatomy 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- 230000000111 anti-oxidant Effects 0.000 description 3
- 230000003143 atherosclerotic Effects 0.000 description 3
- 230000023555 blood coagulation Effects 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000001447 compensatory Effects 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 230000000378 dietary Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 238000001647 drug administration Methods 0.000 description 3
- 230000004064 dysfunction Effects 0.000 description 3
- 229960001123 epoprostenol Drugs 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 210000002865 immune cell Anatomy 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000006011 modification reaction Methods 0.000 description 3
- 229960003512 nicotinic acid Drugs 0.000 description 3
- 235000001968 nicotinic acid Nutrition 0.000 description 3
- 239000011664 nicotinic acid Substances 0.000 description 3
- 210000000056 organs Anatomy 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 230000004962 physiological condition Effects 0.000 description 3
- 235000017924 poor diet Nutrition 0.000 description 3
- 230000002335 preservative Effects 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000000241 respiratory Effects 0.000 description 3
- 230000000717 retained Effects 0.000 description 3
- 235000020942 vitamer Nutrition 0.000 description 3
- 239000011608 vitamer Substances 0.000 description 3
- UCSJYZPVAKXKNQ-HZYVHMACSA-N 1-[(1S,2R,3R,4S,5R,6R)-3-carbamimidamido-6-{[(2R,3R,4R,5S)-3-{[(2S,3S,4S,5R,6S)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy}-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy}-2,4,5-trihydroxycyclohexyl]guanidine Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- PFRQBZFETXBLTP-RCIYGOBDSA-N 2-[(2E,6E,10E,14E,18E)-3,7,11,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaen-1-yl]-3-methyl-1,4-dihydronaphthalene-1,4-dione Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CC/C=C(C)/CC/C=C(C)/CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)=C(C)C(=O)C2=C1 PFRQBZFETXBLTP-RCIYGOBDSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 2
- 230000002407 ATP formation Effects 0.000 description 2
- 208000009304 Acute Kidney Injury Diseases 0.000 description 2
- 102000011690 Adiponectin Human genes 0.000 description 2
- 108010076365 Adiponectin Proteins 0.000 description 2
- 206010002027 Amyotrophy Diseases 0.000 description 2
- 210000001772 Blood Platelets Anatomy 0.000 description 2
- 241000589969 Borreliella burgdorferi Species 0.000 description 2
- 108010075254 C-Peptide Proteins 0.000 description 2
- 102100012036 CCL23 Human genes 0.000 description 2
- 101700065817 CCL23 Proteins 0.000 description 2
- 102100003729 CD40LG Human genes 0.000 description 2
- 210000004323 Caveolae Anatomy 0.000 description 2
- 206010009802 Coagulopathy Diseases 0.000 description 2
- 229960003624 Creatine Drugs 0.000 description 2
- 102000012192 Cystatin C Human genes 0.000 description 2
- 108010061642 Cystatin C Proteins 0.000 description 2
- 206010012680 Diabetic neuropathy Diseases 0.000 description 2
- 108010024212 E-Selectin Proteins 0.000 description 2
- 206010014418 Electrolyte imbalance Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- BJHIKXHVCXFQLS-UYFOZJQFSA-N Fructose Natural products OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 description 2
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 2
- 108010054147 Hemoglobins Proteins 0.000 description 2
- 102000001554 Hemoglobins Human genes 0.000 description 2
- 108090001007 Interleukin-8 Proteins 0.000 description 2
- 210000003734 Kidney Anatomy 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 206010025135 Lupus erythematosus Diseases 0.000 description 2
- 102100019096 MB Human genes 0.000 description 2
- 210000002540 Macrophages Anatomy 0.000 description 2
- 208000002780 Macular Degeneration Diseases 0.000 description 2
- 102000018697 Membrane Proteins Human genes 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 230000035633 Metabolized Effects 0.000 description 2
- 206010027476 Metastasis Diseases 0.000 description 2
- 208000005264 Motor Neuron Disease Diseases 0.000 description 2
- 206010028003 Motor neurone disease Diseases 0.000 description 2
- 108010062374 Myoglobin Proteins 0.000 description 2
- 101700050622 NOS1 Proteins 0.000 description 2
- 102100002468 NOS1 Human genes 0.000 description 2
- 101700049309 NOS2 Proteins 0.000 description 2
- 102100002496 NOS2 Human genes 0.000 description 2
- 229910003251 Na K Inorganic materials 0.000 description 2
- 210000000440 Neutrophils Anatomy 0.000 description 2
- 206010029400 Nicotinic acid deficiency Diseases 0.000 description 2
- 101710026292 Os02g0104700 Proteins 0.000 description 2
- 102000004316 Oxidoreductases Human genes 0.000 description 2
- 108090000854 Oxidoreductases Proteins 0.000 description 2
- 108010035766 P-Selectin Proteins 0.000 description 2
- 102100010349 PPID Human genes 0.000 description 2
- 101700011177 PPID Proteins 0.000 description 2
- 206010034576 Peripheral ischaemia Diseases 0.000 description 2
- DRBBFCLWYRJSJZ-UHFFFAOYSA-N Phosphocreatine Chemical compound OC(=O)CN(C)C(=N)NP(O)(O)=O DRBBFCLWYRJSJZ-UHFFFAOYSA-N 0.000 description 2
- 206010034960 Photophobia Diseases 0.000 description 2
- 208000001280 Prediabetic State Diseases 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- 210000003324 RBC Anatomy 0.000 description 2
- 206010038436 Renal failure acute Diseases 0.000 description 2
- 239000008156 Ringer's lactate solution Substances 0.000 description 2
- 102100003520 SELE Human genes 0.000 description 2
- 102100003519 SELP Human genes 0.000 description 2
- 206010039580 Scar Diseases 0.000 description 2
- 210000003491 Skin Anatomy 0.000 description 2
- 206010040925 Skin striae Diseases 0.000 description 2
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 210000003462 Veins Anatomy 0.000 description 2
- 206010047654 Vitreous floaters Diseases 0.000 description 2
- 230000001594 aberrant Effects 0.000 description 2
- 230000000758 acidotic Effects 0.000 description 2
- 230000000996 additive Effects 0.000 description 2
- 201000004384 alopecia Diseases 0.000 description 2
- 231100000360 alopecia Toxicity 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 230000001668 ameliorated Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003613 bile acid Substances 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 235000021170 buffet Nutrition 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 229910052804 chromium Inorganic materials 0.000 description 2
- VYZAMTAEIAYCRO-UHFFFAOYSA-N chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 2
- 239000011651 chromium Substances 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- 230000035602 clotting Effects 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 239000006046 creatine Substances 0.000 description 2
- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine zwitterion Chemical compound NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 description 2
- 201000004624 dermatitis Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 238000004868 gas analysis Methods 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 235000011167 hydrochloric acid Nutrition 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 200000000018 inflammatory disease Diseases 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 230000000670 limiting Effects 0.000 description 2
- 239000008176 lyophilized powder Substances 0.000 description 2
- 229960005201 menadione Drugs 0.000 description 2
- 230000037323 metabolic rate Effects 0.000 description 2
- 230000004065 mitochondrial dysfunctions Effects 0.000 description 2
- ZOKXTWBITQBERF-UHFFFAOYSA-N molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 2
- 229910052750 molybdenum Inorganic materials 0.000 description 2
- 239000011733 molybdenum Substances 0.000 description 2
- 201000008895 mood disease Diseases 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 230000001537 neural Effects 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 101700050775 oct-1 Proteins 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000011164 ossification Effects 0.000 description 2
- 210000000963 osteoblast Anatomy 0.000 description 2
- 230000000790 osteoblast Effects 0.000 description 2
- 235000019161 pantothenic acid Nutrition 0.000 description 2
- 239000011713 pantothenic acid Substances 0.000 description 2
- 230000036961 partial Effects 0.000 description 2
- 229950007002 phosphocreatine Drugs 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 230000003389 potentiating Effects 0.000 description 2
- 201000009104 prediabetes syndrome Diseases 0.000 description 2
- 238000002203 pretreatment Methods 0.000 description 2
- 230000002035 prolonged Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 230000000284 resting Effects 0.000 description 2
- 230000000630 rising Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 231100000241 scar Toxicity 0.000 description 2
- 230000037387 scars Effects 0.000 description 2
- 230000000276 sedentary Effects 0.000 description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 230000000087 stabilizing Effects 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002459 sustained Effects 0.000 description 2
- 235000019157 thiamine Nutrition 0.000 description 2
- 239000011721 thiamine Substances 0.000 description 2
- 201000008827 tuberculosis Diseases 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 230000037303 wrinkles Effects 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- AOFUBOWZWQFQJU-SNOJBQEQSA-N (2R,3S,4S,5R)-2,5-bis(hydroxymethyl)oxolane-2,3,4-triol;(2S,3R,4S,5S,6R)-6-(hydroxymethyl)oxane-2,3,4,5-tetrol Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O.OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O AOFUBOWZWQFQJU-SNOJBQEQSA-N 0.000 description 1
- DTHNMHAUYICORS-KTKZVXAJSA-N 107444-51-9 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 1
- MBWXNTAXLNYFJB-NKFFZRIASA-N 2-methyl-3-[(2E,7R,11R)-3,7,11,15-tetramethylhexadec-2-en-1-yl]-1,4-dihydronaphthalene-1,4-dione Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CCC[C@H](C)CCC[C@H](C)CCCC(C)C)=C(C)C(=O)C2=C1 MBWXNTAXLNYFJB-NKFFZRIASA-N 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-M 3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]propanoate Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O GHOKWGTUZJEAQD-ZETCQYMHSA-M 0.000 description 1
- 101710038331 ARHGEF12 Proteins 0.000 description 1
- 208000002223 Abdominal Aortic Aneurysm Diseases 0.000 description 1
- ZSLZBFCDCINBPY-ZSJPKINUSA-N Acetyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-ZSJPKINUSA-N 0.000 description 1
- ZSLZBFCDCINBPY-ZZSFXRQLSA-N Acetyl-CoA Natural products S(C(=O)C)CCNC(=O)CCNC(=O)[C@H](O)C(CO[P@@](=O)(O[P@](=O)(OC[C@@H]1[C@@H](OP(=O)(O)O)[C@H](O)[C@@H](n2c3ncnc(N)c3nc2)O1)O)O)(C)C ZSLZBFCDCINBPY-ZZSFXRQLSA-N 0.000 description 1
- 210000004100 Adrenal Glands Anatomy 0.000 description 1
- 208000005223 Alkalosis Diseases 0.000 description 1
- 206010002368 Anger Diseases 0.000 description 1
- 208000007474 Aortic Aneurysm Diseases 0.000 description 1
- 102000005666 Apolipoprotein A-I Human genes 0.000 description 1
- 108010059886 Apolipoprotein A-I Proteins 0.000 description 1
- 102000009081 Apolipoprotein A-II Human genes 0.000 description 1
- 108010087614 Apolipoprotein A-II Proteins 0.000 description 1
- 108010024284 Apolipoprotein C-II Proteins 0.000 description 1
- 108010056301 Apolipoprotein C-III Proteins 0.000 description 1
- 102000030703 Apolipoprotein C-III Human genes 0.000 description 1
- 206010059512 Apoptosis Diseases 0.000 description 1
- 102000004452 Arginases Human genes 0.000 description 1
- 108020001204 Arginases Proteins 0.000 description 1
- 206010003119 Arrhythmia Diseases 0.000 description 1
- 206010003178 Arterial thrombosis Diseases 0.000 description 1
- 206010003549 Asthenia Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 210000002469 Basement Membrane Anatomy 0.000 description 1
- 108010081589 Becaplermin Proteins 0.000 description 1
- 230000036912 Bioavailability Effects 0.000 description 1
- 206010004938 Bipolar disease Diseases 0.000 description 1
- 230000035639 Blood Levels Effects 0.000 description 1
- 230000037227 Blood Loss Effects 0.000 description 1
- 206010061590 Blood disease Diseases 0.000 description 1
- 210000001218 Blood-Brain Barrier Anatomy 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 210000001185 Bone Marrow Anatomy 0.000 description 1
- 241000589968 Borrelia Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000001183 Brain Injury Diseases 0.000 description 1
- 102000004219 Brain-Derived Neurotrophic Factor Human genes 0.000 description 1
- 108090000715 Brain-Derived Neurotrophic Factor Proteins 0.000 description 1
- 102000025380 C-Reactive Protein Human genes 0.000 description 1
- 108010074051 C-Reactive Protein Proteins 0.000 description 1
- 102100019485 CCL13 Human genes 0.000 description 1
- 101700034979 CCL13 Proteins 0.000 description 1
- 102100016449 CCL5 Human genes 0.000 description 1
- 102100016451 CCL8 Human genes 0.000 description 1
- 101700045693 CCL8 Proteins 0.000 description 1
- 101710040446 CD40 Proteins 0.000 description 1
- 102100013137 CD40 Human genes 0.000 description 1
- 108010029697 CD40 Ligand Proteins 0.000 description 1
- 101710003804 CD40LG Proteins 0.000 description 1
- 102100005992 CPB2 Human genes 0.000 description 1
- 101700012665 CPB2 Proteins 0.000 description 1
- 102100015724 CRP Human genes 0.000 description 1
- 102100005176 CSF1 Human genes 0.000 description 1
- 102000014823 Calbindins Human genes 0.000 description 1
- 108060001061 Calbindins Proteins 0.000 description 1
- 208000004434 Calcinosis Diseases 0.000 description 1
- 102000005701 Calcium-Binding Proteins Human genes 0.000 description 1
- 108010045403 Calcium-Binding Proteins Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- UHBYWPGGCSDKFX-UHFFFAOYSA-N Carboxyglutamic acid Chemical compound OC(=O)C(N)CC(C(O)=O)C(O)=O UHBYWPGGCSDKFX-UHFFFAOYSA-N 0.000 description 1
- 206010007270 Carcinoid syndrome Diseases 0.000 description 1
- 206010007521 Cardiac arrhythmias Diseases 0.000 description 1
- 206010007541 Cardiac disease Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 210000000170 Cell Membrane Anatomy 0.000 description 1
- 210000003169 Central Nervous System Anatomy 0.000 description 1
- 210000001638 Cerebellum Anatomy 0.000 description 1
- 108010055166 Chemokine CCL5 Proteins 0.000 description 1
- 206010008570 Chloasma Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 206010008874 Chronic fatigue syndrome Diseases 0.000 description 1
- 206010057668 Cognitive disease Diseases 0.000 description 1
- 210000002808 Connective Tissue Anatomy 0.000 description 1
- JYGXADMDTFJGBT-VWUMJDOOSA-N Cortisol Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 1
- QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 description 1
- 208000008960 Diabetic Foot Diseases 0.000 description 1
- 208000007342 Diabetic Nephropathy Diseases 0.000 description 1
- 208000001636 Diabetic Neuropathy Diseases 0.000 description 1
- 206010061835 Diabetic nephropathy Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 102000014469 EC 4.6.1.2 Human genes 0.000 description 1
- 108010078321 EC 4.6.1.2 Proteins 0.000 description 1
- 229940047652 Ear Drops Drugs 0.000 description 1
- 208000005679 Eczema Diseases 0.000 description 1
- 230000035695 Efflux Effects 0.000 description 1
- 230000035538 Efflux Rate Effects 0.000 description 1
- 208000002197 Ehlers-Danlos Syndrome Diseases 0.000 description 1
- 241000605314 Ehrlichia Species 0.000 description 1
- 241000605312 Ehrlichia canis Species 0.000 description 1
- 229940088598 Enzyme Drugs 0.000 description 1
- 229960002061 Ergocalciferol Drugs 0.000 description 1
- 210000003414 Extremities Anatomy 0.000 description 1
- 102100009906 F7 Human genes 0.000 description 1
- 101700045735 FABP3 Proteins 0.000 description 1
- 102100007651 FABP3 Human genes 0.000 description 1
- 101700086436 FCN3 Proteins 0.000 description 1
- 102100007698 FCN3 Human genes 0.000 description 1
- 229950003499 FIBRIN Drugs 0.000 description 1
- 102100011941 FMO5 Human genes 0.000 description 1
- 101700054986 FMO5 Proteins 0.000 description 1
- 108010023321 Factor VII Proteins 0.000 description 1
- 108010014173 Factor X Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 229940013640 Flavin Mononucleotide Drugs 0.000 description 1
- 229940093632 Flavin-Adenine Dinucleotide Drugs 0.000 description 1
- 206010017374 Friedreich's ataxia Diseases 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 101710042131 GCG Proteins 0.000 description 1
- 102100003273 GDF15 Human genes 0.000 description 1
- 101700071595 GRZ1 Proteins 0.000 description 1
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 1
- 206010018048 Gaucher's disease Diseases 0.000 description 1
- 102000037828 Glucose transporter family Human genes 0.000 description 1
- 108091006272 Glucose transporter family Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 240000007842 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 108010041834 Growth Differentiation Factor 15 Proteins 0.000 description 1
- 208000005721 HIV Infections Diseases 0.000 description 1
- 101700028041 HOC1 Proteins 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 206010018987 Haemorrhage Diseases 0.000 description 1
- 208000002672 Hepatitis B Diseases 0.000 description 1
- 229940088597 Hormone Drugs 0.000 description 1
- 201000001971 Huntington's disease Diseases 0.000 description 1
- 208000006575 Hypertriglyceridemia Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 208000007646 Hypoprothrombinemias Diseases 0.000 description 1
- 101700086956 IFNG Proteins 0.000 description 1
- 102100016020 IFNG Human genes 0.000 description 1
- 102100018955 IL1A Human genes 0.000 description 1
- 208000000509 Infertility Diseases 0.000 description 1
- 102000003777 Interleukin-1 beta Human genes 0.000 description 1
- 108090000193 Interleukin-1 beta Proteins 0.000 description 1
- 229940076144 Interleukin-10 Drugs 0.000 description 1
- 102000014158 Interleukin-12 Subunit p40 Human genes 0.000 description 1
- 108010011429 Interleukin-12 Subunit p40 Proteins 0.000 description 1
- 102000013691 Interleukin-17 Human genes 0.000 description 1
- 108050003558 Interleukin-17 family Proteins 0.000 description 1
- 108010082786 Interleukin-1alpha Proteins 0.000 description 1
- 108010065637 Interleukin-23 Proteins 0.000 description 1
- 102000013264 Interleukin-23 Human genes 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- 208000007906 Intestinal Disease Diseases 0.000 description 1
- 210000002977 Intracellular Fluid Anatomy 0.000 description 1
- 210000004731 Jugular Veins Anatomy 0.000 description 1
- 201000007313 Kawasaki disease Diseases 0.000 description 1
- 208000002260 Keloid Diseases 0.000 description 1
- 210000001117 Keloid Anatomy 0.000 description 1
- 102000016551 L-Selectin Human genes 0.000 description 1
- 108010092694 L-Selectin Proteins 0.000 description 1
- XUIIKFGFIJCVMT-LBPRGKRZSA-N L-thyroxine zwitterion Chemical compound IC1=CC(C[C@H]([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-LBPRGKRZSA-N 0.000 description 1
- 102100001083 LPA Human genes 0.000 description 1
- 101700086454 LPA Proteins 0.000 description 1
- 206010049694 Left ventricular dysfunction Diseases 0.000 description 1
- 208000005230 Leg Ulcer Diseases 0.000 description 1
- 210000004072 Lung Anatomy 0.000 description 1
- 102000004083 Lymphotoxin-alpha Human genes 0.000 description 1
- 108090000542 Lymphotoxin-alpha Proteins 0.000 description 1
- 210000003712 Lysosomes Anatomy 0.000 description 1
- 210000004322 M2 macrophage Anatomy 0.000 description 1
- AEUKDPKXTPNBNY-XEYRWQBLSA-N MCP 2 Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)C1=CC=CC=C1 AEUKDPKXTPNBNY-XEYRWQBLSA-N 0.000 description 1
- 102100014893 MMP3 Human genes 0.000 description 1
- 101700040359 MMP3 Proteins 0.000 description 1
- 102100006844 MMP9 Human genes 0.000 description 1
- 101700067851 MMP9 Proteins 0.000 description 1
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 206010025476 Malabsorption Diseases 0.000 description 1
- 206010027417 Metabolic acidosis Diseases 0.000 description 1
- 229960003105 Metformin Drugs 0.000 description 1
- 210000000274 Microglia Anatomy 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M Monopotassium phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 210000000214 Mouth Anatomy 0.000 description 1
- 208000001725 Mucocutaneous Lymph Node Syndrome Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000003627 Muscular Dystrophy Diseases 0.000 description 1
- 102000003896 Myeloperoxidases Human genes 0.000 description 1
- 108090000235 Myeloperoxidases Proteins 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 210000000329 Myocytes, Smooth Muscle Anatomy 0.000 description 1
- 101710042084 NAP1L4 Proteins 0.000 description 1
- 102100011908 NRCAM Human genes 0.000 description 1
- 101700048788 NRCAM Proteins 0.000 description 1
- 206010029305 Neurological disorder Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- BAWFJGJZGIEFAR-NNYOXOHSSA-N Nicotinamide adenine dinucleotide 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](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 description 1
- 210000003463 Organelles Anatomy 0.000 description 1
- 241000283898 Ovis Species 0.000 description 1
- 101710043203 P23p89 Proteins 0.000 description 1
- 102100012897 PGF Human genes 0.000 description 1
- 101710014083 PGF Proteins 0.000 description 1
- 101700019061 POSTN Proteins 0.000 description 1
- 102100013748 POSTN Human genes 0.000 description 1
- 102100009687 PPBP Human genes 0.000 description 1
- 101710030036 PPBP Proteins 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 229940055726 Pantothenic Acid Drugs 0.000 description 1
- 206010061536 Parkinson's disease Diseases 0.000 description 1
- 208000002141 Pellagra Diseases 0.000 description 1
- 206010062585 Peripheral arterial occlusive disease Diseases 0.000 description 1
- 206010034674 Peritonitis Diseases 0.000 description 1
- MBWXNTAXLNYFJB-ODDKJFTJSA-N Phylloquinone Natural products C1=CC=C2C(=O)C(C\C=C(C)/CCC[C@H](C)CCC[C@H](C)CCCC(C)C)=C(C)C(=O)C2=C1 MBWXNTAXLNYFJB-ODDKJFTJSA-N 0.000 description 1
- 229960001898 Phytomenadione Drugs 0.000 description 1
- 206010062080 Pigmentation disease Diseases 0.000 description 1
- 208000002744 Pituitary Disease Diseases 0.000 description 1
- 229940012957 Plasmin Drugs 0.000 description 1
- 102000012335 Plasminogen Activator Inhibitor 1 Human genes 0.000 description 1
- 108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 description 1
- 206010057041 Poikiloderma Diseases 0.000 description 1
- 229920000265 Polyparaphenylene Polymers 0.000 description 1
- 206010036229 Post inflammatory pigmentation change Diseases 0.000 description 1
- 208000002787 Pregnancy Complications Diseases 0.000 description 1
- 108010076181 Proinsulin Proteins 0.000 description 1
- 208000008425 Protein Deficiency Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 210000001147 Pulmonary Artery Anatomy 0.000 description 1
- 206010037867 Rash macular Diseases 0.000 description 1
- 206010038428 Renal disease Diseases 0.000 description 1
- 206010038444 Renal failure chronic Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 102000007156 Resistin Human genes 0.000 description 1
- 108010047909 Resistin Proteins 0.000 description 1
- 206010039020 Rhabdomyolysis Diseases 0.000 description 1
- 229960002477 Riboflavin Drugs 0.000 description 1
- 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 1
- AUNGANRZJHBGPY-OUCADQQQSA-N Riboflavin Natural products OC[C@@H](O)[C@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-OUCADQQQSA-N 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- 241001303601 Rosacea Species 0.000 description 1
- 102100003386 S100A12 Human genes 0.000 description 1
- 108010008458 S100A12 Protein Proteins 0.000 description 1
- 102100007444 SERPINF1 Human genes 0.000 description 1
- 101710039390 SERPINF1 Proteins 0.000 description 1
- 102100014750 SHBG Human genes 0.000 description 1
- 101700040907 SHBG Proteins 0.000 description 1
- 102100007381 SORT1 Human genes 0.000 description 1
- 229940055619 Selenocysteine Drugs 0.000 description 1
- ZKZBPNGNEQAJSX-REOHCLBHSA-N Selenocysteine Chemical compound [SeH]C[C@H](N)C(O)=O ZKZBPNGNEQAJSX-REOHCLBHSA-N 0.000 description 1
- FDKWRPBBCBCIGA-UWTATZPHSA-N Selenocysteine Natural products [Se]C[C@@H](N)C(O)=O FDKWRPBBCBCIGA-UWTATZPHSA-N 0.000 description 1
- 208000006641 Skin Disease Diseases 0.000 description 1
- 206010040829 Skin discolouration Diseases 0.000 description 1
- 210000000278 Spinal Cord Anatomy 0.000 description 1
- 210000000952 Spleen Anatomy 0.000 description 1
- 229960005322 Streptomycin Drugs 0.000 description 1
- 102000008221 Superoxide Dismutase-1 Human genes 0.000 description 1
- 108010021188 Superoxide Dismutase-1 Proteins 0.000 description 1
- 101710038524 TNFRSF1B Proteins 0.000 description 1
- 102100003105 TNFRSF1B Human genes 0.000 description 1
- 206010043709 Thyroid disease Diseases 0.000 description 1
- 229940034208 Thyroxine Drugs 0.000 description 1
- 108010031374 Tissue Inhibitor of Metalloproteinase-1 Proteins 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 210000001585 Trabecular Meshwork Anatomy 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 102000013394 Troponin I Human genes 0.000 description 1
- 108010065729 Troponin I Proteins 0.000 description 1
- 108009000571 Tryptophan metabolism Proteins 0.000 description 1
- 108010001801 Tumor Necrosis Factor-alpha Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- 230000036462 Unbound Effects 0.000 description 1
- 102100009661 VTN Human genes 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 208000001756 Virus Disease Diseases 0.000 description 1
- 229940046008 Vitamin D Drugs 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- 206010047634 Vitamin K deficiency Diseases 0.000 description 1
- 206010047642 Vitiligo Diseases 0.000 description 1
- 108010031318 Vitronectin Proteins 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 102100005236 ZGLP1 Human genes 0.000 description 1
- 101700078733 ZGLP1 Proteins 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- ZKJOXOJMGXFSPF-QYZPTAICSA-N [[(2R,3R,4R,5R)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2R,3S,4R,5R)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate;hydrate Chemical compound O.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 ZKJOXOJMGXFSPF-QYZPTAICSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000035508 accumulation Effects 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000002340 alkalosis Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229920002892 amber Polymers 0.000 description 1
- 230000001195 anabolic Effects 0.000 description 1
- 230000003444 anaesthetic Effects 0.000 description 1
- 230000000049 anti-anxiety Effects 0.000 description 1
- 230000000844 anti-bacterial Effects 0.000 description 1
- 230000002429 anti-coagulation Effects 0.000 description 1
- 230000002605 anti-dotal Effects 0.000 description 1
- 230000003110 anti-inflammatory Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 230000000386 athletic Effects 0.000 description 1
- 230000003416 augmentation Effects 0.000 description 1
- 201000007185 autism spectrum disease Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000035514 bioavailability Effects 0.000 description 1
- 231100000319 bleeding Toxicity 0.000 description 1
- 230000000740 bleeding Effects 0.000 description 1
- 231100001015 blood dyscrasias Toxicity 0.000 description 1
- 201000002393 blood protein disease Diseases 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000018678 bone mineralization Effects 0.000 description 1
- 231100000874 brain damage Toxicity 0.000 description 1
- 210000003008 brain-resident macrophage Anatomy 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N cAMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L cacl2 Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229960002079 calcium pantothenate Drugs 0.000 description 1
- 230000003185 calcium uptake Effects 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2S)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- 230000001914 calming Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000035569 catabolism Effects 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 235000013351 cheese Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 201000000522 chronic kidney disease Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000001010 compromised Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000005824 corn Nutrition 0.000 description 1
- 230000002498 deadly Effects 0.000 description 1
- 230000003247 decreasing Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 231100000406 dermatitis Toxicity 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 239000008356 dextrose and sodium chloride injection Substances 0.000 description 1
- 239000008355 dextrose injection Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000008286 diarrhea Diseases 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 235000018823 dietary intake Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003221 ear drop Substances 0.000 description 1
- 235000006694 eating habits Nutrition 0.000 description 1
- 231100001003 eczema Toxicity 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940012413 factor VII Drugs 0.000 description 1
- 229940012426 factor X Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 230000004129 fatty acid metabolism Effects 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 235000019162 flavin adenine dinucleotide Nutrition 0.000 description 1
- 239000011714 flavin adenine dinucleotide Substances 0.000 description 1
- VWWQXMAJTJZDQX-UYBVJOGSSA-N flavin adenine dinucleotide Chemical compound C1=NC2=C(N)N=CN=C2N1[C@@H]([C@H](O)[C@@H]1O)O[C@@H]1CO[P@](O)(=O)O[P@@](O)(=O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C2=NC(=O)NC(=O)C2=NC2=C1C=C(C)C(C)=C2 VWWQXMAJTJZDQX-UYBVJOGSSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000004110 gluconeogenesis Effects 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-L glutamate group Chemical group N[C@@H](CCC(=O)[O-])C(=O)[O-] WHUUTDBJXJRKMK-VKHMYHEASA-L 0.000 description 1
- 235000021384 green leafy vegetables Nutrition 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 201000002138 hematopoietic system disease Diseases 0.000 description 1
- 230000002949 hemolytic Effects 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- 210000001981 hip bone Anatomy 0.000 description 1
- 230000003284 homeostatic Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 201000001820 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 230000000260 hypercholesteremic Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 230000002757 inflammatory Effects 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000037041 intracellular level Effects 0.000 description 1
- 230000012105 intracellular pH reduction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000002642 intravenous therapy Methods 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000012464 large buffer Substances 0.000 description 1
- 229950008325 levothyroxine Drugs 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 230000013190 lipid storage Effects 0.000 description 1
- 230000004130 lipolysis Effects 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 238000011068 load Methods 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 230000035168 lymphangiogenesis Effects 0.000 description 1
- 230000001868 lysosomic Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated Effects 0.000 description 1
- 230000003340 mental Effects 0.000 description 1
- 230000004066 metabolic change Effects 0.000 description 1
- 230000003818 metabolic dysfunction Effects 0.000 description 1
- 230000035511 metabolization Effects 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 238000007837 multiplex assay Methods 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- 230000004220 muscle function Effects 0.000 description 1
- 201000006938 muscular dystrophy Diseases 0.000 description 1
- 230000002107 myocardial Effects 0.000 description 1
- 201000002481 myositis Diseases 0.000 description 1
- 229950006238 nadide Drugs 0.000 description 1
- 230000002887 neurotoxic Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 230000005064 nitric oxide mediated signal transduction Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000000414 obstructive Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- 230000001009 osteoporotic Effects 0.000 description 1
- 230000033116 oxidation-reduction process Effects 0.000 description 1
- 108010071584 oxidized low density lipoprotein Proteins 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N pantothenic acid Natural products OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000007981 phosphate-citrate buffer Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 235000019175 phylloquinone Nutrition 0.000 description 1
- 239000011772 phylloquinone Substances 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 230000000896 plasminic Effects 0.000 description 1
- 229920003255 poly(phenylsilsesquioxane) Polymers 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 230000003244 pro-oxidative Effects 0.000 description 1
- 230000000750 progressive Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 201000004681 psoriasis Diseases 0.000 description 1
- 230000002685 pulmonary Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 230000003014 reinforcing Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000035812 respiration Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 229950001574 riboflavin phosphate Drugs 0.000 description 1
- 201000004700 rosacea Diseases 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 235000016491 selenocysteine Nutrition 0.000 description 1
- 230000025185 skeletal muscle atrophy Effects 0.000 description 1
- 230000025175 skeletal muscle hypertrophy Effects 0.000 description 1
- 230000001340 slower Effects 0.000 description 1
- 230000000391 smoking Effects 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 108010014657 sortilin Proteins 0.000 description 1
- 230000003595 spectral Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 230000004936 stimulating Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002889 sympathetic Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- XVTUQDWPJJBEHJ-KZCWQMDCSA-N tetrastearoyl cardiolipin Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCCCC)CO[P@@](O)(=O)OCC(O)CO[P@](O)(=O)OC[C@H](OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC XVTUQDWPJJBEHJ-KZCWQMDCSA-N 0.000 description 1
- 200000000020 tissue injury Diseases 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000005891 transamination reaction Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000000472 traumatic Effects 0.000 description 1
- 201000011528 vascular disease Diseases 0.000 description 1
- 230000003639 vasoconstrictive Effects 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 235000001892 vitamin D2 Nutrition 0.000 description 1
- 239000011653 vitamin D2 Substances 0.000 description 1
- 201000000839 vitamin K deficiency bleeding Diseases 0.000 description 1
- 230000003442 weekly Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Abstract
The present invention relates to stable therapeutic compositions of pharmaceutical grade acids and pH buffering agents. The present invention also is directed to methods of treatment for mitochondrial disorders, metabolic conditions, diabetic conditions, and cardiovascular conditions, by administration of compositions of the present disclosure.
Description
FIELD OF THE INVENTION
The présent invention relates to stable therapeutic compositions comprising pharmaceutical grade acids and pH buffering agents. The présent invention also is directed to methods of treatment; for conditions and disorders characterized by mitochondrial dysfonction, metabolic conditions, diabetic conditions, cardiovascular conditions, and bone and tissue modeling dysfonction, comprising administration of compositions of the présent 10 disclosure.
BACKGROUND OF THE INVENTION
Homeostasis is the ability of an organisai to maintain a condition of equilibrium or stability within its internai environment, particularly when faced with external changes. Some examples of homeostatically-controlled Systems in humans include the régulation of a 15 constant body température, blood glucose levels, and extracellular ionic species concentrations. Acid-base homeostasis relates to the proper balance of acids and bases in extracellular fluids, i.e., the pH of the extracellular fluid. In humans, the pH of plasma is approximately 7.4, and is tightly maintained around that value by three interconnected control Systems: 1) buffering(agents, including bicarbonate, phosphate, and proteins, 2) the respiratory system, which impacts the partial pressure of carbon dioxide in blood plasma, and 3) the rénal system, which excretes waste acids and bases. Acid homeostasis is also influenced by metabolic load, which serves as a primary source of acid in the body. For instance, a high glucqse diet can increase total acid burden from metabolic sources, to place a bigger burden on acid homeostasis control mechanisms.
Inefficiencies in these control Systems and factors, which increase acid, such as from metabolic sources, may gradually resuit in unstable internai environments that increase the risk of illness, or exacerbate existing conditions. These inefficiencies may be caused by natural aging processes or may be self-inflicted through various lifestyle choices. For example, a high-glucose diet and a sedentary lifestyle can lead, over time, to the development 30 of insulin insensitivity and type 2 diabètes. Diabètes is associated with other conditions such as obesity, hypertension, hyperlipidemia, fatty liver disease, nephropathy, neuropathy, rénal faiiure, retinopathy, diabetic ulcer, cataracte, insulin résistance syndrome, cacbexia, diabetic foot ulcers and diabetic leg ulcers.
Cardiovascular diseases may also be caused by a poor diet and sedentaiy lifestyle, and include coronary heart disease (heart attacks), cerebrovascular disease, raised blood pressure (hypertension), peripheral artery disease, rheumatic heart disease, congénital heart disease and heart failure. Such dysfunctional conditions of the heart, arteries, and veins impair the supply of oxygen to vital life-sustaining organs, including the brain and the heart itself.
Heart attacks and strokes are mainly caused by a blockage in the inner walls of the blood vessels that prevents blood from flowing to the heart or the brain. Arteriosclerosis (also called athéroscléroses) is a condition involving excess buildup of fat or plaque deposits, respectively, that cause narrowing of the veins that supply oxygenated blood to the tissues. In arteries serving the heart for instance, this may lead to ischémie heart disease, an obstruction of blood flow to the heart. Excess fat or plaque buildup may also cause high blood pressure (hypertension), a disease known as “The Silent Killer” because the first warning sign is an angina attack, a deadly heart attack or a stroke. Kidney disorders, obesity, diabètes, smoking, excess alcohol, stress, and thyroid and adrenal gland problems can also exacerbate a high blood pressure condition.
These conditions and many others are brought on by inefficient, ineffective, or overstressed homeostatic processes. Over time, the resulting imbalances cause damage at the cellular and intracellular level. Often the mechanisms for cellular repair are so compromised that the cells cannot recover, or the mechanisms that cause the damage simply overwhelm the cell. The clinical significance of the damage generated in living cells is manifested in a diseased cell, or symptoms of an underlying condition. It would be bénéficiai to develop methods to facilitate the inhibition of cellular damage or boost recovery. The presently disclosed subject matter addresses, in whole or in part, these and other needs in the art. SUMMARY OF THE INVENTION '
It is therefore an object of the invention to provide solutions to the aforementioned needs.
To this end, the présent disclosure provides a stable therapeutic composition formulated for intravenous administration to a subject, comprising an intravenous buffer solution, comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution, wherein the concentration of the pharmaceutical grade) acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmolL to 3000 mmolL when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
In some embbdiments, the pharmaceutical grade acid is hydrochloric acid, ascorbic acid, acetic acid, (other physiologically acceptable acids), or a combination thereof. In some embodiments, the at least one pH buffering agent is sodium bicarbonate, a phosphate, organic acid, organic amine, ammonia. citrate buffer, a synthetic buffer creatîng spécifie alkaline conditions (e.g.,, tris-hydroxymethyl amino methane), (other physiologically acceptable buffets), or a combination thereof.
In some embodiments, the composition further comprises one or more ingrédients selected from the group consisting of vitamins, salts, acids, amino acids or salts thereof, and stabilized oxidative species. In some embodiments, the composition further comprises ascorbic acid. In some embodiments, the composition comprises dehydroascorbic acid In some embodiments, the composition comprises other recognized antioxidant defense compounds, including nonenzymatic compounds, such as tocopherol (aTCP), coenzyme Q10 (Q), cytochrome c (C) and glutathione (GSH), and enzymatic components including manganèse superoxide dismutase (MnSOD), catalase (Cat), glutathione peroxidase (GPX), phospholipid hydroperoxide glutathione peroxidase (PGPX), glutathione reductase (GR); peroxiredoxins ( PRX3 5), glutaredoxin (GRX2), thioredoxin (TRX2) and thioredoxin reductase (TRXR2). In some embodiments, the composition further comprises one or more of a sodium sait, a magnésium sait, a potassium sait, and a calcium sait. In some embodiments, the composition further comprises one or more of a B vitamin, vitamin C, and vitamin K.
In some embodiments, the composition is formulated in hypotonie, isotonie, or hypertonie form. In some embodiments, the composition is formuljated for intravenous, bolus, dermal, oral, otic, suppository, buccal, ocular, or inhalation delivery. In some embodiments, the composition is formulated as a topical liquid, gel, or paste. In some embodiments, the composition is formulated for ocular administration in the form of eye drops. In some embodiments, the composition is lyophilized or firozen. In some embodiments, the composition is stored in a spectral-blocking vial. In some embodiments, the composition is formed by combining components from two or more vials.
In another aspect, the présent disclosure provides a stable therapeutic composition formulated for intravenous administration to a subject comprising pharmaceutical grade 900 ± 90 mg of L-Ascorbic Acid; 63.33 ± 6.33 mg Thiamine HCl; 808 ± 80.8 mg of Magnésium Sulfate; 1.93 ± .193 mg ofCyanocobalamin: 119- 11.9 mg ofNiacinamide; 119± 11.9 mg of Pyridoxine HCl; 2.53 ± .253 mg of Riboflavin 5’Phosphate; 2.93 ± .293 mg of Calcium DPantothenate; 840 ± 84 mg of Sodium Bicarbonate; 4.5 ± .45 mM of HCl; and water in an amount to obtain a final composition volume of 20 mL. In one embodiment of the invention, the composition further comprises 100 ± 10 mg of dehydroascorbic acid.
In another aspect, the présent disclosure provides a method of treating or ameliorating acidosis in a subject, the method comprising administering to the subject a stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol L to 3000 mmol L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
In yet another aspect, the présent disclosure provides a method of treating or ameliorating base excess in a subject, the method comprising administering to the subject a stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total ! titratable acid content of from 60 mmol/L to 3000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
In yet another aspect, the présent disclosure provides a method of elevating blood oxygen in a subject, the method comprising administering to the subject a stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical gradé acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7. In one i
.5 embodiment of the invention, the method comprises elevating the pO: in the venons blood in a subject.
In still a further aspect, the présent disclosure provides a method of treating or ameliorating a mitochondrial disorder, metabolic disorder, a condition associated with diabètes or a cardiovascular dysfonction in a subject in need thereof, the method comprising administering to the subject a stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufïicient to provide a total titratable acid content of from 60 mmol/L to 3000 mmpl/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
In some embodiments, the metabolic disorder is diabètes, insulin résistance, glucose intolérance, hyperglyçemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia. In some embodiments, the condition associated with diabètes is hypertension, hyperlipidemia, fatty liver disease, nephropathy, neuropathy, rénal failure, retinopathy, diabetic ulcer, cataracts, insulin résistance syndromes and cachexia. In some embodiments, the cardiovascular dysfonction is coronary heart disease, cerebrovascular disease, hypertension, peripheral artery disease, occlusive arterial disease, angina, rheumatic heart disease, congénital heart disease, heart failure, cardiac insuffleiency, palpitations, supraventricular tachycardia, fibrillation, faintness, dizziness, fatigue, migraine, high levels of total blood cholestérol and/or LDL cholestérol, low level of HDL cholestérol, high level of lipoprotein, infections of the heart such as carditis and endocarditis, diabetic ulcer, thrombophlebitis, Raynaud’s disease, anorexia nervosa, claudication, gangrené, atherosclerosis and peripheral artery disease. In some embodiments, the mitochondrial disorder is a neurodegenerative disorder, a cardiovascular disease, a metabolic syndrome, an autoimmune disease, a neurobehavioral or psychiatrie disease, a gastrointestinal disorder, a fatiguing illness, a chronic musculoskeletal disease, or a chronic infection. In some embodiments, the ocular condition is glaucoma, macular degeneration, eye floaters, ocular lens stiffening, or light sensitivity.
In some embodiments, the composition further comprises dehydroascorbic acid. In some embodiments, the composition further comprises one or more of a magnésium ion source, a potassium ion source, and a calcium ion source. In some embodiments, the composition further qomprises one or more of a B vitamin, vitamin C, and vitamin K. In some embodiments, the composition further comprises other recognized antioxidant defense compounds including nonenzymatic compounds such as tocopherol (aTCP), coenzyme Q10 (Q), cytochrome c (C ) and glutathione (GSH). and enzymatic components including manganèse superoxi^e dismutase (MnSOD), catalase (Cat), glutathione peroxidase (GPX), phospholipid hydroperoxide glutathione peroxidase (PGPX). glutathione reductase (GR); peroxiredoxins (PRX3/5), glutaredoxin (GRX2), thioredoxin (TRX2) and thioredoxin reductase (TRXR2).
In some embodiments, the composition is formulated in hypotonie, isotonie, or hypertonie form. In some embodiments, the composition is administered intravenously, by bolus, dermally, orally, otically, via suppository, buccally, ocularly, or via inhalation.
In some embodiments, the administering comprises introducing said composition by infusion over a period of about 1 minute to about 1 hour, and said infusion is repeated as necessary over a period of time selected from about 1 day to about 1 year.
In another aspect, the présent disclosure provides a method of modifying the metabolism of a subject, the method comprising administering to the subject a stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent, in a stérile aqueous solution, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmolL to 3000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
In another aspect, the présent disclosure provides a method of treating a central nervous system disorder in a subject in need thereof, the method comprising administering to the subject a stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent, in a stérile aqueous solution, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
In another aspect, the présent disclosure provides a method of treating chronic wounds of a subject, the method comprising administering to the subject a stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent, in a 5 stérile aqueous solution, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pli buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical ^ade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
In another aspect, the présent disclosure provides a method of enhancing mental or physical performance; of a subject, the method comprising administering to the subject a stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent, in a stérile aqueous solution, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
In another aspect, the présent disclosure provides a method of reducing lactate burden 20 of a subject, the method comprising administering to the subject a stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent, in a stérile aqueous solution, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutic|al grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7. In one embodiment of the invention, the lactate burden is acidosis, sepsis, or multiple System atrophy (MSA). In another embodiment, the lactate burden is the resuit of physical exertion.
In another aspect, the présent disclosure provides a method of improving hypoxie stress of a subject, the method comprising administering to the subject a stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent, in a stérile aqueous solution, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3000 mmol L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
In another aspect, the présent disclosure provides a method of removing vascular plaque from the arteries of a subject, the method comprising administering to the subject a stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent, in a stérile aqueous solution, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 inmol L to 3000 mmol L when administered to a subject, and wherein the sélection of tire pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
In some embodiments of the invention, in the methods of the invention provide a buffer solution that is sufficient to reduce the physiological bioodstream pH of a subject by 0.01 to 1.1. In other embodiments of the invention, the buffer solution is sufficient to reduce the physiological bioodstream pH of a subject by 0.015 to 0.075. In other embodiments of the invention, the buffer solution is sufficient to reduce the physiological bioodstream pH of a subject by 0.02 to 0.05. In other embodiments of the invention, the buffer solution is sufficient to reduce the physiological bioodstream pH of a subject by 0.01 to 0.15. In other embodiments of the invention, the buffer solution is sufficient to reduce the physiological bioodstream pH of a subject by 0.01 to 0.2. In other embodiments of the invention, the buffer solution is sufficient to reduce the physiological bioodstream pH of a subject by 0.02 to 0.05. In other embodiments of the invention, the buffer solution has a buffer capacity sufficient to sustain the réduction of the physiological bioodstream pH of the subject for between 1 minute i and 1 week. In other embodiments of the invention, the buffer solution has a buffer capacity sufficient to sustain the réduction of the physiological bioodstream pH of the subject for between 1 minute and 1 hour.
In one embodiment of any of the methods of the invention, the subject is a human or 30 veterinary subject.
In another aspect, the présent disclosure provides a kit comprising (a) a first vial containing a stable therapeutic composition comprising a buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent, wherein the buffer solution is sufficient to reduce the physiological bioodstream pH of a subject by 0.1 to 1.1, and wherein the buffer solution has a buffer capacity sufficient to sustain the réduction of the physiological bloodstream pH of the subject for between 1 minute and 1 week; and (b) instructions for use.
In another aspect, the présent disclosure provides a kit comprising (a) a first vial containing an intravehous buffer solution comprising at least one pharmaceutical grade acid in a stérile aqueous solution;
(b) a second vial containing at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution, wherein, when combined, the contents of the two vials form an intravenous buffer solution, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 nunoi/L to 3000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7; and (c) instructions for use.
The details ofone or more embodiments of the invention are set forth in the description below. Other features, objectives, and advantages of the invention will be apparent from the description and from the claims.
BRIEF DESCRIPTION OF THE FIGURES
The accompanying drawings, which are incorporated herein and constitute part of this spécification, illustrate the presently preferred embodiments of the invention, and, together with the general description above and the detailed description given below, serve to explain the features of the inyention. In the drawings:
Figure 1 depicts a diagram of the typical chemiosmotic gradient of hydrogen ions between the inner-mémbrane and matrix in a normally functioning mitochondria in a mammalian cell.
Figure 2 depicts a diagram of the reduced chemiosmotic gradient of hydrogen ions in a mitochondria in a mammalian cell with a dysfunctional metabolism, as may occur after a prolonged exposure tp a poor diet, or lack of exercise.
Figure 3 depicts a diagram of the chemiosmotic flow of ions into and out of the cell of a subject having a hypoxie crisis, or as observed in phases of acid-base disturbance, such as during or following exercise, or as observed during or following use of the composition of the invention.
Figure 4 depicts a diagram of the chemiosmotic flow of ions into and out of the cell of a subject having had the hypoxie crisis corrected by use of the composition of the invention.
Figure 5 shows a diagram of the amplitude and duration of an acid state shift caused by different formulations of compositions of the présent disclosure.
Figures 6,7, 8,9,10 and 11 show a graphie représentation of the pH and HCOs response (Figure 6 - Acid Shifting Composition; Dose 1, Day 1); sO?, pCOz, pOz response (Figure 7 - Acid Shifting Composition; Dose 1, Day 1 ): pH and HCOv response (Figures 8 - Acid Shifting Composition with Vitamins and Minerais; Dose 4„ Day 6); sOz, pCOz, pO; response (Figure 9 - Acid Shifting Composition with Vitamins and Minerais; Dose 4, Day 6); pH and HCOf response (Figures 10 - Acid Shifting Composition with Vitamins and Minerais; Dose 5, Day 8); and sOz, pCOz, pOj response (Figure 11 - Acid Shifting Composition with Vitamins and Minerais; Dose 5, Day 8) of Subject 2, after administration of the therapeutic composition.
Figures 12 and 13 show a graphie représentation of the pH and HCOf response (Figure 12 - Acid Shifting Composition; Dose 1, Day 8); and sOz, pCO?, pOz response (Figure 9 - Acid Shifting Composition; Dose 1, Day 8) of Subject 3, after administration of the therapeutic composition.
DETAILED DESCRIPTION OF THE INVENTION
The présent invention will now be described more fully hereinafter. However, many modifications and other embodiments of the présent invention set forth herein, e.g., for the amelioration and/or treatment of spécifie conditions and disease States, will corne to mind to one skilled in the art to which the invention pertains having the benefit of the teachings presented in the foregoing descriptions. Therefore, it is to be understood that the présent invention is not to be'limited to the spécifie embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims.
As used herein, the term “mammal” refers to humans as well as ail other mammalian animais. As used herein, the term “mammal” includes a “subject” or “patient” and refers to a warm-blooded animal. It is understood that guinea pigs, dogs, cats, rats, mice, horses, goats, cattle, sheep, zoo animais, livestock, primates, and humans are ail examples of animais within the scope of the meaning of the term. As used herein, “a mammal in need thereof’ may be a subject who could hajve been, but is not required to hâve been, diagnosed as suffering from the condition intended to be treated. In one aspect, the présent method is directed to conditions that are noticeable to the subject and the subject wishes to treat or ameliorate the condition without a formai diagnosis. Altematively, a mammal in need thereof is one who has been diagnosed as having a condition and is in need of spécifie treatment. In other embodiments, a mammal may also be functioning normally relative to common standards but electively seeks to enhance performance for various purposes, such as for enhanced mental acuity or athletic interests.
The ternis “subject” and “patient” are used interchangeably, and are meant to refer to any mammal, including humans, that has, or is at risk of developing, a dysfunctional cardiovascular condition. The subject or patient is typically human. however, other suitable subjects or patients include, but are not limited to, laboratory animais, such as mouse, rat, rabbit, or guinea pig, farm animais and domestic animais or pets. Non-human primates are also included.
As used herein, a “therapeutically effective amount” is an amount effective to elicit a cellular response that is cIinica 1 ly significant.
As used herein, the ternis “treating” and “ameliorating” are intended to refer to ail processes wherein there may be a slowing, interrupting, arresting, or stopping of the progression of the condition or symptoms, and does not necessarily indicate a total élimination of the underlying condition. The tenus also encompass the administration of a pharmaceutical grade, physiological component, or natural physiological buffer composition wherein the mammal | has a condition or symptom or a prédisposition towards a condition or symptom, where the purpose is to cure, heal, alleviate, relieve, aller, improve or affect the condition or symptom or the prédisposition to the same. Also contemplated is preventing the condition or symptom or the prédisposition to the same, by prophylactically administering a pharmaceutical grade buffer composition as described herein.
As used herein, the term “pharmaceutical grade” means that certain specifîed biologically active and/or inactive components in the drug must be within [certain specifîed absolute and/or relative concentration, purity and/or toxicity limits and/or that the components must exhibit certain activity levels, as measured by a given bioactivity assay. Further, a “pharmaceutical grade compound” includes any active or inactive drug, biologie or 1 reagent, for which a Chemical purity standard has been established by a recognized national or régional pharmacopeia (e.g., the U.S. Pharmacopeia (USP), British Pharmacopeia (BP), National Formulary (NF), European Pharmacopoeia (EP), Japanese Pharmacopeia (JP), etc.). Pharmaceutical gradé further incorporâtes suitability for administration by means including topical, ocular, parentéral, nasal, pulmonary tract, mucosal, vaginal, rectal, intravenous and the like.
The présent disclosure is based on the unexpected discovery that reducing physiological bloodstream pH in a subject is useful in treating, ameliorating, and preventing many conditions and diseases and symptoms thereof in a subject in need. The invention provides a stable therapeutic composition that can be administered to a subject in need thereof, in order to provide the requisite shift in blood pli.
Figure 1 depicts a diagram of the chemiosmotic gradient potential of hydrogen ions in a normally functioning mitochondria in a mammalian cell. As shown therein, blood and interstitial fluid typically has a pH of around 7.4, the intracellular fluid within a cell has a pH of around 7.28, and intermembrane space of a mitochondria within the cell has a pH of around 6.88. Ionic pumps concentrate H' ions in the intermembrane space of the mitochondria, resulting in a large H“ gradient between the intermembrane space and mitochondrial matrix across the inner membrane. The concentrations of other ionic species, such as Ca2\ Na\ K\ Mg2-, and Cl· are also manipulated to create an electrochemical gradient across the various membranes, and intramitochondrial Ca2' in particular is important for managing the flow of H' ions within the mitochondria. Hydrogen ions flow across tire inner membrane into the mitochondrial matrix through ATP synthase, creating ATP from ADP. The électron transport chain is used to pump the H- ions back across the inner membrane to maintain the proton gradient. A small percentage of électron transfer occurs directly to oxygen, leading to free-radical formation, which contributes to oxidative stress and may resuit in membrane damage if insufficient antioxidants are présent.
Figure 2 depicts a diagram of the chemiosmotic gradient potential of hydrogen ions in a mitochondria in a mammalian cell with a dysfunctional metabolism, as may occur after a prolonged exposure to a poor diet, or lack of exercise. As shown in Figure 2, the blood, interstitial space, andjintracellular fluid hâve undergone acidotic shifts, i.e., increased the concentration of H+ ions and reduced the pH. At the same time, the pH in the mitochondrial matrix is increased from normal due to membrane leaks or reduced H+ ion pumping action from the électron chain transport. As a resuit, the net H electrochemical gradient available for the formation of ATP is reduced. Furthermore, the cell and mitochondria must increasingly rely on other ionic species to provide the necessary electrochemical gradient on demand, such as through higher than normal concentrations of Ca24 within the intermembrane space “pushing” hydrogen ions across the inner membrane and a higher concentration of Cl' within the mitochondrial matrix “pulling” the hydrogen ions. This dysfunctional ionic balance results in increased development of supmsxidatîve species and increased membrane damage, and the metabolism of the cell slows down as a resuit. This reduces the amount of available ATP, causing a negatively reinforcing feedback loop that can lead to various adverse conditions and disorders.
A similar metàbolic dysfonction occurs as a resuit of poor perfusion leading to a lactate burden, called metabolic acidosis in chronic State, which may be caused by, e.g., sepsis, multiple system atrophy (MSA), and ischémie conditions in peripheral limbs. For individuals incurring a chronic lactate burden, high blood levels of lactate steadily displace bicarbonate buffers to maintain acid-base homeostasis. A fraction of bicarbonate could then be removed by rénal action to maintain homeostasis, and to reduce bloodstream bicarbonate levels. In addition, chronic disturbances in electrolytes can shift the setpoint for bicarbonate rétention to additionallv reduce stores. Such forces would in turn make less bicarbonate I accessible for intracellular rétention and intracellular buffering, ultimately reducing intracellular H stores. This réduction in H” stores would require more Ca2” to sustain a desired chemiosmotiç gradient, leading to a dysfunctional ionic balance as described above.
Stable therapeutic compositions of the présent disclosure reduce the physiological bloodstream pH in a subject, and maintain that réduction in physiological bloodstream pH for a duration of time, until rénal and respiratory compensation processes negate the réduction, commonly followed by an alkaline “rebound”. The compositions of the présent disclosure are formulated such that the formulated pH is below the physiologie norm (i.e., below 7.4). Bicarbonate concentration may, in some instances, be above physiologie norm (i.e., above 29 mM). The sudden influx of H ions, together with excess bicarbonate, and the manipulation of the electrochemical gradients that results, allows for a return to normal mitochondrial metabolic processes, while other electrolyte, vitamin, and antioxidant support présent in compositions of the présent disclosure reduce the damage from oxidative stress. Other benefits of administration of compositions of the présent <|iisclosure include improvement of at least one of cardiovascular conditions, vasodilation, wound healing, vascular plaque, bicarbonate servicing electrolyte economy, metabolic dysfonction, oxygen deficiency, Ci trie Acid Cycle, rénal system operation, antioxidant dysfonction, angiogenesis, nitric oxide (NO) dysfonction, hormone fonction, and anémia.
In one embodiment of the invention, the compositions of the présent invention are suitable for improvement of cardiovascular conditions, by reducing or removing vascular plaques. Plaque forms in the arteries as a resuit of a number of factors, which are rooted in a wound-related signal dysfonction, including for example, lipid dysfonction, nitric oxide dysfonction and excessive ROS, which are caused, in part, by the presence of an acidic environment in the cells. For example, in an acidic environment, exogenous ROS levels become elevated. Smooth muscle contains several sources of ROS, which hâve been shown to fonction as important signaling molécules in the cardiovascular system. The elevated ROS signais to the smooth muscles to accrue in the arteries. as though recruited to fill wounds that do not actually exist. Additionally, in an acidic environment with ROS and an absence of nitric oxide, macrophages are signaled to respond to a non-existent threat. causing them to convert from the Ml to the M2 form, and begin sequestering lipids. The fat laden lipids become accumulations of foam cells. Also, in acidic environment, an endothélial nitric oxide synthase (eNOS) dysfonction occurs, causing an increased availability of arginase, which is necessary for the synthesis of collagen. and thus works with acid-pH stimulated action of fibroblasts to promote an accrual of collagen in the arteries. The élévations of retained intracellular Ca2-, and increases in unbound phosphate that occur from the metabolic dysfonction associated with an acidic environment (because less phosphate is complexed with ADP to form ATP), resuit in the promotion of calcifie mineralized components of plaque. By restoring an alkaline environment in the cells, the compositions of the invention are able to reduce or reverse vascular plaque by correcting or improving at least one of, nitric oxide dysfonction (thereby restoring NO signaling), lipid dysfunction, eNOS dysfonction, réduction in smooth muscle recruiting, réduction of endogenous and exogenous reactive oxygen species (ROS), elevated Ca2, or restoration of fatty acid metabolism. For example, upon the introduction of an alkaline environment, the smooth muscles, in the absence of the ROS signal, recognize the absence of a wound, and consequently, they down-regulate, and begin to directionally orient towards their vasodilation and vasoconstriction tasks. Also, for example, in an alkaline, low ROS environment in the presence of eNOS nitric oxide signaling, foam cells are signaled to release their lipids. Along with the calcifie plaque reversai or réduction, the supplen|ess of the vascular vessel returns. In addition, the acid- | shilling action of the drug libérâtes atomic components of the minerai deposits, while magnésium in the composition of the invention aids in the prévention of plaque re-deposition, to reduce the hardening of the arteries from the minerai deposit components.
In one embodiment of the invention, the compositions of the présent invention are suitable for preventing or minimizing hypoxia in a subject. The lack of sufficient oxygen reaching cells or tissues in a subject can occur even when blood flow is normal. This can cause many serious, sometimes life-threatening complications. Use of the compositions of the invention enable the resolution or improvement of conditions commonly associated with hypoxia, such as. for example, heart attack, cardiovascular problems, lung conditions, concussive cascade, reperfusion injury, myocardial infarction. hypoxia associated with diabètes, tissue trauma, and the like. Many of these conditions are associated with vasoconstriction. Thq composition can counteract such vasoconstriction by promoting vasodilation via at least one of three pathway s, namely endothelin, prostacyclin, or NOsoluble guanylyl cyclase (NO-sGC). For the endothelin pathway, the compositions elevate Mg2” in the bloodstream to antagonize Ca2”. This blocks Ca2 from potentiating vasoconstriction, allowing the arteries to relax and dilate. Meanwhile, the compositions also provide metabolic corrections to reduce metabolic sources of ROS. and reduce the présentation of endothelin stimulants at the cell surface, thereby reversing Ca2* overstimulation. For the prostacyclin pathway, niacinamide in the composition elevates adenosine 3’,5'-cyclic monophosphate (cAMP) activity, which complétés prostacyclin potentiation towards yasodilation. For the NO-sGC pathway, as noted above, the compositions of the invention provide a gradient of H” flowing into the cells to promote Ca2' efflux, which corrects elevated Ca2' présentation. One effect of high levels of Ca2” is the élévation of caveolin. As the caveolin elevate, they take résidence in the caveoli on the cell surface, causing the displacement of eNOS, which migrâtes to the Golgi System. The combination of low ROS and low intracellular Ca2” achievable using the composition of the invention, allows eNOS, to return from the Golgi to the cell membrane, thereby to restoring eNOS’s ability to promote vasodilation. As the eNOS retums to the membrane, the bloodstream pH shifts, promoting NO release via the NO-sGC pathway, and promoting vasodilation. In addition, rénal responses to rebalance pH produce a second “pH shift” towards alkaline, once again stimulating NO / NO-sGC vasodilation to extend the duration of the effect.
As shown in Figure 3, when a subject’s body is under a State of metabolic crisis, such | as a hypoxie crisis, intracellular acidification drives the intracellular accrual of Ca2+. This occurs because adenosine triphosphate (ATP) is required to résolve the sodium burden created as H” leaves the cell. However, in the hypoxie state, ATP becomes impaired, and as a conséquence, the Na”/K” ATPase pump becomes inactive. The Ca2”/Na' exchange must résolve the Na” burden by accumulating Ca2* in the cell. To reverse this process, the hypoxie state must be resolved to restore ATP production (and Na/K” ATPase), or extracellular H must be presented. As shown in Figure 4, the compositions of the invention achieve both of these things, enabling the rapid resolution of the Ca2+ overburden and the corresponding metabolic crisis. The composition adjusts the pH of the bloodstream, acidifying it, and in doing so, causes H to enter through the Na'ÆT exchange roule. As the H enters, it pushes Na out. As noted above, the composition of the invention promotes vessel vasodilation to improve blood flow. With this increased blood flow cornes increased oxygen, entering, which enables the création of ATP through aérobic metabolism. The composition also elevates Mg in the bloodstream. The increased Mg2 facilitâtes the transport of the ATP, as Mg-ATP, to the Na K ATPase. providing the stimulus to push Na+ out. Some of the increased Na in the bloodstream reenters through the Ca2~'Na exchange. Additionally, the bloodstream présentation of H . in concert with elevated bloodstream bicarbonate, promotes bicarbonate entry into the cell This process provides an antidote to reverse calcium accrual in the cell, improving the cells’ capacity to restore a chemiosmotic gradient with less reliance on Ca2“ and more utility of HCO3- buffered H“ to ultimately reduce metabolic acid burden and metabolic ROS, to promote restoration of the intracellular towards alkaline, with improved redox status. The steady biasing towards alkaline and low ROS promotes positive rebalancing of electrolytes and pH in the cytosol, organelles, lysosomes, peroxisomes, calcium status, magnésium status and ROS status within the cell. Additionally, it changes the cellular economy to restore potassium and bicarbonate, while at the same time reducing intracellular calcium.
The vasodilation that can be achieved by use of the composition of the invention makes the composition useful for wound care. It was unexpectedly discovered that use of the compositions of the invention may provide wound recovery even in subjects who hâve exhausted conventional treatment methods, including those with gangrenons présentation, or chronic, diabetic or traumatic wounds. Metabolic changes are among the effects observed following trauma injury and surgical trauma. These include inflammatory responses, which trigger a constriction of blood flow to the affected régions. While this advantageously minimizes blood loss at the site of an open wound or internai bleed, it may impair healing by prc|moting a hypoxie intracellular environment. In trauma situations where bleeding risk is absent or reduced (for example by compression), it may be desired to suppress the inflammatory response, to avoid secondary injuries from hypoxia. In cases of chronic inflammation, such as with chronic critical limb ischemia (CLI), the suppression of inflammation can expedite healing. The vasodilation promotion and improved perfusion caused by the composition of the invention contribute towards breaking the cycle of inflammation. In addition to promoting vasodilation in order to increase oxygen servicing, the compositions of the invention are also capable of correcting key metabolic aberrancies that are présent in wounds. The compositions may, for example improve at least one of restoring acid-buffer status and correction of elevated Ca2\ reducing metabolic sourced ROS; correcting acidosis; correcting over-active iNOS and restoration of eNOS and nNOS function; promotion of bénéficiai angiogenesis after eNOS is corrected; and suppression of iNOS promoted aberrant angiogenesis, ail of which are important for wound care.
Because H also administrâtes acétylcholine uptake, which is part of muscle support, and is a part of the cerebellum control process, and ATP is relevant for ail of these Systems, disorders of the central nervous system are another treatment target. Additionally, action to résolve intracellular acid, calcium accrual, reduced ROS, and increased Mg, are factors that can enhance function in the peroxisome, to better maintain catalase antioxidant supply, and additionally support the lipid modeling required for myelin maintenance of nerve sheaths.
In some instances, the réduction in physiologie bloodstream pH caused by the composition of the invention may be minimal, or not observed. due to the particular formulation of an administered composition, the rate at which a composition is administered, or both. However, the therapeutic benefits described herein may stiH be achieved due to the net élévation of bicarbonate concentration that occurs. Due to an excess of H~ upon administration, the body prioritizes rétention of, and augmentation of, the buffer components (e.g., bicarbonate), as acid balancing processes proceed. Thus, a greater fraction of the buffering agent is retained within the cells and bloodstream as the system alkalinizes and retums the physiological pH towards baseline. Such an alkaline rebound” may resuit in bloodstream pH overshooting slightly for a net alkaline stabilization relative to the starting pH. The alkaline rebound' achieves a higher residual concentration of intercellular and bloodstream buffer components, including bicarbonate. Alternatively, the System may regulate to a final pH équivalent to that présent prior to treatment, but with bloodstream buffering, with regard to acidic species, being increased. Altemately, the bloodstream pH may settle to be moré acidic than prior to the treatment, yet while a vanety of aforementioned exchange phenomena are promoted. In contrast to infusion of a simply buffer, such as bicarbonate, in the absence of acidic components, co-administration of acid and buffer are key to limiting the H efflux rate, while the intracellular calcium correction is achieved.
In one embodiment of the invention, the compositions of the présent invention are suitable for increasing nitric oxide synthase (NOS) in a subject. The pH biasing and increase in bicarbonate concentration as provided by compositions of the présent disclosure (including decreases in pH upon administration and “alkaline rebounds” as homeostasis is restored) may also restore endothélial and neuronal NOS, leading to a sélective increase in nitric oxide production. Nitric oxide is a gaseous signaling molécule with a rôle in, e.g., hemostasis, smooth muscle (particularly surrounding vasculature), neuronal signaling, and in the gastrointestinal tract.1 NO has been implicated in a \ariety of physiological Systems, and the increased levels resulting from administration of the compositions described herein may serve a rôle in providing the therapeutic benefîts described herein. For example, in glaucoma, NO may play a rôle in regulating intraocular pressure via the trabecular meshwork. In atherosclerotic plaques, NO stops the aberrant perpétuation of smooth muscle recruitment, foam cell accrual and lipid storage, and collagen déposition, and it may ultimately lead to reversai of plaque damage and a retum of the vascular section to physiological norms.
In one embodiment of the invention, the compositions of the présent invention are suitable for reducing lactate burden in a subject in need thereof. As used herein, the term “lactate burden” means any physiological condition characterized by elevated lactate levels. This may include, for example and without limitation, chronic lactate burdens such as acidosis, sepsis, and MSA, or acute lactate burdens such as may occur during and after physical exertion such as exercise. Lactate circulating oxygen debt burden that is retained in muscles, can be stimulated to be released by bicarbonate, and subsequently metabolized thus lowering the subject’s lactate burden. The ability to eliminate lactate burden is important for a subject who has had, for example, an organ transplant. Where the transplant procedure involves the use of citrate anticoagulant, the citrate must be metabolized. This metabolization can induce a lactate burden in those individuals. Additionally, lactate burden is a component of sepsis and a chronic burden in diabetics. In the above instances, as well as in others involving a lactate burden, the use of the compositions of the invention may reduce that burden.
In one embodiment of the invention, the compositions of the présent invention are suitable for reducing acidosis in a subject in need thereof, by administering to the subject the composition of the invention. One of the metabolic effects of trauma is the suppression of insulin, resulting in a réduction of the normal anabolic effect of insulin towards an increase in catabolic effects. This leads to a shift towards free fatty acids as the primary source of energy, with triglycérides providing 50 to 80% of the energetic need. Reducing the catabolic response encourages faster healing after surgery. These same mechanisms are in play in the diabetic patient, and become a larger challenge as subjects progress in their metabolic dysfunction. Underlying this catabolic process are aberrations in the metabolic chain that tend towards incomplète oxidation; leading to an increase in acidic products and an élévation of ROS from metabolic sources. As noted herein above, in trauma, this catabolic shift is driven by the i
hypoxie State, as inflammation and the vasoconstrictive response impair circulation. In diabètes, the shift is, marked by glucose intolérance, and compounded by plaque-induced circulatory impairments and a sedentary lifestyle. In both cases, incomplète oxidation results in acidification in the cell and the promotion of transport biases which cause Ca’ to concentrâte in the cytosol. This concentration of Ca2 cascades to the mitochondrial inner-membrane so that Ca2- takes on a larger rôle in the chemiosmotic gradient, reducing the rôle of H- itself. Such a shift in Ca2 and H initiâtes a progressive shutdown in the électron chain transport (ECT), so that Ca2 takes on a greater rôle in controlling the chemiosmotic potential. This also leads to an increase in metabolic ROS from ECT stages. Over time, impaired circulation reduces B-vitamin servicing, which impairs both the Krebs cycle and ECT, further increasing metabolic ROS. At the same time, impaired circulatory servicing reduces antioxidant maintenance to leaveithe élévation in ROS unchecked. While such aberrations hâve bénéficiai qualities, such as promoting the création of NAPDH oxidases for bactericidal function during infection, they also présent impairment to the healing process, as they promote catabolism. Furthermore, a balance of signais including acidosis, hypoxia, Ca2, ROS and iNOSNO. collectively suppress emergence of M2 macrophages, as desired, to promote healing. To address these aberrancies, the composition of the invention facilitâtes Ca2 correction, and enhances B-vitamin servicing and ascorbic acid anti-oxidant servicing via elevated présentation. Additionally, acid burden is reduced, promoting an alkaline bias. Elevated HCO?' buffer levels also serve to preserve this alkaline bias.
The éléments of metabolism referenced above also affect insulin management. For example, insulin release is stimulated from the pancréas when a signal of elevated Ca2- is released to the bloodstream. For Ca2- to be released to the pancréas, hydrogens must be created, through incomplète metabolism, to displace Ca2 from the cytosol to the bloodstream. As noted herein-above, the NaVK” ATPase must be served with Mg2 and ATP to facilitate the flooding Na to the bloodstream to ultimately stimulate the Na+/Ca2~ exchanger to release Ca2 to the bloodstream. Additionally, for sensing of élévation to occur, the background level pf Ca2 in the bloodstream needs to be low enough for the pancréas to observe the change. In acidosis, this would be impaired as Ca2 solubility is elevated in the blood and in the cytosol. As a further example, ROS, such as peroxide, can promote insulin function, when presented at low levels, and prevent présentation and action of insulin when presented at high levéls. Thus, correction of acidosis and enhancement of Mg2 are key to restore insulin management. So too are suppression of ROS (e.g., H2O2) through antioxidant support and facilitation of TCA and ECT function to achieve near-complete oxidation of Acetyl-CoA to CO: and H:O.
Compositions
In one embodiment of the invention, the composition of the invention is a stable therapeutic composition that has been formulated to make it suitable for intravenous administration to a subject. The composition contains an intravenous buffer solution, containing at least one pharmaceutical grade acid, and at least one pharmaceutical grade pH buffering agent. To ensure their suitability for pharmaceutical use, the acid and buffer solution are présent in a stérile aqueous solution. The concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmoLL to 3000 mmol/L when administered to a subject. The acid and base are selected so that they are able together, to provide a buffer solution having a pH of between 4 and 7.7.
In one embodiment of the invention, the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 80 mmoL'L to 3000 mmol/L when administered to a subject, where the buffer solution is effective to provide a buffer solution pH of less than 5.5. In another embodiment of the invention, the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 100 mmol/L to 2000 mmol/L when administered to a subject, where the buffer solution is effective to provide a buffer solution i pH of less than 5.5. embodiment of the invention, the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 200 mmol/L to 1000 mmol/L when administered to a subject, where the buffer solution is effective to provide a buffer solution pH of less than 5.5. I
In one embodiment of the invention, the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 40 mmoL'L to 3000 mmol/L when administered to a subject, where the buffer solution is effective to provide a buffer solution pH of less than greater than or equal to 5.5. In another embodiment of the invention, the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 2000 mmol/L when administered to a subject, where the buffer solution is effective to provide a buffer solution pH of less than greater than or equal to 5.5. embodiment of the invention, the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 80 mmol/L to 3000 mmol L when administered to a subject, where the buffer solution is effective to provide a buffer solution pH of less than greater than or equal to 5.5.
An acid is a molécule or ion that is capable of donating a hydrogen ion H“. The amount of H“ ions in a solution is measured by its pH, where a pH of less than 7 constitutes an acidic pH. Humans typically hâve a bloodstream pH of 7.4. Compositions of the présent disclosure comprise an acid that provides an amount of H' ions to decrease the physiological bloodstream pH in a subject. Without being bound to any theory, it is believed compositions of the présent disclosure increase the H gradient in various cellular environments, including, e.g., mitochondria. This increased mitochondrial H* gradient drives higher production of ATP and, through other physiological homeostatic Systems, causes changes in concentration gradients of the cellular membranes which in tum rebalances physiological ions such as sodium, magnésium, potassium, and calcium. For example, an increased H- gradient in the bloodstream may stimulate calcium pumps in cellular membranes, thereby increasing intracellular H- and reducing intracellular Ca2. The concentration gradients of sodium, magnésium, and potassium are also affected. By manipulating ionic gradients using compositions of the présent disclosure, many conditions and diseases and symptoms thereof may be treated, ameliorated, or prevented.
In some embodiments, compositions of the présent disclosure are sufficient to reduce the bloodstream pH of a subject by a small, moderate, or large amount. In some embodiments, the amount of acid in a composition of the présent disclosure is sufficient to reduce the bloodstream pH of a subject by 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, <p.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, or 1.1, or more. Th|e réduction in pH may also be expressed by the desired pH level of the bloodstream after administration of a composition of the présent disclosure, e.g., 7.2. In some embodiments, a composition of the présent disclosure comprises sufficient acid to reduce the bloodstream pH of a subject to 7.3, 7.2, 7.1, 7.0, 6.9, 6.8, 6.7, 6.6, 6.5, 6.4, or 6.3. A réduction of bloodstream pH to below 6.3 is not typically advised,, as it may pose a cell health risk and threaten the integrity of cellular phospholipid bilayers. In cases of alkalosis where nominal pH may exceed 7.4, a “réduction” in pH provided by administration may still resuit in a bloodstream pH exceeding 7.4. For example, administration of a composition of the présent disclosure may shift the physiological pH from 7.7 to 7.5 .
Compositions of the présent disclosure may contain one or more pharmaceutical grade acids. In some embodiments, compositions of the présent disclosure comprise a mixture of one or more pharmaceutical grade acids. Acids may include any physiological acceptable acid, including, without limitation, hydrochloric acid, ascorbic acid, citric acid, lactic acid, phosphoric acid, or combinations thereof The pH of a composition of the présent disclosure may be between about 4 and 7.7. In some embodiments, the pH of a composition of the présent disclosure is between about 6.1.In embodiments where the pH of the composition is very low, the rate of administration may hâve to be managed to avoid tissue damage adjacent to the injection site as dilution is effected in the bloodstream.
In another aspect, compositions of the présent disclosure comprise a pH buffering agent. A pH buffering agent is a weak acid or base that is used to maintain the pH of a solution near a desired value. Compositions of the présent disclosure comprise a pH buffering agent such that the réduction in bloodstream pH may be sustained for a desired duration. In some embodiments, the pH buffering agent may comprise a conjugale acid or a conjugate base. In some embodiments, the pH buffering agent may comprise any physiological acceptable buffering agent, including, without limitation, sodium bicarbonate, a phosphate buffer, citrate buffer, or a synthetic buffer creating spécifie alkaline conditions (e.g., tris-hydroxymethyl amino methane), or combinations thereof.
The buffer capacity of a solution is a measure of the solution’s ability to resist pH change, Le., to maintain a spécifie pH level. As discussed above, acid-base homeostasis relates to the proper balance of acids and bases in extracellular fluids, i.e., the pH of the extracellular fluid. In humans, the pH of plasma is approximately 7.4 and is tightly maintained around that value by three interconnected Systems: 1) buffering agents, including bicarbonate^ phosphate, and proteins), 2) the respiratory system, which impacts the partial pressure of carbon dioxide in blood plasma, and 3) the rénal system, which excretes waste acids and bases. Accordingly, in some embodiments, compositions of the présent disclosure comprise a pH buffering agent in order to maintain the desired bloodstream pH level below the typical pH value of about 7.4 in the face of pressures exerted by the physiological Systems that regulate acid-bas^ homeostasis. In some embodiments, compositions of the présent disclosure comprise a pH buffering agent in an amount sufficient to maintain the réduction in bloodstream pH, or to maintain the desired pH level, for a duration of 1 minute to 1 week. The desired duration of the reduced bloodstream pH level will dépend on the particular i
indication being treated as well as the individual being treated. In some embodiments, a small, moderate, or large buffer capacity may be desired. In one means of administration, a small quantity of drug and/or a slow administration of a drug product could stimulate compensatory processes that can be respiratory or rénal, so as to mitigate observable acid shifting potential, but having stimulateà respiratory and rénal activity. In such cases, a blood stream response may be neutral or may tend toward alkaline. AIternatively. administration of a high dose, and or a dose with a fast administration rate, such as a bolus or fast IV drip could introduce the acid and overwhelm the compensatory' processes to yield an observable downstream pH toward acidic. Such a stimulus would coin mon 1 y be expected to be followed by a rebound of bloodstream pH towards alkaline throughout the treatment or post- treatment. The outcome resulting from a given dose level and/or administration rate may be different from patient to patient and from administration to administration as the patient’s health. electrolytic status , pH status and compensatory process status evolve. Different buffer capacities may be sufficient to maintain the réduction in bloodstream pH for a duration of 1 minute to 1 week. In other embodiments. the buffer capacity may also be expressed in molar équivalent of common buffets, such as bicarbonate.
In some embodiments, the composition has a buffer capacity betw een 0.1 mM HCCU équivalent and 1200|inM HCOb' équivalent. In other embodiments, the buffer capacity' is between 0.1 mM HCCV équivalent and 10 mM HCOb* équivalent. In some embodiments, the buffer capacity is between 10 mM HCO.f équivalent and 50 mM HCOJ équivalent. In some embodiments, the buffer capacity is between 10 mM HCOb' équivalent and 1000 mM HCOb’ équivalent. In some embodiments, the buffer capacity is between 50 mM HCOb’ équivalent and 800 mM HCOb' équivalent. In some embodiments, the buffer capacity is between 100 mM HCOf équivalent and 600 mM HCOb' équivalent. In some embodiments, the buffer capacity is between 20p mM HCOb’ équivalent and 550 mM HCOb’ équivalent. Ih some embodiments, the buffer capacity is between 20 mM HCOb équivalent and 100 mM HCOb' équivalent. In other embodiments, buffer capacity may be expressed by the molar concentration of HCOb', or other common buffers. For example, in some embodiments, the molar concentration of HCOb may be between 0.01 molar and 10 M. In other embodiments, the molar concentration of HCOb' may be between 0.5 and 2 M.
In another embodiment, the présent disclosure provides a composition having a pH below physiological pH (i.e., below 7.4) and an HCOb’ concentration above physiological levels (i.e., above 29 mM). In some embodiments, the pH of the composition may be between 4 and 7.7 and the HCO?' concentration may be between 30 mM and 2 M). In other embodiments, the pH of die composition may be between 5.5 and 7.4. In further embodiments, the pH of the composition may be around 6.
Figure 5 shows a diagram of the amplitude and duration of an acid state shift caused by different formulations of compositions of the présent disclosure. The black lines, both solid and dotted, depict a large acid shift, i.e., a composition with a high concentration of H~ ions. However, the buffering capacity of the composition depicted by the dotted black line is smaller than that of the solid line, such that the acid shift is maintained for a shorter duration. The gray lines, both solid and dotted, depict a smaller acid shift, i.e., a composition with a lower concentration of H ions. Again, the buffer capacity between these compositions varies such that the acid shift caused by the composition depicted by the dotted gray line is maintained for a shorter duration. Compositions of the présent disclosure may be designed along these two spectrums. amplitude of shift and duration of shift, according to desired therapeutic properties and administration schedules.
In another embodiment, the présent disclosure provides a stable therapeutic composition comprising a buffer solution comprising a pharmaceutical grade base and at least one pharmaceutical grade conjugate acid, wherein the buffer solution is sufficient to raise the physiological bloodstream pH of a subject by 0.1 to 1.1, and wherein the buffer solution has a buffer capacity sufficjent to sustain the élévation of the physiological bloodstream pH. In some embodiments the buffer capacity may be sustained for a period of time for example 1 minute or Iweek. The compositions may further comprise vitamins, salts, acids, amino acids or salts thereof, and stabilized oxidative species.
In another aspect, compositions of the présent disclosure may further comprise salts to provide sources of physiological relevant ionic species, such as Na-, K-, Mg2-, Cl', POT', or Ca2-. These may include, without limitation, sodium chloride, disodium phosphate, potassium chloride, monopotassium phosphate, magnésium chloride, and [calcium chloride. The compositions may further comprise other trace éléments and their salts, including, but not limited to, sélénium, copper, chromium, iodine, fluoride, zinc, manganèse, molybdenum, and iron.
Sodium ions are required in relatively large concentrations for normal physiological functioning. It is the major cation of the extracellular fluid. It plays an important rôle in many physiological processes, including the régulation of blood volume, blood pressure, osmotic equilibrium, and pH, as well as the génération of nerve impulses.
i
Potassium ions are the major cation ©f intraœlâular fluid, and, with the sodium ions of the extracellular fluid, is a primary generator of the electrical potential across cellular membranes. Accordingly. it plays a significant rôle in normal functioning, and is critical in such body functions as neurotransmissîon, muscle contraction, and heart function.
Calcium ions are likewise important to many physiological processes. In particular,
Ca2- ions are one of the most widespread second messengers used in signal transduction. In endothélial cells, Ca2 ions may regulate several signaling pathways which cause smooth muscles surrounding blood vessels to relax. Dysfunction within Ca2“-activated pathways can lead to an increase in tone caused by unregulated smooth muscle contraction. This type of 10 dysfunction can be seen in cardiovascular diseases, hypertension, and diabètes.
Magnésium ions are required in relatively large concentrations in normal metabolism. It is recognized that deficiency of magnésium is rare unless it is accompanied by severe losses in other electrolytes such as in vomiting and diarrhea. It is however frequently recognized as déficient in the modem diet with symptoms such as muscle tremors and weakness. This minerai is important in many enzymatic reactions and will stabilize excitable membranes. Adminis'tered intravenously, magnésium may produce an anesthetic action and this is indirect evidence of its action on the vascular wall endothélial component to stabilize and normalize the surface of the vascular wall.
In some embodiments, a composition of the présent disclosure comprises Na- at a concentration between 0.1 mM and 1 M. In other embodiments, a composition of the présent disclosure comprises K at a concentration between 0.0 mM and 1 M. In some embodiments, a composition of the présent disclosure comprises Mg2’ at a concentration between 0.1 mM and 1 M. In other embodiments, a composition of the présent disclosure comprises Ca2 at a concentration between 0.1 mM and 1 M.
As described above, the interplay between the various ionic species is disrupted in various physiological conditions, and compositions of the présent disclosure may include these species to aid in the restoration of normal physiological conditions and concentrations. For example, high intracellular Ca2’ may be restored to a lower level as offset by Mg2’, K’, and H+, which may lead to NOS présentation in the cytosol and restoration of NO levels.
As stated above, the compositions described herein may include vitamins and vitamers, which is a substance(s) that has vitamin-like activity. Vitamins selected from the group consisting of the water soluble and lipid soluble group, and a combination of two or more thereof may also be added to the pharmaceutical composition. Preferably, the pharmaceutical composition includes ascorbic acid. Ascorbic acid is included as a strong antioxidant component and to maintain the structural integrity of connective tissue, including épithélial basement membranes and to promote wound healing. It may also play a distinct rôle as an agent with strong anti-inflammatory actions. The oxidized form of the vitamin, dehydroascorbic acidi has been shown to transfer intracellularly where some of it is reduced within the cell via action of glutathione. Deficiencies of other B group and A and E are also protected by ascorbic acid and corresponding interactions of dehydroascorbic acid and glutathione. In some embodiments, a composition of the présent disclosure comprises dehydroascorbic acid, an oxidized form of ascorbic acid that is actively imported into the endoplasmic réticulum of cells via glucose transporters. Présentation of dehydroascorbic acid can also stimulate production of glutathione in the liver, which facilitâtes recycling of dehydroascorbic acid into ascorbic acid. Thus, dehydroascorbic acid indirectly enhances intracellular antioxidant resources. Dehydroascorbic acid may be présent via direct inclusion of pharmaceutical grade dehydroascorbic acid, or by conversion of ascorbic acid via contact with a reactive oxygen species such as HOC1, H2O2, or OC1.
The B Group bf Vitamins has been shown to be important in human food intake, and plays an important rôle acting as co-enzymes in cellular metabolism and energy production. The entire B group of vitamins may be included in the formulation to address any deficiencies in the patient population to be treated.
The B group xdtamins are found to occur naturally together in foods and are generally included comprehensively for this reason. The B group includes: 1) Thiamine (B 1 ), which plays an important rôle in energy production within the cell, specifically as co-enzyme in metabolism of carbohydrates. At least 24 enzymes are known to use thiamine as a coenzyme; 2) Riboflavin (B2) in the form of flavin mononucleotide and flavin adenine dinucleotide are part pf ail dehydrogenase enzymes. Deficiency of this vitamin causes inflammation of the mouth, tongue, dermatitis, defective vision and blood dyscrasias; 3) I
Niacinamide (B3) i|s included, as part of the B group of vitamins as deficiencÿ syndromes in clinical pellagra are well known clinical manifestations of deficiencies. The deficiency States of this vitamin are associated with intestinal diseases and alcohol misuse. It also occurs in diabètes mellitus and (carcinoid syndrome. The active forms of this vitamin include the nicotinamide dinucleotides NAD and NADP, which are the co-enzymes and co-substrates for numerous dehydrogenases responsible for oxidation-reduction Systems within the human cell, which are indispensable for energy production. The formation of nicotinic acid from the administered nicotinamide in the formulation produce nicotinic acid possessing additional actions not shared by Inicotinamide, such as inhibition of cholestérol synthesis; 4) Calcium DI
Pantothenate (B5), pantothenic acid forms a major part of the molécule of co-enzyme A, which is important in the energy producing meta bol ic cycles in the mitochondria of ail cells. The effect of this vitam in on various disease syndromes has been recognized. Such as its use in neurotoxicity produced by streptomycin and ifs use in diabetic neuropathy, skin diseases and adynamie iléus; and 5) Pyridoxine (B6) is widely utilized as a co-enzyme in over 40 types of enzymatic reactions. The B Group of vitamins may also aid in providing an increase of antioxidants and stimulated glutathione to reduce reactive oxygen species, which ultimately aids in NQ expression.
The most important of these are the transamination reactions and the influence of pyridoxine on tryptophan metabolism. Kynureminase, which is an enzyme used to identify pyridoxine deficienciès, loses its activity when pyridoxine is not présent and may resuit in secondary* nicotinic acid deficiency as a resuit of lack of the kynureminase conversion of nicotinic acid from tryptophan.
Cyanocobalamin (B 12) is used because of the frequent reports of mal-absorption of cyanocobalamin, caused by poor dietary habits, senescence, and certain drugs (metformin) used as a hypoglycémie agent in diabètes mellitus. This vitamin is essential for normal erythropoiesis to occur, and recent findings hâve also implicated this vitamin with improvement of neuronal transmission in motor neuron disease. (Rosenfeld, Jeffrey and Ellis, Amy, 2008, Nutrition and Dietary* Suppléments in Motor Neuron Disease, Phys Med Rehabil Clin N Am., 19(3):573-589).
Vitamin K is a fat-soluble vitamin. There are two naturally occurring forms of the vitamin. Vitamin Kl is the dietary Vitamin K and is abundant in green leafy vegetables, whereas vitamin K2 is présent in tissues. Vitamin K2 is synthesized by bacteria. It is found mainly in fermented products like fermented soybeans, cheese, curds and to some extent also in méat and méat products (Thijssen, H. H., M. J. Drittij-Reijnders, and M. A. Fischer, 1996, Phylloquinone and menaquinone-4 distribution in rats: synthesis rather than uptake détermines menaquinone-4 organ concentrations, JNutr 126:537-43). Vitamin K2 is found in animais as menaquinone. It is the human activated form of vitamin K and is said to promote the healing of bone fractures. It is essential for the carboxylation of glutamate residues in many calcium binding proteins such as calbindin and osteocalcin. These proteins are involved in calcium uptake and bone mineralization.
There is an established daily dosage for vitamin Kl for, but not for vitamin K2. A typical therapeutic oral dose for vitamin K2 for osteoporosis is 45 mg/day. Unlike for coagulation, a much higher level of vitamin K is needed for complété gamma-carboxylation i
of osteocalcin (Booth, S. L., and J. W. Suttie, 1998, Dietary intake and adequacy of vitamin K, J. Nmr 128:785-8). Vitamin K deficiency is associated with reduced hip bone minerai density and increased fracture risk in healthy elderly women. Animal studies bave shown that the most potent form pf vitamin K is vitamin K2, which was administered to rats at 0.1 mg/kg oraliy (Akiyama, Y., K. Hara, A. Matsumoto, S. Takahashi, and T. Tajima, 1995, Comparison of intestinal absorption of vitamin K2 (menaquïnone) homologues and their effects on blood coagulation in rats with hypoprothrombinaemia, Biochem
Pharmacol 49:1801-7). Vitamin K2, in the form of menaquinone-4, is the most biologically active form. It has been extensively studied in the treatment of osteoporosis. In one of these studies, 241 osteoporotic women were given 45 mg/day vitamin K2 and 150 mg elemental calcium. After two years, vitamin K2 was shown to maintain lumbar bone minerai density, significant lower fracture incidence ( 10% versus 30% in the control group (Shiraki, M., Y. Shiraki, C. Aoki, and M. Miura, 2000, Vitamin K2 (menatetrenone) effectively prevents fractures and sustains lumbar bone minerai density- in osteoporosis, J Bone Miner Res 15:51515 21).
Vitamin K2, but not vitamin Kl, may inhibit the calcification of arterial plaque. In 1996, animal studies involving rats found high dose of vitamin K2 (100 mg/kg body weight I daily) inhibited the intrease in calcium in both kidneys and aorta induced by megadose of synthetic vitamin D (Seyama, Y., M. Horiuch, M. Hayashi, and Y. Kanke, 1996, Effect of vitamin K2 on experimental calcinosis induced by vitamin D2 in rat soft tissue, Int J Vitam Nutr Res 66:36-8). A similar study was conducted with rabbits. High dose of Vitamin K2 (ΙΙΟ mg/kg daily for 10 weeks) inhibited the atherosclerotic plaque progression in the aorta and pulmonary arteries (Kawashima, H., Y. Nakajima, Y. Matubara, J. Nakanowatari, T. Fukuta, S. Mizuno, S. Takahashi, T. Tajima, and T. Nakamura, 1997, Effects of vitamin K2 (menatetrenone) on atherosclerosis and blood coagulation in hypercholesterolemic rabbits, Jpn JPharmacol 75:135-43). |
Vitamin K2 was also seen to reduce total cholestérol levels, lipid peroxidation, ester cholestérol déposition in the aorta and factor X activity in plasma compared to the control group. A study involving more than 500 postmenopausal women investigated the relation between vitamin Kl and vitamin K2 intake and coronary calcification. Sixty-two percent of the women sampled for the study had coronary calcification. Only vitamin K2 intake was associated with the trend toward decreasing coronary calcification (Beulens, J. W., M. L. Bots, F. Atsma, M. L. Bartelink, M. Prokop, J. M. Geleijnse, J. C. Witteman, D. E. Grobbee, and Y. T. van der Schouw, 2009, High dietary menaquinone intake is associated with reduced coronary calcification, Alherosclerosis 203:489-93).
In some embodiments. a composition of the présent disclosure comprises one or more of the vitamins or vitamers above. A composition may comprise one or more of the vitamins or vitamers above in amounts between 1 pg and 1,000 mg per dose.
In some embodiments, a composition of the présent disclosure may further comprise antioxidant compounds. These may include, but are not limited to, nonenzymatic compounds such as tocopherol (aTCP), coenzyme Q10 (Q). cytochrome c (C) and glutathione (GSH). and enzymatic components such as manganèse superoxide dismutase (MnSOD), catalase (Cat). glutathione peroxidase (GPX), phospholipid hydroperoxide glutathione peroxidase (PGPX), glutathione reductase (GR); peroxiredoxins (PRX3/5), glutaredoxin (GRX2), thioredoxin (TRX2) and thioredoxin reductase (TRXR2). A composition may comprise one or more of the antioxidant compounds above in amounts between 1 pg and 1000 mg per dose.
In some embodiments, a composition of the présent disclosure may further comprise a stabilized oxidative species. The stabilized oxidative species may be, without limitation, one or more of H2O, O2, H2O2, CLO and HsO.
Other adjuncts may include sélénium and/or selenocysteine at concentrations of 60 to 90 pg per dose. Othër adjuncts may also include other trace éléments and their salts, including, but not limited to, copper, chromium, iodine, fluoride, zinc, manganèse, molybdenum, and iron.
In some embodiments, compositions of the présent disclosure may be formulated by combining pharmaceutical grade compounds into a stable therapeutic composition. Compounds may be added in desired amounts to a vessel, with water added to complété a final volume. In some embodiments, a composition of the présent disclosure comprises a final volume of between 5 mL and 500 mL. In other embodiments, a composition comprises a final volume of about 250 i|nL. In some embodiments, the composition may be provided in 20 mL vials. A composition of the présent invention may be further diluted prior to administration. For example, a 20 mL vial may be diluted with saline to a 100 mL dispensed volume for administration. In other embodiments, the liquid formulation may be reduced to dry solid via lyophilization. The lyophilized formulation may then be reconstituted to a particular volume prior to administration.
Table 1 shows various formulations of the composition according to exemplary embodiments of the présent disclosure per 20 mL vial:
Table 1
Component | mg/dose | mg/dose | mg/dose | mg/dose | mg/dose | mg/dose | mg/dose | mg/dose |
L-Ascorbic Acid USP | 0 | 450 | 900 | 900 | 12 | 2,000 | 2,000 | 0 |
Dehydroascorbi c Acid | 0 | 0 | 0 | 12 | 900 | 2,000 | 2,000 | 4,000 |
Thiamine HCl USP | 63.33 | 63.33 | 63.33 | 53.33 | 63.33 | 63.33 | 63.33 | 63.33 |
Magnésium Sulfate USP | 808 | 808 | §08 | 808 | 808 | §08 | 808 | §08 |
Cyanocobalami n USP | 1.93 | 1.93 | 1.93 | 1.93 | 1.93 | 1.93 | 1.93 | 1.93 |
Niacinamide USP | 119 | 119 | 119 | 119 | 119 | 119 | 119 | 119 |
Pyridoxine HCl USP | 119 | 119 | 119 | 119 | 119 | 119 | 119 | 119 |
Riboflavin 5'Phosphate USP | 2.53 | 2.53 | 2.53 | 2.53 | 2.53 | 2.53 | 2.53 | 2.53 |
Calcium D- Pantothenate USP | 2.93 | 2.93 | 2.93 | 2.93 | 2.93 | 2.93 | 2.93 | 2.93 |
Sodium Bicarbonate USP | 840 | 840 | 840 | 840 | §40 | 3,360 | 3,360 | 3,360 |
WFI (water for injection) | balance | balance | 1 balance | balance | balance | balance | balance | balance |
mM/dos e 1 | mM/dos e | mM/dos e | mM/dos e | mM/dos e | mM/dos e | mM/dos e | mM/dos e | |
HCl USP diluted with WFI (mM @ 20ml) | 250 | 125 | 0 | 6.5 | 6.5 | 0 | 250 | 0 |
I
In some embodiments, the components of the compositions in Table 1 may be varied from the listed values by plus or minus 1%, 2%, 5%, or 10% according to therapeutic need. The compositions of ifable 1 may also further comprise additional components as described above according to therapeutic need.
In some embodiments, compositions of the présent disclosure may be stabilized to enhance shelf life. The compositions may be stabilized by suitable techniques as known to those of ordinary skill in the art, including, but not limited to, freezing, lyophilization, use of UV or spectral biocking vials (e.g., amber vials), overfilling with stabilizing gases such as nitrogen, bubbling a stabilizing gas through the solution, separating reactive species into multiple vials to be combined upon use, and cold chain storage. As one non-limiting example, the acid and buffer components of a composition may be separated into two vials. Other components of compositions of the présent disclosure (e.g., cyanocobalamin, calcium d-pantothenate, and/or others) may be included in these vials or frirther separated into additional vials.
Methods of Treatment
In another aspect, the présent disclosure provides methods of treatment. The methods of the invention involve administering the composition of the invention to subjects in need thereof.
One embodiment of the invention is a method of treating or ameliorating a mitochondrial disorder, metabolic disorder, a condition associated with diabètes, a cardiovascular dysfunction, or an ocular condition in a subject in need thereof, by administering to the subject a stable therapeutic composition of the présent disclosure.
Mitochondrial dysfunction, characterized by a loss of efficiency in the électron transport chain and réductions in the synthesis of high-energy molécules, such as ATP, is a characteristic of aging, and essentially, of ail chronic diseases. As used herein, the term “mitochondrial disorder” refers to a condition or disorder characterized by mitochondrial dysfunction, and inclpdes, for example, neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophie latéral sclerosis, and Friedreich’s ataxia, cardiovascular diseases, such as atherosclerosis and other heart and vascular conditions, diabètes and metabolic syndrome, autoimmune diseases, such as multiple sclerosis, systemic lupus erythematosus, and type 1 diabètes, neurobehavioral and psychiatrie diseases, such as autism spectrum disorders, schizophrenia, and bipolar and mood disorders, gastrointestinal disorders, fatiguing illness.es, such as chronic fatigue syndrome and Gulf War illnesses, musculoskeletal diseases. such as fibromyalgia and skeletal muscle hypertrophy/atrophy, and chronic infections.
As used herein, a “metabolic disorder” refers to diabètes, insulin résistance, glucose intolérance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia. The terms “diabètes” and “diabètes mellitus” are intended to encompass both insulin dépendent and non-insulin dépendent (Type 1 and Type 2, respectively) diabètes mellitus, gestational diabètes, as well as pre-diabetes, unless one condition or the other is specifically indicated.
As used herein, a “condition associated with diabètes” includes obesity, hypertension, hyperlipidemia, fatty liver disease, nephropathy, neuropathy, rénal failure, retinopathy, diabetic ulcer, cataraçts, insulin résistance syndromes and cachexia.
As used herein, “cardiovascular dysfunction” includes conditions and diseases such as coronary heart disease, cerebrovascular disease, hypertension, peripheral artery7 disease, occlusive arterial disease. angina. rheumatic heart disease, congénital heart disease, heart failure, cardiac insufficiency, palpitations, supraventricular tachycardia, fibrillation, faintness, dizziness, fatigue, migraine, high levels of total blood cholestérol and/or LDL cholestérol, low level of HDL cholestérol, high level of lipoprotein, infections of the heart such as carditis and endocarditis, diabetic ulcer, thrombophlebitis, Raynaud’s disease, anorexia nervosa. claudication and gangrené, atherosclerosis and peripheral artery disease. Diseases and conditions that are especially suited for treating or ameliorating with a pharmaceutical grade buffer composition as described herein are peripheral artery disease and atherosclerosis.
As used herein, the term “ocular condition” refers to pathological conditions pertaining to the eye, and may include, but is not limited to, glaucoma, macular degeneration, light sensitivity issues, calcifie and collagen-based floaters, lens rigidity correction.
Another embodin|ient of the invention is a method of treating or ameliorating a dermatological condition by administering to the subject a stable therapeutic composition of the présent disclosure; As used herein, the term “dermatological condition” refers to skinrelated disorders, conditions and disease such as skin aging, wrinkles (including, e.g., laugh lines and wrinkles surrounding the eye), acné, photodamage, rosacea, scars, eczema, alopecia, hypertrophie scars, keloids, stretch marks or Striae distensae, psoriasis, pruritus, ehlersdanlos syndrome, scléroderma, post inflammatory hyperpigmentation, melasma, alopecia, poikiloderma of civatie, vitiligo, skin dyschromia, bums and blotchy pigmentation.
In another aspect, the présent disclosure provides a method of modifying the metabolism of a subject, the method comprising administering to the subject a stable therapeutic composition comprising a buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent, wherein the buffer solution is sufficient to reduce the physiological bloodstream pH of a subject by 0.01 to 1.1, and wherein the buffer solution has a buffer capacity sufficient to sustain the réduction of the physiological bloodstream pH of the subject for between 1 minute and 1 week.
A different embodiment of the invention provides a method of reducing lactate burden in a subject in need thereof, by administering to the subject the composition of the invention. The réduction of lactate burden has been described extensivelv herein-above.
i
In another embodiment of the invention, the présent disclosure provides a method of reducing acidosis in a subject in need thereof, by administering to the subject the composition of the invention. The réduction of acidosis has been described extensively herein-above.
In another embodiment, the présent disclosure provides a method of treating a central nervous system disorder in a subject in need thereof, by administering the composition of the invention. As used herein, the term “central nervous System disorder” means any neurological disorder, affecting the structure or function of the brain or spinal cord.
In another embodiment, the présent disclosure provides a method of treating chronic wounds of a subject, by administering the composition of the invention. In some embodiments, the présent disclosure provides a method for inducing accelerated wound healing in a subject, the method by administering a stable therapeutic composition of the présent disclosure.
In another embodiment, the présent disclosure provides a method of enhancing mental or physical performance of a subject, by administering the composition of the invention.
Routes of administration for a therapeutically effective amount of a composition of the présent disclosure include, bijt are not limited to, intravenous, intramuscular, or parente^al administration, oral administration, otic administration, topical administration, inhalation or otherwise nebulized administration, transmucosal administration and transdennal administration. Compositions of the présent disclosure may also be formulated for intravenous, bolus, dermal, oral, otic, suppository, buccal, ocular, or inhalation delivery. For intravenous or parentéral administration, i.e., injection or infusion, the composition may also contain suitable pharmaceutical diluents and carriers, such as water, saline, dextrose solutions, fructose solutions, éthanol, or oils of animal, végétative, or synthetic origin. It may also contain preservatives, and buffers as are known in the art. When a therapeutically effective amount is administered by intravenous, cutaneous or subcutaneous injection, the solution can also contain components to adjust pH, tonicity, stability, and the like, ail of which is within the skill in the art. For topical administration, the composition may be formulated in, e.g., liquid, gel, paste, or cream, In some embodiments, the composition may be administered via a topical patch. For ocular administration, the composition may be formulated in, e.g., liquid eye drops, or as a gel, paste, or cream to be applied to the surface of the eye and/or surrounding tissue. For otic administration, the composition may be formulated in, e.g., ear drops.
A composition for intravenous, cutaneous, or subcutaneous injection should contain, in addition to peptide an isotonie vehicle such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection. Dextrose and Sodium Chloride Injection, Lactated Ringer’s Injection Citrate Buffer pH 5.5, or other carriers, diluents and additives as known in the art. As described fully efrewliere herein, the pharmaceutical composition of the présent invention may also contain stabilizers, preservatives, buffers, antioxidants, or other additive known to those of skill in the art. The pharmaceutical compositions are formulated for intravenous or parentéral administration. Typically, compositions for intravenous or parentéral administration comprise a suitable stérile solvent, which may be an isotonie aqueous buffer or pharmaceutically acceptable organic solvent.
As described fully elsewhere herein, where necessary, the compositions can also include a solubilizing agent. Compositions for intravenous or parentéral administration can optionally include a local anesthetic to lessen pain at the site of the injection. Generally, the ingrédients are supplied either separately or mixed together in unit dosage form in a hermetically sealed container such as an ampoule or sachet. The pharmaceutical compositions for administration by injection or infusion can be dispensed, for example, with an infusion bottle containing, for example, stérile pharmaceutical grade water or saline. Where the pharmaceutical compositions ^re administered by injection, an ampoule of stérile water for injection, saline, or other solvent such as a pharmaceutically acceptable organic solvent can be provided so that the ingrédients can be mixed prior to administration.
The duration of intravenous therapy using the pharmaceutical composition of the présent invention will vary, depending on the condition being treated or ameliorated and the condition and potential idiosyncratic response of each individual mammal. The duration of each infusion is from <1 minute (e.g., bolus injection) to about 1 hour (intravenous delivery). The infusion can be repeated within 24 hours. Thus, a mammal can receive about 1 to about 25 infusions per day. Preferably, the number of infusions per day is 1 or 2. The period between each infusion can be 1, 2, 5, 10, 20, 30, 40, 50 minutes, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours or more. The administration may also be administered at any of a variety of cadences, including hourly, daily, weekly, monthly, quarterly, bi-annually, annually, etc., or any other particular timeframe depending on the condition to be treated and/or the response of each individual mammal. In other embodiments, a pharmaceutical composition of the présent invention may be administered as a single event, or may be administered over weeklong, multi-week, month-long, year-long. or multi-year durations, or for any other desired duration as may be warranted.
Altematively,i the infusions can be given one after another without a substantial period in between. In one embodiment, the infusion lasts about 45 minutes. The dose may be repeated 2-3 times a week depending on the severity of the relative or absolute déficits of nutrients in the patient. A clinical assessment may be necessary in order to establish the status, but can be limited to a review of medical history, subjective review of symptoms, the subjective opinion of|the mammal when human or upon review of any spécifie déficits.
In another embodiment of administration, administration is alternated between two solutions: one acid shifting (AS) and one base shifting (BS) as described above. Alternating administration of AS/BS/AS/BS in various cadences would be expected to induce more pH swings from acidic towards basic or from basic towards acidic. Such events, as induced through exercise, are recognized for their value in promoting nitric oxide (NO) release for vasodilation (Capellini, Verena K., et al., 2013, The Effect of Extracellular pH Changes on Intracellular pH and Nitric Oxide Concentration in Endothélial and Smooth Muscle Cells from Rat Aorta, PLOS One, 8(5):e62887), and to promote cardiolipin repair and remodeling (Khalafat, Nada, et al., 2011, Lipid Packing Variations Induced by pH in CardiolipinContaining bilayers: The Driving Force for the Cristae-Like Shape Instability, Biochimica et Biophysica Acta - Biomembranes, 1808(11):2724-2733). These alternating administrations njtay each last between 0.5 and 60 minutes, and may be alternated one, two, or more times as necessary to achieve the desired therapeutic effect. The AS and BS administrations need not necessarily be identical in either their shifting effect or duration of administration. That is, for example, an AS composition may affect a larger shift over a shorter administration, while the BS composition may affect a smaller shift over a longer administration. In some embodiments, an exemplary administration profile may be a 5 minute AS administration followed by a 10 minute BS administration, repeated two times (i.e., 5/10/5/10). Other exemplary administration profiles may be, e.g., 10/10/10/10 or 0.5/0.5/0.5/0.5.
Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, mtramuscular, intrathecal or intraperitoneal injection. Useful injectable préparations include stérile suspensions, solutions or émulsions of the active compoundf s) in aqueous or oily vehicles. The compositions also can contain solubilizing agents, formulating agents, such as suspending, stabilizing and/or dispersing agent. The formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, । and can contain added preservatives. For prophylactic administration, the compound can be 'administered to a patient at risk of developing one of the previously described conditions or diseases. Altematively, prophylactic administration can be applied to avoid the onset of symptoms in a patient suffering from or formally diagnosed with the underlying condition.
The amount of compound administered will dépend upon a variety of factors, including, for example, the particular indication being treated, the mode of administration, whether the desired benefit is prophylactic or therapeutic, the severity of the indication being treated and the âge and weight of the patient, the bioavailability of the particular active compound, and the like. Détermination of an effective dosage is well within the capabilities of those skilled in the' art coupled with the general and spécifie examples disclosed herein.
Formulations can comprise other ingrédients for the treatment of the organisai as a whole. For example, an anti-oxidant additive and/or pro-oxidant additive can be présent. The latter may be an agent that acts as a préventive, while the former may be an agent that acts to treat a spécifie medical condition.
Efficacy of treatment may be determined by measuring biomarkers before, during, andor after administration of a composition of the présent disclosure, or before, during and/or after administration of a course of treatment using compositions of the présent disclosure. Exemplary biomarkers, and the indications for which they may be used, are shown in| Table 2, and may include, e.g., AlMicro, tubular disorders and electrolyte imbalance; A2Macro, cérébral small vessel disease, liver fibrosis; ACE, high blood pressure, heart failure, diabetic nephropathy; Adiponectin, vascular disease, metabolic syndromes; Apo A-I, high density lipid particles; Apo A-II, HDL metabolism; Apo C-II, ischémie stroke, heart disease; Apo C-III, metabolic syndrome and hypertriglyceridemia; Apo H, type 2 diabètes, metabolic syndrome; AT-ΠΙ, venous thrombosis, abnormal coagulation; B2M, peripheral arterial disease; BDNF, psychiatrie disorders; CD163, HIV infection, inflammation, cardiovascular disease; CD40, atherosclerotic instability; CD40-L, cellular prolifération; CgA, tumors; C-Peptide, metabolic syndrome; CRP, inflammation and tissue damage; Cystatin-C, cardiovascular disease, electrolyte imbalance; EGF, cellular prolifération; EN-RAGE, inflammation, heait disease; EPO, anémia, chronic kidney disease;; E-Selectin. inflammation, electrolytic imbalances; Factor VII, thrombosis (blood clotting); Ficolin-3, diabetic peripheral neuropathy; FRTN, blood disorders, anémia; FSH, pregnancy complications; GDF-15, mitochondrial diseases; GLP-1 total, type 2 diabètes, insulin sécrétion; ΗΒ-EGF, épithélial cell prolifération (inflammation); ICAM-1, inflammation; IFNgamma. inflammation and immune response; IL-1 alpha, inflammation; IL-1 beta.
inflammation; IL-10, inflammation; IL-12p40, inflammation, multiple sclerosis, Alzheimer’s disease; IL-12p70, peritonitis, inflammation; IL-15, Alzheimer’s disease; IL-17, inflammation, lupus, cérébral vasculitis; IL-18, metabolic syndrome, acute kidney injury; ILIra, inflammation; IL-2, inflammation; IL-23, inflammation, lupus; IL-3, inflammation, cell growth, prolifération, and différentiation; IL-4, inflammation; IL-5, inflammatory factors, asthma, chronic obstructive pulmonary disease; IL-6, inflammation; IL-6r, coronary heart disease; IL-7, immune-mediated inflammatory diseases; IL-8, inflammation; IP-10, tuberculosis related complications; LH, infertility; Lp(a). cardiovascular diseases; MCP-1, inflammation; MCP-2, tuberculosis; MCP-4, asthma, metastasis; M-CSF, metabolic, hématologie and immunologie abnormalities; MIG, heart failure and left ventricular dysfunction; MIP-1 alpha, cytokine expression for high fat diet, wound healing; MIP-1 beta, autoimmune disorders; MIP-3 alpha, tissue injury in ischémie stroke and autoimmune diseases; MMP-3, ischémie and hémorrhagie stroke; MMP-9, ischémie and hémorrhagie stroke; MPIF-1, Kawasaki disease (inflammation in the walls of some blood vessels); MPO, inflammation and ischemia; Myoglobin, inflammation and ischemia; NAP-2, hepatitis B; NGF-betac, Alzheimer’s disease, psychological disorders; Nr-CAM, Alzheimer’s disease, cognitive disorders; Osteocalcin, osteoporosis, bone formation; PAI-1, metabolic syndrome; PARC, Gaucher disease (enlargement of liver/spleen); PDGF-BB, osteoblast development ^nd bone formation, liver fibrosis; PEDF, cardiometabolic] disorders; Periostin, asthma; PLGF, angiogenesis, yasculogenesis and lymphangiogenesis; PPP, endocrine pancreatic tumors; PRL; P-Selectin, inflammation; RAGE, chronic inflammatory diseases; RANTES, abdominal aortic aneurysm, viral diseases; Resistin, inflammation, cardiovascular disease; S100-B, brain damage and blood-brain barrier disruption; S AA, inflammation; SAP, acute and chronic inflammation; SCF, tumor prolifération; SHBG, thyroid disorders, pituitary diseases; SOD-1, amyotrophie latéral sclerosis; Sortilin, coronary artery disease, affective disorders; ST2, inflammation and adhesion; TAFI, arterial thrombosis, acute ischemia; TBG, thyroid related disorders; TIMP-1, tissue remodeling, wound healing and tumor metastasis;
TN-C, myocarditis; TNF-alpha. inflammation: TNF-beta, inflammation, cardiovascular disease; TNFR2, ischémie stroke, insulin disorders; TTR, metabolic and septic disorders: VCAM-1, inflammation; VEGF, angiogenesis, hypoxia: Vitronectin, Alzheimer's disease; and vWF, arrhythmia. acute arterial damage.
Table 2 1
Tier II Biomarkers | Reference Range | Régulation during diseased state | Pathological relevance |
E-Selectin | 30 pg ml 18000pgml* | Up | Inflammation |
L-Selectin | 100 pg/ml - 25 ng/ml | Up | Inflammation |
P-Selectin ! | 20 pg ml - 30 ng/ml | Up | Inflammation |
Intercellular Adhesion Molécule-1 (ICAM-1) | 150 pg/ml - 20 ng/ml | Up | Inflammation |
Vascular Cell Adhesion 1 Molécule-1 (VCAM-1) [ | 0.3 ng/ml - 60 ng/ml | Up | Inflammation |
Epidermal Growth Factor (EGF) | 1 pg/ml - 200 pg/ml | Up | Cellular Prolifération |
Interferon-g (IFN-g) | 15.6- 1,000 pg/mL | Up | Inflammation and Immune Response |
Interleukin-la (IL-la) | 0.5 pg/ml - 300 pg/ml | Up | Inflammation |
Interleukin-lb (IL-lb) | 0.3 pg/ml - 100 pg/ml | Up | Inflammation |
Interleukin-2 (IL-2) | 4 pg/ml - 1,500 pg/ml | Up | Inflammation |
Interleukin-4 (IL-4) | 5 pg/ml - 200 pg/ml | Up | Inflammation |
Interleukin-6 (IL-6) | 3 pg/ml - 1,000 pg/ml | Up | Inflammation |
Tier II Biomarkers 1 ) | Reference Range | Régulation during diseased state | Pathological relevance |
lnterIeukin-8 (IL-8) i ; | 1 pg/ml - 600 pg/ml | Up | Inflammation |
Interleukin-10 (IL-10 ) | 1 pg/ml - 1.50 pg/ml | Up | Inflammation |
Monocyte Chemotactic Protein-1 (MCP-1) | 2 pg/ml - 500 pg/ml | Up | Inflammation |
Tumour Necrosis Factor-a (TNF-a) | 30 pg/ml 6,000 pg/ml | Up | Inflammation |
Vascular Endothélial Growth Factor (VEGF) | 31-86 pg/mL | Up | Hypoxia |
SAA | 0.5 ng/ ml - 300 ng/ml | Up | Inflammation |
Fibrinogen | 150-400 mg dL | Up | Thrombosis |
C-Reactive Protein (lCRP) | 0-1 OmgdL | Up | Inflammation and Tissue Damage |
Apo Al | Males:94-176 mg/dL; Females:10119 8 mg/dL | Up | Hight Density Lipid Particles |
Apo B 1 | Male:52-109 mg/dL;Female:4 9-103 mg/dL | Up | Low Density Lipid Particles 1 |
Insulin | 4 pIU/ml - 300 plU/ml | Up | Metabolic Syndrome |
Proinsulin | 0.313 ng/ml - 20 ng/ml | Up | Metabolic Syndrome |
C-peptide | 0.156 ng/ml - 10 ng/ml | Up | Metabolic Syndrome |
Tier Π Biomarkers | Reference Range | Régulation during diseased State | Pathological relevante |
Myeloperoxidase | Adult Male-<50 mcg L; Adult Female= <30 mcg L | Up | Inflammation and Ischemia |
CD40 Ligand | 32-2,000 pg mL | Up | Cellular Prolifération |
Bile Acid Panel (16 bile acids) | Varies | Varies | Cardiovascular Disease |
pl80 Kit (188 endogenous métabolites from 5 compound classes) | Varies | Varies | Cardiometabolic Risk |
Oxidized LDL | 30-2,000pg/mL | Up | Oxidative Stress and Low Density Lipid Particle |
ST2 | 0.156--10ng/mL | Up | Inflammation and Adhesion |
Creatine Kinase Muscle Brain (CK-MB) | 0-5.0 ng/mL | Up | Inflammation |
Heart Type Fatty Acid Binding Protein (H-I^ABP) | 102-25,000 pg/ml | Up | Inflammation and Thrombosi^ |
Myoglobin (Myo) 1 | Adult Male=<50 mcg/L; Adult Female=<30 mcg/L | Up | Inflammation and Ischemia |
Troponin I (cTnl) | <0.05 ng/mL | Up | Cardiovascular Disease |
Tier II Biomarkers | Reference Range | Régulation during diseased State | Pathological relevance |
Adiponectin 1 | 0.38-12 ng/mL(www.kassay.com) | Up | Inflammation and Cardiac Disease |
Cystatin C | 0.3 ng/ml - 20 ng ml | Up | Cardiovascular Disease |
Catalase | 0.313 ng/ml - 20 ng/ml | Up | Oxidative Stress |
p53 | 3.1 U/ml - 100 U/ml | Down | Apoptosis |
Kits
One embodiment of the invention includes a kit for administering the stable therapeutic composition of the présent disclosure to a subject. In this embodiment, the kit may contain the composition in a single vial or in more than one vial. The vial can preferably be an injection vial wjith a membrane that is suitable for inserting a syringe to pull the solution from the vial or a soft I.V. infusion bag. The composition of the invention is contained in the vial in a stérile aqueous solution. The solution can be provided as a concentrated solution to which a diluent is added prior to administration. The diluent can be stérile water. The kit may further comprise a pre-filled container which contains the diluent. In a preferred embodiment, a soft infusion bag is pre-filled writh diluent. Alternatively, the composition vial can contain a solution that is at a concentration which is suitable for injection without any dilution. Preferably, the solution for injection is isotonie. That is, the solution can contain sait, carbohydrates, such as glucose, NaHCCb or amino acids, such as glycine, and is isotonie with blood plasma. In other instances, the solution may be hypotonie so as to promote more rapid intracellular uptake or hypertonie so as to promote slower intracellular uptake.
In one embodiment of the invention, the kit contains two vials. The first vial at least i one pharmaceutical grade acid in a stérile aqueous solution. For example, the first vial may contain pharmaceutical grade ascorbic acid, thiamine HCl, magnésium sulfate, cyanocobalamin. nîacînamide, pyroxidine HCl, riboflavin 5’ phosphate, calcium Dpantothenate, and an aqueous solvent containing sodium chloride and water (for injection). The second vial contains at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution. For example, the second vial may contain pharmaceutical grade sodium bicarbonate and an aqueous solvent containing sodium chloride and water (for injection). The contents of the vials may be stored under réfrigération or under freezing conditions.
In another embodiment, the kit may contain a container of a lyophilized powder that may be reconstituted prior to administration. The lyophilized powder may be an isotonie solution.
Each kit described herein may further comprise instructions for use. The instructions will, of course, dépend upon the kit itself and whether a diluent is to be used or other components to be admixed with the pharmaceutical grade buffer solution prior to administration.
EXAMPLES
Example 1
Experiments described herein were designed to validate key aspects of using buffered acidic solutions to acidically shift bloodstream pH for therapeutic purposes. Specifically, several aspects are illustrated: (1) Blood has acid-base properties that can be notionalized as a solution having a physiological pH and buffer capacity. Furthermore, therapeutic compositions designed to shift blood pH upon administration can be notionalized as solutions having a target pH and buffer capacity. (2) pH shifting of the bloodstream towards acidic conditions can be achieved via intravenous or intraarterial administration of an acid solution. (3) Alternative formulations having higher concentrations of buffer components hâve increased capacity to impede the restoration of bloodstream pH back towards physiologie. (4) Faster dissolution of calcified minerai forms can be achieved when the conditions are shifted from equilibrium at a given pH to lower pH levels.
The rationale, protocol, and results of these experiments are described in the following sections.
Acid-base properties of blood
At physiologie norm conditions, blood is recognized to commonly hâve a pH value near 7.41. The is due to the presence of various acids within it (primarily HCl) and various buffers (primarily bicarbonate). In the interest of developing a surrogate to emulate the acid
I 43 base properties of blood, a water-based solution was prepared that contained HCl and HCO?. HCl and HCOs were chosen for this surrogate as they are the primary acid and buffer species in blood. For this blood surrogate, 0.0024 M HCl in 5,000 ml of aqueous solution was buffered with 0.025 M of NaHCOs, to produce a résultant pH of 7.41 (Table 3). This surrogate was freshly prepared for each of the tests that were performed as CO2 loss will influence the pH over time if left to atmospheric exposure.
Similarly, drug products designed to shift blood pH could be formulated using a variety of physiologically compatible acids and buffers. To illustrate this, 4 example drug products (C1-C4: Table 3) were formulated using HCl and NaHCO? as example acid and buffer components (Blood and Drug Compositions per Table 3 Below). By design, these would hâve pH below physiologie and be comprised of buffer products as well. CI was i designed to provide a small pH shift for a short time, C2 was designed to provide a small pH shift for a long time, C3 was designed to provide a large pH shift for a short time, and C4 was designed to provide a large pH shift for a long time.
HC03- (Bicarbonate) pKa_________6.4________|pH = plpH = pKa + loglO (base/acid)
Table 3
pH shift of I | blood*Cl | ? t | g 2 as | Γ WI8 | o «χΓ O | |
1 amount | 4.5 | FM | 16.7 | |||
X | ] | |||||
2 | 1 | |||||
1 concentration | 0.2233 | 0.0024 | 0,00332 | _ __0.00332 | ||
X | : | |||||
actual | X X | 6.9S | I 7M I | | 731 1 | 17M 1 | |
cale | pH | 1 θ·75 | | 9 | 1 7.31 | | S | |
5 £ | ||||||
C □ O | O | 1Λ S- | 135 | S: | m S | |
HCO3- | 1 | |||||
-J | ||||||
2 | ||||||
C O | 1 | |||||
m c φ | 0.5000 | 0.0250 | 0.0269 | 0.0289 | ||
o | | | |||||
HCO3- | v | I | ||||
i: | ||||||
f E 5 O > | 07 | | I 5000 | | 5020 | | ___5020 _ | ||
£ Ch C O | ig time | | force | | ||||
£ s <υ Ch | O £ JZ «0 Φ | d | restoring 1 | h Cl + BiC< | ||
5 □ | | Cl: larg | | Blood | O O O CÛ | | Bicarb | | Blood - |
pH shift ofl | blood*C2 | pappe Md | gram of | BiCarb | | 0.004 | | |
[mM)| | ||||||
amount 1 | 0'8 | 12.2 | 20.2 | O | ||
[HCI | ||||||
2 | ||||||
concentration | 0.3991 - | 0.0024 ’ | 0.00402 | 0.00402 | ||
U X | ||||||
actual | pH | «7 | 1 îpî | 7.31 | | 7.35 | | |
cale | X CL | 7.10 | 1741 1 | 1 7.31 I | 7.34 | | |
2 E. | ||||||
amount | O *3· | 125 | 165 | O | 175 | |
ff) O U X | ||||||
(M, | ||||||
C O | ||||||
Φ c Φ W | 2.0000 | 0SZ0O | 0.0329 | 0.0349 | ||
O | ||||||
m O u X | Ih | |||||
0) E □ | 20 | | | ooos | 5020 | 5020 | ||
o > | ||||||
Q) ,E C) c •c V) 0) «31 6 | |C2: large shift long time | | | Blood | | | Blood+C2 | | |Bicarb restoring force | | [Blood + C2 + BiCarb | |
pH shift of I | m o o Λ | peppetad | gram of | «I «1 a | i) o | |
amount (mM)! | 55.0 | [ 12.2...................... | 67.2 | | δ | ||
U X | ||||||
concentration (M/L)| | S FM | 0.0024 I | 0.01338 | 0.01338 | | ||
u X | ||||||
actual | pH | \S.75 | 7.41 I | 6,70 | | Ch | |
cale | X Q. | 5.66 | 5 | K9 | K MD | |
2 E, | ||||||
amount | O | m Ci | 135 | i | 165 | |
en O U X | ||||||
C7 | ||||||
S c o | ||||||
2 c Φ u | 0.5000 | 05Ζ0Ό | 0.0269 | 0.0329 | ||
o | ||||||
en O u X | ||||||
Έ © E □ | 5000 | 5020 | | 5020 | | |||
o > | ||||||
CU 1 en C 5 5 <u E1 0 | | C3: large shift long time | | | Blood | | m U + D O O CQ | |Bicarb restoring force | | Blood+C3 +BiCarb | |
hof | 5 | 1 •G | « | |||
I pH shf | blood | per ad | gram | «F CO | O[ O[ | |
2 | ||||||
(m | ||||||
sunt | PM ΓΜ | Î3.3 | m CO | |||
E | ||||||
w | ||||||
X | - | |||||
(M/L | ||||||
ration | 566 | 024 | L660 | - | L660 | |
G | m | O | O | O | ||
Φ u | c*> | o | ô | ô | ||
cor | ||||||
□H | ||||||
ï | 5 | g | ch | |||
t Q | Cl | MS | MÎ | MD | ||
| cale | | PH I | | 6.15 ' | 17·41 1 | | 6.68 1 | | 6.81 I | |
2 | ||||||
E. | ||||||
moun | O *3· | 125 | 165 | O 1Λ | 215 | |
« | ||||||
o | ||||||
X | ||||||
(Ί/ΙΛΙ) | ||||||
C o | ||||||
Λ | O | O | Ch | 00 | ||
G | O | PM O | m Q | o | ||
PM | O | O | ό | |||
O u | ||||||
en | ||||||
o | ||||||
X | )b | |||||
Ë | ||||||
O | P | o | ||||
um< | R | )0S | o LD | o m | ||
Vol | ||||||
<u | ||||||
JE | ||||||
» | i | Φ | ||||
C o | M | E o | _Q x. | |||
£ -c | Ift Ion | ringf | h BiCa | |||
V) ω Ch | ;e shi | 3 | resto | H MH | ||
5 | E» JS | Q | JD | TO 0 | ||
5 | O | ô | 5 | Ô | ||
o | u | CÛ | CÛ | œ | CQ |
First, Cl, C2. C3, and C4 were formulated. as vas the blood surrogate, and the pH was measured. The pli was also calculated per the Henderson-Hasselbalch équation. Second, the compositions Cl, C2, C3, and C4 were added to the surrogate blood. Again, a pH value was calculated, and a pH value was measured. Upon administration into the bloodstream, each ofthe example therapeutic solutions shift the bloodstream pH from physiologie norm conditions (e.g., 7.41 pH) to reduced pH (e.g., 7.31 - 6.70 pH). This is demonstrated through addition of the Cl (or 2,3,4 ) to the blood surrogate solution, as summarized in Table 3. In this case, the therapeutic formulations with the lowest pH and or larger buffer fraction are capable of imparting a larger shift in bloodstream pH.
To demonstrate the resilience of therapeutically shifted blood to resist retum to physiologie, a fixed quantity of bicarbonate was added into each of the therapeutically shifted blood solutions. This was done to simulate pH restoring effects such as stimulation of additional buffer sources, CO2 respiration, and rénal action to remove H and re-cycling of HCOs'. Such restorative forces were simulated by administering a fixed allocation of HCOs' to the therapeutically shifted blood surrogate solution. For a given quantity- of added bicarbonate, the differing resilience of the C1-C4 compositions to resist blood pH restoration could be demonstrated- As shown in Table 3, the resilience to restoration can be expressed in tenus of delta pH / gram HCO3, where a lower value implies a greater capacity to resist pH restoration forces. In this example, the formulations with more buffer capacity (C2 or C4) are more résistant to restore towards physiologie per gram of pH restoring bicarbonate added.
To demonstrate the ability of calcium salts to dissolve more readily in lower pH solutions, such as would be the case for calcifîed plaques in a pH-shifted bloodstream, calcium salts were submerged in therapeutically pH-shifted blood surrogate solution and dry weighed after select time intervals of submersion.
To this end the blood surrogate w^s first exposed to a large quantity of calcium sait for an extended period while at pH 7.41 to establish equilibrium of the sait at the start pH. Then residual solid calcium salts were removed, leaving a blood surrogate solution that was near-saturated with the calcium sait at the 7.41 pH. Then Cl (or 2, 3, 4) formulations were added to the calcium saturated blood surrogate to reduce the pH. Then the 2g pellets of the calcium salts were submerged in therapeutically pH-shifted solution and dry weighed at select time intervals tb establish a rate of weight loss (Table 4). Because the surface area and shape of the calcium minerai was common to ail tests, the test demonstrates that lower pH solutions promote higher dissolution rates than higher pH solutions 0.043-0.044g min for pH 7.31 vs 0.054-0.059g min for pH = 6.7)).
Table 4.
Cl Bloodstream pH 7.31 | ||
Time minutes | Ca2+ weight (g) | Rate of Dissolution (g/min) |
10 | 1.9667 | |
20 | 1.5257 | 0.044 |
C2 Bloodstream pH 7.31 | ||
Time minutes | Ca2+ weight (g) | Rate of Dissolution (g min) |
10 | 1.9578 | |
20 | 1.5267 | 0.043 |
C3 Bloodstream pH 6.7 | ||
Time minutes | Ca2+ weight (g) 1 | Rate of Dissolution (g/min) |
10 | ' 1.9887 | |
20 | 1.4517 | 0.054 |
C4 Bloodstream pH 6.7 | ||
Time minutes | Ca2+ weight (g) | Rate of Dissolution (gtinin) |
10 | 1.978 | |
20 | 1 1.3901 | 0.059 |
It will be apparent to one of ordinary skill in the art that various combinations and/or modifications and variations can be made in the compositions of the présent disclosure depending upon and as dictated by the therapeutic needs of the patient. Moreover, features illustrated or described as being part of one embodiment may be used on another embodiment 10 to yield a still further[embodiment.
Example 2
Studies were conducted by administering the therapeutic composition to three horses. The following materials were prepared for the study:
1. Subject 1 - mare, 34 years old, Welsh Cross, 739 pounds, with a history of pre-diabetes, Laminitis with Cushing’s disease, and Lymes présentation.
2. Subject 2 - male neutered (gelding). 13 years old, Welsh Cross, 724 pounds, history7 of Laminitis with Cushing’s disease, and Lymes présentation.
3. Subject 3 - mare, 12 years old, Welsh Cross, 652 pounds, history of Lymes présentation.
4. Each Treatment involved the administration of an intravenous buffer solution:
a. 100 ml of A-Vial AS* Solution (containing ascorbic acid, hydrochloric acid, and aqueous solvent containing sodium chloride and water), or
100 ml of A-Vial ASVM** Solution (containing ascorbic acid , dehydroascorbic acid, hydrochloric acid, thiamine HCl, magnésium sulfate, cyanocobalamin crystalline, niacinamide, pyroxidine HCl, riboflavin 5’ phosphate, and calcium D-pantothenate, and aqueous solvent containing sodium chloride and water).
b. 100 ml ofB-Vial Bicarbonate Solution (containing sodium bicarbonate and an aqueous solvent containing sodium chloride and water).
c. 1000 ml Saline in an IV-ready bag, or 2000 ml Saline in an IV ready bag.
। * AS - grade sourced Acid Shifting Composition ** ASVM - grade sourced Acid Shifting Composition additionally containing select Vitamins and Minerais
Methods:
Doses of the therapeutic composition were managed as follows:
Table 5. Subject 1 Dosing
DOSE 1 | DOSE 2 | DOSE 3 | DOSE 4 | DOSE 5 |
DAY 1 | DAY2 | DAY 3 | DAY 6 | DAY 8 | |
100 ml A-Vial AS | |||||
100 ml A-Vial ASVM | X | X | X | X | X |
100 ml B-Vial Bicarb | X | X | X | X | X |
1000 ml Saline | X | X | X | X | X |
2000 ml Saline |
Table 6. Subject 2 Dosing
DOSE 1 DAY 1 | DOSE 2 DAY2 | DOSE 3 DAY 3 | DOSE 4 DAY 6 | DOSE 5 DAY 8 | |
100 ml A-Vial AS | X | ||||
lOOmlA-Vial ASVM | X | X | X | X | |
100 ml B-Vial Bicarb | X | X | X | X | X |
1000 ml Saline | X | X | X | X | |
2000 ml Saline |
Table 7, Subject 3 Dosing i
DOSE 1 DAY 1 | DOSE 2 DAY2 | DOSE 3 DAY 3 | DOSE 4 DAY 6 | DOSE 5 DAY 8 | |
lOOmlA-Vial AS | X | ||||
lOOmlA-Vial ASVM | X | X | X | X | |
lOOmlB-Viàl Bicarb | X | X | X | X | X |
1000 ml Saline | X | X | X | X | X |
2000 ml Saline |
Dosing was administered as follows:
A Vial products were refrigerated at 40°F prior to use, while B Vial products were stored at 70°F. 100 ml of A Vial product was combined into a saline IV bag, and then 100 ml 10 of B Vial product was combined into the IV bag. The IV bag was hung from an élévation point,
18” above infusion point. A cathéter was inserted into the jugular vein of the subject. Pretreatment venons blood samples were extracted from the patient for IDEXX analysis (hematology, chemistry, endocrinology and serology) and blood gas analysis (acid/base status, 49
Oximetry. Electrolytes, métabolites) (T = -5 min ). Five minutes (T = 0 min) later, the IV bag was connected to a cathéter, and the drip was opened to begin infusion. Forty fîve minutes (T =4 5 minjlater, the drip rate was adjusted to complété infusion. Venons blood samples were extracted from the subject during treatment, 15 minutes (T = 15 min) and 30 minutes (T = 30 min) after the treatment began. Post-treatment venons blood samples were extracted 60 minutes (T = 60 min) and 120 minutes (T = 120 min) after the treatment began. Post-treatment sample were subjected to blood gas analysis (acid/base status, Oximetry, Electrolytes and Métabolites) * Note: Subject l’s “pre-treatment” venons blood samples for IDEXX analysis (hematology, chemistry, endocrinology and serology) were mistakenly sampled 60 minutes after treatment began. The results likely reflect post-dose changes in plasma volume, as large changes were observed for concentration-based markers (e.g., RBC, hematocrit).
RESULTS
Results Section 1: Blood g\Gas and Acid-base Response:
Subject 2 AS Dose 1 and ASVM Doses 4 and 5 - Observed Response: Blood pH, blood HCOs-, and oximetry were observed at time intervals of 5 min pre-dose commencement (T = 5), 20 min post dose commencement (T = 20), and 5 minutes post-dose complété (dose complété at T = 45, measurement at T = 50) as shown in Table 8.
Table 8. Subject 2 Response for Dose 1 AS, Dose 4 ASVM, Dose 5 ASVM
AS Day 1 | Dose 1 | ASVM Day 6 Dose 4 | ASVM | |||||||
Day 8 | Dose 5 | |||||||||
Time | min | -5 | 20 | 50 | -5 20 | 50 | -5 | 20 | 50 | |
pH | - | 7.392 | 7.437 | 7.431 | 7.350 j 7.416 | 7.394 | 7.453 | 7.426 | 7.417 | |
cHCO3- | mmol/L | 33.2 | 31.0 | 3 | 1.0 | 26.7 ! 26.4 | 26.6 | 29.4 | 27.8 | 27.3 |
pCO2 | mmHg | 54.5 | 45.9 | 46.5 | 57.3 ! 43.2 | 47.7 | 44.3 | 44.5 | 45.1 | |
pO2 | mmHg | 30 | 34 | 35 | i 24 i 39 | 31 | 37 | 39 | 33 | |
sO2 | % | 55 | 67 | 69 | 39 | 76 | 59 | 73 | 76 | 66 |
Subject 2 - Observed Response for Dose 1 AS:
As shown in Figure 6, venons pH was observed to rise from a borderline acidotic start at 7.392, towards alkaline at T = 20, and then reduce back towards acidic at T = 50. Althoush the AS I solution should shift the blood stream towards acidic, this was not observed, perhaps because the observation point; at T - 20 occurred after rénal compensation processes had already begun 5 to manage acid-base status. At the same time, venons HCO.- was first measured to hâve a high value of 33.2 mmol/L, consistent with Cushing’s disease. Over treatment, the values reduced to 31 mmol/L at the other time points, consistent with a flow to the intracellular or rénal extraction. As shown in Figure 7, venons sOz and pOz were observed to rise during this time, from low start levels at 55% sOz and 30 mm Hg pO \ consistent with an enhanced servicing of oxygen to tissues. pCOz was seen to reduce, consistent with a réduction in metabolism, plasma volume expansion, or reduced hemoglobin affinity for COz, with heightened affinity for Oz.
Subject 2 - Observed Response for Dose 4 ASV.X1:
As shown in Figure 8, venons pH was observed to rise towards alkaline at T = 20, and then 15 reduce back towards acidic at T = 50, in a response that was similar to Dose 1 using AS. At the same time, venons HCOs- was observed at T = -5 to be 26.7 mmol/L, consistent with a Cushing’s résolution/ and largely unchanged throughout the observation period. As shown in Figure 9, venons s€L and pOz were again observed to rise during drug administration, along with a réduction in pCOz.
Subject 2 - Observed Response for Dose 5 ASVM:
As shown in Figure 10, dose 5 provoked a response unlike doses 1 and 4, where venous pH was observed to drop towards acidic throughout the observation frame. This could be attributed to the more alkaline starting bias for the bloodstream. At the same time, venous HCO3- was 25 observed at T = -5 tolbe 29.4mmol/L, again consistent with a Cushing’s resolution. Instead of rising or remaining unchanged, bloodstrjeam HCO3. reduced throughout the observation period, consistent with flow into the intracellular. As shown in Figure 11, venous sOz and pOz were observed to hâve higher start levels at 73% sOz and 37 mmHg pOz, constent with a more durable restoration of enhanced servicing of oxygen to tissues. sOz and pOz were again 30 observed to rise further during drug administration. pCOz remained largely unchanged. The différence in behavior at dose 5, relative to doses 1 and 4, is consistent with achievement of an enhanced homeostasis regarding acid/base status.
Subject 3 Doses 1 and 4 ASVM and Dose 5 AS - Observed Response: Blood pH, blood HCO?-, and oximeiry were observed at time interva] s of 5 min pre-dose commencement (T = 5), 2© min post dose commencement (T = 20), and 5 minutes post-dose complété (dose complété at T = 45. measurement at T = 50) as shown in Table 5.
Subject 3 Doses 1 and 4 ASVM and Dose 5 AS - Observed Response: Blood pH, blood HCO3-, and oximetry were observed at time inten als of 5 min pre-dose commencement (T = -5), 20 min post dose commencement (T = 20). and 5 minutes post-dose complété (dose complété at T = 45, measurement at T = 50) as shown in Table 9.
Table 9: Subject 3 Response for Dose 1 and 4 ASVM. Dose 5 AS
ASVM Day 1 Dose 1 | ASVM Day 6 Dose 4 | AS Day 8 Dose 5 | ||||||||
Time | min | -5 | 20 | 50 | -5 20 50 | -5 | 20 | 50 | ||
pH | 1 | 7.455 j | * | * | 7.437 | 7.392 | 7.428 | 7.423 | 7.412 | 7.375 |
cHCO3- | mmol/L | 32.5 | | 27.1 | 27.3 | 27.7 | 26.2 | 26.0 | 25.5 | ||
pCO2 | mmHg | 46.2 | * | * | 42.6 | 49.9 | 45.0 | 42.4 | 43.6 | 49.9 |
pO2 | mniHg | 29 | | ❖ | » | 32 | 29 | 34 | 34 | 31 | 20 |
sO2 | % | 57 | î | ❖ | i? | 67 | 57 | 69 | 70 | 64 | 34 |
* Sample not available
Subject 3 - Observed Response for Dose 1, 4 ASVM:
Not presented, materially similar to Subject 2.
Subject 3 - Observed Response for Dose 5 AS:
As shown in Figure 12, dose 5 provoked a response similar to dose 5 in Subject 2, where venons pH was observed to drop towards acidic throughout the observation frame. At the same time, venons HCO3- was observed at T = -5 to lie 27.7 mmol/L, again consistent with a Cushing’s résolution^ Instead of rising or remaining unchanged, bloodstream HCO3- reduced throughout the observation period, consistent with flow into the intracellular. As shown in Figure 13, venons SO2 and pÛ2 were observed to hâve relatively high start levels at 70% SO2 and 34 mm Hg pO?, consistent with a biasing towards enhanced sen icing of oxygen to tissues, relative to pre-treatment levels. In contrast to Subject 2’s Dose 5 response using AS product, SO2 and pO? responded to AS product infusion by dropping during drug administration, which is a stimulus that is recognized to hâve the potential to stimulate EPO release from the liver to promote RBC store supplémentation. This différence in response could hâve been caused by the formulation différences between the AS and ASVM configurations. pCO: rose correspondingly during this time.
Subject 1 Dose 1, 4, 5 ASVM Data (Exhibited for completeness, Similar to Subject 2 and Subject 3): Blood pH, blood HCOs-, and oximetry were observed at time intervals of 5 min pre-dose commencement (T = -5), 20 min post dose commencement (T = 20), and 5 minutes post-dose complété (dose complété at T = 45, measurement at T = 50) as shown in Table 10. Table 10: Subject 1 Response for ASVM Dose 1, 4, 5
ASVM Day 1 Dose 1 | ASVM Day 6 Dose 4 | ASVM Day 8 Dose 5 | ||||||||
Time | min | -5 | 20 | 50 | -5 | 20 | 50 | -5 | 20 | 50 |
pH | - | 7.444 ï | * | * | 7.426 | 7.435 | 7.448 | 7.429 | 7.447 | 7.431 |
cHCO3- | mmol/L | 34.1 ï 1 | * | * | 30.1 | 31.1 | 31.3 | 30.1 | 29.9 | 29.6 |
pCO2 | mmHg | 49.7 ï | * | 50.8 | 50,5 | 48.5 | 49.6 | 45.8 | 47.7 | |
pO2 | mmHg | 30 1 | * | 24 | 29 | 35 | 36 | 37 | 36 | |
sO2 | % | 59 1 i | » | 48 | 59 | 71 | 73 | 76 | 73 |
Results Section 2: Electrolyte, Hb, Glu, and Lac Response:
Subject 2 AS Dose 1 and ASVM Doses 4 and 5 - Observed Response: Blood electrolytes, hemoglobin (Hb), Glucose (Glu) and Lactate (Lac) were observed at time intervals of 5 min pre-dose commencement (T = -5), 20 min post dose commencement (T = 20), and 5 minutes 15 post-dose complété (dose complété at T = 45, measurement at T =50) as shown in Table 7.
Table 7: Subject 2 Response for ASVM t)ose 4, 5
ASVM Day 6 Dose 4 | ASVM Day 8 Dose 5 | ||||||
Time | min | -5 | 20 | 50 | -5 | 20 | 50 |
cK+ | mmol/L | 4.6 | 4.2 | 2.9 | 4.4 | 4.0 | 3.7 |
cNa+ | mmol/L | 140.0 | 138.0 | 144.0 | 137.0 | 137.0 | 138.0 |
cCa2+ | mmol/L 1 | 1.7 | 1.7 | 1.6 | 1.7 | 1.6 | 1.6 |
cCl- | mmol'L | 103.0 | 103.0 | 105.0 | 100.0 | 101.0 | 101.0 |
ctHb | gdl. | 14.8 | 11.9 | 13.2 | 13.2 | 11.2 | 11.0 |
cGlu | mgdL | 105.0 | 115.0 | 99.0 | 91.0 | 83.0 | 89.0 |
cLac | mmol'L | 13 | 0.7 ; | 03 | 0.4 | 0.5 | 0.5 |
Subject 2 ASVM Doses 4 and 5-Observed Hb Response and Inférence of Plasma Volume Changes: Over the observation timeframe, Hb reduced from its start value, sometimes showing evidence of rebound during the observation period. This cannot be interpreted as hemolysis, as a rebound on this timescale would be impossible. The change in Hb concentration is consistent with a change in blood volume, likely due to a change in plasma volume. Such exchange is required during exercise-like stimulus to maintain vascular pressure, under conditions of vasodilation, where vascular volume increases.
Subject 2 ASVM Doses 4 and 5 - Observed Glucose Response: Over the observation timeframe, Glucose was perturbed (up and down) from its start value, while showing evidence of rebound during the observation period. While the réduction could be attributable to increased blood volume, élévations in Glucose concentration cannot. Observed Glucose élévation is consistent with perturtbation of glucose exchange, such as happens during exercise.
Subject 2 ASVM Doses 4 and 5 - Observed Lactate Response: Over the observation i timeframe, Lactate was observed to hâve a low présentation value, which further reduced in Dose 4, and ele\ ated slightly in Dose 5. This is consistent with the lactate burden steadily dropping with successive doses, as improved perfusion increased aérobic metabolism, so as to résolve lactate debt. Elevated lactate was seen in Dose 5, despite s suspected plasma volume dilution. This is consistent with présentation of HCO3- into muscles to release stored lactate.
Subject 2 ASVM Doses 4^ηά 5 - Observed Electrolyte Response: Over the observation timeframe, electrolyte exchange was observed. Potassium and Sodium were observed to drop during treatment, which could be attributed to increased plasma volume. It is consistent with a flow of H+ into the cell, elevating the Chemiosmotic gradient to improve ATP yield and enhancing action of the Na/K ATPase to transport K into the cell. At the same time, a réduction in bloodstream Calcium was observed. H+/Na exchange and K+/Na+ exchange would promote an élévation of bloodstream Na, to promote Ca2+ exchange to the blood via the Ca2 TNa’ exchanger. Elévations in bloodstream Cl· were also observed during the observation period.
Results Section 4: Hematology, Chemistry, Endocrinology, and Serology:
Observed Response between Day 1 and Day 8 encompassing 4 doses in 3 horses: Hematology, Chemistry, Endocrinology, and Serology were observed on Day 1, before Dose 1, and on Day 8, before dose 5, thus encompassing 4 doses of ASVM, or in some dose instances, AS. The following effects can be observed in the data, as shown in Table 8.
• White blood cell (WBC) and neutrophil counts were observed to drop for ail subjects, consistent w ith an alleviation of the inflammation response.
• Platelet counts and fibrinogen were observed to rise for ail subjects, consistent with control over clotting cascade and reduced consumption of clotting products. It is also consistent with increased production of platelets in bone marrow upon resolution of Throinbocvtopenia. and increased présentation of fibrinogen through enhanced liver function.
• Créatinine was observed to rise in ail subjects, consistent with an increase in muscle mass and improved capacity to store ATP in muscle as Phosphocreatine.
• BUNrCreatinine ratio was observed to fall for ail subjects, consistent with increased flow through the kidneys.
• Ca2- and K“ were observed to drop for ail subjects, consistent with intracellular uptake of K via Na7K“ ATPase, and rénal extraction of Ca2-, so as to reduce bloodstream présentation. Réductions in Ca2 and increases in K~ could hâve the potential to reduce chemiosmotic gradient dependence on Ca2 so as to restore électron chain transport function, reduce corresponding ROS corresponding to the électron chain transport, and increase basal metabolic rate. |A réduction in intracellular calcium, along with ROS réduction and alkaline conditions and elevated Mg2, would also hâve the potential to improve peroxisome function to restore long-chain fatty acid réduction for metabolic use, increased capacity to repair myelin for enhanced nerve function, and improving catalase servicing from the peroxisome. Additionally lower Ca2 could restore eNOS function by reducing caveolae bound Caveolin to allow eNOS to translocate from the Golgi back to the membrane caveolae. Lower intracellular calcium could also signal more M2 prenotype présentation for macrophages, microglia, and osteoblasts among others. Increased K could act to enhance muscle function and nerve transmission, reduce cramping of muscles, and provide other [benefits.
• Creatine kinase was observed to drop for ail subjects, consistent with a potential increase of consumption of creatine kinase in enzymatic action to promote storage of A TP with creatine as Phosphocreatine to enhanced stored energy in muscles.
Altemately, the réduction in blood plasma can indicate a réduction in the ongoing rate of tissue damage, such as in myocardial infaction (heart attack), rhabdomyolysis (severe muscle breakdown), muscular dystrophy, autoimmune myositides, and acute kidney injury, so as to minimize présentation of damaged tissue contents to the bloodstream.
• Total T4 was observed to rise for ail subjects, potentially indicating improved thyroid fonction to produce more thyroxine. This, among other things, is associated with increases in synthesis of Na K ATPases, glucose absorption, gycogenolysis, gluconeogenesis, lipolysis. protein synthesis, net catabolic dégradation, cardiac beta-l receptors for enhanced sympathetic nervous control, and basal metabolic rate.
• Equine endogenous ACTH was observed to fall for ail subjects, consistent with a réduction in cortisol levels, so as to promote calming and anti-anxiety effects. Additionally consistent with promoting resolution of Cushing’s disease.
• Lyme’s antibodies were shown to reduce in ratio présentation, as indicated by a smaller divisor. This is consistent with resolution of Lyme’s disease and progression towards immune quiescing, with réduction of inflammation response.
• Lyme’s proteins were observed to increase in présentation, consistent with enhanced action of plasmin during alkaline rebound phases, which could reduce the fibrin layer associated with borrelia, so as to expose its surface proteins. ,
I
Table 8: Hematology, Cheinistry, Endocrinology, and Serology Evolving Over 4 doses in days
L&a lia .. | Cj * — fil | t Tl | ||||||
Test HEMATOLOGY WBC | 14-Nov pre-sample 6.1 | 21-Nov | post-sample~ 4.4 | 14-Nov pre-sample 73 | 21-Nov | pre-sample 72 | 14-Nov pre-sample i '88 | 21-Nov pre-sample 9.® | 4.3 - 11.4 K/pL | |
Neutrophils | 3-251 | 2.275 | 3.962 | 3.168 | 3.382 | 4.329 | 2.46 - 7.23 K/pL | |
Piaielets | 106 | 141 | 129 | 192 | 148’ | 198 | 70 - 250 K/pL | |
Fibrinogen | 116 | 127 | 129 | 16B | 131 | 147 | 135 - 249 mg/dL | |
CHEM1STRY CreaSirune | 0.7 | OS | 12 | 1 4 | 12 | 1.4 | 0.8 -1..8 mg/dL | |
BON: Creâfinine Ratio Calcium | 30.0 13.0 | 23.3 11.8 | 1-08 12.4 | 1WD 11.6 | 11.7 122 | 78 11.6 | 102 -12.8 mg'dL | |
Sodium | 136 | 136 | 136 | 137 | 136 | 137 | 132-141 mmol/L | |
Potassium | 4.8 | 4.1 | 5.2 | 37 | 5.4 | 3.9 | 2.5 - 52 mmol/L | |
Creatine iKinase | 334 | 221 | 271 | 210 | 349 | 259 | 130-497 IM. | |
ENDOCRINOLOGY TotalT4 | 1.5 | 1.8 | 2.5 | 3 | 1.7 | 2.6 | 1 - 3.8 pg ’dL | |
Equine Endogenous | a3 | 26 | 24 | 19 | 18 | 26 | 16 | |
ACTH SEROLOGY Lyme Antibody by IFA | a4 | Positive @ 1:3200 Positive© 1:300 | Positive © 1:800 Positive© 1.200 | Positive© 1:800 Positive © 1:200 | 9-35 pg/ml | |||
Lyme OspA Lyme OspC Lyme OspF | b2 | 123 négative 73 négative 3000 Positive | 129 NegaÉve 77 Negâtive 3936 Positive | 197 négative 238 négative 318 négative | 242 négative 272 négative 390 négative | 225 Négative 79 Négative 464 Négative | 201 Négative 69 Négative 498 Négative | |
EhtriichÉa cents Antibody t | c2 | Négative | Positive© 1:100 | Négative | Négative | Négative | Négative |
Notes a3 · Signifient variations in endogenous ACTH concentration associated with the season hâve been reported. An endegenous ACTH measured between November and July of > 35 pgrmL is consistent with equine Cushing’s disease (PPID). Cases with early PPID may fai to demonstraie significant élévations in resting ACTH concentrations during these months. Retesting resting ACTH levels dunng August and Ocicbar, when test sensitiwty is highesi. or performing a TRM stimulation test (December to June) Is recommended. Between August and October. an endogenous ACTH concentration of >100 pg/mL îs consistent with equine Cushing’s disease.
a4 - Interprétation: if your resuit Is négative, the interprétation is No antibody présent © 1:1£XT: positive © (titer), the interprétation is Antibody présent @ (titer).
b2 - CorneH no longer effets the Lyme Western Blot test. In ifs place they are offering the Lyme Equine Multiplex.
Lyme Disease Equine - Multiplex: The Lyme multiplex assay détermines antibodies to three antigens, called outer surface proteins (Osp), of B. burgdorferi which hâve been sLoati to correlate with vaccinal antibodies. or acute and chronic stages gS Lyme disease.
Négative: Négative values for antibodies to ail three Osp antigens are prédictive thaï the herse is not infected. If only one or two values are in the négative range see interprétation for equivocal or positive values for the corresponding Osp antigen.
Equivocal: Equivocal values can indicate very early infection or can be induced by non-specific sérum reactions, if there are no positive values for any of the three Osp antigens. the horse should be retested in 2-3 weeks to confirm or exclude earfy infection. If one or two values are in the positive range see interprétation for positive values for that corresponding Osp antigen.
Postive/OspA (>2000): Positive values for antibodies to OspA æe typically observed in vaccinated animais. In horses. however. antibodies to OspA also seem to rise during infection. Thus, the interprétation of results on antibodies to OspA is more complex m horses. If antibodies to OspC and/or OspF are positive, along with OspA the horse should be considered as infected with B. burgdorferi.
PositiveOspC (>1000): Positive values for antibodies to OspC only are indicative for early infection. Antibody values for OspA can also be elevated during early infection. ' i
Posïtive^OspF (>1250): Positive values for antibodies to OspF only are prédictive for chronic|infection stages. Positive values for antibodies to OspC and OspF in the same sample are indicators for an infection that occurred several weeks ago and it rnoving towards the chronic stage. Referral test performed at Comell University.
c2 - Interprétation: If your resuit is: The interprétation is: NEGATIVE No antibody présent @ 125: POSITIVE @ (titer) Antibody présent @ (titer). Positive samples are testai in incrémental dilutions to 1:3^00. Titers beyond 1:3200 are usually of limited clinical value. If you wish an endpoint titer there is an additions! charge. A positive titer indicates exposure to E.canis or similar antigen but does not confirm the presence of disease. A CBC is recommended to identify abnormatities consistent with infection. If confirmation of infection is desired, Ehrlichia PCR test, code 2634 can be useful, especially Én clinically sick animais.
What is claimed is :
Claims (65)
- What is claimed is :1. A stable therapeutic composition formulâtes for intravenous administration to a subject, comprising an intravenous buffer solution, comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol L to 3,000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent isi effective to provide a buffer solution pH of between 4 and 7.7.
- 2. The composition of claim 1, wherein the pharmaceutical grade acid is hydrochloric acid, ascorbic acid, acetic acid, (other physiologically acceptable acids), or a combination thereof.
- 3. The composition of claim 1, wherein the at least one pH buffering agent is sodium bicarbonate, a phosphate buffer, sodium hydroxide, organic acid, organic amine, ammonia, citrate buffer, a synthetic buffer creating spécifie alkaline conditions (e.g., tris-hydroxymethyl amino methane), (other physiologically acceptable buffers), or a combination thereof.
- 4. The composition of claim 1, further comprising one or more ingrédients selected from the group consisting qf vitamins, salts, acids, amino acids or salts thereof, and stabilized oxidative species.
- 5. The|composition of claim 4, further comprising ascorbic acid. |
- 6. The composition of claim 4, further comprising dehydroascorbic acid
- 7. The composition of claim 4, further comprising other recognized antioxidant defense compounds including nonenzymatic compounds such as tocopherol (aTCP), coenzyme Q10 (Q), cytochrome c (C) and glutathione (GSH) and enzymatic components including manganèse superoxide dismutase (MnSOD), catalase (Cat), glutathione peroxidase (GPX), phospholipid hydroperoxide glutathione peroxidase (PGPX), glutathione reductase (GR);peroxiredoxïns (PRX3/5), glutaredoxin (GRX2), thioredoxin (TRX2) and thioredoxin reductase (TRXR2). ,
- 8. The composition of claim 4, further comprising one or more of a sodium sait, a magnésium sait, a potassium sait, and a calcium sait.
- 9. The composition of claim 4, further comprising one or more of a B vitamin, vitamin C, and vitamin K.
- 10. The composition of claim 1, wherein the composition is formulated for intravenous, bolus, dermal, oral, otic, suppository, buccal, ocular, or inhalation delivery.
- 11. The composition of claim 1, wherein the composition is formulated as a topical liquid, gel, or paste.
- 12. The composition of claim 1, wherein the composition is formulated for ocular administration in the form of eye drops.
- 13. The composition of claim 4, formulated in hypotonie, isotonie, or hypertonie form.
- 14. The composition of claim 1, wherein the intravenous administration is a bolus delivery7.
- 15. The composition of claim 1, wherein the composition is lyophilized or frozen.
- 16. The composition of claim 1, wherein the composition is stored in a spectral-blocking vial.
- 17. The composition of claim 1, wherein composition is formed by combining components from two or more vials.
- 18. A stable therapeutic composition formulated for intravenous administration to a subject comprising pharmaceutical grade:900 ± 90 mg of L-Ascorbic Acid;63.33 ± 6.33 mg Thiamine HCl;808 ± 80.8 mg of Magnésium Sulfate;1.93 ± .193 mg of Cyanocobalamin;119 ± ï 1.9 mg of Niacinamide;119 ± 11.9 mg of Pyridoxine HCl;2.53 ± .253 mg of Riboflavin 5 Phosphate;2 93 * .293 mg of Calcium D-Pantothenate;840 ± 84 mg of Sodium Bicarbonate;4.5 ± .45 mM of HCl; and water in an amount to obtain a final composition volume of 20 mL.
- 19. The composition according to claim 18, further comprising 100 ± 10 mg of dehvdroascorbic acidi
- 20. A stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution for use in a method of treating or ameliorating acidosis in a subject, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol L to 3,000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
- 21. Use of an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in the manufacture of a stable therapeutic composition comprising the intravenous buffer solution comprising the at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution, for treating or ameliorating acidosis in a subject, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and | wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
- 22. A stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution for use in a method of treating or ameliorating base excess in a subject.wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol L to 3,000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
- 23. Use of an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in the manufacture of a stable therapeutic composition comprising the intravenous buffer solution comprising the at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution, for treating or ameliorating base excess in a subject, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol'L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
- 24. A stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution for use in a method of elevating blood oxygen in a subject, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pHj buffering agent is effective to provide a buffer solution p(l of between 4 and 7.7.
- 25. Use of an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in the manufacture of a stable therapeutic composition comprising the intravenous buffer solution comprising the at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution, for elevating blood oxygen in a subject, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and w herein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
- 26. The composition for use, according to claim 24, or the use, according to claim 25, wherein the method comprises ele^'ating the pO2 in tire venons blood in a subject.
- 27. A stable therapeutic composition comprising an intravenous buffer solution comprising at least ohe pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution for use in a method of treating or ameliorating a mitochondrial disorder, metabolic disorder, a condition associated with diabètes or a cardiovascular dysfunction, in a subject in need thereof, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
- 28. Use of an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in the manufacture of a stable therapeutic composition comprising the intravenous buffer solution comprising the at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution, treating or ameliorating a mitochondrial disorder, metabolic disorder, a condition associated with diabètes or a cardiovascular dysfunction, in a subject in need thereof, | wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
- 29. The composition for use of claim 27 or the use of claim 28, wherein the metabolic disorder is diabètes, insu!in résistance, glucose intolérance, hyperglycemia. hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia.
- 30. The composition for use of of claim 27 or the use of claim 28, wherein the condition associated with diabètes is hypertension, hyperlipidemia, fatty liver disease, nephropathy, neuropathy, rénal failure, retinopathy, diabetic ulcer, cataracts, insulin résistance syndromes and cachexia.
- 31. The composition for use of claim 27 or the use of claim 28, wherein the cardiovascular dysfonction is coronary heart disease, cerebrovascular disease, hypertension, peripheral anery disease, occlusive arterial disease, angina, rheumatic heart disease, congénital heart disease, heart failure, cardiac insufficiency, palpitations, supraventricular tachycardia, fibrillation, fainmess, dizziness, fatigue, migraine, high levels of total blood cholestérol and/or LDL cholestérol, low level of HDL cholestérol, high level of lipoprotein, infections of the heart such as carditis and endocarditis, diabetic ulcer, thrombophlebitis, Raynaud’s disease, anorexia nervosa, claudication, gangrené, atherosclerosis and peripheral artery disease.
- 32. The composition for use of claim 27 or the use of claim 28, wherein the mitochondrial disorder is a neurodegenerative disorder, a cardiovascular disease, a metabolic syndrome, an autoimmune disease, a neurobehavioral or psychiatrie disease, a gastrointestinal disorder, a fatiguing illness, a chronic musculoskeletal disease, or a chronic infection.
- 33. The composition for use of claim 27 or the use of claim 28, wherein the composition further comprises dehydroascorbic acid.
- 34. The composition for use of claim 27 or the use of claim 28, further conpprising one or more of a magnésium ion source, a potassium ion source, and a calcium ion source.
- 35. The composition for use of claim 27 or the use of claim 28, further comprising one or more of a B vitamin, vitamin C, and vitamin K.
- 36. The composition for use of claim 27 or the use of claim 28, further comprising other recognized antioxidant defense compounds including nonenzymatic compounds such as tocopherol (aTCP), coenzyme Q10 (Q), cytochrome c (C) and glutathione (GSH) and enzymatic components including manganèse superoxide dismutase (MnSODX catalase (Cat), glutathione peroxidase ( GPX ), phospholipid hydroperoxide glutathione peroxidase ( PGPX ). glutathione reductase (GR); peroxiredoxins (PRX3/5), glutaredoxin (GRX2 ), thioredoxin (TRX2) and thioredoxin reductase (TRXR2).
- 37. The composition for use of claim 27 or the use of claim 28, formulated in hypotonie, isotonie, or hypertonie form.
- 38. The composition for use of claim 27 or the use of claim 28, wherein the composition is for administration intravenously, by bolus, dermally, orally, optically, via suppository, buccally, or via inhalation.
- 39. The composition for use of claim 27 or the use of claim 28, wherein said administration comprises introducing said composition by infusion over a period of about 1 minute to about 1 hour, and said infusion is repeated as necessary over a period of time selected from about 1| day to about 1 year.
- 40. A stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution for use in a method of modifying the metabolism of a subject, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
- 41. Use of aln intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in the manufacture of a stable therapeutic composition comprising the intravenous buffer solution comprising the at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution, for modifying the metabolism of a subject, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
- 42. A stable therapeutic composition comprising an intravenous buffer solution comprising at least ohe pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution for use in a method of treating a central nervous system disorder in a subject in need thereof, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmolL when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and Ί.Ί.
- 43. Use of an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in the manufacture of a stable therapeutic composition comprising the intravenous buffer solution comprising the at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution, for treating a central nervous system disorder in a subject in need thereof, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
- 44. A stable therapeutic composit|ion comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution for use in a method of treating chronic wounds of a subject, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
- 45. Use of an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in the manufacture of a stable therapeutic composition comprising the intravenous buffer solution comprising the at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution, for treating chronic wounds of a subject, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol L to 3,000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
- 46. A stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution for use in a method of enhancing mental or physical performance of a subject, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
- 47. Use of an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in the manufacture of a stable therapeutic composition comprising the intravenous buffer solution comprising the at least one pharmaceutical grade acid and at least one pharmaceutical gijade pH buffering agent in a stérile aqueous solution, for enhancing mental or physical performance of a subject, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
- 48. A stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stenle aqueous solution for use in a method of reducing lactate burden in a subject in need thereof, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol L to 3,000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
- 49. Use of an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in the manufacture of a stable therapeutic composition comprising the intravenous buffer solution comprising the at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution, for reducing lactate burden in a subject in need thereof, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmoL'L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
- 50. The method of claim 40, wherein the lactate burden is acidosis, sepsis, or multiple system atrophy (MSA)
- 51. The method of claim 40, wherein the lactate burden is the resuit of physical exertion.I I
- 52. A stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution for use in a method of resolving or improving hypoxie stress in a subject in need thereof, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
- 53. Use of an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in the manufacture of a stable therapeutic composition comprising the intravenous buffer solution comprising the at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution, for resoiving or improving hypoxie stress in a subject in need thereof, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol L to 3,000 mmol L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.
- 54. A stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution for use in a method of removing vascular plaque from the arteries of a subject and thereby resoiving metabolic crisis resulting from Ca2’ accrual, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.I I
- 55. Use of an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in the manufacture of a stable therapeutic composition comprising the intravenous buffer solution comprising the at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution, for removing vascular plaque from the arteries of a subject and thereby resoiving metabolic crisis resulting from Ca2+ accrual, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol L to 3.000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and Ί.Ί.
- 56. The composition for use or the use according to any one of claims 20-55. wherein the subject is a human or vetermary subject.
- 57. The composition for use or the use according to any one of claims 20-55, wherein the buffer solution is sufficient to reduce the physiological bloodstream pH of a subject by 0.01 to 1.1.
- 58. The composition for use or the use according to claim 56, wherein the buffer solution has a buffer capacity sufficient to sustain the réduction of the physiological bloodstream pH of the subject for between 1 minute and 1 week.
- 59. The composition for use or the use according to claim 56, wherein the buffer solution is sufficient to reduce the physiological bloodstream pH of a subject by 0.15 to 0.75.
- 60. The composition for use or the use according to claim 56, wherein the buffer solution is sufficient to reduce the physiological bloodstream pH of a subject by 0.15 to 0.5.
- 61. The composition for use or the use according to claim 56, wherein the buffer solution has a buffer capacity sufficient to sustain the réduction of the physiological bloodstream pH of the subject for between 1 minute and 1 hour.
- 62. The composition for use or the use according to claim 56, wherein the buffer solution has a buffer capacity sufficient to sustain the réduction of the physiological bloodstream jpH of the subject for between 1 hour and 1 day.
- 63. The composition for use or the use according to claim 56, wherein the buffer solution has a buffer capacity sufficient to sustain the réduction of the physiological bloodstream pH of the subject for between 1 day and 1 week.
- 64. A kit comprising:a. a first via] containing a stable therapeutic composition comprising an intravenous buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution, wherein die concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution pH of between 4 and 7.7.; andb. instructions for use.
- 65. A kit comprising:a. a first vial containing an intravenous buffer solution comprising at least one pharmaceutical grade acid in a stérile aqueous solution, andb. a second vial containing at least one pharmaceutical grade pH buffering agent in a stérile aqueous solution;wherein, when combined, the contents of the two vials form an intravenous buffer solution, wherein the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of from 60 mmol/L to 3,000 mmol/L when administered to a subject, and wherein the sélection of the pharmaceutical grade acid and the pharmàceutical| grade pH buffering agent is effective to provide a buffer | solution pH of between 4 and 7.7; and c. instructions for use.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US62/595,909 | 2017-12-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
OA19913A true OA19913A (en) | 2021-07-14 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11344529B2 (en) | Compositions and methods for the treatment of metabolic conditions | |
Canavese et al. | Long-term, low-dose, intravenous vitamin C leads to plasma calcium oxalate supersaturation in hemodialysis patients | |
Racek et al. | Influence of chromium-enriched yeast on blood glucose and insulin variables, blood lipids, and markers of oxidative stress in subjects with type 2 diabetes mellitus | |
US20060128805A1 (en) | Methods of treating erythropoietin-resistance | |
Teplan et al. | Enhanced metabolic effect of erythropoietin and keto acids in CRF patients on low-protein diet: Czech multicenter study | |
CA2821613A1 (en) | Preparation comprising insulin, nicotinamide and an amino acid | |
Ditzel et al. | Disturbance of inorganic phosphate metabolism in diabetes mellitus: its impact on the development of diabetic late complications | |
US20210346327A1 (en) | Method for enhancing energy production and metabolism in cells | |
CA3141418A1 (en) | Methods and compositions for improving outcomes of cancer patients | |
OA19913A (en) | Compositions and methods for the treatment of metabolic conditions. | |
US20160095824A1 (en) | Use of vitamin k for weight maintenance and weight control | |
JP6447716B2 (en) | Amino acid-containing composition for the treatment of stroke in patients with dysphagia | |
AU2011343162A1 (en) | Use of vitamin K for weight maintenance and weight control | |
Ljunghall et al. | Effects on serum parathyroid hormone of intravenous treatment with alphacalcidol in patients on chronic hemodialysis | |
HamaSalih et al. | Effects of vitamin D supplementation on red cell indices and cytokines in patients with thalassemia: An open-label randomized clinical trial | |
Fouque | Low protein, amino acid and ketoacid diets to slow the progression of chronic kidney disease and improve metabolic control of uremia | |
Domrose et al. | Vitamins are associated with survival in patients with end-stage renal disease: a 4-year prospective study | |
Patoulias et al. | EFFECT OF A GLP-1 RECEPTOR AGONIST AND SGLT-2 INHIBITOR COMBINATION ON BLOOD PRESSURE LEVELS COMPARED TO SGLT-2 INHIBITOR ALONE: A SYSTEMATIC REVIEW AND META-ANALYSIS | |
Berger et al. | Micronutrient Homeostasis | |
Allison et al. | Insulin Resistance in Catabolic Diseases | |
Cano Noël | Nutritional support in renal failure Topic 15 |