US20150216820A1 - Quinone derivatives for use in the modulation of redox status of individuals - Google Patents
Quinone derivatives for use in the modulation of redox status of individuals Download PDFInfo
- Publication number
- US20150216820A1 US20150216820A1 US14/426,130 US201314426130A US2015216820A1 US 20150216820 A1 US20150216820 A1 US 20150216820A1 US 201314426130 A US201314426130 A US 201314426130A US 2015216820 A1 US2015216820 A1 US 2015216820A1
- Authority
- US
- United States
- Prior art keywords
- subject
- glutathione
- concentration
- oxidized
- reduced
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 150000004059 quinone derivatives Chemical class 0.000 title abstract 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims abstract description 380
- 108010024636 Glutathione Proteins 0.000 claims abstract description 199
- 229960003180 glutathione Drugs 0.000 claims abstract description 155
- 108010053070 Glutathione Disulfide Proteins 0.000 claims abstract description 76
- YPZRWBKMTBYPTK-BJDJZHNGSA-N glutathione disulfide Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@H](C(=O)NCC(O)=O)CSSC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O YPZRWBKMTBYPTK-BJDJZHNGSA-N 0.000 claims abstract description 76
- 238000000034 method Methods 0.000 claims abstract description 74
- YPZRWBKMTBYPTK-UHFFFAOYSA-N oxidized gamma-L-glutamyl-L-cysteinylglycine Natural products OC(=O)C(N)CCC(=O)NC(C(=O)NCC(O)=O)CSSCC(C(=O)NCC(O)=O)NC(=O)CCC(N)C(O)=O YPZRWBKMTBYPTK-UHFFFAOYSA-N 0.000 claims abstract description 54
- 238000011282 treatment Methods 0.000 claims abstract description 37
- 150000001875 compounds Chemical class 0.000 claims description 148
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 90
- LNOVHERIIMJMDG-KTWAZNHYSA-N 2-[(6e,10e)-3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl]-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CCC(C)(O)CCC1=C(C)C(=O)C(C)=C(C)C1=O LNOVHERIIMJMDG-KTWAZNHYSA-N 0.000 claims description 40
- OTXNTMVVOOBZCV-UHFFFAOYSA-N 2R-gamma-tocotrienol Natural products OC1=C(C)C(C)=C2OC(CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1 OTXNTMVVOOBZCV-UHFFFAOYSA-N 0.000 claims description 35
- RZFHLOLGZPDCHJ-DLQZEEBKSA-N alpha-Tocotrienol Natural products Oc1c(C)c(C)c2O[C@@](CC/C=C(/CC/C=C(\CC/C=C(\C)/C)/C)\C)(C)CCc2c1C RZFHLOLGZPDCHJ-DLQZEEBKSA-N 0.000 claims description 35
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 33
- FGYKUFVNYVMTAM-UHFFFAOYSA-N (R)-2,5,8-trimethyl-2-(4,8,12-trimethyl-trideca-3t,7t,11-trienyl)-chroman-6-ol Natural products OC1=CC(C)=C2OC(CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1C FGYKUFVNYVMTAM-UHFFFAOYSA-N 0.000 claims description 24
- FGYKUFVNYVMTAM-YMCDKREISA-N beta-Tocotrienol Natural products Oc1c(C)c2c(c(C)c1)O[C@@](CC/C=C(\CC/C=C(\CC/C=C(\C)/C)/C)/C)(C)CC2 FGYKUFVNYVMTAM-YMCDKREISA-N 0.000 claims description 24
- 210000004027 cell Anatomy 0.000 claims description 24
- FGYKUFVNYVMTAM-MUUNZHRXSA-N epsilon-Tocopherol Natural products OC1=CC(C)=C2O[C@@](CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1C FGYKUFVNYVMTAM-MUUNZHRXSA-N 0.000 claims description 24
- OTXNTMVVOOBZCV-YMCDKREISA-N gamma-Tocotrienol Natural products Oc1c(C)c(C)c2O[C@@](CC/C=C(\CC/C=C(\CC/C=C(\C)/C)/C)/C)(C)CCc2c1 OTXNTMVVOOBZCV-YMCDKREISA-N 0.000 claims description 24
- 235000019151 β-tocotrienol Nutrition 0.000 claims description 24
- 239000011723 β-tocotrienol Substances 0.000 claims description 24
- 235000019150 γ-tocotrienol Nutrition 0.000 claims description 24
- 239000011722 γ-tocotrienol Substances 0.000 claims description 24
- OTXNTMVVOOBZCV-WAZJVIJMSA-N γ-tocotrienol Chemical compound OC1=C(C)C(C)=C2O[C@@](CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)(C)CCC2=C1 OTXNTMVVOOBZCV-WAZJVIJMSA-N 0.000 claims description 24
- FGYKUFVNYVMTAM-WAZJVIJMSA-N β-tocotrienol Chemical compound OC1=CC(C)=C2O[C@@](CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)(C)CCC2=C1C FGYKUFVNYVMTAM-WAZJVIJMSA-N 0.000 claims description 23
- 235000018102 proteins Nutrition 0.000 claims description 21
- 102000004169 proteins and genes Human genes 0.000 claims description 21
- 108090000623 proteins and genes Proteins 0.000 claims description 21
- 210000004698 lymphocyte Anatomy 0.000 claims description 17
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 16
- GZIFEOYASATJEH-VHFRWLAGSA-N δ-tocopherol Chemical compound OC1=CC(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 GZIFEOYASATJEH-VHFRWLAGSA-N 0.000 claims description 16
- 238000005259 measurement Methods 0.000 claims description 15
- 210000002381 plasma Anatomy 0.000 claims description 15
- WGVKWNUPNGFDFJ-DQCZWYHMSA-N β-tocopherol Chemical compound OC1=CC(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C WGVKWNUPNGFDFJ-DQCZWYHMSA-N 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- SFVAYPRWECRHTF-QRCIITMISA-N 2-[(6e,10e)-3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl]-6-methylcyclohexa-2,5-diene-1,4-dione Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CCC(C)(O)CCC1=CC(=O)C=C(C)C1=O SFVAYPRWECRHTF-QRCIITMISA-N 0.000 claims description 13
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims description 13
- 229960004308 acetylcysteine Drugs 0.000 claims description 13
- 210000002966 serum Anatomy 0.000 claims description 11
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 9
- GZIFEOYASATJEH-UHFFFAOYSA-N D-delta tocopherol Natural products OC1=CC(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 GZIFEOYASATJEH-UHFFFAOYSA-N 0.000 claims description 8
- 229940066595 beta tocopherol Drugs 0.000 claims description 8
- 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 8
- 235000010389 delta-tocopherol Nutrition 0.000 claims description 8
- 235000010382 gamma-tocopherol Nutrition 0.000 claims description 8
- 230000009467 reduction Effects 0.000 claims description 8
- 230000002829 reductive effect Effects 0.000 claims description 8
- 239000011590 β-tocopherol Substances 0.000 claims description 8
- 235000007680 β-tocopherol Nutrition 0.000 claims description 8
- 239000002478 γ-tocopherol Substances 0.000 claims description 8
- 239000002446 δ-tocopherol Substances 0.000 claims description 8
- QUEDXNHFTDJVIY-DQCZWYHMSA-N γ-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-DQCZWYHMSA-N 0.000 claims description 7
- LTVDFSLWFKLJDQ-IEOSBIPESA-N 2-[(3r,7r,11r)-3-hydroxy-3,7,11,15-tetramethylhexadecyl]-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione Chemical compound CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC[C@@](C)(O)CCC1=C(C)C(=O)C(C)=C(C)C1=O LTVDFSLWFKLJDQ-IEOSBIPESA-N 0.000 claims description 5
- LTVDFSLWFKLJDQ-DKGMKSHISA-N alpha-Tocopherolquinone Natural products CC(C)CCC[C@H](C)CCC[C@@H](C)CCC[C@@](C)(O)CCC1=C(C)C(=O)C(C)=C(C)C1=O LTVDFSLWFKLJDQ-DKGMKSHISA-N 0.000 claims description 5
- 235000017471 coenzyme Q10 Nutrition 0.000 claims description 5
- 210000001175 cerebrospinal fluid Anatomy 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 98
- 201000010099 disease Diseases 0.000 abstract description 72
- 239000000203 mixture Substances 0.000 abstract description 59
- 208000024891 symptom Diseases 0.000 abstract description 27
- 230000001629 suppression Effects 0.000 abstract description 9
- 210000001124 body fluid Anatomy 0.000 abstract description 4
- 238000012423 maintenance Methods 0.000 abstract description 4
- 230000002265 prevention Effects 0.000 abstract description 4
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 114
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 49
- 230000037396 body weight Effects 0.000 description 41
- 239000000090 biomarker Substances 0.000 description 35
- 208000006136 Leigh Disease Diseases 0.000 description 31
- 208000017507 Leigh syndrome Diseases 0.000 description 31
- 239000003814 drug Substances 0.000 description 29
- 206010058799 Mitochondrial encephalomyopathy Diseases 0.000 description 28
- 208000035475 disorder Diseases 0.000 description 25
- 150000003839 salts Chemical class 0.000 description 24
- -1 tocotrienol quinones Chemical class 0.000 description 23
- 230000006872 improvement Effects 0.000 description 22
- 208000012268 mitochondrial disease Diseases 0.000 description 19
- 0 *C1=CC(O)=C([3*])C([2*])=C1O.*CCC(C)(O)CCcc(C)CCcc(C)C.[1*]C1=CC(=O)C([3*])=C([2*])C1=O Chemical compound *C1=CC(O)=C([3*])C([2*])=C1O.*CCC(C)(O)CCcc(C)CCcc(C)C.[1*]C1=CC(=O)C([3*])=C([2*])C1=O 0.000 description 18
- 229940079593 drug Drugs 0.000 description 18
- 230000008859 change Effects 0.000 description 17
- 238000009472 formulation Methods 0.000 description 15
- 239000000651 prodrug Substances 0.000 description 14
- 229940002612 prodrug Drugs 0.000 description 14
- 235000013305 food Nutrition 0.000 description 13
- 210000001519 tissue Anatomy 0.000 description 13
- 150000003573 thiols Chemical class 0.000 description 12
- ODADKLYLWWCHNB-UHFFFAOYSA-N 2R-delta-tocotrienol Natural products OC1=CC(C)=C2OC(CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1 ODADKLYLWWCHNB-UHFFFAOYSA-N 0.000 description 11
- 230000002411 adverse Effects 0.000 description 11
- 229940064063 alpha tocotrienol Drugs 0.000 description 11
- 210000004369 blood Anatomy 0.000 description 11
- 239000008280 blood Substances 0.000 description 11
- BTNBMQIHCRIGOU-UHFFFAOYSA-N delta-tocotrienol Natural products CC(=CCCC(=CCCC(=CCCOC1(C)CCc2cc(O)cc(C)c2O1)C)C)C BTNBMQIHCRIGOU-UHFFFAOYSA-N 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- RZFHLOLGZPDCHJ-XZXLULOTSA-N α-Tocotrienol Chemical compound OC1=C(C)C(C)=C2O[C@@](CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)(C)CCC2=C1C RZFHLOLGZPDCHJ-XZXLULOTSA-N 0.000 description 11
- 235000019145 α-tocotrienol Nutrition 0.000 description 11
- 239000011730 α-tocotrienol Substances 0.000 description 11
- 235000019144 δ-tocotrienol Nutrition 0.000 description 11
- 239000011729 δ-tocotrienol Substances 0.000 description 11
- ODADKLYLWWCHNB-LDYBVBFYSA-N δ-tocotrienol Chemical compound OC1=CC(C)=C2O[C@@](CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)(C)CCC2=C1 ODADKLYLWWCHNB-LDYBVBFYSA-N 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000013543 active substance Substances 0.000 description 9
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 9
- WDEABJKSGGRCQA-UHFFFAOYSA-N docebenone Chemical compound CC1=C(C)C(=O)C(CCCCC#CCCCC#CCO)=C(C)C1=O WDEABJKSGGRCQA-UHFFFAOYSA-N 0.000 description 9
- 230000004044 response Effects 0.000 description 9
- 239000003981 vehicle Substances 0.000 description 9
- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical compound NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000002560 therapeutic procedure Methods 0.000 description 8
- 229930003802 tocotrienol Natural products 0.000 description 8
- 239000011731 tocotrienol Substances 0.000 description 8
- 235000019148 tocotrienols Nutrition 0.000 description 8
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 230000036541 health Effects 0.000 description 7
- 239000002502 liposome Substances 0.000 description 7
- 230000035772 mutation Effects 0.000 description 7
- 230000002232 neuromuscular Effects 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- 229930003799 tocopherol Natural products 0.000 description 7
- 239000011732 tocopherol Substances 0.000 description 7
- 235000010384 tocopherol Nutrition 0.000 description 7
- 229960001295 tocopherol Drugs 0.000 description 7
- LNOVHERIIMJMDG-XZXLULOTSA-N 2-[(3r,6e,10e)-3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl]-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CC[C@@](C)(O)CCC1=C(C)C(=O)C(C)=C(C)C1=O LNOVHERIIMJMDG-XZXLULOTSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 235000015872 dietary supplement Nutrition 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000002708 enhancing effect Effects 0.000 description 6
- 230000001965 increasing effect Effects 0.000 description 6
- 239000002207 metabolite Substances 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 6
- 230000036542 oxidative stress Effects 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000003642 reactive oxygen metabolite Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 208000016285 Movement disease Diseases 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 210000003169 central nervous system Anatomy 0.000 description 5
- 230000007812 deficiency Effects 0.000 description 5
- 235000005911 diet Nutrition 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 230000010534 mechanism of action Effects 0.000 description 5
- 230000007659 motor function Effects 0.000 description 5
- 238000010606 normalization Methods 0.000 description 5
- 235000016709 nutrition Nutrition 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 4
- WXHLLJAMBQLULT-UHFFFAOYSA-N 2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-n-(2-methyl-6-sulfanylphenyl)-1,3-thiazole-5-carboxamide;hydrate Chemical compound O.C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1S WXHLLJAMBQLULT-UHFFFAOYSA-N 0.000 description 4
- 206010003594 Ataxia telangiectasia Diseases 0.000 description 4
- 206010061818 Disease progression Diseases 0.000 description 4
- 208000014094 Dystonic disease Diseases 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 4
- 229960003624 creatine Drugs 0.000 description 4
- 239000006046 creatine Substances 0.000 description 4
- 208000010118 dystonia Diseases 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 125000000687 hydroquinonyl group Chemical group C1(O)=C(C=C(O)C=C1)* 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 239000008159 sesame oil Substances 0.000 description 4
- 235000011803 sesame oil Nutrition 0.000 description 4
- XTCLGZZKAQZZJC-UHFFFAOYSA-N 2,3,5-trimethyl-6-[2-(2-methyl-5-oxooxolan-2-yl)ethyl]cyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(C)=C(C)C(=O)C(CCC2(C)OC(=O)CC2)=C1C XTCLGZZKAQZZJC-UHFFFAOYSA-N 0.000 description 3
- WAXIFTIATZBGGS-UHFFFAOYSA-N 2-(10-hydroxydeca-5,8-dienyl)-3-methylnaphthalene-1,4-dione Chemical compound CC1=C(CCCCC=CCC=CCO)C(=O)c2ccccc2C1=O WAXIFTIATZBGGS-UHFFFAOYSA-N 0.000 description 3
- 241000251468 Actinopterygii Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 208000008238 Muscle Spasticity Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 108060007963 Surf-1 Proteins 0.000 description 3
- 102000046669 Surf-1 Human genes 0.000 description 3
- LRYFTDGIIUTFFA-UHFFFAOYSA-N Tocopheronic acid Chemical compound CC1=C(C)C(=O)C(CCC(C)(O)CCC(O)=O)=C(C)C1=O LRYFTDGIIUTFFA-UHFFFAOYSA-N 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000000969 carrier Substances 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
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 3
- 235000018417 cysteine Nutrition 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 230000005750 disease progression Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000003701 inert diluent Substances 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- AHEWZZJEDQVLOP-UHFFFAOYSA-N monobromobimane Chemical compound BrCC1=C(C)C(=O)N2N1C(C)=C(C)C2=O AHEWZZJEDQVLOP-UHFFFAOYSA-N 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 230000004770 neurodegeneration Effects 0.000 description 3
- 208000015122 neurodegenerative disease Diseases 0.000 description 3
- 208000018360 neuromuscular disease Diseases 0.000 description 3
- 231100000062 no-observed-adverse-effect level Toxicity 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000002417 nutraceutical Substances 0.000 description 3
- 235000021436 nutraceutical agent Nutrition 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- 230000035764 nutrition Effects 0.000 description 3
- 201000008152 organic acidemia Diseases 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 230000007310 pathophysiology Effects 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 208000018198 spasticity Diseases 0.000 description 3
- 239000013589 supplement Substances 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 235000013311 vegetables Nutrition 0.000 description 3
- 229940088594 vitamin Drugs 0.000 description 3
- 229930003231 vitamin Natural products 0.000 description 3
- 235000013343 vitamin Nutrition 0.000 description 3
- 239000011782 vitamin Substances 0.000 description 3
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 3
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 description 2
- JOURHZSBLWSODQ-IEOSBIPESA-N 2-[(3r,7r,11r)-3-hydroxy-3,7,11,15-tetramethylhexadecyl]-3,5,6-trimethylbenzene-1,4-diol Chemical compound CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC[C@@](C)(O)CCC1=C(C)C(O)=C(C)C(C)=C1O JOURHZSBLWSODQ-IEOSBIPESA-N 0.000 description 2
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 2
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 2
- 102000014461 Ataxins Human genes 0.000 description 2
- 108010078286 Ataxins Proteins 0.000 description 2
- 208000001992 Autosomal Dominant Optic Atrophy Diseases 0.000 description 2
- 238000000035 BCA protein assay Methods 0.000 description 2
- 208000014644 Brain disease Diseases 0.000 description 2
- 206010008025 Cerebellar ataxia Diseases 0.000 description 2
- 201000000915 Chronic Progressive External Ophthalmoplegia Diseases 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 208000032274 Encephalopathy Diseases 0.000 description 2
- 208000024412 Friedreich ataxia Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 208000032087 Hereditary Leber Optic Atrophy Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000973778 Homo sapiens NAD(P)H dehydrogenase [quinone] 1 Proteins 0.000 description 2
- 208000000420 Isovaleric acidemia Diseases 0.000 description 2
- 206010048804 Kearns-Sayre syndrome Diseases 0.000 description 2
- 201000000639 Leber hereditary optic neuropathy Diseases 0.000 description 2
- 201000009035 MERRF syndrome Diseases 0.000 description 2
- 108020005196 Mitochondrial DNA Proteins 0.000 description 2
- 208000014844 Mitochondrial neurogastrointestinal encephalomyopathy Diseases 0.000 description 2
- HDFGOPSGAURCEO-UHFFFAOYSA-N N-ethylmaleimide Chemical compound CCN1C(=O)C=CC1=O HDFGOPSGAURCEO-UHFFFAOYSA-N 0.000 description 2
- 102100022365 NAD(P)H dehydrogenase [quinone] 1 Human genes 0.000 description 2
- 208000033716 Organic aciduria Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 208000009415 Spinocerebellar Ataxias Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- JOURHZSBLWSODQ-UHFFFAOYSA-N alpha-Tocopherolhydroquinone Natural products CC(C)CCCC(C)CCCC(C)CCCC(C)(O)CCC1=C(C)C(O)=C(C)C(C)=C1O JOURHZSBLWSODQ-UHFFFAOYSA-N 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 208000013414 ataxia-telangiectasia-like disease Diseases 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 201000004562 autosomal dominant cerebellar ataxia Diseases 0.000 description 2
- 150000007514 bases Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 235000013361 beverage Nutrition 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 235000013339 cereals Nutrition 0.000 description 2
- 210000004289 cerebral ventricle Anatomy 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 230000000378 dietary effect Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 150000002019 disulfides Chemical class 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 210000004700 fetal blood Anatomy 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 235000020256 human milk Nutrition 0.000 description 2
- 210000004251 human milk Anatomy 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 201000003694 methylmalonic acidemia Diseases 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 230000004065 mitochondrial dysfunction Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000008057 potassium phosphate buffer Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 150000004053 quinones Chemical class 0.000 description 2
- 125000004151 quinonyl group Chemical group 0.000 description 2
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 2
- 230000027756 respiratory electron transport chain Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 210000000582 semen Anatomy 0.000 description 2
- 238000002603 single-photon emission computed tomography Methods 0.000 description 2
- 238000007390 skin biopsy Methods 0.000 description 2
- 230000000391 smoking effect Effects 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 210000003954 umbilical cord Anatomy 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- UKGFZBSSRVYBPG-PLEMKBATSA-N (2S)-2-amino-5-[[(2R)-1-(carboxymethylamino)-1-oxo-3-sulfanylpropan-2-yl]amino]-5-oxopentanoic acid Chemical compound N[C@H](C(=O)O)CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O.N[C@H](C(=O)O)CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O.N[C@H](C(=O)O)CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O.N[C@H](C(=O)O)CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O UKGFZBSSRVYBPG-PLEMKBATSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- WOAHJDHKFWSLKE-UHFFFAOYSA-N 1,2-benzoquinone Chemical group O=C1C=CC=CC1=O WOAHJDHKFWSLKE-UHFFFAOYSA-N 0.000 description 1
- WMKDFHJGEGZOQZ-UHFFFAOYSA-N 13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-dienenitrile Chemical compound CC1=C(C)C(=O)C(CCCCC=CCC=CCCCC#N)=C(C)C1=O WMKDFHJGEGZOQZ-UHFFFAOYSA-N 0.000 description 1
- SRZOVFGPTNSKBA-UHFFFAOYSA-N 13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-dienoic acid Chemical compound CC1=C(C)C(=O)C(CCCCC=CCC=CCCCC(O)=O)=C(C)C1=O SRZOVFGPTNSKBA-UHFFFAOYSA-N 0.000 description 1
- NTEBTKUNZLUBJT-UHFFFAOYSA-N 13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-diynamide Chemical compound CC1=C(C)C(=O)C(CCCCC#CCC#CCCCC(N)=O)=C(C)C1=O NTEBTKUNZLUBJT-UHFFFAOYSA-N 0.000 description 1
- DCRHZVLNHPPKMB-UHFFFAOYSA-N 13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-diynenitrile Chemical compound CC1=C(C)C(=O)C(CCCCC#CCC#CCCCC#N)=C(C)C1=O DCRHZVLNHPPKMB-UHFFFAOYSA-N 0.000 description 1
- AVHUPFJIKBFLEM-UHFFFAOYSA-N 13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-diynoic acid Chemical compound CC1=C(C)C(=O)C(CCCCC#CCC#CCCCC(O)=O)=C(C)C1=O AVHUPFJIKBFLEM-UHFFFAOYSA-N 0.000 description 1
- WZDMDZDQIITTBR-UHFFFAOYSA-N 2-(10-hydroxydeca-5,8-dienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione Chemical compound CC1=C(C)C(=O)C(CCCCC=CCC=CCO)=C(C)C1=O WZDMDZDQIITTBR-UHFFFAOYSA-N 0.000 description 1
- UJXWAYSLVBVFQH-UHFFFAOYSA-N 2-(10-hydroxydeca-5,8-diynyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione Chemical compound CC1=C(C)C(=O)C(CCCCC#CCC#CCO)=C(C)C1=O UJXWAYSLVBVFQH-UHFFFAOYSA-N 0.000 description 1
- XMWXOHKOYPKUIA-UHFFFAOYSA-N 2-(10-hydroxydeca-5,8-diynyl)-3-methylnaphthalene-1,4-dione Chemical compound C1=CC=C2C(=O)C(C)=C(CCCCC#CCC#CCO)C(=O)C2=C1 XMWXOHKOYPKUIA-UHFFFAOYSA-N 0.000 description 1
- SWNANEREBNQAHT-UHFFFAOYSA-N 2-(11-hydroxyundeca-5,8-diynyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione Chemical compound CC1=C(C)C(=O)C(CCCCC#CCC#CCCO)=C(C)C1=O SWNANEREBNQAHT-UHFFFAOYSA-N 0.000 description 1
- CJLIXNWFWRIRCB-UHFFFAOYSA-N 2-(11-hydroxyundeca-5,8-diynyl)-3-methylnaphthalene-1,4-dione Chemical compound C1=CC=C2C(=O)C(C)=C(CCCCC#CCC#CCCO)C(=O)C2=C1 CJLIXNWFWRIRCB-UHFFFAOYSA-N 0.000 description 1
- DUSWGTOWKNQCKJ-UHFFFAOYSA-N 2-(12-hydroxydodeca-5,8-dienyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione Chemical compound CC1=C(C)C(=O)C(CCCCC=CCC=CCCCO)=C(C)C1=O DUSWGTOWKNQCKJ-UHFFFAOYSA-N 0.000 description 1
- GVZVAFKQMKOVLO-UHFFFAOYSA-N 2-(12-hydroxydodeca-5,8-diynyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione Chemical compound CC1=C(C)C(=O)C(CCCCC#CCC#CCCCO)=C(C)C1=O GVZVAFKQMKOVLO-UHFFFAOYSA-N 0.000 description 1
- OJJQALAXOMKIMM-UHFFFAOYSA-N 2-(12-hydroxydodeca-5,8-diynyl)-3-methylnaphthalene-1,4-dione Chemical compound C1=CC=C2C(=O)C(C)=C(CCCCC#CCC#CCCCO)C(=O)C2=C1 OJJQALAXOMKIMM-UHFFFAOYSA-N 0.000 description 1
- PNDBLWYXQSXNKD-UHFFFAOYSA-N 2-(9-hydroxynon-5-ynyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione Chemical compound CC1=C(C)C(=O)C(CCCCC#CCCCO)=C(C)C1=O PNDBLWYXQSXNKD-UHFFFAOYSA-N 0.000 description 1
- GJJVAFUKOBZPCB-UHFFFAOYSA-N 2-methyl-2-(4,8,12-trimethyltrideca-3,7,11-trienyl)-3,4-dihydrochromen-6-ol Chemical compound OC1=CC=C2OC(CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1 GJJVAFUKOBZPCB-UHFFFAOYSA-N 0.000 description 1
- KVZLHPXEUGJPAH-UHFFFAOYSA-N 2-oxidanylpropanoic acid Chemical compound CC(O)C(O)=O.CC(O)C(O)=O KVZLHPXEUGJPAH-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- HGFIOWHPOGLXPU-UHFFFAOYSA-N 4,7-diphenyl-1,10-phenanthroline 4',4''-disulfonic acid Chemical compound C1=CC(S(=O)(=O)O)=CC=C1C1=CC=NC2=C1C=CC1=C(C=3C=CC(=CC=3)S(O)(=O)=O)C=CN=C21 HGFIOWHPOGLXPU-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 241001550224 Apha Species 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 102000007371 Ataxin-3 Human genes 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- PELWLJQIZNFTHK-UHFFFAOYSA-N CCC#CCCCC#CCCCCC1=C(C)C(=O)C(C)=C(C)C1=O Chemical compound CCC#CCCCC#CCCCCC1=C(C)C(=O)C(C)=C(C)C1=O PELWLJQIZNFTHK-UHFFFAOYSA-N 0.000 description 1
- NSTDVBZFXODKIW-UHFFFAOYSA-N CCCC[Y] Chemical compound CCCC[Y] NSTDVBZFXODKIW-UHFFFAOYSA-N 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 208000002155 Cytochrome-c Oxidase Deficiency Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 102000015782 Electron Transport Complex III Human genes 0.000 description 1
- 108010024882 Electron Transport Complex III Proteins 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- BPNZYADGDZPRTK-UDUYQYQQSA-N Exametazime Chemical compound O/N=C(\C)[C@@H](C)NCC(C)(C)CN[C@H](C)C(\C)=N\O BPNZYADGDZPRTK-UDUYQYQQSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010063907 Glutathione Reductase Proteins 0.000 description 1
- 102100036442 Glutathione reductase, mitochondrial Human genes 0.000 description 1
- 208000016988 Hemorrhagic Stroke Diseases 0.000 description 1
- 101000938567 Homo sapiens Persulfide dioxygenase ETHE1, mitochondrial Proteins 0.000 description 1
- 101000630267 Homo sapiens Probable glutamate-tRNA ligase, mitochondrial Proteins 0.000 description 1
- 101000661446 Homo sapiens Succinate-CoA ligase [ADP-forming] subunit beta, mitochondrial Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical class OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- ZUKPVRWZDMRIEO-VKHMYHEASA-N L-cysteinylglycine Chemical compound SC[C@H]([NH3+])C(=O)NCC([O-])=O ZUKPVRWZDMRIEO-VKHMYHEASA-N 0.000 description 1
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000002569 Machado-Joseph Disease Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010059521 Methylmalonic aciduria Diseases 0.000 description 1
- 201000002169 Mitochondrial myopathy Diseases 0.000 description 1
- 206010065271 Mitochondrial neurogastrointestinal encephalopathy Diseases 0.000 description 1
- 208000007379 Muscle Hypotonia Diseases 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- HHMICWBPTAEOOA-UHFFFAOYSA-N NC(CCC(=O)NC(CS)C(=O)CCC(=O)O)C(=O)O Chemical compound NC(CCC(=O)NC(CS)C(=O)CCC(=O)O)C(=O)O HHMICWBPTAEOOA-UHFFFAOYSA-N 0.000 description 1
- 229910004878 Na2S2O4 Inorganic materials 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108091093105 Nuclear DNA Proteins 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 206010068786 Overlap syndrome Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102100030940 Persulfide dioxygenase ETHE1, mitochondrial Human genes 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 102100026125 Probable glutamate-tRNA ligase, mitochondrial Human genes 0.000 description 1
- 208000020853 Progressive neurologic deterioration Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 101100008569 Rattus norvegicus Cst4 gene Proteins 0.000 description 1
- 208000007014 Retinitis pigmentosa Diseases 0.000 description 1
- HYHSBSXUHZOYLX-WDSKDSINSA-N S-nitrosoglutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CSN=O)C(=O)NCC(O)=O HYHSBSXUHZOYLX-WDSKDSINSA-N 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 206010039438 Salmonella Infections Diseases 0.000 description 1
- 208000032140 Sleepiness Diseases 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 208000036834 Spinocerebellar ataxia type 3 Diseases 0.000 description 1
- 208000035286 Spontaneous Remission Diseases 0.000 description 1
- 208000013200 Stress disease Diseases 0.000 description 1
- 102100037811 Succinate-CoA ligase [ADP-forming] subunit beta, mitochondrial Human genes 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- YTGJWQPHMWSCST-UHFFFAOYSA-N Tiopronin Chemical compound CC(S)C(=O)NCC(O)=O YTGJWQPHMWSCST-UHFFFAOYSA-N 0.000 description 1
- 108010058907 Tiopronin Proteins 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 239000007984 Tris EDTA buffer Substances 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 229930003427 Vitamin E Chemical class 0.000 description 1
- 238000001793 Wilcoxon signed-rank test Methods 0.000 description 1
- GWZOLWLJEJRQMZ-UHFFFAOYSA-N [S].S Chemical compound [S].S GWZOLWLJEJRQMZ-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- FSHXODRICVTBJO-UHFFFAOYSA-N benzene-1,2-diol;benzene-1,4-diol Chemical group OC1=CC=C(O)C=C1.OC1=CC=CC=C1O FSHXODRICVTBJO-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000005251 capillar electrophoresis Methods 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 230000000112 colonic effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 1
- 108010016616 cysteinylglycine Proteins 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 235000018823 dietary intake Nutrition 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229950003667 docebenone Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000002888 effect on disease Effects 0.000 description 1
- 238000000835 electrochemical detection Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 235000013376 functional food Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000023266 generation of precursor metabolites and energy Effects 0.000 description 1
- 238000010448 genetic screening Methods 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- 229940045883 glutathione disulfide Drugs 0.000 description 1
- 108700031746 glutathione persulfide Proteins 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000034659 glycolysis Effects 0.000 description 1
- 230000007407 health benefit Effects 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 235000008216 herbs Nutrition 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 235000006486 human diet Nutrition 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229960004135 idebenone Drugs 0.000 description 1
- JGPMMRGNQUBGND-UHFFFAOYSA-N idebenone Chemical class COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O JGPMMRGNQUBGND-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 208000023692 inborn mitochondrial myopathy Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000030309 inherited neurodegenerative disease Diseases 0.000 description 1
- 238000011283 initial treatment period Methods 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 208000020658 intracerebral hemorrhage Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 108700036927 isovaleric Acidemia Proteins 0.000 description 1
- 238000009592 kidney function test Methods 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000007449 liver function test Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229960003151 mercaptamine Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 230000004898 mitochondrial function Effects 0.000 description 1
- GVZFUVXPTPGOQT-UHFFFAOYSA-M mitoq Chemical class CS([O-])(=O)=O.O=C1C(OC)=C(OC)C(=O)C(CCCCCCCCCC[P+](C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1C GVZFUVXPTPGOQT-UHFFFAOYSA-M 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 230000003990 molecular pathway Effects 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- OULQFGOQJHWSJR-UHFFFAOYSA-N n,n-dimethyl-13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-diynamide Chemical compound CN(C)C(=O)CCCC#CCC#CCCCCC1=C(C)C(=O)C(C)=C(C)C1=O OULQFGOQJHWSJR-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- 230000002956 necrotizing effect Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 108010007425 oligomycin sensitivity conferring protein Proteins 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000010627 oxidative phosphorylation Effects 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000863 peptide conjugate Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920002627 poly(phosphazenes) Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 235000021067 refined food Nutrition 0.000 description 1
- 201000010384 renal tubular acidosis Diseases 0.000 description 1
- 230000035806 respiratory chain Effects 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 206010039447 salmonellosis Diseases 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000037321 sleepiness Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 125000002640 tocopherol group Chemical group 0.000 description 1
- 125000003036 tocotrienol group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000011709 vitamin E Chemical class 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- WGVKWNUPNGFDFJ-UHFFFAOYSA-N β-tocopherol group Chemical group CC1(OC2=C(C=C(C(=C2CC1)C)O)C)CCCC(CCCC(CCCC(C)C)C)C WGVKWNUPNGFDFJ-UHFFFAOYSA-N 0.000 description 1
- 125000000255 β-tocotrienol group Chemical group 0.000 description 1
- 125000003810 γ-tocopherol group Chemical group 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C66/00—Quinone carboxylic acids
Definitions
- redox-active compounds such as tocotrienol quinones, for example, alpha-tocotrienol quinone
- a proper balance between oxidation and reduction reactions in cells, tissues, and organisms is vital for health. Maintenance of such a proper redox balance is, for example, critical for proper functioning of processes such as glycolysis, the citric acid cycle, and oxidative phosphorylation, which depend upon electron-transfer reactions in order to produce ATP, the major energy carrier in living organisms.
- the current invention provides compositions and methods for modulating, adjusting, and maintaining the redox status of an individual at an appropriate level to improve or enhance the health of the individual.
- the invention provides compounds and methods to address the common glutathione cycle defect associated with several diseases, including mitochondrial and neurodegenerative diseases. Specifically, the compounds and methods regenerate reduced glutathione and increase the glutathione charge couple, resulting in: i) restoration of redox balance and metabolic control; ii) reduction in the generation of reactive oxygen species; and iii) arrest and reversal of disease.
- the methods of the invention encompass modulating, adjusting, and maintaining a healthy glutathione redox potential in an individual, or in the cells, tissues, organs, or bodily fluids of an individual, by altering the ratios of reduced glutathione (GSH) to oxidized glutathione (GSSG) in the individual, or in the cells, tissues, organs, or bodily fluids of the individual.
- GSH reduced glutathione
- GSSG oxidized glutathione
- the present invention comprises multiple aspects, features and embodiments, where such multiple aspects, features and embodiments can be combined and permuted in any desired manner.
- FIG. 1 shows clinical outcomes prior to and following three months of EPI-743 treatment. There was significant improvement on NPMDS ( FIG. 1A , FIG. 1B and FIG. 1C ), neuromuscular function ( FIG. 1D ), health related quality of life ( FIG. 1E ) and dystonia and spasticity ( FIG. 1F ).
- FIG. 2 shows biomarker outcome measurements. Ratio of lymphocyte oxidized glutathione (GSSG) to reduced glutathione (GSH) and ratio of GSSG to total glutathione (GSH+GSSG) over treatment time are shown. In all patients, there was rapid normalization of overall glutathione charge attributable to repletion of reduced glutathione levels.
- FIG. 3 shows the proposed normal physiology ( FIG. 3A ), disease pathophysiology ( FIG. 3B ), and drug mechanism of action of EPI-743 ( FIG. 3C ).
- Inherited mitochondria diseases result in the generation of increased quantities of reactive oxygen species, which are neutralized by the glutathione cycle.
- EPI-743 acts to replete glutathione cycle capacity by shuttling reducing equivalents from NADPH to glutathione reductase, via NQO1.
- FIG. 4 shows an analysis of Leigh syndrome cohort clinical course.
- FIG. 5 (Table 1) shows baseline patient characteristics for the patients of Example 2.
- FIG. 6 (Table 2) summarizes the outcomes for the patients treated in Example 2.
- FIG. 7 shows analysis of the natural history of the clinical course of a cohort with Leigh syndrome.
- the natural history from published case reports of children with Leigh syndrome with mutations evaluated in this study was categorized as improved, stable, progressed or death. Of the 180 children described in the literature, 179 either died or had progressive neurologic deterioration.
- the invention embraces compositions and methods for modulating, adjusting, and maintaining the redox status of an individual at an appropriate level to improve or enhance the health of the individual, or to treat, prevent, or suppress certain diseases or symptoms of certain diseases.
- subject By “subject,” “individual,” or “patient” is meant an individual organism, preferably a vertebrate, more preferably a mammal, most preferably a human.
- Treating” a disease with the compounds and methods discussed herein is defined as administering one or more of the compounds discussed herein, with or without additional therapeutic agents, in order to reduce or eliminate either the disease or one or more symptoms of the disease, or to retard the progression of the disease or of one or more symptoms of the disease, or to reduce the severity of the disease or of one or more symptoms of the disease.
- “Suppression” of a disease with the compounds and methods discussed herein is defined as administering one or more of the compounds discussed herein, with or without additional therapeutic agents, in order to suppress the clinical manifestation of the disease, or to suppress the manifestation of adverse symptoms of the disease.
- treatment occurs after adverse symptoms of the disease are manifest in a subject, while suppression occurs before adverse symptoms of the disease are manifest in a subject. Suppression may be partial, substantially total, or total. Because many of the mitochondrial disorders are inherited, genetic screening can be used to identify patients at risk of the disease. The compounds and methods of the invention can then be administered to asymptomatic patients at risk of developing the clinical symptoms of the disease, in order to suppress the appearance of any adverse symptoms. “Therapeutic use” of the compounds discussed herein is defined as using one or more of the compounds discussed herein to treat or suppress a disease, as defined above.
- a “therapeutically effective amount” of a compound is an amount of a compound which, when administered to a subject, is sufficient to reduce or eliminate either one or more symptoms of a disease, or to retard the progression of one or more symptoms of a disease, or to reduce the severity of one or more symptoms of a disease, or to suppress the clinical manifestation of a disease, or to suppress the manifestation of adverse symptoms of a disease.
- a therapeutically effective amount can be given in one or more administrations.
- An “effective amount” of a compound embraces both a therapeutically effective amount, as well as an amount effective to modulate, normalize, or enhance one or more energy biomarkers in a subject.
- Modulation of, or to “modulate,” an energy biomarker means to change the level of the energy biomarker towards a desired value, or to change the level of the energy biomarker in a desired direction (e.g., increase or decrease). Modulation can include, but is not limited to, normalization and enhancement as defined below.
- an energy biomarker is defined as changing the level of the energy biomarker from a pathological value towards a normal value, where the normal value of the energy biomarker can be 1) the level of the energy biomarker in a healthy person or subject, or 2) a level of the energy biomarker that alleviates one or more undesirable symptoms in the person or subject.
- to normalize an energy biomarker which is depressed in a disease state means to increase the level of the energy biomarker towards the normal (healthy) value or towards a value which alleviates an undesirable symptom; to normalize an energy biomarker which is elevated in a disease state means to decrease the level of the energy biomarker towards the normal (healthy) value or towards a value which alleviates an undesirable symptom.
- Energy biomarkers means to intentionally change the level of one or more energy biomarkers away from either the normal value, or the value before enhancement, in order to achieve a beneficial or desired effect. For example, in a situation where significant energy demands are placed on a subject, it may be desirable to increase the level of ATP in that subject to a level above the normal level of ATP in that subject.
- Enhancement can also be of beneficial effect in a subject suffering from a disease or pathology such as a mitochondrial disease, in that normalizing an energy biomarker may not achieve the optimum outcome for the subject; in such cases, enhancement of one or more energy biomarkers can be beneficial, for example, higher-than-normal levels of ATP, or lower-than-normal levels of lactic acid (lactate) can be beneficial to such a subject.
- a disease or pathology such as a mitochondrial disease
- the salts of the compounds comprise pharmaceutically acceptable salts.
- Pharmaceutically acceptable salts are those salts which can be administered as drugs or pharmaceuticals to humans and/or animals and which, upon administration, retain at least some of the biological activity of the free compound (neutral compound or non-salt compound).
- the desired salt of a basic compound may be prepared by methods known to those of skill in the art by treating the compound with an acid.
- inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.
- organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid. Salts of basic compounds with amino acids, such as aspartate salts and glutamate salts, can also be prepared.
- the desired salt of an acidic compound can be prepared by methods known to those of skill in the art by treating the compound with a base.
- inorganic salts of acid compounds include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and aluminum salts.
- organic salts of acid compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, N,N′-dibenzylethylenediamine, and triethylamine salts. Salts of acidic compounds with amino acids, such as lysine salts, can also be prepared.
- Several pharmaceutically acceptable salts are disclosed in Berge, J. Pharm. Sci. 66:1 (1977).
- the invention also includes all stereoisomers and geometric isomers of the compounds, including diastereomers, enantiomers, and cis/trans (E/Z) isomers.
- the invention also includes mixtures of stereoisomers and/or geometric isomers in any ratio, including, but not limited to, racemic mixtures. Unless stereochemistry is explicitly indicated in a structure, the structure is intended to embrace all possible stereoisomers of the compound depicted. If stereochemistry is explicitly indicated for one portion or portions of a molecule, but not for another portion or portions of a molecule, the structure is intended to embrace all possible stereoisomers for the portion or portions where stereochemistry is not explicitly indicated.
- the compounds can be administered in prodrug form.
- Prodrugs are derivatives of the compounds which are themselves relatively inactive, but which convert into the active compound when introduced into the subject in which they are used, by a chemical or biological process in vivo, such as an enzymatic conversion.
- Suitable prodrug formulations include, but are not limited to, peptide conjugates of the compounds of the invention and esters of compounds of the inventions. Further discussion of suitable prodrugs is provided in H. Bundgaard, Design of Prodrugs, New York: Elsevier, 1985; in R. Silverman, The Organic Chemistry of Drug Design and Drug Action, Boston: Elsevier, 2004; in R. L.
- the various compounds of the invention can be administered either as therapeutic agents in and of themselves, or as prodrugs which will convert to other therapeutically effective or effective substances in the body.
- alkyl refers to saturated aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms.
- “Straight-chain alkyl” or “linear alkyl” group refers to alkyl groups that are neither cyclic nor branched, commonly designated as “n-alkyl” groups.
- alkyl groups is —(C 1 -C 6 )alkyl which include groups such as methyl, ethyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, n-pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and any other alkyl group containing between one and five carbon atoms, where the —(C 1 -C 6 )alkyl groups can be attached via any valence on the —(C 1 -C 6 ) alkyl groups.
- Gluthathione is the molecule (2S)-2-amino-5-[[(2R)-1-(carboxymethylamino)-1-oxo-3-sulfanylpropan-2-yl]amino]-5-oxopentanoic acid (IUPAC), and has the following structure:
- Glutathione which can be described as the tripeptide gamma-Glu-Cys-Gly.
- Glutathione is commonly abbreviated as GSH.
- the oxidized form of glutathione is the disulfide-bridged dimeric form of the tripeptide, and is abbreviated as GSSG.
- Glutathione can also form mixed disulfides with cysteine-containing proteins; the glutathione-protein molecule is abbreviated as GS-Pro.
- Glutathione can also form persulfides by reaction with hydrogen sulfide or sulfane sulfur. Glutathione persulfide is abbreviated as GSSH.
- Glutathione is an example of an energy biomarker that can be modulated, normalized, or enhanced using the methods of the invention and the compounds disclosed herein, and which can be modulated, normalized, or enhanced to adjust the redox status of an individual in accordance with the invention.
- compounds of Formula I are useful in the invention for modulating glutathione levels:
- R is selected from: where the asterisk * indicates the attachment of R in Formula I; where R 1 , R 2 , and R 3 are independently H or C 1 -C 6 alkyl, m is an integer from 0 to 9 inclusive, and the bonds indicated by a dashed line can be either double or single bonds. In some embodiments m is selected from 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, m is selected from 1, 2, or 3. In some embodiments, m is 2. In another embodiment, R 1 , R 2 , and R 3 are CH 3 . In another embodiment, m is 2 and R 1 , R 2 , and R 3 are CH 3 .
- compounds of Formula I-ox and Formula I-red are useful in the invention for modulating glutathione levels:
- R 1 , R 2 , and R 3 are independently H or C 1 -C 6 alkyl
- m is an integer from 0 to 9 inclusive, and the bonds indicated by a dashed line can be either double or single bonds.
- m is selected from 1, 2, 3, 4, 5, 6, 7, 8, or 9.
- m is selected from 1, 2, or 3.
- m is 2.
- R 1 , R 2 , and R 3 are CH 3 .
- m is 2 and R 1 , R 2 , and R 3 are CH 3 .
- compounds of Formula I-D-ox and Formula I-D-red are useful in the invention for modulating glutathione levels:
- R 1 , R 2 , and R 3 are independently H or C 1 -C 6 alkyl, and m is an integer from 0 to 9 inclusive. In some embodiments m is selected from 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, m is selected from 1, 2, or 3. In some embodiments, m is 2. In another embodiment, R 1 , R 2 , and R 3 are CH 3 . In another embodiment, m is 2 and R 1 , R 2 , and R 3 are CH 3 .
- compounds of Formula I-S-ox and Formula I-S-red are useful in the invention for modulating glutathione levels:
- R 1 , R 2 , and R 3 are independently H or C 1 -C 6 alkyl, and m is an integer from 0 to 9 inclusive. In some embodiments m is selected from 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, m is selected from 1, 2, or 3. In some embodiments, m is 2. In another embodiment, R 1 , R 2 , and R 3 are CH 3 . In another embodiment, m is 2 and R 1 , R 2 , and R 3 are CH 3 .
- the compounds of Formula I-ox that are useful in the invention for modulating glutathione levels are tocotrienol quinones of the following structures:
- R 2 CH 3
- R 3 CH 3 beta-tocotrienol quinone
- R 1 CH 3
- R 2 H
- R 3 CH 3 gamma-tocotrienol quinone
- R 1 H
- R 2 CH 3
- R 3 CH 3 delta-tocotrienol quinone
- R 1 H
- R 2 H
- R 3 CH 3 including stereoisomers and salts thereof.
- the compound of Formula I-ox is a tocotrienol quinone. In other embodiments, the compound of Formula I-ox is alpha-tocotrienol quinone. In other embodiments, the compound of Formula I-ox is beta-tocotrienol quinone. In other embodiments, the compound of Formula I-ox is gamma-tocotrienol quinone. In other embodiments, the compound of Formula I-ox is delta-tocotrienol quinone.
- the compounds of Formula I-ox used to modulate glutathione levels comprise an effective amount of a mixture of two or more tocotrienol quinones selected from alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone and delta-tocotrienol quinone.
- the compounds of Formula I-red that are useful in the invention for modulating glutathione levels are tocotrienol hydroquinones of the following structures:
- the compound of Formula I-red is a tocotrienol hydroquinone. In other embodiments, the compound of Formula I-red is alpha-tocotrienol hydroquinone. In other embodiments, the compound of Formula I-red is beta-tocotrienol hydroquinone. In other embodiments, the compound of Formula I-red is gamma-tocotrienol hydroquinone. In other embodiments, the compound of Formula I-red is delta-tocotrienol hydroquinone.
- the compounds of Formula I-red used to modulate glutathione levels comprise an effective amount of a mixture of two or more tocotrienol hydroquinones selected from alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma-tocotrienol hydroquinone and delta-tocotrienol hydroquinone.
- the compounds of Formula I-ox that are useful in the invention for modulating glutathione levels are tocopherol quinones of the following structures:
- R 2 CH 3
- R 3 CH 3 beta-tocopherol quinone
- R 1 CH 3
- R 2 H
- R 3 CH 3 gamma-tocopherol quinone
- R 1 H
- R 2 CH 3
- R 3 CH 3 delta-tocopherol quinone
- R 1 H
- R 2 H
- R 3 CH 3 including stereoisomers and salts thereof.
- the compound of Formula I-ox is a tocopherol quinone. In other embodiments, the compound of Formula I-ox is alpha-tocopherol quinone. In other embodiments, the compound of Formula I-ox is beta-tocopherol quinone. In other embodiments, the compound of Formula I-ox is gamma-tocopherol quinone. In other embodiments, the compound of Formula I-ox is delta-tocopherol quinone.
- the compounds of Formula I-ox used to modulate glutathione levels comprise an effective amount of a mixture of two or more tocopherol quinones selected from alpha-tocopherol quinone, beta-tocopherol quinone, gamma-tocopherol quinone and delta-tocopherol quinone.
- the compounds of Formula I-red that are useful in the invention for modulating glutathione levels are tocopherol hydroquinones of the following structures:
- the compound of Formula I-red is a tocopherol hydroquinone. In other embodiments, the compound of Formula I-red is alpha-tocopherol hydroquinone. In other embodiments, the compound of Formula I-red is beta-tocopherol hydroquinone. In other embodiments, the compound of Formula I-red is gamma-tocopherol hydroquinone. In other embodiments, the compound of Formula I-red is delta-tocopherol hydroquinone.
- the compounds of Formula I-red used to modulate glutathione levels comprise an effective amount of a mixture of two or more tocopherol hydroquinones selected from alpha-tocopherol hydroquinone, beta-tocopherol hydroquinone, gamma-tocopherol hydroquinone and delta-tocopherol hydroquinone.
- the quinones described herein can be used in their oxidized form (Formula I-ox, Formula I-D-ox, Formula I-S-ox), or can be used in their reduced hydroquinone form (Formula I-red, Formula I-D-red, Formula I-S-red).
- the quinone (cyclohexadienedione) form and hydroquinone (benzenediol) form are readily interconverted with appropriate reagents.
- the quinone form can be treated in a biphasic mixture of an ethereal solvent with a basic aqueous solution of Na 2 S 2 O 4 (Vogel, A. I. et al.
- compounds of Formula II are useful in the invention for modulating glutathione levels:
- R′ is selected from
- R 21 and R 22 are independently of each other hydrogen, —(C 1 -C 6 )alkyl or —O—(C 1 -C 6 )alkyl; or R 21 and R 22 together represent —CH ⁇ CH—CH ⁇ CH—;
- R 23 is (C 1 -C 6 )alkyl
- X is —CH ⁇ CH— or —C ⁇ C—
- n is 1-10; n is 1-5; k is 1-3, with the proviso that when k is an integer of 2 to 3, n is optionally variable from 1-5 in each occurrence of the —X—(CH 2 ) n — group;
- Y is —OR 24 , —CN or —COOR 25 ;
- R 24 and R 25 are independently of each other selected from hydrogen, —CN, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl; —C( ⁇ O)—(C 1 -C 6 )alkyl; —C( ⁇ O)—(C 1 -C 6 )haloalkyl; —C( ⁇ O)—NH(C 1 -C 6 )alkyl; —C( ⁇ O)—N((C 1 -C 6 )alkyl) 2 and —C( ⁇ O)—NH 2 ; or any stereoisomer, mixture of stereoisomers, prodrug, metabolite, salt, crystalline form, non-crystalline form, hydrate or solvate thereof.
- R 21 , R 22 , and R 23 are independently selected from —(C 1 -C 6 )alkyl. In another embodiment, R 21 and R 22 are independently selected from —O(C 1 -C 6 )alkyl. In another embodiment, R 21 and R 22 are hydrogen and R 23 is —(C 1 -C 6 )alkyl. In another embodiment, R 21 , R 22 and R 23 are hydrogen. In another embodiment, R 21 and R 22 together represent —CH ⁇ CH—CH ⁇ CH—. In another embodiment, X is —CH ⁇ CH—. In another embodiment, X is —C ⁇ C—. In another embodiment, Y is —OR 24 . In another embodiment Y is —CN or —COOR 25 .
- R 24 is hydrogen, —C( ⁇ O)—(C 1 -C 6 )alkyl, or —C( ⁇ O)—(C 1 -C 6 )haloalkyl.
- R 25 is hydrogen or —(C 1 -C 6 )alkyl.
- m is 1-5. In another embodiment, m is 2-5.
- n is 1-4. In another embodiment, n is 1-3. In another embodiment n is 1-2. In another embodiment, k is 2-3.
- R 21 , R 22 and R 23 are —CH 3 ; X is —CH ⁇ CH—; m is 4; n is 1-3; k is 1-2; and Y is —OH.
- R 21 , R 22 and R 23 are CH 3 ; X is —C ⁇ C—; m is 4; n is 1-3; k is 1-2; and Y is —OH.
- R 21 and R 22 together represent —CH ⁇ CH—CH ⁇ CH—; R 23 is CH 3 ; X is —CH ⁇ CH—; m is 4; n is 1-3, k is 1-2; and Y is —OH.
- R 21 and R 22 together represent —CH ⁇ CH—CH ⁇ CH—; R 23 is CH 3 ; X is —C ⁇ C—; m is 4; n is 3, k is 1-3 and Y is —OH.
- compounds of Formula II-ox or Formula II-red are useful in the invention for modulating glutathione levels:
- R 21 and R 22 are independently of each other hydrogen, —(C 1 -C 6 )alkyl or —O—(C 1 -C 6 )alkyl; or R 21 and R 22 together represent —CH ⁇ CH—CH ⁇ CH—;
- R 23 is (C 1 -C 6 )alkyl
- X is —CH ⁇ CH— or —C ⁇ C—
- n is 1-10; n is 1-5; k is 1-3, with the proviso that when k is an integer of 2 to 3, n is optionally variable from 1-5 in each occurrence of the —X—(CH 2 ) n — group;
- Y is —OR 24 , —CN or —COOR 25 ;
- R 24 and R 25 are independently of each other selected from hydrogen, —CN, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl; —C( ⁇ O)—(C 1 -C 6 )alkyl; —C( ⁇ O)—(C 1 -C 6 )haloalkyl; —C( ⁇ O)—NH(C 1 -C 6 )alkyl; —C( ⁇ O)—N((C 1 -C 6 )alkyl) 2 and —C( ⁇ O)—NH 2 ; or any stereoisomer, mixture of stereoisomers, prodrug, metabolite, salt, crystalline form, non-crystalline form, hydrate or solvate thereof.
- R 21 , R 22 , and R 23 are independently selected from —(C 1 -C 6 )alkyl. In another embodiment, R 21 and R 22 are independently selected from —O(C 1 -C 6 )alkyl. In another embodiment, R 21 and R 22 are hydrogen and R 23 is —(C 1 -C 6 )alkyl. In another embodiment, R 21 , R 22 and R 23 are hydrogen. In another embodiment, R 21 and R 22 together represent —CH ⁇ CH—CH ⁇ CH—. In another embodiment, X is —CH ⁇ CH—. In another embodiment, X is —C ⁇ C—. In another embodiment, Y is —OR 24 . In another embodiment Y is —CN or —COOR 25 .
- R 24 is hydrogen, —C( ⁇ O)—(C 1 -C 6 )alkyl, or —C( ⁇ O)—(C 1 -C 6 )haloalkyl.
- R 25 is hydrogen or —(C 1 -C 6 )alkyl.
- m is 1-5. In another embodiment, m is 2-5.
- n is 1-4. In another embodiment, n is 1-3. In another embodiment n is 1-2. In another embodiment, k is 2-3.
- R 21 , R 22 and R 23 are —CH 3 ; X is —CH ⁇ CH—; m is 4; n is 1-3; k is 1-2; and Y is —OH.
- R 21 , R 22 and R 23 are CH 3 ; X is —C ⁇ C—; m is 4; n is 1-3; k is 1-2; and Y is —OH.
- R 21 and R 22 together represent —CH ⁇ CH—CH ⁇ CH—; R 23 is CH 3 ; X is —CH ⁇ CH—; m is 4; n is 1-3, k is 1-2; and Y is —OH.
- R 21 and R 22 together represent —CH ⁇ CH—CH ⁇ CH—; R 23 is CH 3 ; X is —C ⁇ C—; m is 4; n is 3, k is 1-3 and Y is —OH.
- the compound of Formula II for modulating glutathione levels includes, but is not limited to:
- the invention embraces 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone or any stereoisomer, mixture of stereoisomers, prodrug, metabolite, salt, crystalline form, non-crystalline form, hydrate or solvate thereof, for use in modulating glutathione levels.
- 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone, (CAS Registry number 80809-81-9) is also known as Docebenone, AA861 or aa-861, and has the structure:
- the invention embraces the lactone; 2,3,5-trimethyl-6-(2-(2-methyl-5-oxotetrahydrofuran-2-yl)ethyl)cyclohexa-2,5-diene-1,4-dione (CAS Registry numbers 3121-68-4, 15716-16-2, 22625-17-8, 816456-29-8):
- Measurement of the redox potential of the glutathione pool provides a snapshot of the redox balance of the cell, tissue, or organism in which the potential is measured.
- the glutathione potential of a sample can be determined using the Nernst equation:
- E o is the redox potential of the glutathione couple under standard conditions
- R is the gas constant
- T is the absolute temperature (that is, in degrees Kelvin, K)
- n is the number of electrons transferred in the reaction
- F is Faraday's constant.
- [GSSG] represents the concentration of oxidized glutathione
- [GSH] is the concentration of reduced glutathione. See, for example, Jones, Dean P., “Redox Potential of GSH/GSSG Couple: Assay and Biological Significance” in Methods of Enzymology: Protein Sensors and Reactive Oxygen Species—Part B: Thiol Enzymes and Proteins (Sies, H. and Packer, L., editors), Vol. 348, pp. 93-112 (2002); and Jonas et al., American Journal of Clinical Nutrition, 72:181-189 (2000).
- glutathione redox potentials in individuals are negative, between ⁇ 170 mV and ⁇ 90 mV, changes in the glutathione redox potential are indicated by the absolute value of the change and the direction of the change.
- a change in redox potential of an absolute value 10 mV more negative indicates that the redox potential of the subject has changed to ⁇ 130 mV.
- a change in glutathione redox potential of an absolute value of at least about 10 mV more negative indicates that the absolute value of the change is greater than 10, and the change is more negative.
- Glutathione concentration can be measured using a variety of methods, such as that described by Pastore, A., et al. “Fully automated assay for total homocysteine, cysteine, cysteinylglycine, glutathione, cysteamine, and 2-mercaptopropionylglycine in plasma and urine,” Clin. Chem . (Washington, D.C.) 44:825-832 (1998) (see Example 1 below). Other glutathione assays have been described in Serru et al., “Quantification of Reduced and Oxidized Glutathione in Whole Blood Samples by Capillary Electrophoresis,” Clin. Chem .
- Plasma levels of GSH, GSSG, Cys, and CySS can be used to calculate the in vivo E h values.
- Samples are collected using the procedure of Jones et al (2009 Free Radical Biology & Medicine 47(10):1329-1338). This method uses bromobimane to alkylate free thiols and HPLC and either electrochemical or MSMS to separate, detect, and quantify the molecules.
- One method of analyzing the most common monothiols and disulfides (cystine, cysteine, reduced (GSH) and oxidized glutathione (GSSG)) present in human plasma is to use bathophenanthroline disulfonic acid as the internal standard (IS), with complete separation of all the target analytes and IS at 35° C.
- IS internal standard
- a “subject having a glutathione redox potential disorder,” “individual having a glutathione redox potential disorder,” or “patient having a glutathione redox potential disorder,” is a subject, individual, or patient having a glutathione redox potential lying outside the normal range for a healthy age-matched individual.
- the range of glutathione redox potentials compatible with life is roughly ⁇ 170 millivolts to ⁇ 90 millivolts in human plasma. Comparison of the glutathione potential of an individual to a healthy age-matched individual serving as control will indicate whether the potential is at a pathological value.
- Comparison can be made to a healthy age-matched, sex-matched individual who has the same smoking status as the person being tested (that is, smokers should be compared to healthy age-matched, sex-matched smokers; non-smokers should be compared to healthy age-matched, sex-matched non-smokers).
- the comparison can be made to an average value over a group of control individuals who are matched (by age, sex, and smoking status) to the test individual.
- a group of ten, fifty, or one hundred people can be used.
- Using a group for comparison will allow calculation of a standard deviation for the control group, and the test individual can be considered for therapy (that is, considered as having a glutathione redox potential disorder) if the subject's glutathione redox potential is at least one standard deviation, at least two standard deviations, or at least three standard deviations away from the mean value of the control group.
- the standard deviation of the group of control subjects is no more than +/ ⁇ 5 mV.
- an individual undergoes therapy by virtue of having a glutathione redox potential which is at least one standard deviation, at least two standard deviations, or at least three standard deviations away from the mean value, they can undergo therapy according to the invention until their glutathione redox potential is within no more than three standard deviations, two standard deviations, or one standard deviation of the mean value of the control group.
- the individual can undergo therapy to shift their glutathione redox potential to an absolute value of about 10 mV, about 20 mV, about 30 mV, or about 40 mV more negative relative to their glutathione redox potential prior to undergoing therapy. In some embodiments, the individual can undergo therapy to shift their glutathione redox potential to an absolute value of about at least 10 mV, about at least 20 mV, about at least 30 mV, or about at least 40 mV more negative relative to their glutathione redox potential prior to undergoing therapy.
- Examples of values for healthy individuals in plasma would be about ⁇ 156 mV at age 34, ⁇ 149 mV at age 49, and ⁇ 140 mV at age 59.
- an example range is ⁇ 160 mV to ⁇ 150 mV.
- an example range is ⁇ 150 mV to ⁇ 140 mV.
- an example range is ⁇ 140 mV to ⁇ 120 mV.
- Other ranges can be used as target ranges depending on other specific characteristics of the control group, such as body mass index, hematocrit, cholesterol levels, or other biomarkers or clinical test results.
- Glutathione levels are preferably measured in plasma, but can also be measured in whole blood, blood serum, cerebrospinal fluid, semen, breast milk, umbilical cord blood, and tissues or tissue homogenates such as umbilical cord tissue and skin biopsy.
- Mitochondrial diseases are one type of disease that can be treated by modulation of glutathione redox potential. These diseases include Myoclonic Epilepsy with Ragged Red Fibers (MERRF); Mitochondrial Myopathy, Encephalopathy, Lactacidosis, and Stroke (MELAS); Leber's Hereditary Optic Neuropathy (LHON); Dominant Optic Atrophy (DOA); Chronic Progressive External Ophthalmoplegia (CPEO); Leigh Disease (Leigh Syndrome); Leigh-like Syndrome; Kearns-Sayre Syndrome (KSS); Friedreich's Ataxia (FA); Mitochondrial Neurogastrointestinal Encephalopathy disease (MNGIE); Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP); Spinocerebellar Ataxia (SCA), also called Machado-Joseph disease; overlap syndromes; Co-Enzyme Q10 (CoQ10) Deficiency; Complex I deficiency; Complex II defici
- Organic acidurias can also be treated by modulation of glutathione redox potential.
- Methylmalonic aciduria methylmalonic acidemia, MMA
- isovaleric aciduria isovaleric acidemia; IVA
- other organic acidurias can be treated using the compounds and methods described herein.
- Ataxia-telangiectasia (also known as Boder-Sedgwick syndrome or Louis-Bar syndrome), and Ataxia-telangiectasia-like disorder (ATLD) can also be treated by modulation of glutathione redox potential, by using the compounds and methods described herein.
- Alzheimer's disease amyotrophic lateral sclerosis (ALS); epilepsy; Huntington's Disease; schizophrenia; bipolar disorder; aging and age-associated diseases (Kretzschmar et al., Sports Medicine 15(3)196-209 (1993); Samiec et al., Free Radical Biology and Medicine 24(5):699-704 (1998); Sekhar et al., American Journal of Clinical Nutrition, 94:847-853 (2011)); macular degeneration (Samiec et al., Free Radical Biology and Medicine 24(5):699-704 (1998)); diabetes (Samiec et al., Free Radical Biology and Medicine 24(5):699-704 (1998)); cerebrovascular accidents, such as ischemic stroke and hemorrhagic stroke; certain cancers which display mitochondrial dysfunction; and cystic fibrosis (Roum et al., J. Appl. Physiol. 75(6):2419-2424 (1993)). Alteration of glutathione reduction of glutathione reduction of
- a subject having a glutathione redox potential disorder who also manifests one of the diseases above, can be treated according to the invention in order to modulate the redox status of the subject, in order to treat the disease.
- Example 2 demonstrates the correlation between modulation of the glutathione redox potential and improvement in clinical measures of Leigh syndrome (Leigh disease), an illness characterized by redox dysfunction and oxidative stress.
- Leigh syndrome is a rare, fatal inherited neurodegenerative disorder with an incidence of 1 in 40,000, and which predominantly affects children.
- Leigh syndrome is characterized by an overproduction of reactive oxygen species (ROS) and decompensation of the glutathione cycle.
- ROS reactive oxygen species
- Example 2 describes a subject-controlled Phase 2 clinical trial of alpha-tocotrienol quinone in genetically confirmed Leigh syndrome subjects ranging in ages from one to 13, spanning seven distinct and defined nDNA or mtDNA mutations. All subjects were treated for three months with 100 mg of alpha-tocotrienol quinone orally administered, three times daily. No drug related adverse events were recorded. All children exhibited arrest and reversal of clinical disease progression regardless of age, genetic mutation or disease severity. The primary endpoints of the study were the Newcastle Pediatric Mitochondrial Disease Scale (NPMDS), the Gross Motor Function Measure (GMFM) and PedsQL Neuromuscular Module (PedsQL). All demonstrated statistically significant improvement.
- NPMDS Newcastle Pediatric Mitochondrial Disease Scale
- GMFM Gross Motor Function Measure
- PedsQL PedsQL Neuromuscular Module
- Section 4 of the NPMDS (quality of life) scores improved an average of 4.6 (p 0.01).
- MD-CRS Movement Disorder-Childhood Rating Scale
- Alpha-tocotrienol quinone is a small-molecule therapeutic which can ameliorate reduced glutathione levels through NQO1-catalyzed electron transfer from NADPH (Enns, G. M., et al., Mol. Genet. Metab. 105, 91-102 (2012); Shrader, W. D., et al., Bioorg. Med. Chem. Lett. 21, 3693-3698 (2011)).
- alpha-tocotrienol quinone prevents ROS-mediated cell injury and death.
- Alpha-tocotrienol quinone has been recently reported to be safe and effective in the treatment of several inherited mitochondrial diseases (Enns, G. M., et al., Mol. Genet. Metab. 105, 91-102 (2012); Sadun, A. A., et al., Arch Neurol 69, 331-338 (2012); Blankenberg, F., et al., Ann. Neurol. 70, S148-S148 (2011)).
- a total of 10 children with genetically confirmed Leigh syndrome were enrolled in the study and treated with alpha-tocotrienol quinone for at least 3 months.
- Baseline patient characteristics, including the specific genetic mutation, are shown in Table 1 ( FIG. 5 ).
- Mean patient age was 6.3 (range 1-13) and six of the 10 children were male.
- the average baseline Newcastle Pediatric Mitochondrial Disease Scale (NPMDS) (Phoenix, C., et al., Neuromuscul Disord 16, 814-820 (2006)) score was 45.4 (range 19.6-62) signifying that these children all had advanced disease.
- the enrolled subjects had seven different mutations associated with Leigh syndrome. Following three months of treatment, all children demonstrated evidence of disease arrest and reversal with statistically significant improvement in all clinical outcomes measured.
- MD-CRS movement disorder-childhood rating scale
- Plasma creatine levels were also obtained in all patients. All patients had markedly elevated plasma creatine levels prior to treatment and there was an overall average decrease in creatine of 20.2 points (p 0.15).
- the initial clinical dose was selected based on laboratory and human patient pharmacokinetic modeling data. Specifically, a three-compartment model for oral administration was employed that included GI absorption delay, as well as one central and one peripheral compartment. A plasma trough drug concentration was targeted 10-20 fold above the ⁇ 10 nM in vitro EC 50 value of alpha-tocotrienol quinone that protected Leigh syndrome (SURF1) primary cells against glutathione depletion-mediated apoptotic cell death. Based on serum values of alpha-tocotrienol quinone obtained in two Leigh syndrome subjects after a single 100 mg dose of alpha-tocotrienol quinone was administered, a clinical dose of 100 mg three times daily was calculated and selected as the initial dose.
- SURF1 protected Leigh syndrome
- the glutathione cycle was targeted as the translational keystone to link Leigh syndrome pathophysiology and alpha-tocotrienol quinone drug action (Iuso, A., et al., J. Biol. Chem. 281, 10374-10380 (2006)). Specifically, drug action was measured as a function of lymphocyte oxidized and reduced glutathione and total serum thiol content. These blood-based glutathione cycle pharmacodynamic biomarkers were serially measured and correlated with their normalization and, secondarily, with clinical response.
- the serum glutathione cycle data reported herein for Leigh syndrome subjects is also consistent with recently reported data on non-invasive measurement of brain glutathione levels using 99-Tc HMPAO SPECT imaging for patients with Leigh syndrome and other mitochondrial diseases treated with alpha-tocotrienol quinone (Enns, G. M., et al., Mol. Genet. Metab. 105, 91-102 (2012); Blankenberg, F., et al., Ann. Neurol. 70, S148-S148 (2011)). Together these data confirm that the instantiated defect in glutathione cycle observed in Leigh syndrome and mitochondrial disease can be detected through blood and/or noninvasive imaging metrics. The data further show that alpha-tocotrienol quinone effects a restoration of glutathione charge and capacity consistent with the pathophysiology of Leigh syndrome and the mechanism of action of alpha-tocotrienol quinone.
- Example 2 demonstrates that alpha-tocotrienol quinone: i) records a favorable EC 50 (rescue) in patient primary cell lines with Leigh syndrome depleted in glutathione; ii) clinically restores the glutathione cycle charge and thiol content; iii) results in neurological and neuromuscular improvement in genetically defined Leigh syndrome subjects independent of genotype; iv) causes disease arrest and reversal, a result which has not previously been recorded in a progressive neurodegenerative disease; and v) can represent a first-in-class drug targeting a first-in-class pathway—the glutathione cycle—for the treatment of Leigh syndrome.
- Compounds and compositions for use in the invention can be prepared as a medicinal preparation or in various other media, such as foods for humans or animals, including medical foods and dietary supplements.
- a “medical food” is a product that is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements exist (see United States Code, Title 21, Chapter 9, Subchapter V, Part B, Section 360ee).
- medical foods may include vitamin and mineral formulations fed through a feeding tube (referred to as enteral administration).
- enteral administration a feeding tube
- a “dietary supplement” is a product that is intended to supplement the human diet and is typically provided in the form of a pill, capsule, and tablet or like formulation.
- a dietary supplement may include one or more of the following ingredients: vitamins, minerals, herbs, botanicals; amino acids, dietary substances intended to supplement the diet by increasing total dietary intake, and concentrates, metabolites, constituents, extracts or combinations of any of the foregoing.
- Dietary supplements may also be incorporated into food, including, but not limited to, food bars, beverages, powders, cereals, cooked foods, food additives and candies; or other functional foods designed to promote health, to treat a disease or disorder, to halt the progression of a disease or disorder, or to suppress symptoms of a disease or disorder.
- the composition can be administered, either as a prophylaxis or treatment, to a patient in any of a number of methods.
- the compositions may be administered alone or in combination with other pharmaceutical agents and can be combined with a physiologically acceptable carrier thereof.
- the effective amount and method of administration of the particular formulation can vary based on the individual subject, the stage of disease or disorder, and other factors evident to one skilled in the art.
- the concentration of the compounds or compositions may be monitored to insure that the desired level is maintained.
- the compounds or compositions may be compounded with other physiologically acceptable materials which can be ingested including, but not limited to, foods.
- compositions falling under the label “nutraceutical” may range from isolated nutrients, dietary supplements and specific diets to genetically engineered designer foods, herbal products, and processed foods such as cereals, soups and beverages.
- the term has been used to refer to a product isolated or purified from foods, and generally sold in medicinal forms not usually associated with food and demonstrated to have a physiological benefit or provide protection against chronic disease.
- nutraceutical or nutritional formulations with additives such as nutraceutically or nutritionally acceptable excipients, nutraceutically or nutritionally acceptable carriers, and nutraceutically or nutritionally acceptable vehicles.
- Suitable nutraceutically acceptable excipients may include liquid solutions such as a solution comprising one or more vegetable-derived oils, such as sesame oil, and/or one or more animal-derived oils, and/or one or more fish-derived oils.
- compositions can be formulated as pharmaceutical compositions by formulation with additives such as pharmaceutically acceptable excipients, pharmaceutically acceptable carriers, and pharmaceutically acceptable vehicles.
- suitable pharmaceutically acceptable excipients, carriers and vehicles include processing agents and drug delivery modifiers and enhancers, such as, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl- ⁇ -cyclodextrin, polyvinylpyrrolidinone, low melting waxes, ion exchange resins, and the like, as well as combinations of any two or more thereof.
- processing agents and drug delivery modifiers and enhancers such as, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl- ⁇ -cycl
- a pharmaceutical composition can comprise a unit dose formulation, where the unit dose is a dose sufficient to have a therapeutic or suppressive effect on a disease or disorder or an amount effective to modulate, normalize, or enhance an energy biomarker.
- the unit dose may be sufficient as a single dose to have a therapeutic or suppressive effect on a disease or disorder, or an amount effective to modulate, normalize, or enhance an energy biomarker.
- the unit dose may be a dose administered periodically in a course of treatment or suppression of a disease or disorder, or to modulate, normalize, or enhance an energy biomarker.
- compositions containing the compounds of the invention may be in any form suitable for the intended method of administration, including, for example, a solution, a suspension, or an emulsion.
- Liquid carriers are typically used in preparing solutions, suspensions, and emulsions.
- Liquid carriers contemplated for use in the practice of the present invention include, for example, water, saline, pharmaceutically acceptable organic solvent(s), pharmaceutically acceptable oils or fats, and the like, as well as mixtures of two or more thereof.
- the liquid carrier may contain other suitable pharmaceutically acceptable additives such as solubilizers, emulsifiers, nutrients, buffers, preservatives, suspending agents, thickening agents, viscosity regulators, stabilizers, and the like.
- Suitable organic solvents include, for example, monohydric alcohols, such as ethanol, and polyhydric alcohols, such as glycols.
- Suitable oils include, for example, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, and the like.
- the carrier can also be an oily ester such as ethyl oleate, isopropyl myristate, and the like.
- Compositions useful in the present invention may also be in the form of microparticles, microcapsules, liposomal encapsulates, and the like, as well as combinations of any two or more thereof.
- Time-release or controlled release delivery systems may be used, such as a diffusion controlled matrix system or an erodible system, as described for example in: Lee, “Diffusion-Controlled Matrix Systems”, pp. 155-198 and Ron and Langer, “Erodible Systems”, pp. 199-224, in “Treatise on Controlled Drug Delivery”, A. Kydonieus Ed., Marcel Dekker, Inc., New York 1992.
- the matrix may be, for example, a biodegradable material that can degrade spontaneously in situ and in vivo for, example, by hydrolysis or enzymatic cleavage, e.g., by proteases.
- the delivery system may be, for example, a naturally occurring or synthetic polymer or copolymer, for example in the form of a hydrogel.
- exemplary polymers with cleavable linkages include polyesters, polyorthoesters, polyanhydrides, polysaccharides, poly(phosphoesters), polyamides, polyurethanes, poly(imidocarbonates) and poly(phosphazenes).
- the compounds used in the methods of the invention may be administered to the individual in any suitable form that will provide a sufficient concentration of the compounds in the cell(s), tissue(s) or body compartment(s) of interest, such as in the plasma and/or central nervous system levels of the individual.
- Compounds for use in the invention may be administered enterally, orally, parenterally, sublingually, by inhalation (e.g. as mists or sprays), rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
- suitable modes of administration include oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intraarterial, intramuscular, intraperitoneal, intranasal (e.g. via nasal mucosa), subdural, rectal, vaginal, gastrointestinal, and the like, and directly to a specific or affected organ or tissue.
- spinal and epidural administration, or administration to cerebral ventricles can be used.
- Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
- parenteral as used herein includes subcutaneous injections, intravenous injection, intraarterial injection, intramuscular injection, intrasternal injection, or infusion techniques.
- the compounds are mixed with pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for the desired route of administration.
- Oral administration is a preferred route of administration, and formulations suitable for oral administration are preferred formulations. Oral administration is advantageous due to its ease of implementation and patient (or caretaker) compliance.
- introduction of medicine via feeding tube, feeding syringe or gastrostomy can be employed in order to accomplish enteric administration.
- the active compound (and, if present, other co-administered agents) can be enterally administered in sesame oil, or any other pharmaceutically acceptable carrier suitable for formulation for administration via feeding tube, feeding syringe, or gastrostomy.
- Compounds for use in the invention can be administered in solid form, in liquid form, in aerosol form, or in the form of tablets, pills, powder mixtures, capsules, granules, injectables, creams, solutions, suppositories, enemas, colonic irrigations, emulsions, dispersions, food premixes, and in other suitable forms.
- the compounds can also be administered in liposome formulations.
- the compounds can also be administered as prodrugs, where the prodrug undergoes transformation in the treated subject to a form which is therapeutically effective. Additional methods of administration are known in the art.
- compounds that cross the blood-brain barrier can be delivered to the central nervous system by spinal and epidural administration, or administration to cerebral ventricles.
- Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in propylene glycol.
- a nontoxic parenterally acceptable diluent or solvent for example, as a solution in propylene glycol.
- the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables.
- the formulations and preparations used in the methods of the invention are sterile.
- Sterile pharmaceutical formulations are compounded or manufactured according to pharmaceutical-grade sterilization standards (United States Pharmacopeia Chapters 797, 1072, and 1211; California Business & Professions Code 4127.7; 16 California Code of Regulations 1751, 21 Code of Federal Regulations 211) known to those of skill in the art.
- Suppositories for rectal administration of a compound can be prepared by mixing the compound with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols that are solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum and release the compound.
- a suitable nonirritating excipient such as cocoa butter and polyethylene glycols that are solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum and release the compound.
- Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
- the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch.
- Such dosage forms may also comprise additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
- the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
- Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents. Alternatively, the compound may also be administered in neat form if suitable.
- liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
- the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
- the preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y., p. 33 et seq (1976).
- the invention also provides articles of manufacture and kits containing materials useful for treating, preventing or suppressing symptoms associated with a disease or disorder, or modulating, normalizing, or enhancing an energy biomarker.
- the article of manufacture comprises a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. The containers may be formed from a variety of materials such as glass or plastic.
- the container holds a composition having an active agent which is effective for treating, preventing or suppressing symptoms associated with a disease or disorder, or modulating, normalizing, or enhancing an energy biomarker.
- the active agent in the composition is one or more of the compounds of the invention.
- the label on the container indicates that the composition is used for treating, preventing or suppressing symptoms associated with a disease or disorder, or modulating, normalizing, or enhancing an energy biomarker, and may also indicate directions for either in vivo or in vitro use, such as those described above.
- kits comprising any one or more of the compounds of the invention.
- the kit of the invention comprises the container described above.
- the kit of the invention comprises the container described above and a second container comprising a buffer. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for performing any methods described herein.
- kits may be used for any of the methods described herein, including, for example, to treat an individual with symptoms associated with a disease or disorder, to prevent symptoms associated with a disease or disorder, or to suppress symptoms associated with a disease or disorder in an individual, or for modulating, normalizing, or enhancing an energy biomarker.
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host to which the active ingredient is administered and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, body area, body mass index (BMI), general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the type, progression, and severity of the particular disease or disorder undergoing therapy.
- the unit dosage chosen is usually fabricated and administered to provide a defined final concentration of drug in the blood, cerebrospinal fluid, brain tissues, spinal cord tissues, other tissues, other organs, or other targeted region of the body. The effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.
- Examples of dosages which can be used are an effective amount of compounds within the dosage range of about 0.1 ⁇ g/kg to about 300 mg/kg body weight, or within about 0.1 mg/kg to about 300 mg/kg body weight, or within about 1.0 ⁇ g/kg to about 40 mg/kg body weight, or within about 1.0 ⁇ g/kg to about 20 mg/kg body weight, or within about 1.0 ⁇ g/kg to about 10 mg/kg body weight, or within about 10.0 ⁇ g/kg to about 10 mg/kg body weight, or within about 100 ⁇ g/kg to about 10 mg/kg body weight, or within about 0.1 mg/kg to about 100 mg/kg body weight, or within about 0.1 mg/kg to about 80 mg/kg body weight, or within about 0.1 mg/kg to about 50 mg/kg body weight, or within about 0.1 mg/kg to about 30 mg/kg body weight, or within about 1.0 mg/kg to about 80 mg/kg body weight, or within about 1.0 mg/kg to about 50 mg/kg body weight, or within about 1.0
- Other dosages which can be used are about 0.01 mg/kg body weight, about 0.1 mg/kg body weight, about 1 mg/kg body weight, about 10 mg/kg body weight, about 20 mg/kg body weight, about 30 mg/kg body weight, about 40 mg/kg body weight, about 50 mg/kg body weight, about 75 mg/kg body weight, about 100 mg/kg body weight, about 125 mg/kg body weight, about 150 mg/kg body weight, about 175 mg/kg body weight, about 200 mg/kg body weight, about 225 mg/kg body weight, about 250 mg/kg body weight, about 275 mg/kg body weight, or about 300 mg/kg body weight, or about 0.1, about 5, about 10, about 15, about 20, about 25, about 30, about 40, about 50, about 60, about 70, about 75, about 80, about 90, about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 500, about
- Compounds useful in the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided dosage of two, three or four times daily. These dosages can be administered for a short term, such as days or weeks, or for a long term, for example, over months, years, or even over the entire lifetime of the patient.
- While the compounds useful in the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more other agents used in the treatment or suppression of diseases or disorders.
- the additional active agents may generally be employed in therapeutic amounts as indicated in the Physicians' Desk Reference (PDR) 53rd Edition (1999), which is incorporated herein by reference, or such therapeutically useful amounts as would be known to one of ordinary skill in the art.
- PDR Physicians' Desk Reference
- Compounds useful in the invention and the other therapeutically active agents can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient.
- the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
- the particular dosage appropriate for a specific patient is determined by dose titration.
- the starting dose can be estimated based on the United States Food and Drug Administration guidelines titled “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers” (July 2005) as well as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines titled “Guidance on Non-clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals” (July 2008).
- ICH guidelines predicted exposures from the starting dose should not exceed 1/50 th the NOAEL (No-Adverse-Observed-Effect-Level) in the more sensitive species on a mg/m 2 basis.
- Representative additional agents useful in combination with the compounds of the invention for the treatment, prevention or suppression of mitochondrial diseases include, but are not limited to, Coenzyme Q, vitamin E, idebenone, MitoQ, vitamins, and antioxidant compounds.
- NAC N-acetyl cysteine
- NAC N-acetyl cysteine
- About 50 mg to about 1200 mg of NAC, about 50 mg to about 1000 mg of NAC, about 300 mg to about 1200 mg of NAC, or about 300 mg to about 1000 mg of NAC can be co-administered with compounds useful in the invention on a daily basis. This is particularly useful for individuals with low total glutathione levels, such as individuals with a total serum glutathione level below about 30 nmol/mg cell protein, or individuals with a total serum glutathione level below about 1 micromolar.
- the co-administered agents can be administered simultaneously with, prior to, or after, administration of the primary compound.
- the invention also provides articles of manufacture and kits containing materials.
- the article of manufacture comprises a container with a label.
- Suitable containers include, for example, bottles, vials, and test tubes.
- the containers may be formed from a variety of materials such as glass or plastic.
- the kit may also contain directions for use in treatment.
- kits comprising any one or more of a compound selected from alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma-tocotrienol hydroquinone, and delta-tocotrienol hydroquinone, or a composition comprising an active agent selected from alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma-tocotrienol hydroquinone, and delta-tocotrienol hydroquinone.
- a composition comprising an active agent selected from alpha-tocotrienol quinone, beta-tocot
- the kit of the invention comprises the container described above, which holds a compound selected from alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma-tocotrienol hydroquinone, and delta-tocotrienol hydroquinone, or a composition comprising an active agent selected from alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma-tocotrienol hydroquinone, and delta-tocotrienol hydroquinone.
- a composition comprising an active agent selected from alpha-tocotrienol quinone
- the kit of the invention comprises the container described above, which holds a compound selected from alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma-tocotrienol hydroquinone, and delta-tocotrienol hydroquinone, or a composition comprising an active agent selected from alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma-tocotrienol hydroquinone, and delta-tocotrienol hydroquinone, and a second container comprising a vehicle for the compound or composition, such as one
- the kit of the invention comprises the container described above, which holds a compound selected from alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma-tocotrienol hydroquinone, and delta-tocotrienol hydroquinone, or a composition comprising an active agent selected from alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma-tocotrienol hydroquinone, and delta-tocotrienol hydroquinone, where the compound or composition has been pre-mixed with a vehicle for the compound
- kits may be used for any of the methods described herein.
- the determination of the different forms of GSH obtained from lymphocytes can be performed in a manner similar to the method previously reported by Pastore et al. ( Clin. Chem . (Washington, D.C.) 44, 825-832 (1998)). Briefly, 30 ⁇ l of 4 M NaBH 4 , 20 ⁇ l of 2 mM EDTA/DTT, 10 ⁇ l of 1-octanol and 20 ⁇ l of 1.8 M HCl are placed in the derivatization vial containing 30 ⁇ l of sample.
- the analytes are separated for detection using a C 18 column (Hypersil ODS; 150 ⁇ 4.6 mm, 3 micron) at 1.5 ml/min using an aqueous phase of aqueous 30 mM ammonium nitrate and 40 mM ammonium formate at pH 3.6 with an increasing acetonitrile gradient.
- HPLC determinations of the various forms of GSH are carried out on lymphocytes sonicated three times for two sec in 0.1 ml of 0.1 M potassium-phosphate buffer, pH 7.2 using a Model VC 130 Vibra CellTM ultrasonic processor.
- Subjects were children with a genetically confirmed diagnosis of Leigh syndrome who had a Newcastle Pediatric Mitochondrial Disease Scale (NPMDS) on sections 1-3 greater than 15—signifying at least moderately severe disease progression. All participants were required to have MRI confirmation of necrotizing encephalopathy. In addition, all children were required to discontinue the use of CoQ 10 and any other antioxidant supplements for the duration of the trial. Informed consent was obtained from the parents of each child.
- NPMDS Newcastle Pediatric Mitochondrial Disease Scale
- the primary endpoints of this study were the Newcastle Pediatric Mitochondrial Disease Scale (NPMDS), the Gross Motor Function Measure (GMFM-66 item) and the PedsQL Neuromuscular Module (PedsQL).
- NPMDS Newcastle Pediatric Mitochondrial Disease Scale
- GMFM-66 item Gross Motor Function Measure
- PedsQL PedsQL Neuromuscular Module
- the NPDMS is a scale developed for and validated in children with inherited mitochondrial diseases to assess disease severity and progression. Sections 1-3 of the NPDMS assess organ specific function and section 4 is a quality of life assessment.
- serial NPMDS measurements were utilized to assess alpha-tocotrienol quinone effect on disease progression.
- the GMFM is an observational tool used to assess gross motor function over time in children with neuromuscular disorders.
- the GMFM has been validated as an outcome measurement instrument in the intervention trials of children with neuromuscular disorders.
- the PedsQL is a validated measurement of pediatric quality of life and the neuromuscular module utilized in this study is specific to children with neuromuscular disorders.
- clinical response was measured using the Movement-Disorder-Childhood Rating Scale (MD-CRS), a validated instrument for assessing dystonia and spasticity in children. Results are shown in FIG. 1 and in FIG. 6 (Table 2).
- MD-CRS Movement-Disorder-Childhood Rating Scale
- Intracellular reduced glutathione serves as the cell's principal endogenous antioxidant. Leigh syndrome and other mitochondrial diseases are associated with decreased GSH levels as the high level of oxidative stress and free oxygen radicals deplete cellular GSH reserves.
- intracellular (lymphocyte) glutathione levels were measured in all patients. The ratio of recued-to-oxidized glutathione and reduced glutathione to total glutathione levels were calculated to assess the effect of alpha-tocotrienol quinone on repleting reduced intracellular glutathione. Results are shown in FIG. 2 .
- total serum thiol levels were measured prior to and following initiation of treatment. Plasma creatine levels—an exploratory biomarker for mitochondrial disease—was also obtained.
- venous blood samples were layered on the top of a discontinuous gradient consisting of 3 ml of Hystopaque®-1119 and 3 mL of Hystopaque®-1077. Gradients were centrifuged at 750 g for 40 min at 4° C. The lymphocyte layer was transferred to a 15 ml centrifuge tube, diluted to a volume of 10 ml with 0.9% NaCl and centrifuged at 750 g for 40 min. The supernatant was removed and, if necessary, the lysis of erythrocytes was performed by adding 2 ml H2O.
- the analytes were separated for detection using a C 18 column (Hypersil ODS; 150 ⁇ 4.6 mm, 3 micron) at 1.5 ml/min using an aqueous phase of aqueous 30 mM ammonium nitrate and 40 mM ammonium formate at pH 3.6 with an increasing acetonitrile gradient.
- HPLC determinations of the various forms of GSH were carried out on lymphocytes sonicated three times for two sec in 0.1 ml of 0.1 M potassium-phosphate buffer, pH 7.2 using a Model VC 130 Vibra CellTM ultrasonic processor.
- a method of treating a subject having a glutathione redox potential disorder comprising the steps of: a) altering the redox potential of glutathione in the subject by administering a compound to the subject at an initial dosage level that alters the concentration of reduced glutathione in the subject, the concentration of oxidized glutathione in the subject, or both the concentration of reduced glutathione and the concentration of oxidized glutathione in the subject; b) subsequent to administering the compound to the subject, measuring the concentration of reduced glutathione and oxidized glutathione in the subject; c) calculating the redox potential of glutathione in the subject; d) adjusting the dosage of the compound administered to the subject; and e) repeating steps b), c), and d) until a ratio of oxidized glutathione concentration to reduced glutathione concentration between about 0.01 and about 0.5 is attained.
- a method of treating a subject having a glutathione redox potential disorder comprising the steps of: a) altering the redox potential of glutathione in the subject by administering a compound to the subject at an initial dosage level that alters the concentration of reduced glutathione in the subject, the concentration of oxidized glutathione in the subject, or both the concentration of reduced glutathione and the concentration of oxidized glutathione in the subject; b) subsequent to administering the compound to the subject, measuring the concentration of reduced glutathione and oxidized glutathione in the subject; c) calculating the redox potential of glutathione in the subject; d) adjusting the dosage of the compound administered to the subject; and e) repeating steps b), c), and d) until the subject has a redox potential of at least about an absolute value of 10 mV more negative than the redox potential of the subject prior to treatment.
- Embodiment 1 wherein the subject having a glutathione redox potential disorder has a ratio of oxidized glutathione concentration to reduced glutathione concentration of about 2 or greater prior to administering the compound.
- the step of measuring the concentration of reduced glutathione and the concentration of oxidized glutathione in the subject comprises measuring the concentration of reduced glutathione and the concentration of oxidized glutathione in the blood plasma, blood serum, whole blood, cerebrospinal fluid, semen, breast milk, umbilical cord blood, umbilical cord tissue, or skin biopsy of the subject.
- the step of measuring the concentration of reduced glutathione and the concentration of oxidized glutathione in the subject comprises measuring the concentration of reduced glutathione and the concentration of oxidized glutathione in the lymphocytes of the subject.
- step a) and step d) additionally comprise measuring the concentration of total glutathione in the subject, or calculating the concentration of total glutathione in the subject from the measured concentration of reduced glutathione and concentration of oxidized glutathione in the subject, and step a) additionally comprises administering a therapeutically effective amount of N-acetyl cysteine to the subject if the concentration of total glutathione in the subject is below about 30 nmol/mg cell protein, or if the concentration of total glutathione in the subject is below about 1 micromolar.
- Embodiment 7 wherein sufficient N-acetyl cysteine is administered to the subject to adjust the concentration of total glutathione in the subject above about 30 nmol/mg cell protein, or to adjust the concentration of total glutathione in the subject above about 1 micromolar.
- Embodiment 7 wherein a dosage of about 50 mg to about 1000 mg N-acetyl cysteine is administered to the subject.
- the compound administered to the subject that alters the concentration of reduced glutathione in the subject, the concentration of oxidized glutathione in the subject, or both the concentration of reduced glutathione and the concentration of oxidized glutathione in the subject is selected from the group consisting of pharmaceutically acceptable two-electron redox-active molecules having a reduction potential between about ⁇ 350 millivolts and about +150 millivolts versus the standard hydrogen electrode.
- the compound administered to the subject that alters the concentration of reduced glutathione in the subject, the concentration of oxidized glutathione in the subject, or both the concentration of reduced glutathione and the concentration of oxidized glutathione in the subject is selected from the group consisting of pharmaceutically acceptable two-electron redox-active molecules having a reduction potential between about 20 millivolts more reductive than Coenzyme Q and about 250 millivolts more reductive than Coenzyme Q.
- R is selected from:
- R 1 , R 2 , and R 3 are independently H or C 1 -C 6 alkyl, m is an integer from 0 to 9 inclusive, and the bonds indicated by a dashed line can be either double or single bonds.
- R 1 , R 2 , and R 3 are independently H or C 1 -C 6 alkyl; m is an integer from 0 to 9 inclusive; and the bonds indicated by a dashed line can be either double or single bonds.
- Embodiment 13 wherein the compound administered to the subject that alters the concentration of reduced glutathione in the subject, the concentration of oxidized glutathione in the subject, or both the concentration of reduced glutathione and the concentration of oxidized glutathione in the subject is selected from the group consisting of: alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, alpha-tocopherol quinone, beta-tocopherol quinone, gamma-tocopherol quinone, and delta-tocopherol quinone, or any combination thereof.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Ophthalmology & Optometry (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pain & Pain Management (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Emergency Medicine (AREA)
- Vascular Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Nutrition Science (AREA)
- Hospice & Palliative Care (AREA)
- Toxicology (AREA)
- Biochemistry (AREA)
- Endocrinology (AREA)
- Pulmonology (AREA)
Abstract
Description
- This application claims priority benefit of U.S. Provisional Patent Application No. 61/698,431 filed Sep. 7, 2012, and of U.S. Provisional Patent Application No. 61/792,797 filed Mar. 15, 2013. The entire contents of those applications are hereby incorporated by reference herein.
- The application discloses compositions and methods useful for modulation of the glutathione redox status and redox potential of an individual, useful in treatment, prevention, or suppression of diseases, by administering redox-active compounds (such as tocotrienol quinones, for example, alpha-tocotrienol quinone).
- A proper balance between oxidation and reduction reactions in cells, tissues, and organisms is vital for health. Maintenance of such a proper redox balance is, for example, critical for proper functioning of processes such as glycolysis, the citric acid cycle, and oxidative phosphorylation, which depend upon electron-transfer reactions in order to produce ATP, the major energy carrier in living organisms.
- Several diseases are associated with disrupted redox processes in cells, tissues, or organisms. Atkuri et al. (Proc. Nat'l. Acad. Sci. USA, 106(10):3941 (2009)) showed that patients with disorders affecting mitochondrial function suffered from systemic oxidative stress. However, the appropriate treatment for diseases involving oxidative stress is by no means clear. Jones (Antioxid. Redox Signal. 8(9&10):1865 (2006)) notes that administration of antioxidants demonstrates mixed results in improving health.
- The current invention provides compositions and methods for modulating, adjusting, and maintaining the redox status of an individual at an appropriate level to improve or enhance the health of the individual.
- The invention provides compounds and methods to address the common glutathione cycle defect associated with several diseases, including mitochondrial and neurodegenerative diseases. Specifically, the compounds and methods regenerate reduced glutathione and increase the glutathione charge couple, resulting in: i) restoration of redox balance and metabolic control; ii) reduction in the generation of reactive oxygen species; and iii) arrest and reversal of disease.
- The methods of the invention encompass modulating, adjusting, and maintaining a healthy glutathione redox potential in an individual, or in the cells, tissues, organs, or bodily fluids of an individual, by altering the ratios of reduced glutathione (GSH) to oxidized glutathione (GSSG) in the individual, or in the cells, tissues, organs, or bodily fluids of the individual.
- The present invention comprises multiple aspects, features and embodiments, where such multiple aspects, features and embodiments can be combined and permuted in any desired manner. These and other aspects, features and embodiments of the present invention will become evident upon reference to the remainder of this application, including the following detailed description. In addition, various references are set forth herein that describe in more detail certain compositions, and/or methods; all such references are incorporated herein by reference in their entirety.
-
FIG. 1 shows clinical outcomes prior to and following three months of EPI-743 treatment. There was significant improvement on NPMDS (FIG. 1A ,FIG. 1B andFIG. 1C ), neuromuscular function (FIG. 1D ), health related quality of life (FIG. 1E ) and dystonia and spasticity (FIG. 1F ). -
FIG. 2 shows biomarker outcome measurements. Ratio of lymphocyte oxidized glutathione (GSSG) to reduced glutathione (GSH) and ratio of GSSG to total glutathione (GSH+GSSG) over treatment time are shown. In all patients, there was rapid normalization of overall glutathione charge attributable to repletion of reduced glutathione levels. -
FIG. 3 shows the proposed normal physiology (FIG. 3A ), disease pathophysiology (FIG. 3B ), and drug mechanism of action of EPI-743 (FIG. 3C ). Inherited mitochondria diseases result in the generation of increased quantities of reactive oxygen species, which are neutralized by the glutathione cycle. EPI-743 acts to replete glutathione cycle capacity by shuttling reducing equivalents from NADPH to glutathione reductase, via NQO1. -
FIG. 4 shows an analysis of Leigh syndrome cohort clinical course. -
FIG. 5 (Table 1) shows baseline patient characteristics for the patients of Example 2. -
FIG. 6 (Table 2) summarizes the outcomes for the patients treated in Example 2. -
FIG. 7 (Table 3) shows analysis of the natural history of the clinical course of a cohort with Leigh syndrome. The natural history from published case reports of children with Leigh syndrome with mutations evaluated in this study was categorized as improved, stable, progressed or death. Of the 180 children described in the literature, 179 either died or had progressive neurologic deterioration. - The invention embraces compositions and methods for modulating, adjusting, and maintaining the redox status of an individual at an appropriate level to improve or enhance the health of the individual, or to treat, prevent, or suppress certain diseases or symptoms of certain diseases.
- By “subject,” “individual,” or “patient” is meant an individual organism, preferably a vertebrate, more preferably a mammal, most preferably a human.
- “Treating” a disease with the compounds and methods discussed herein is defined as administering one or more of the compounds discussed herein, with or without additional therapeutic agents, in order to reduce or eliminate either the disease or one or more symptoms of the disease, or to retard the progression of the disease or of one or more symptoms of the disease, or to reduce the severity of the disease or of one or more symptoms of the disease. “Suppression” of a disease with the compounds and methods discussed herein is defined as administering one or more of the compounds discussed herein, with or without additional therapeutic agents, in order to suppress the clinical manifestation of the disease, or to suppress the manifestation of adverse symptoms of the disease. The distinction between treatment and suppression is that treatment occurs after adverse symptoms of the disease are manifest in a subject, while suppression occurs before adverse symptoms of the disease are manifest in a subject. Suppression may be partial, substantially total, or total. Because many of the mitochondrial disorders are inherited, genetic screening can be used to identify patients at risk of the disease. The compounds and methods of the invention can then be administered to asymptomatic patients at risk of developing the clinical symptoms of the disease, in order to suppress the appearance of any adverse symptoms. “Therapeutic use” of the compounds discussed herein is defined as using one or more of the compounds discussed herein to treat or suppress a disease, as defined above. A “therapeutically effective amount” of a compound is an amount of a compound which, when administered to a subject, is sufficient to reduce or eliminate either one or more symptoms of a disease, or to retard the progression of one or more symptoms of a disease, or to reduce the severity of one or more symptoms of a disease, or to suppress the clinical manifestation of a disease, or to suppress the manifestation of adverse symptoms of a disease. A therapeutically effective amount can be given in one or more administrations. An “effective amount” of a compound embraces both a therapeutically effective amount, as well as an amount effective to modulate, normalize, or enhance one or more energy biomarkers in a subject.
- “Modulation” of, or to “modulate,” an energy biomarker means to change the level of the energy biomarker towards a desired value, or to change the level of the energy biomarker in a desired direction (e.g., increase or decrease). Modulation can include, but is not limited to, normalization and enhancement as defined below.
- “Normalization” of, or to “normalize,” an energy biomarker is defined as changing the level of the energy biomarker from a pathological value towards a normal value, where the normal value of the energy biomarker can be 1) the level of the energy biomarker in a healthy person or subject, or 2) a level of the energy biomarker that alleviates one or more undesirable symptoms in the person or subject. That is, to normalize an energy biomarker which is depressed in a disease state means to increase the level of the energy biomarker towards the normal (healthy) value or towards a value which alleviates an undesirable symptom; to normalize an energy biomarker which is elevated in a disease state means to decrease the level of the energy biomarker towards the normal (healthy) value or towards a value which alleviates an undesirable symptom.
- “Enhancement” of, or to “enhance,” energy biomarkers means to intentionally change the level of one or more energy biomarkers away from either the normal value, or the value before enhancement, in order to achieve a beneficial or desired effect. For example, in a situation where significant energy demands are placed on a subject, it may be desirable to increase the level of ATP in that subject to a level above the normal level of ATP in that subject. Enhancement can also be of beneficial effect in a subject suffering from a disease or pathology such as a mitochondrial disease, in that normalizing an energy biomarker may not achieve the optimum outcome for the subject; in such cases, enhancement of one or more energy biomarkers can be beneficial, for example, higher-than-normal levels of ATP, or lower-than-normal levels of lactic acid (lactate) can be beneficial to such a subject.
- While the compounds described herein can occur and can be used as the neutral (non-salt) compound, the description is intended to embrace all salts of the compounds described herein, as well as methods of using such salts of the compounds. In one embodiment, the salts of the compounds comprise pharmaceutically acceptable salts. Pharmaceutically acceptable salts are those salts which can be administered as drugs or pharmaceuticals to humans and/or animals and which, upon administration, retain at least some of the biological activity of the free compound (neutral compound or non-salt compound). The desired salt of a basic compound may be prepared by methods known to those of skill in the art by treating the compound with an acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid. Salts of basic compounds with amino acids, such as aspartate salts and glutamate salts, can also be prepared. The desired salt of an acidic compound can be prepared by methods known to those of skill in the art by treating the compound with a base. Examples of inorganic salts of acid compounds include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and aluminum salts. Examples of organic salts of acid compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, N,N′-dibenzylethylenediamine, and triethylamine salts. Salts of acidic compounds with amino acids, such as lysine salts, can also be prepared. Several pharmaceutically acceptable salts are disclosed in Berge, J. Pharm. Sci. 66:1 (1977).
- The invention also includes all stereoisomers and geometric isomers of the compounds, including diastereomers, enantiomers, and cis/trans (E/Z) isomers. The invention also includes mixtures of stereoisomers and/or geometric isomers in any ratio, including, but not limited to, racemic mixtures. Unless stereochemistry is explicitly indicated in a structure, the structure is intended to embrace all possible stereoisomers of the compound depicted. If stereochemistry is explicitly indicated for one portion or portions of a molecule, but not for another portion or portions of a molecule, the structure is intended to embrace all possible stereoisomers for the portion or portions where stereochemistry is not explicitly indicated.
- The description of compounds herein also includes all isotopologues, for example, partially deuterated or perdeuterated analogs of all compounds herein.
- The compounds can be administered in prodrug form. Prodrugs are derivatives of the compounds which are themselves relatively inactive, but which convert into the active compound when introduced into the subject in which they are used, by a chemical or biological process in vivo, such as an enzymatic conversion. Suitable prodrug formulations include, but are not limited to, peptide conjugates of the compounds of the invention and esters of compounds of the inventions. Further discussion of suitable prodrugs is provided in H. Bundgaard, Design of Prodrugs, New York: Elsevier, 1985; in R. Silverman, The Organic Chemistry of Drug Design and Drug Action, Boston: Elsevier, 2004; in R. L. Juliano (ed.), Biological Approaches to the Controlled Delivery of Drugs (Annals of the New York Academy of Sciences, v. 507), New York: N.Y. Academy of Sciences, 1987; and in E. B. Roche (ed.), Design of Biopharmaceutical Properties Through Prodrugs and Analogs (Symposium sponsored by Medicinal Chemistry Section, APhA Academy of Pharmaceutical Sciences, November 1976 national meeting, Orlando, Fla.), Washington: The Academy, 1977.
- The various compounds of the invention can be administered either as therapeutic agents in and of themselves, or as prodrugs which will convert to other therapeutically effective or effective substances in the body.
- The term “alkyl” refers to saturated aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms. “Straight-chain alkyl” or “linear alkyl” group refers to alkyl groups that are neither cyclic nor branched, commonly designated as “n-alkyl” groups. One subset of alkyl groups is —(C1-C6)alkyl which include groups such as methyl, ethyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, n-pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and any other alkyl group containing between one and five carbon atoms, where the —(C1-C6)alkyl groups can be attached via any valence on the —(C1-C6) alkyl groups.
- Gluthathione is the molecule (2S)-2-amino-5-[[(2R)-1-(carboxymethylamino)-1-oxo-3-sulfanylpropan-2-yl]amino]-5-oxopentanoic acid (IUPAC), and has the following structure:
- which can be described as the tripeptide gamma-Glu-Cys-Gly. Glutathione is commonly abbreviated as GSH. The oxidized form of glutathione is the disulfide-bridged dimeric form of the tripeptide, and is abbreviated as GSSG. Glutathione can also form mixed disulfides with cysteine-containing proteins; the glutathione-protein molecule is abbreviated as GS-Pro. Glutathione can also form persulfides by reaction with hydrogen sulfide or sulfane sulfur. Glutathione persulfide is abbreviated as GSSH. Glutathione is an example of an energy biomarker that can be modulated, normalized, or enhanced using the methods of the invention and the compounds disclosed herein, and which can be modulated, normalized, or enhanced to adjust the redox status of an individual in accordance with the invention.
- In one embodiment, compounds of Formula I are useful in the invention for modulating glutathione levels:
- where R is selected from:
where the asterisk * indicates the attachment of R in Formula I; where R1, R2, and R3 are independently H or C1-C6 alkyl, m is an integer from 0 to 9 inclusive, and the bonds indicated by a dashed line can be either double or single bonds. In some embodiments m is selected from 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, m is selected from 1, 2, or 3. In some embodiments, m is 2. In another embodiment, R1, R2, and R3 are CH3. In another embodiment, m is 2 and R1, R2, and R3 are CH3. - In one embodiment, compounds of Formula I-ox and Formula I-red are useful in the invention for modulating glutathione levels:
- where R1, R2, and R3 are independently H or C1-C6 alkyl, m is an integer from 0 to 9 inclusive, and the bonds indicated by a dashed line can be either double or single bonds. In some embodiments m is selected from 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, m is selected from 1, 2, or 3. In some embodiments, m is 2. In another embodiment, R1, R2, and R3 are CH3. In another embodiment, m is 2 and R1, R2, and R3 are CH3.
- In another embodiment, compounds of Formula I-D-ox and Formula I-D-red are useful in the invention for modulating glutathione levels:
- where R1, R2, and R3 are independently H or C1-C6 alkyl, and m is an integer from 0 to 9 inclusive. In some embodiments m is selected from 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, m is selected from 1, 2, or 3. In some embodiments, m is 2. In another embodiment, R1, R2, and R3 are CH3. In another embodiment, m is 2 and R1, R2, and R3 are CH3.
- In another embodiment, compounds of Formula I-S-ox and Formula I-S-red are useful in the invention for modulating glutathione levels:
- where R1, R2, and R3 are independently H or C1-C6 alkyl, and m is an integer from 0 to 9 inclusive. In some embodiments m is selected from 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, m is selected from 1, 2, or 3. In some embodiments, m is 2. In another embodiment, R1, R2, and R3 are CH3. In another embodiment, m is 2 and R1, R2, and R3 are CH3.
- In another embodiment, the compounds of Formula I-ox that are useful in the invention for modulating glutathione levels are tocotrienol quinones of the following structures:
-
alpha-tocotrienol quinone R1 = CH3 R2 = CH3 R3 = CH3 beta-tocotrienol quinone R1 = CH3 R2 = H R3 = CH3 gamma-tocotrienol quinone R1 = H R2 = CH3 R3 = CH3 delta-tocotrienol quinone R1 = H R2 = H R3 = CH3
including stereoisomers and salts thereof. - In other embodiments, the compound of Formula I-ox is a tocotrienol quinone. In other embodiments, the compound of Formula I-ox is alpha-tocotrienol quinone. In other embodiments, the compound of Formula I-ox is beta-tocotrienol quinone. In other embodiments, the compound of Formula I-ox is gamma-tocotrienol quinone. In other embodiments, the compound of Formula I-ox is delta-tocotrienol quinone.
- In other embodiments, the compounds of Formula I-ox used to modulate glutathione levels comprise an effective amount of a mixture of two or more tocotrienol quinones selected from alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone and delta-tocotrienol quinone.
- In another embodiment, the compounds of Formula I-red that are useful in the invention for modulating glutathione levels are tocotrienol hydroquinones of the following structures:
-
alpha-tocotrienol R1 = CH3 R2 = CH3 R3 = CH3 hydroquinone beta-tocotrienol R1 = CH3 R2 = H R3 = CH3 hydroquinone gamma-tocotrienol R1 = H R2 = CH3 R3 = CH3 hydroquinone delta-tocotrienol R1 = H R2 = H R3 = CH3 hydroquinone
including stereoisomers and salts thereof. - In other embodiments, the compound of Formula I-red is a tocotrienol hydroquinone. In other embodiments, the compound of Formula I-red is alpha-tocotrienol hydroquinone. In other embodiments, the compound of Formula I-red is beta-tocotrienol hydroquinone. In other embodiments, the compound of Formula I-red is gamma-tocotrienol hydroquinone. In other embodiments, the compound of Formula I-red is delta-tocotrienol hydroquinone.
- In other embodiments, the compounds of Formula I-red used to modulate glutathione levels comprise an effective amount of a mixture of two or more tocotrienol hydroquinones selected from alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma-tocotrienol hydroquinone and delta-tocotrienol hydroquinone.
- In another embodiment, the compounds of Formula I-ox that are useful in the invention for modulating glutathione levels are tocopherol quinones of the following structures:
-
alpha-tocopherol quinone R1 = CH3 R2 = CH3 R3 = CH3 beta-tocopherol quinone R1 = CH3 R2 = H R3 = CH3 gamma-tocopherol quinone R1 = H R2 = CH3 R3 = CH3 delta-tocopherol quinone R1 = H R2 = H R3 = CH3
including stereoisomers and salts thereof. - In other embodiments, the compound of Formula I-ox is a tocopherol quinone. In other embodiments, the compound of Formula I-ox is alpha-tocopherol quinone. In other embodiments, the compound of Formula I-ox is beta-tocopherol quinone. In other embodiments, the compound of Formula I-ox is gamma-tocopherol quinone. In other embodiments, the compound of Formula I-ox is delta-tocopherol quinone.
- In other embodiments, the compounds of Formula I-ox used to modulate glutathione levels comprise an effective amount of a mixture of two or more tocopherol quinones selected from alpha-tocopherol quinone, beta-tocopherol quinone, gamma-tocopherol quinone and delta-tocopherol quinone.
- In another embodiment, the compounds of Formula I-red that are useful in the invention for modulating glutathione levels are tocopherol hydroquinones of the following structures:
-
alpha-tocopherol R1 = CH3 R2 = CH3 R3 = CH3 hydroquinone beta-tocopherol R1 = CH3 R2 = H R3 = CH3 hydroquinone gamma-tocopherol R1 = H R2 = CH3 R3 = CH3 hydroquinone delta-tocopherol R1 = H R2 = H R3 = CH3 hydroquinone
including stereoisomers and salts thereof. - In other embodiments, the compound of Formula I-red is a tocopherol hydroquinone. In other embodiments, the compound of Formula I-red is alpha-tocopherol hydroquinone. In other embodiments, the compound of Formula I-red is beta-tocopherol hydroquinone. In other embodiments, the compound of Formula I-red is gamma-tocopherol hydroquinone. In other embodiments, the compound of Formula I-red is delta-tocopherol hydroquinone.
- In other embodiments, the compounds of Formula I-red used to modulate glutathione levels comprise an effective amount of a mixture of two or more tocopherol hydroquinones selected from alpha-tocopherol hydroquinone, beta-tocopherol hydroquinone, gamma-tocopherol hydroquinone and delta-tocopherol hydroquinone.
- The quinones described herein, such as tocotrienol quinones and tocopherol quinones, can be used in their oxidized form (Formula I-ox, Formula I-D-ox, Formula I-S-ox), or can be used in their reduced hydroquinone form (Formula I-red, Formula I-D-red, Formula I-S-red). The quinone (cyclohexadienedione) form and hydroquinone (benzenediol) form are readily interconverted with appropriate reagents. The quinone form can be treated in a biphasic mixture of an ethereal solvent with a basic aqueous solution of Na2S2O4 (Vogel, A. I. et al. Vogel's Textbook of Practical Organic Chemistry, 5th Edition, Prentice Hall: New York, 1996; Section 9.6.14 Quinones, “Reduction to the Hydroquinone”). Standard workup in the absence of oxygen yields the desired hydroquinone form. The hydroquinone form can be oxidized to the quinone form with oxidizing agents such as ceric ammonium nitrate (CAN) or ferric chloride. The quinone and hydroquinone forms are also readily interconverted electrochemically, as is well known in the art. See, e.g., Section 33.4 of Streitweiser & Heathcock, Introduction to Organic Chemistry, New York: Macmillan, 1976.
- In another embodiment, compounds of Formula II are useful in the invention for modulating glutathione levels:
- where R′ is selected from
- wherein R21 and R22 are independently of each other hydrogen, —(C1-C6)alkyl or —O—(C1-C6)alkyl; or R21 and R22 together represent —CH═CH—CH═CH—;
- R23 is (C1-C6)alkyl;
- X is —CH═CH— or —C≡C—;
- m is 1-10; n is 1-5; k is 1-3, with the proviso that when k is an integer of 2 to 3, n is optionally variable from 1-5 in each occurrence of the —X—(CH2)n— group;
- Y is —OR24, —CN or —COOR25; and
- R24 and R25 are independently of each other selected from hydrogen, —CN, —(C1-C6)alkyl, —(C1-C6)haloalkyl; —C(═O)—(C1-C6)alkyl; —C(═O)—(C1-C6)haloalkyl; —C(═O)—NH(C1-C6)alkyl; —C(═O)—N((C1-C6)alkyl)2 and —C(═O)—NH2; or any stereoisomer, mixture of stereoisomers, prodrug, metabolite, salt, crystalline form, non-crystalline form, hydrate or solvate thereof.
- In another embodiment, R21, R22, and R23 are independently selected from —(C1-C6)alkyl. In another embodiment, R21 and R22 are independently selected from —O(C1-C6)alkyl. In another embodiment, R21 and R22 are hydrogen and R23 is —(C1-C6)alkyl. In another embodiment, R21, R22 and R23 are hydrogen. In another embodiment, R21 and R22 together represent —CH═CH—CH═CH—. In another embodiment, X is —CH═CH—. In another embodiment, X is —C≡C—. In another embodiment, Y is —OR24. In another embodiment Y is —CN or —COOR25. In another embodiment R24 is hydrogen, —C(═O)—(C1-C6)alkyl, or —C(═O)—(C1-C6)haloalkyl. In another embodiment R25 is hydrogen or —(C1-C6)alkyl. In another embodiment, m is 1-5. In another embodiment, m is 2-5. In another embodiment n is 1-4. In another embodiment, n is 1-3. In another embodiment n is 1-2. In another embodiment, k is 2-3.
- In another embodiment, R21, R22 and R23 are —CH3; X is —CH═CH—; m is 4; n is 1-3; k is 1-2; and Y is —OH. In another embodiment, R21, R22 and R23 are CH3; X is —C≡C—; m is 4; n is 1-3; k is 1-2; and Y is —OH. In another embodiment, R21 and R22 together represent —CH═CH—CH═CH—; R23 is CH3; X is —CH═CH—; m is 4; n is 1-3, k is 1-2; and Y is —OH. In another embodiment, R21 and R22 together represent —CH═CH—CH═CH—; R23 is CH3; X is —C≡C—; m is 4; n is 3, k is 1-3 and Y is —OH.
- In another embodiment, compounds of Formula II-ox or Formula II-red are useful in the invention for modulating glutathione levels:
- wherein R21 and R22 are independently of each other hydrogen, —(C1-C6)alkyl or —O—(C1-C6)alkyl; or R21 and R22 together represent —CH═CH—CH═CH—;
- R23 is (C1-C6)alkyl;
- X is —CH═CH— or —C≡C—;
- m is 1-10; n is 1-5; k is 1-3, with the proviso that when k is an integer of 2 to 3, n is optionally variable from 1-5 in each occurrence of the —X—(CH2)n— group;
- Y is —OR24, —CN or —COOR25; and
- R24 and R25 are independently of each other selected from hydrogen, —CN, —(C1-C6)alkyl, —(C1-C6)haloalkyl; —C(═O)—(C1-C6)alkyl; —C(═O)—(C1-C6)haloalkyl; —C(═O)—NH(C1-C6)alkyl; —C(═O)—N((C1-C6)alkyl)2 and —C(═O)—NH2; or any stereoisomer, mixture of stereoisomers, prodrug, metabolite, salt, crystalline form, non-crystalline form, hydrate or solvate thereof.
- In another embodiment, R21, R22, and R23 are independently selected from —(C1-C6)alkyl. In another embodiment, R21 and R22 are independently selected from —O(C1-C6)alkyl. In another embodiment, R21 and R22 are hydrogen and R23 is —(C1-C6)alkyl. In another embodiment, R21, R22 and R23 are hydrogen. In another embodiment, R21 and R22 together represent —CH═CH—CH═CH—. In another embodiment, X is —CH═CH—. In another embodiment, X is —C≡C—. In another embodiment, Y is —OR24. In another embodiment Y is —CN or —COOR25. In another embodiment R24 is hydrogen, —C(═O)—(C1-C6)alkyl, or —C(═O)—(C1-C6)haloalkyl. In another embodiment R25 is hydrogen or —(C1-C6)alkyl. In another embodiment, m is 1-5. In another embodiment, m is 2-5. In another embodiment n is 1-4. In another embodiment, n is 1-3. In another embodiment n is 1-2. In another embodiment, k is 2-3.
- In another embodiment, R21, R22 and R23 are —CH3; X is —CH═CH—; m is 4; n is 1-3; k is 1-2; and Y is —OH. In another embodiment, R21, R22 and R23 are CH3; X is —C≡C—; m is 4; n is 1-3; k is 1-2; and Y is —OH. In another embodiment, R21 and R22 together represent —CH═CH—CH═CH—; R23 is CH3; X is —CH═CH—; m is 4; n is 1-3, k is 1-2; and Y is —OH. In another embodiment, R21 and R22 together represent —CH═CH—CH═CH—; R23 is CH3; X is —C≡C—; m is 4; n is 3, k is 1-3 and Y is —OH.
- In another embodiment the compound of Formula II for modulating glutathione levels includes, but is not limited to:
- 2-(12-hydroxydodeca-5,8-dien-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
- 2-(10-hydroxydeca-5,8-diyn-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
- 2-(12-hydroxydodeca-5,8-diyn-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
- 2-(10-hydroxydeca-5,8-dien-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
- 2-(9-hydroxynon-5-yn-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
- 2-(11-hydroxyundeca-5,8-diyn-1-yl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
- 13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-diynenitrile;
- 13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-diynoic acid;
- 13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-dienenitrile;
- 13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-dienoic acid;
- N,N-dimethyl-13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-diynamide;
- 13-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)trideca-5,8-diynamide;
- 2-(12-hydroxydodeca-5,8-diyn-1-yl)-3-methylnaphthalene-1,4-dione;
- 2-(11-hydroxyundeca-5,8-diyn-1-yl)-3-methylnaphthalene-1,4-dione;
- 2-(10-hydroxydeca-5,8-diyn-1-yl)-3-methylnaphthalene-1,4-dione;
- 2-(10-hydroxydeca-5,8-dien-1-yl)-3-methylnaphthalene-1,4-dione;
- 2-(10-hydroxydeca-5,8-dien-1-yl)-3-methylnaphthalene-1,4-dione;
- 2-(10-hydroxydeca-5,8-dien-1-yl)-3-methylnaphthalene-1,4-dione;
or any stereoisomer, mixture of stereoisomers, prodrug, metabolite, salt, crystalline form, non-crystalline form, hydrate or solvate thereof. - In another embodiment, the invention embraces 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone or any stereoisomer, mixture of stereoisomers, prodrug, metabolite, salt, crystalline form, non-crystalline form, hydrate or solvate thereof, for use in modulating glutathione levels. 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone, (CAS Registry number 80809-81-9) is also known as Docebenone, AA861 or aa-861, and has the structure:
- In another embodiment, the invention embraces the lactone; 2,3,5-trimethyl-6-(2-(2-methyl-5-oxotetrahydrofuran-2-yl)ethyl)cyclohexa-2,5-diene-1,4-dione (CAS Registry numbers 3121-68-4, 15716-16-2, 22625-17-8, 816456-29-8):
- and its open chain carboxylic acid 4-hydroxy-4-methyl-6-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)hexanoic acid (CAS Registry number 1948-76-1):
- or any stereoisomer, mixture of stereoisomers, prodrug, metabolite, salt, crystalline form, non-crystalline form, hydrate or solvate thereof, for use in modulating glutathione levels.
- The compounds described herein can be readily synthesized by a variety of methods known in the art. The syntheses of the compounds of Formula II described herein are detailed in, for example, U.S. Pat. No. 4,393,075 hereby incorporated by reference in its entirety. 2,3,5-Trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone can be purchased from Sigma-Aldrich, St. Louis, Mo. (catalog number A3711, CAS Registry Number 80809-81-0, under the name AA-861 or 2-(12-hydroxydodeca-5,10-diynyl)-3,5,6-trimethyl-p-benzoquinone).
- Measurement of the redox potential of the glutathione pool provides a snapshot of the redox balance of the cell, tissue, or organism in which the potential is measured.
- The glutathione potential of a sample can be determined using the Nernst equation:
-
E=E o−(RT/nF)(ln([GSSG]/[GSH]2)) - where Eo is the redox potential of the glutathione couple under standard conditions, R is the gas constant, T is the absolute temperature (that is, in degrees Kelvin, K), n is the number of electrons transferred in the reaction, and F is Faraday's constant. [GSSG] represents the concentration of oxidized glutathione, while [GSH] is the concentration of reduced glutathione. See, for example, Jones, Dean P., “Redox Potential of GSH/GSSG Couple: Assay and Biological Significance” in Methods of Enzymology: Protein Sensors and Reactive Oxygen Species—Part B: Thiol Enzymes and Proteins (Sies, H. and Packer, L., editors), Vol. 348, pp. 93-112 (2002); and Jonas et al., American Journal of Clinical Nutrition, 72:181-189 (2000).
- Since glutathione redox potentials in individuals are negative, between −170 mV and −90 mV, changes in the glutathione redox potential are indicated by the absolute value of the change and the direction of the change. Thus, if a subject has a glutathione redox potential of −120 mV, a change in redox potential of an
absolute value 10 mV more negative indicates that the redox potential of the subject has changed to −130 mV. A change in glutathione redox potential of an absolute value of at least about 10 mV more negative indicates that the absolute value of the change is greater than 10, and the change is more negative. If the individual's starting glutathione redox potential was −120 mV, then an example of a change in redox potential of an absolute value of at least about 10 mV more negative would be a change of the glutathione redox potential to −135 mV; the absolute value of the change is 15, which is at least about the absolute value of 10, and the change to the potential is in the negative direction. - Glutathione concentration can be measured using a variety of methods, such as that described by Pastore, A., et al. “Fully automated assay for total homocysteine, cysteine, cysteinylglycine, glutathione, cysteamine, and 2-mercaptopropionylglycine in plasma and urine,” Clin. Chem. (Washington, D.C.) 44:825-832 (1998) (see Example 1 below). Other glutathione assays have been described in Serru et al., “Quantification of Reduced and Oxidized Glutathione in Whole Blood Samples by Capillary Electrophoresis,” Clin. Chem. (Washington, D.C.) 47:1321-1324 (2001); Giustarini et al., “An improved HPLC measurement for GSH and GSSG in human blood,” Free Radic. Biol. Med. 35:1365-1372 (2003); Harfield et al., “Electrochemical determination of glutathione: a review,” Analyst 137(10):2285-96 (2012); Yap et al., “Determination of GSH, GSSG, and GSNO using HPLC with electrochemical detection,” Methods Enzymol. 473:137-47 (2010); and Monostori et al., “Determination of glutathione and glutathione disulfide in biological samples: an in-depth review,” J Chromatogr B Analyt Technol Biomed Life Sci. 877(28):3331-46 (2009).
- Plasma levels of GSH, GSSG, Cys, and CySS can be used to calculate the in vivo Eh values. Samples are collected using the procedure of Jones et al (2009 Free Radical Biology & Medicine 47(10):1329-1338). This method uses bromobimane to alkylate free thiols and HPLC and either electrochemical or MSMS to separate, detect, and quantify the molecules. One method of analyzing the most common monothiols and disulfides (cystine, cysteine, reduced (GSH) and oxidized glutathione (GSSG)) present in human plasma is to use bathophenanthroline disulfonic acid as the internal standard (IS), with complete separation of all the target analytes and IS at 35° C. on a C18 RP column (250 mm×4.6 mm, 3 micron) achieved using 0.2% TFA:Acetonitrile as a mobile phase pumped at the rate of 0.6 ml per minute using an electrochemical detector in DC mode at the detector potential of 1475 mV. The protocol detailed below in the examples can also be used for HPLC analysis of thiols.
- A “subject having a glutathione redox potential disorder,” “individual having a glutathione redox potential disorder,” or “patient having a glutathione redox potential disorder,” is a subject, individual, or patient having a glutathione redox potential lying outside the normal range for a healthy age-matched individual. The range of glutathione redox potentials compatible with life is roughly −170 millivolts to −90 millivolts in human plasma. Comparison of the glutathione potential of an individual to a healthy age-matched individual serving as control will indicate whether the potential is at a pathological value. Comparison can be made to a healthy age-matched, sex-matched individual who has the same smoking status as the person being tested (that is, smokers should be compared to healthy age-matched, sex-matched smokers; non-smokers should be compared to healthy age-matched, sex-matched non-smokers).
- In another embodiment, the comparison can be made to an average value over a group of control individuals who are matched (by age, sex, and smoking status) to the test individual. A group of ten, fifty, or one hundred people can be used. Using a group for comparison will allow calculation of a standard deviation for the control group, and the test individual can be considered for therapy (that is, considered as having a glutathione redox potential disorder) if the subject's glutathione redox potential is at least one standard deviation, at least two standard deviations, or at least three standard deviations away from the mean value of the control group. Preferably, the standard deviation of the group of control subjects is no more than +/−5 mV.
- If an individual undergoes therapy by virtue of having a glutathione redox potential which is at least one standard deviation, at least two standard deviations, or at least three standard deviations away from the mean value, they can undergo therapy according to the invention until their glutathione redox potential is within no more than three standard deviations, two standard deviations, or one standard deviation of the mean value of the control group.
- In some embodiments, the individual can undergo therapy to shift their glutathione redox potential to an absolute value of about 10 mV, about 20 mV, about 30 mV, or about 40 mV more negative relative to their glutathione redox potential prior to undergoing therapy. In some embodiments, the individual can undergo therapy to shift their glutathione redox potential to an absolute value of about at least 10 mV, about at least 20 mV, about at least 30 mV, or about at least 40 mV more negative relative to their glutathione redox potential prior to undergoing therapy.
- Examples of values for healthy individuals in plasma would be about −156 mV at age 34, −149 mV at age 49, and −140 mV at age 59. For persons aged 30 to 40 years, an example range is −160 mV to −150 mV. For persons aged 40 to 50 years, an example range is −150 mV to −140 mV. For persons aged 50 to 60 years, an example range is −140 mV to −120 mV. Other ranges can be used as target ranges depending on other specific characteristics of the control group, such as body mass index, hematocrit, cholesterol levels, or other biomarkers or clinical test results.
- Glutathione levels are preferably measured in plasma, but can also be measured in whole blood, blood serum, cerebrospinal fluid, semen, breast milk, umbilical cord blood, and tissues or tissue homogenates such as umbilical cord tissue and skin biopsy.
- Several diseases and symptoms can be treated or suppressed using the invention. Addressing the underlying redox imbalance provides a broad mechanism for alleviating several pathological metabolic processes.
- Mitochondrial diseases are one type of disease that can be treated by modulation of glutathione redox potential. These diseases include Myoclonic Epilepsy with Ragged Red Fibers (MERRF); Mitochondrial Myopathy, Encephalopathy, Lactacidosis, and Stroke (MELAS); Leber's Hereditary Optic Neuropathy (LHON); Dominant Optic Atrophy (DOA); Chronic Progressive External Ophthalmoplegia (CPEO); Leigh Disease (Leigh Syndrome); Leigh-like Syndrome; Kearns-Sayre Syndrome (KSS); Friedreich's Ataxia (FA); Mitochondrial Neurogastrointestinal Encephalopathy disease (MNGIE); Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP); Spinocerebellar Ataxia (SCA), also called Machado-Joseph disease; overlap syndromes; Co-Enzyme Q10 (CoQ10) Deficiency; Complex I deficiency; Complex II deficiency; Complex III deficiency; Complex IV deficiency; and Complex V deficiency.
- Organic acidurias (organic acidemias) can also be treated by modulation of glutathione redox potential. Methylmalonic aciduria (methylmalonic acidemia, MMA), isovaleric aciduria (isovaleric acidemia; IVA), or other organic acidurias can be treated using the compounds and methods described herein.
- Ataxia-telangiectasia (A-T) (also known as Boder-Sedgwick syndrome or Louis-Bar syndrome), and Ataxia-telangiectasia-like disorder (ATLD) can also be treated by modulation of glutathione redox potential, by using the compounds and methods described herein.
- There are also several diseases which, while not usually categorized primarily as redox dysfunction disorders or oxidative stress disorders, are exacerbated by, or have significant involvement from, redox potential imbalance and/or oxidative stress. These include diseases beyond the “classic” mitochondrial diseases that display significant mitochondrial dysfunction. Among such diseases are cardiomyopathy; encephalomyopathy; renal tubular acidosis; neurodegenerative diseases (Johnson et al., Nutrients 4:1399-1440 (2012)); Parkinson's disease (Sian et al., Ann. Neurol. 36:348-355 (1994)); Alzheimer's disease; amyotrophic lateral sclerosis (ALS); epilepsy; Huntington's Disease; schizophrenia; bipolar disorder; aging and age-associated diseases (Kretzschmar et al., Sports Medicine 15(3)196-209 (1993); Samiec et al., Free Radical Biology and Medicine 24(5):699-704 (1998); Sekhar et al., American Journal of Clinical Nutrition, 94:847-853 (2011)); macular degeneration (Samiec et al., Free Radical Biology and Medicine 24(5):699-704 (1998)); diabetes (Samiec et al., Free Radical Biology and Medicine 24(5):699-704 (1998)); cerebrovascular accidents, such as ischemic stroke and hemorrhagic stroke; certain cancers which display mitochondrial dysfunction; and cystic fibrosis (Roum et al., J. Appl. Physiol. 75(6):2419-2424 (1993)). Alteration of glutathione redox potential also occurs in persons undergoing chemotherapy (Jonas et al., American Journal of Clinical Nutrition 72:181-189 (2000)).
- Thus, in one embodiment of the invention, a subject having a glutathione redox potential disorder, who also manifests one of the diseases above, can be treated according to the invention in order to modulate the redox status of the subject, in order to treat the disease.
- Example 2 demonstrates the correlation between modulation of the glutathione redox potential and improvement in clinical measures of Leigh syndrome (Leigh disease), an illness characterized by redox dysfunction and oxidative stress. Leigh syndrome is a rare, fatal inherited neurodegenerative disorder with an incidence of 1 in 40,000, and which predominantly affects children. Leigh syndrome is characterized by an overproduction of reactive oxygen species (ROS) and decompensation of the glutathione cycle.
- Example 2 describes a subject-controlled
Phase 2 clinical trial of alpha-tocotrienol quinone in genetically confirmed Leigh syndrome subjects ranging in ages from one to 13, spanning seven distinct and defined nDNA or mtDNA mutations. All subjects were treated for three months with 100 mg of alpha-tocotrienol quinone orally administered, three times daily. No drug related adverse events were recorded. All children exhibited arrest and reversal of clinical disease progression regardless of age, genetic mutation or disease severity. The primary endpoints of the study were the Newcastle Pediatric Mitochondrial Disease Scale (NPMDS), the Gross Motor Function Measure (GMFM) and PedsQL Neuromuscular Module (PedsQL). All demonstrated statistically significant improvement. Sections 1-3 (organ system function) of the NPMDS improved by a mean of 7.1 (p=0.005).Section 4 of the NPMDS (quality of life) scores improved an average of 4.6 (p=0.01). Consistent withsection 4 of the NPMDS, there was also a statistically significant improvement in the mean PedsQL of 14.6 (p=0.03). The GMFM recorded a mean improvement of 8.9 (p=0.01). In addition, all children had an improvement of one class on the Movement Disorder-Childhood Rating Scale (MD-CRS)—the secondary endpoint of the study. Glutathione cycle biomarkers were measured as an indicator of disease pathology and drug action. All patients showed a statistically significant increase in reduced glutathione derived from isolated lymphocytes from 8.5 to 25.1 nmol/mg cell protein (p=0.002) and a reduction in oxidized glutathione to 0.25 nmol/mg cell protein (p=0.005). - Alpha-tocotrienol quinone is a small-molecule therapeutic which can ameliorate reduced glutathione levels through NQO1-catalyzed electron transfer from NADPH (Enns, G. M., et al., Mol. Genet. Metab. 105, 91-102 (2012); Shrader, W. D., et al., Bioorg. Med. Chem. Lett. 21, 3693-3698 (2011)). By increasing reduced glutathione, alpha-tocotrienol quinone prevents ROS-mediated cell injury and death. Alpha-tocotrienol quinone has been recently reported to be safe and effective in the treatment of several inherited mitochondrial diseases (Enns, G. M., et al., Mol. Genet. Metab. 105, 91-102 (2012); Sadun, A. A., et al., Arch Neurol 69, 331-338 (2012); Blankenberg, F., et al., Ann. Neurol. 70, S148-S148 (2011)).
- A total of 10 children with genetically confirmed Leigh syndrome were enrolled in the study and treated with alpha-tocotrienol quinone for at least 3 months. Baseline patient characteristics, including the specific genetic mutation, are shown in Table 1 (
FIG. 5 ). Mean patient age was 6.3 (range 1-13) and six of the 10 children were male. The average baseline Newcastle Pediatric Mitochondrial Disease Scale (NPMDS) (Phoenix, C., et al.,Neuromuscul Disord 16, 814-820 (2006)) score was 45.4 (range 19.6-62) signifying that these children all had advanced disease. The enrolled subjects had seven different mutations associated with Leigh syndrome. Following three months of treatment, all children demonstrated evidence of disease arrest and reversal with statistically significant improvement in all clinical outcomes measured. - The clinical outcome results are summarized in
FIG. 1 . All children—regardless of age, genotype and starting NPMDS score—demonstrated arrest of disease progression and reversal. NPMDS scores for sections 1-3 (organ function) improved by a mean of 7.1 (p=0.005) and for section 4 (quality of life) scores improved an average of 4.6 (p=0.01). This represents an average improvement of 25% in total NPMDS score from baseline. The three patients treated for six months had continued improvement in their NPMDS scores over time: patient 1 (23.5 to 21.1); patient 2 (54 to 46) and patient 3 (27.8 to 25.7). - Similarly, there was a significant increase in GMFM (Rosenbaum, P. L., et al., JAMA 288, 1357-1363 (2002)) scores over the treatment period with a mean improvement of 8.9 (p=0.01). The majority of patients had marked increase in GMFM scores following three months of treatment except
patients Patient 2 had no change in GMFM score following three months of treatment, however, at six months the GMFM score increased from 7.6 to 19.8.Patient 7 had a high level of motor function prior to treatment with a score of 97.5 (maximum possible score 100) that did not change. - On the movement disorder-childhood rating scale (MD-CRS)—a validated measurement of pediatric movement disorders and dystonia—each child had improvement of one class, indicating significant improvement in dystonia and spasticity symptoms (Battini, R., et al.,
Pediatr Neurol 40, 258-264 (2009); Battini, R., et al.,Pediatr Neurol 39, 259-265 (2008)). - Finally, there was a significant improvement (14.6, p=0.03) in quality of life score on the NQL neuromuscular module (Varni, J. W., et al.,
Ambul Pediatr 3, 329-341 (2003)). This significant improvement is consistent with the improvement observed insection 4 of the NPMDS, which is focused on quality of life. - Biomarker Analysis:
- In order to verify the association of Leigh syndrome with decreased levels of reduced glutathione and to validate alpha-tocotrienol quinone's mechanism of action (repletion of reduced glutathione), serial intracellular glutathione levels were obtained on each subject (
FIG. 2 ) (Pastore, A., et al., Clin. Chem. (Washington, D.C.) 44, 825-832 (1998); Hu, M.-L., Methods Enzymol. 233, 380-385 (1994)). Prior to initiation of treatment, all subjects had markedly elevated ratios of oxidized glutathione to reduced glutathione (mean=3.1+/−2.1). Following treatment with alpha-tocotrienol quinone, there was a rapid and marked increase in reduced glutathione levels (8.5 to 25.1 nmol/mg cell protein, p=0.002) and a decrease in the oxidized-to-reduced glutathione levels to 0.25 nmol/mg cell protein (p=0.005). The changes in reduced glutathione levels and oxidized-to-reduced glutathione ratios occurred rapidly—within 4 weeks in most of the patients. Patients treated for longer than three months demonstrated continued increases in reduced glutathione levels. There was also a significant increase in total serum thiol levels in each subject at the three-month time point (mean change=0.14, p=0.008), with continued increases for patients treated for longer than three months. - Plasma creatine levels were also obtained in all patients. All patients had markedly elevated plasma creatine levels prior to treatment and there was an overall average decrease in creatine of 20.2 points (p=0.15).
- Safety and Tolerability:
- Treatment with alpha-tocotrienol quinone was not associated with any drug-induced adverse events. There were three serious adverse events due to intercurrent illness during the three month trial (two cases of bronchitis and one case of salmonellosis, all resolved). Other reported adverse conditions included mild sleepiness and hypotonia. There were no abnormalities in clinical chemistry laboratory parameters, including liver and kidney function tests and coagulation parameters. All recorded values were within the normal range for the clinical laboratories used for the analysis.
- The initial clinical dose was selected based on laboratory and human patient pharmacokinetic modeling data. Specifically, a three-compartment model for oral administration was employed that included GI absorption delay, as well as one central and one peripheral compartment. A plasma trough drug concentration was targeted 10-20 fold above the ˜10 nM in vitro EC50 value of alpha-tocotrienol quinone that protected Leigh syndrome (SURF1) primary cells against glutathione depletion-mediated apoptotic cell death. Based on serum values of alpha-tocotrienol quinone obtained in two Leigh syndrome subjects after a single 100 mg dose of alpha-tocotrienol quinone was administered, a clinical dose of 100 mg three times daily was calculated and selected as the initial dose. This regimen resulted in an average trough concentration of ˜200 nM at eight hours post dosing. This was consistent with the in vitro target dose and was confirmed in multiple pediatric subjects with inherited mitochondrial disease (Enns, G. M., et al., Mol. Genet. Metab. 105, 91-102 (2012); Blankenberg, F., et al., Ann. Neurol. 70, S148-S148 (2011)). This dose was also safely below the preclinical no observed adverse effect level (NOAEL).
- The glutathione cycle was targeted as the translational keystone to link Leigh syndrome pathophysiology and alpha-tocotrienol quinone drug action (Iuso, A., et al., J. Biol. Chem. 281, 10374-10380 (2006)). Specifically, drug action was measured as a function of lymphocyte oxidized and reduced glutathione and total serum thiol content. These blood-based glutathione cycle pharmacodynamic biomarkers were serially measured and correlated with their normalization and, secondarily, with clinical response.
- Systemic glutathione status was clinically assessed through serial HPLC measurement of lymphocyte oxidized and reduced glutathione. In addition, total serum thiol content was also determined spectrophotometrically as a measure of total glutathione charge capacity. Each subject was employed as his or her own control. While some inter-patient variability was recorded, all subjects showed a remarkably rapid normalization of glutathione charge, as well as repletion of the total glutathione charge capacity. In several subjects, biochemical response was recorded within two weeks, preceding clinical response. Restoration of glutathione charge was durable in all subjects and continued for all subjects treated >90 days in the extension phase of the protocol. The serum glutathione cycle data reported herein for Leigh syndrome subjects is also consistent with recently reported data on non-invasive measurement of brain glutathione levels using 99-Tc HMPAO SPECT imaging for patients with Leigh syndrome and other mitochondrial diseases treated with alpha-tocotrienol quinone (Enns, G. M., et al., Mol. Genet. Metab. 105, 91-102 (2012); Blankenberg, F., et al., Ann. Neurol. 70, S148-S148 (2011)). Together these data confirm that the instantiated defect in glutathione cycle observed in Leigh syndrome and mitochondrial disease can be detected through blood and/or noninvasive imaging metrics. The data further show that alpha-tocotrienol quinone effects a restoration of glutathione charge and capacity consistent with the pathophysiology of Leigh syndrome and the mechanism of action of alpha-tocotrienol quinone.
- To minimize patient-to-patient variability, enrollment was confined to children with the diagnosis of genetically confirmed Leigh syndrome and relatively advanced and progressive stage of disease. Despite these rather narrow selection criteria, there were 10 children in the study who ranged in ages from one to 13. They possessed seven different genetic mutations spanning the respiratory chain and intermediary metabolism. Four outcome measures were used to capture the clinical spectrum of Leigh syndrome and alpha-tocotrienol quinone response to treatment. These included the mitochondrial disease-specific Newcastle Pediatric Mitochondrial Disease score (NPMDS), the more generalized pediatric Gross Motor Function Measure (GMFM), the Movement Disorder-Childhood Rating Scale (MD-CRS) and the Pediatric Quality of Life Inventory (PedsQL). A statistically significant improvement was shown in all four of these outcome measurements. Central nervous system and neuromuscular function improved following treatment with alpha-tocotrienol quinone as assessed by the NPMDS modules 1-3, the GMFM, and the MDCRS. Consistent with improvement in physician-recorded outcome measures, patient families reported improvement in quality of life measures (
module 4 of NPMDS and the PedsQL), both of which were statistically significant. Clinical response was not only rapid—within eight weeks—but was universal and durable. Improvement was independent of genotype, age, sex, and disease severity. Additionally, three of the ten subjects have entered the extension phase of the protocol (treatment from 90-180 days). Each of these patients has demonstrated continued improvement in all outcome measurements, suggesting therapeutic durability and indeterminate net clinical benefit. - Given the well-documented natural history of Leigh syndrome (see Table 3,
FIG. 7 ) and the consistent concordance of biomarker and clinical outcome data (enzymatic target (NQO1), molecular pathway (glutathione cycle), mechanism of action (enhancing glutathione cycle function), disease pathology (ROS neutralization), laboratory/clinical biomarkers (glutathione, 99Tc-HMAPO SPECT) with clinical improvement (NPMDS, MD-CRS, GMFM, PedQL)), it is highly probable that the observed response was alpha-tocotrienol quinone-mediated, and not due to spontaneous remission or placebo response. The calculated overall probability that the mean changes observed in each of the endpoints (NPDMS, GMFM, PedsQL, NMS-CR and glutathione ratios) all occurred (merely) by chance alone is 3.8×10−11. - Example 2 demonstrates that alpha-tocotrienol quinone: i) records a favorable EC50 (rescue) in patient primary cell lines with Leigh syndrome depleted in glutathione; ii) clinically restores the glutathione cycle charge and thiol content; iii) results in neurological and neuromuscular improvement in genetically defined Leigh syndrome subjects independent of genotype; iv) causes disease arrest and reversal, a result which has not previously been recorded in a progressive neurodegenerative disease; and v) can represent a first-in-class drug targeting a first-in-class pathway—the glutathione cycle—for the treatment of Leigh syndrome.
- Compounds and compositions for use in the invention can be prepared as a medicinal preparation or in various other media, such as foods for humans or animals, including medical foods and dietary supplements. A “medical food” is a product that is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements exist (see United States Code,
Title 21,Chapter 9, Subchapter V, Part B, Section 360ee). By way of example, but not limitation, medical foods may include vitamin and mineral formulations fed through a feeding tube (referred to as enteral administration). A “dietary supplement” is a product that is intended to supplement the human diet and is typically provided in the form of a pill, capsule, and tablet or like formulation. By way of example, but not limitation, a dietary supplement may include one or more of the following ingredients: vitamins, minerals, herbs, botanicals; amino acids, dietary substances intended to supplement the diet by increasing total dietary intake, and concentrates, metabolites, constituents, extracts or combinations of any of the foregoing. Dietary supplements may also be incorporated into food, including, but not limited to, food bars, beverages, powders, cereals, cooked foods, food additives and candies; or other functional foods designed to promote health, to treat a disease or disorder, to halt the progression of a disease or disorder, or to suppress symptoms of a disease or disorder. If administered as a medicinal preparation, the composition can be administered, either as a prophylaxis or treatment, to a patient in any of a number of methods. The compositions may be administered alone or in combination with other pharmaceutical agents and can be combined with a physiologically acceptable carrier thereof. The effective amount and method of administration of the particular formulation can vary based on the individual subject, the stage of disease or disorder, and other factors evident to one skilled in the art. During the course of the treatment, the concentration of the compounds or compositions may be monitored to insure that the desired level is maintained. The compounds or compositions may be compounded with other physiologically acceptable materials which can be ingested including, but not limited to, foods. - The term “nutraceutical” has been used to refer to any substance that is a food or a part of a food and provides medical or health benefits, including the prevention and treatment of disease. Hence, compositions falling under the label “nutraceutical” may range from isolated nutrients, dietary supplements and specific diets to genetically engineered designer foods, herbal products, and processed foods such as cereals, soups and beverages. In a more technical sense, the term has been used to refer to a product isolated or purified from foods, and generally sold in medicinal forms not usually associated with food and demonstrated to have a physiological benefit or provide protection against chronic disease. Accordingly, the compounds described for use herein can also be administered as nutraceutical or nutritional formulations, with additives such as nutraceutically or nutritionally acceptable excipients, nutraceutically or nutritionally acceptable carriers, and nutraceutically or nutritionally acceptable vehicles. Suitable nutraceutically acceptable excipients may include liquid solutions such as a solution comprising one or more vegetable-derived oils, such as sesame oil, and/or one or more animal-derived oils, and/or one or more fish-derived oils.
- Compounds for use in the invention can be formulated as pharmaceutical compositions by formulation with additives such as pharmaceutically acceptable excipients, pharmaceutically acceptable carriers, and pharmaceutically acceptable vehicles. Suitable pharmaceutically acceptable excipients, carriers and vehicles include processing agents and drug delivery modifiers and enhancers, such as, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidinone, low melting waxes, ion exchange resins, and the like, as well as combinations of any two or more thereof. Other suitable pharmaceutically acceptable excipients are described in “Remington's Pharmaceutical Sciences,” Mack Pub. Co., New Jersey (1991), and “Remington: The Science and Practice of Pharmacy,” Lippincott Williams & Wilkins, Philadelphia, 20th edition (2003) and 21st edition (2005), incorporated herein by reference.
- A pharmaceutical composition can comprise a unit dose formulation, where the unit dose is a dose sufficient to have a therapeutic or suppressive effect on a disease or disorder or an amount effective to modulate, normalize, or enhance an energy biomarker. The unit dose may be sufficient as a single dose to have a therapeutic or suppressive effect on a disease or disorder, or an amount effective to modulate, normalize, or enhance an energy biomarker. Alternatively, the unit dose may be a dose administered periodically in a course of treatment or suppression of a disease or disorder, or to modulate, normalize, or enhance an energy biomarker.
- Pharmaceutical compositions containing the compounds of the invention may be in any form suitable for the intended method of administration, including, for example, a solution, a suspension, or an emulsion. Liquid carriers are typically used in preparing solutions, suspensions, and emulsions. Liquid carriers contemplated for use in the practice of the present invention include, for example, water, saline, pharmaceutically acceptable organic solvent(s), pharmaceutically acceptable oils or fats, and the like, as well as mixtures of two or more thereof. The liquid carrier may contain other suitable pharmaceutically acceptable additives such as solubilizers, emulsifiers, nutrients, buffers, preservatives, suspending agents, thickening agents, viscosity regulators, stabilizers, and the like. Suitable organic solvents include, for example, monohydric alcohols, such as ethanol, and polyhydric alcohols, such as glycols. Suitable oils include, for example, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, and the like. For parenteral administration, the carrier can also be an oily ester such as ethyl oleate, isopropyl myristate, and the like. Compositions useful in the present invention may also be in the form of microparticles, microcapsules, liposomal encapsulates, and the like, as well as combinations of any two or more thereof.
- Time-release or controlled release delivery systems may be used, such as a diffusion controlled matrix system or an erodible system, as described for example in: Lee, “Diffusion-Controlled Matrix Systems”, pp. 155-198 and Ron and Langer, “Erodible Systems”, pp. 199-224, in “Treatise on Controlled Drug Delivery”, A. Kydonieus Ed., Marcel Dekker, Inc., New York 1992. The matrix may be, for example, a biodegradable material that can degrade spontaneously in situ and in vivo for, example, by hydrolysis or enzymatic cleavage, e.g., by proteases. The delivery system may be, for example, a naturally occurring or synthetic polymer or copolymer, for example in the form of a hydrogel. Exemplary polymers with cleavable linkages include polyesters, polyorthoesters, polyanhydrides, polysaccharides, poly(phosphoesters), polyamides, polyurethanes, poly(imidocarbonates) and poly(phosphazenes).
- The compounds used in the methods of the invention may be administered to the individual in any suitable form that will provide a sufficient concentration of the compounds in the cell(s), tissue(s) or body compartment(s) of interest, such as in the plasma and/or central nervous system levels of the individual. Compounds for use in the invention may be administered enterally, orally, parenterally, sublingually, by inhalation (e.g. as mists or sprays), rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. For example, suitable modes of administration include oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intraarterial, intramuscular, intraperitoneal, intranasal (e.g. via nasal mucosa), subdural, rectal, vaginal, gastrointestinal, and the like, and directly to a specific or affected organ or tissue. For delivery to the central nervous system, spinal and epidural administration, or administration to cerebral ventricles, can be used. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous injection, intraarterial injection, intramuscular injection, intrasternal injection, or infusion techniques. The compounds are mixed with pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for the desired route of administration. Oral administration is a preferred route of administration, and formulations suitable for oral administration are preferred formulations. Oral administration is advantageous due to its ease of implementation and patient (or caretaker) compliance. For patients with difficulty in swallowing, introduction of medicine via feeding tube, feeding syringe or gastrostomy can be employed in order to accomplish enteric administration. The active compound (and, if present, other co-administered agents) can be enterally administered in sesame oil, or any other pharmaceutically acceptable carrier suitable for formulation for administration via feeding tube, feeding syringe, or gastrostomy. Compounds for use in the invention can be administered in solid form, in liquid form, in aerosol form, or in the form of tablets, pills, powder mixtures, capsules, granules, injectables, creams, solutions, suppositories, enemas, colonic irrigations, emulsions, dispersions, food premixes, and in other suitable forms. The compounds can also be administered in liposome formulations. The compounds can also be administered as prodrugs, where the prodrug undergoes transformation in the treated subject to a form which is therapeutically effective. Additional methods of administration are known in the art.
- If administration to the central nervous system is desired, it is preferable to administer compounds that cross the blood-brain barrier. However, compounds that do not cross the blood-brain barrier can be delivered to the central nervous system by spinal and epidural administration, or administration to cerebral ventricles.
- Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in propylene glycol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
- In certain embodiments of the invention, especially those embodiments where a formulation is used for injection or other parenteral administration including the routes listed herein, but also including embodiments used for oral, gastric, gastrointestinal, enteric, or other routes of administration, the formulations and preparations used in the methods of the invention are sterile. Sterile pharmaceutical formulations are compounded or manufactured according to pharmaceutical-grade sterilization standards (United States Pharmacopeia Chapters 797, 1072, and 1211; California Business & Professions Code 4127.7; 16 California Code of
Regulations 1751, 21 Code of Federal Regulations 211) known to those of skill in the art. - Suppositories for rectal administration of a compound can be prepared by mixing the compound with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols that are solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum and release the compound.
- Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
- Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents. Alternatively, the compound may also be administered in neat form if suitable.
- Compounds useful in the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y., p. 33 et seq (1976).
- The invention also provides articles of manufacture and kits containing materials useful for treating, preventing or suppressing symptoms associated with a disease or disorder, or modulating, normalizing, or enhancing an energy biomarker. The article of manufacture comprises a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition having an active agent which is effective for treating, preventing or suppressing symptoms associated with a disease or disorder, or modulating, normalizing, or enhancing an energy biomarker. The active agent in the composition is one or more of the compounds of the invention. The label on the container indicates that the composition is used for treating, preventing or suppressing symptoms associated with a disease or disorder, or modulating, normalizing, or enhancing an energy biomarker, and may also indicate directions for either in vivo or in vitro use, such as those described above.
- The invention also provides kits comprising any one or more of the compounds of the invention. In some embodiments, the kit of the invention comprises the container described above. In other embodiments, the kit of the invention comprises the container described above and a second container comprising a buffer. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for performing any methods described herein.
- In other aspects, the kits may be used for any of the methods described herein, including, for example, to treat an individual with symptoms associated with a disease or disorder, to prevent symptoms associated with a disease or disorder, or to suppress symptoms associated with a disease or disorder in an individual, or for modulating, normalizing, or enhancing an energy biomarker.
- The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host to which the active ingredient is administered and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, body area, body mass index (BMI), general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the type, progression, and severity of the particular disease or disorder undergoing therapy. The unit dosage chosen is usually fabricated and administered to provide a defined final concentration of drug in the blood, cerebrospinal fluid, brain tissues, spinal cord tissues, other tissues, other organs, or other targeted region of the body. The effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.
- Examples of dosages which can be used are an effective amount of compounds within the dosage range of about 0.1 μg/kg to about 300 mg/kg body weight, or within about 0.1 mg/kg to about 300 mg/kg body weight, or within about 1.0 μg/kg to about 40 mg/kg body weight, or within about 1.0 μg/kg to about 20 mg/kg body weight, or within about 1.0 μg/kg to about 10 mg/kg body weight, or within about 10.0 μg/kg to about 10 mg/kg body weight, or within about 100 μg/kg to about 10 mg/kg body weight, or within about 0.1 mg/kg to about 100 mg/kg body weight, or within about 0.1 mg/kg to about 80 mg/kg body weight, or within about 0.1 mg/kg to about 50 mg/kg body weight, or within about 0.1 mg/kg to about 30 mg/kg body weight, or within about 1.0 mg/kg to about 80 mg/kg body weight, or within about 1.0 mg/kg to about 50 mg/kg body weight, or within about 1.0 mg/kg to about 30 mg/kg body weight, or within about 1.0 mg/kg to about 10 mg/kg body weight, or within about 10 mg/kg to about 100 mg/kg body weight, or within about 10 mg/kg to about 80 mg/kg body weight, or within about 50 mg/kg to about 150 mg/kg body weight, or within about 100 mg/kg to about 200 mg/kg body weight, or within about 150 mg/kg to about 250 mg/kg body weight, or within about 200 mg/kg to about 300 mg/kg body weight, or within about 250 mg/kg to about 300 mg/kg body weight. Other dosages which can be used are about 0.01 mg/kg body weight, about 0.1 mg/kg body weight, about 1 mg/kg body weight, about 10 mg/kg body weight, about 20 mg/kg body weight, about 30 mg/kg body weight, about 40 mg/kg body weight, about 50 mg/kg body weight, about 75 mg/kg body weight, about 100 mg/kg body weight, about 125 mg/kg body weight, about 150 mg/kg body weight, about 175 mg/kg body weight, about 200 mg/kg body weight, about 225 mg/kg body weight, about 250 mg/kg body weight, about 275 mg/kg body weight, or about 300 mg/kg body weight, or about 0.1, about 5, about 10, about 15, about 20, about 25, about 30, about 40, about 50, about 60, about 70, about 75, about 80, about 90, about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, or about 1000 mg total. Compounds useful in the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided dosage of two, three or four times daily. These dosages can be administered for a short term, such as days or weeks, or for a long term, for example, over months, years, or even over the entire lifetime of the patient.
- While the compounds useful in the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more other agents used in the treatment or suppression of diseases or disorders.
- When additional active agents are used in combination with compounds useful in the present invention, the additional active agents may generally be employed in therapeutic amounts as indicated in the Physicians' Desk Reference (PDR) 53rd Edition (1999), which is incorporated herein by reference, or such therapeutically useful amounts as would be known to one of ordinary skill in the art.
- Compounds useful in the invention and the other therapeutically active agents can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient. When administered in combination with other therapeutic agents, the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
- The particular dosage appropriate for a specific patient is determined by dose titration. The starting dose can be estimated based on the United States Food and Drug Administration guidelines titled “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers” (July 2005) as well as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines titled “Guidance on Non-clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals” (July 2008). Per ICH guidelines, predicted exposures from the starting dose should not exceed 1/50th the NOAEL (No-Adverse-Observed-Effect-Level) in the more sensitive species on a mg/m2 basis.
- Additional Agents for Co-Administration with Compounds Useful in the Invention
- Representative additional agents useful in combination with the compounds of the invention for the treatment, prevention or suppression of mitochondrial diseases include, but are not limited to, Coenzyme Q, vitamin E, idebenone, MitoQ, vitamins, and antioxidant compounds.
- One particularly advantageous additional agent for co-administration is N-acetyl cysteine (NAC), which is a precursor to glutathione. About 50 mg to about 1200 mg of NAC, about 50 mg to about 1000 mg of NAC, about 300 mg to about 1200 mg of NAC, or about 300 mg to about 1000 mg of NAC can be co-administered with compounds useful in the invention on a daily basis. This is particularly useful for individuals with low total glutathione levels, such as individuals with a total serum glutathione level below about 30 nmol/mg cell protein, or individuals with a total serum glutathione level below about 1 micromolar.
- The co-administered agents can be administered simultaneously with, prior to, or after, administration of the primary compound.
- The invention also provides articles of manufacture and kits containing materials. The article of manufacture comprises a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. The containers may be formed from a variety of materials such as glass or plastic. The kit may also contain directions for use in treatment.
- The invention also provides kits comprising any one or more of a compound selected from alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma-tocotrienol hydroquinone, and delta-tocotrienol hydroquinone, or a composition comprising an active agent selected from alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma-tocotrienol hydroquinone, and delta-tocotrienol hydroquinone. In some embodiments, the kit of the invention comprises the container described above, which holds a compound selected from alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma-tocotrienol hydroquinone, and delta-tocotrienol hydroquinone, or a composition comprising an active agent selected from alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma-tocotrienol hydroquinone, and delta-tocotrienol hydroquinone. In other embodiments, the kit of the invention comprises the container described above, which holds a compound selected from alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma-tocotrienol hydroquinone, and delta-tocotrienol hydroquinone, or a composition comprising an active agent selected from alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma-tocotrienol hydroquinone, and delta-tocotrienol hydroquinone, and a second container comprising a vehicle for the compound or composition, such as one or more vegetable-derived oils, such as sesame oil, and/or one or more animal-derived oils, and/or one or more fish-derived oils. In other embodiments, the kit of the invention comprises the container described above, which holds a compound selected from alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma-tocotrienol hydroquinone, and delta-tocotrienol hydroquinone, or a composition comprising an active agent selected from alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, alpha-tocotrienol hydroquinone, beta-tocotrienol hydroquinone, gamma-tocotrienol hydroquinone, and delta-tocotrienol hydroquinone, where the compound or composition has been pre-mixed with a vehicle for the compound or composition, such as one or more vegetable-derived oils, such as sesame oil, and/or one or more animal-derived oils, and/or one or more fish-derived oils. The kits may further include other materials desirable from a commercial and user standpoint, including other vehicles, buffers, diluents, filters, needles, syringes, and package inserts with instructions for performing any of the methods described herein.
- In other aspects, the kits may be used for any of the methods described herein.
- The invention will be further understood by the following nonlimiting examples.
- The determination of the different forms of GSH obtained from lymphocytes can be performed in a manner similar to the method previously reported by Pastore et al. (Clin. Chem. (Washington, D.C.) 44, 825-832 (1998)). Briefly, 30 μl of 4 M NaBH4, 20 μl of 2 mM EDTA/DTT, 10 μl of 1-octanol and 20 μl of 1.8 M HCl are placed in the derivatization vial containing 30 μl of sample. After the mixture is incubated for three min, 100 μl of 1.5 M N-ethylmorpholine buffer, pH 8.0, 400 μl of distilled water, and 20 μl of 25 mM bromobimane are added. After an additional three-min incubation, 40 μl of acetic acid are added and 20 μl (for free GSH) or 80 μl (for GSSG and GS-Pro) of this mixture are injected into the column. The thiol derivatives are quantified by HPLC (Agilent Technologies 1100 HPLC with a fluorescence detector-excitation at 390 nm and an emission at 478 nm). The analytes are separated for detection using a C18 column (Hypersil ODS; 150×4.6 mm, 3 micron) at 1.5 ml/min using an aqueous phase of aqueous 30 mM ammonium nitrate and 40 mM ammonium formate at pH 3.6 with an increasing acetonitrile gradient. HPLC determinations of the various forms of GSH are carried out on lymphocytes sonicated three times for two sec in 0.1 ml of 0.1 M potassium-phosphate buffer, pH 7.2 using a Model VC 130 Vibra Cell™ ultrasonic processor. For free GSH determinations, 100 μl of 12% sulfosalicylic acid are added to 50 μl of cells lysate, and analytes content on the acid-soluble fraction are determined. The protein pellet is dissolved in 150 μl of 0.1 N NaOH, and protein bound glutathione (GS-Pro) determined. For GSSG determination, cells are sonicated in the presence of 5 mM N-ethylmaleimide (NEM); 100 μl of 12% sulfosalicylic acid are added to 50 μl homogenates, and analytes content on the acid-soluble fraction are determined. Protein concentrations are quantified by BCA-protein assay.
- Study Overview:
- A prospective single arm subject-controlled trial of alpha-tocotrienol quinone was performed in children with genetically-confirmed Leigh syndrome (Table 1,
FIG. 5 ). All subjects were treated for three months and evaluated using a battery of disease-relevant functional, neurologic, physiologic and biomarker assessments. This study was conducted at the Ospedale Pediatrico Bambino Gesù in Rome, Italy. Institutional Review Board approval was obtained prior to study initiation. -
TABLE 1 Baseline patient characteristics Baseline Age at Defect and % of NPMDS Weight Subject enrollment Mutation mutated mtDNA Score Sex (kg) 1 9 ND1-G3697A Blood: homoplasmic 49.4 F 21 2 6 SUCLA2 c.850C > T/c.850C > T 62 M 9.3 3 1 ETHE1 Del Exo4; c.375 + 5G > A 38 F 7.7 4 8 ND5-G13513A Muscle: 65% 36.8 F 21 5 6 EARS2 c.502 > G; 51.6 M 16.2 c.1279_1280insTCC; c.322C > T 6 13 SURF1 c.784 delACCC/not found 53.1 F 28.5 7 8 ND5-G13513A Blood: 61%, Fibroblast: 75% 18.7 M 21.3 8 3 ND1-G3697A Muscle: homoplasmic 59.5 M 15.3 9 7 ND6-T14487C Muscle >95% 45 M 30 10 2 SURF1 c.870delT/c.870delT 32.1 M 7.0 - Subjects:
- Subjects were children with a genetically confirmed diagnosis of Leigh syndrome who had a Newcastle Pediatric Mitochondrial Disease Scale (NPMDS) on sections 1-3 greater than 15—signifying at least moderately severe disease progression. All participants were required to have MRI confirmation of necrotizing encephalopathy. In addition, all children were required to discontinue the use of CoQ10 and any other antioxidant supplements for the duration of the trial. Informed consent was obtained from the parents of each child.
- Intervention:
- All subjects received 100 mg of alpha-tocotrienol quinone three times daily orally or via gastrostomy tube. Total treatment length was three months, with an extension phase for children who completed the initial treatment period. All adverse and serious adverse events were tracked in the trial database. In addition, all held doses due to intolerance of alpha-tocotrienol quinone or any other reason were also recorded.
- Endpoints—Clinical Endpoints:
- The primary endpoints of this study were the Newcastle Pediatric Mitochondrial Disease Scale (NPMDS), the Gross Motor Function Measure (GMFM-66 item) and the PedsQL Neuromuscular Module (PedsQL). The NPDMS is a scale developed for and validated in children with inherited mitochondrial diseases to assess disease severity and progression. Sections 1-3 of the NPDMS assess organ specific function and
section 4 is a quality of life assessment. In this study, serial NPMDS measurements were utilized to assess alpha-tocotrienol quinone effect on disease progression. The GMFM is an observational tool used to assess gross motor function over time in children with neuromuscular disorders. The GMFM has been validated as an outcome measurement instrument in the intervention trials of children with neuromuscular disorders. The PedsQL is a validated measurement of pediatric quality of life and the neuromuscular module utilized in this study is specific to children with neuromuscular disorders. In addition, clinical response was measured using the Movement-Disorder-Childhood Rating Scale (MD-CRS), a validated instrument for assessing dystonia and spasticity in children. Results are shown inFIG. 1 and inFIG. 6 (Table 2). - Biomarker Endpoints:
- Intracellular reduced glutathione (GSH) serves as the cell's principal endogenous antioxidant. Leigh syndrome and other mitochondrial diseases are associated with decreased GSH levels as the high level of oxidative stress and free oxygen radicals deplete cellular GSH reserves. In order to verify alpha-tocotrienol quinone mechanism of action and to correlate this action with clinical benefit, intracellular (lymphocyte) glutathione levels were measured in all patients. The ratio of recued-to-oxidized glutathione and reduced glutathione to total glutathione levels were calculated to assess the effect of alpha-tocotrienol quinone on repleting reduced intracellular glutathione. Results are shown in
FIG. 2 . In addition, total serum thiol levels were measured prior to and following initiation of treatment. Plasma creatine levels—an exploratory biomarker for mitochondrial disease—was also obtained. - Analytical Methods:
- For lymphocytes and erythrocyte isolation from whole blood, venous blood samples were layered on the top of a discontinuous gradient consisting of 3 ml of Hystopaque®-1119 and 3 mL of Hystopaque®-1077. Gradients were centrifuged at 750 g for 40 min at 4° C. The lymphocyte layer was transferred to a 15 ml centrifuge tube, diluted to a volume of 10 ml with 0.9% NaCl and centrifuged at 750 g for 40 min. The supernatant was removed and, if necessary, the lysis of erythrocytes was performed by adding 2 ml H2O. After 90 s, 2 ml of 1.8% NaCl solution was added and cells washed four times with 0.9% NaCl. The pellet of lymphocytes was centrifuged at 750 g for 10 min and stored at −80° C. until HPLC analysis.
- HPLC Determination of Free GSH, Protein Bound GSH and GSSG in Lymphocytes:
- The determination of the different forms of GSH obtained from lymphocytes was performed, with little modification to a method previously reported (Pastore, A., et al. Clin. Chem. (Washington, D.C.) 44, 825-832 (1998)). Briefly, 30 μl of 4 M NaBH4, 20 μl of 2 mM EDTA/DTT, 10 μl of 1-octanol and 20 μl of 1.8 M HCl were placed in the derivatization vial containing 30 μl of sample. After the mixture was incubated for three min, 100 μl of 1.5 M N-ethylmorpholine buffer, pH 8.0, 400 μl of distilled water, and 20 μl of 25 mM bromobimane were added. After an additional three-min incubation, 40 μl of acetic acid was added and 20 μl (for free GSH) or 80 μl (for GSSG and GS-Pro) of this mixture was injected into the column. The thiol derivatives were quantified by HPLC (Agilent Technologies 1100 HPLC with a fluorescence detector-excitation at 390 nm and an emission at 478 nm). The analytes were separated for detection using a C18 column (Hypersil ODS; 150×4.6 mm, 3 micron) at 1.5 ml/min using an aqueous phase of aqueous 30 mM ammonium nitrate and 40 mM ammonium formate at pH 3.6 with an increasing acetonitrile gradient. HPLC determinations of the various forms of GSH were carried out on lymphocytes sonicated three times for two sec in 0.1 ml of 0.1 M potassium-phosphate buffer, pH 7.2 using a Model VC 130 Vibra Cell™ ultrasonic processor. For free GSH determinations, 100 μl of 12% sulfosalicylic acid were added to 50 μl of cells lysate, and analytes content on the acid-soluble fraction was determined. The protein pellet was dissolved in 150 μl of 0.1 N NaOH, and protein bound glutathione (GS-Pro) determined. For GSSG determination, cells were sonicated in the presence of 5 mM N-ethylmaleimide (NEM); 100 μl of 12% sulfosalicylic acid were added to 50 μl homogenates, and analytes content on the acid-soluble fraction was determined. Protein concentrations were quantified by BCA-protein assay.
- Total Free Thiols in Plasma:
- Total thiols were determined in plasma following the method reported by M.-L. Hu (Methods Enzymol. 233, 380-385 (1994)). 50 μl plasma was mixed with 1 ml of the Tris-EDTA buffer and the absorbance at 412 nm was measured. Then, 20 μl of 10 mM DTNB were added. After 15 min incubation at room temperature, the absorption at 412 nm (ε=13,600 cm−1M−1) was measured together with a DTNB blank.
- Statistical Analyses:
- Descriptive statistics were performed on the entire cohort of children enrolled in this study. Changes in outcome measurement were calculated for each subject as a proportion of their baseline level. Overall mean changes from baseline were analyzed using a Wilcoxon signed rank test. Statistical significance defined as p≦0.05. For patients who entered into the extension phase of the study, data are reported but not included in the calculation of mean change from baseline.
- Results of the study are shown in Table 2, demonstrating that treatment with EPI-743 resulted in a significant enhancement of levels of reduced glutathione and a reduction in oxidized glutathione.
-
TABLE 2 Lymphocytes concentrations of various glutathione form in baseline LS patients and after six-months treatment with EPI-743. Group Tot GSH GSH GS-Pro GSSG Patients 18.60a 5.28b 4.93b 7.25b (n = 10) (12.55-37.89) (1.90-13.40) (2.11-12.80) (2.76-21.25) EPI-743 32.47 28.92 0.57 1.47 treatment (13.59-63.47) (12.06-58.31) (0.33-2.05) (0.51-6.68) (n = 10) Controls 44.02 39.10 1.64 2.94 (n = 10) (21.96-60.42) (19.31-54.55) (1.08-3.41) (1.33-3.82) Median values are expressed as nmol/mg proteins. 95% confidence intervals are reported in parenthesis. a-bValues are significantly different between groups at ap < 0.05; bp < 0.001. - The invention is described further by the following embodiments.
- A method of treating a subject having a glutathione redox potential disorder, comprising the steps of: a) altering the redox potential of glutathione in the subject by administering a compound to the subject at an initial dosage level that alters the concentration of reduced glutathione in the subject, the concentration of oxidized glutathione in the subject, or both the concentration of reduced glutathione and the concentration of oxidized glutathione in the subject; b) subsequent to administering the compound to the subject, measuring the concentration of reduced glutathione and oxidized glutathione in the subject; c) calculating the redox potential of glutathione in the subject; d) adjusting the dosage of the compound administered to the subject; and e) repeating steps b), c), and d) until a ratio of oxidized glutathione concentration to reduced glutathione concentration between about 0.01 and about 0.5 is attained.
- A method of treating a subject having a glutathione redox potential disorder, comprising the steps of: a) altering the redox potential of glutathione in the subject by administering a compound to the subject at an initial dosage level that alters the concentration of reduced glutathione in the subject, the concentration of oxidized glutathione in the subject, or both the concentration of reduced glutathione and the concentration of oxidized glutathione in the subject; b) subsequent to administering the compound to the subject, measuring the concentration of reduced glutathione and oxidized glutathione in the subject; c) calculating the redox potential of glutathione in the subject; d) adjusting the dosage of the compound administered to the subject; and e) repeating steps b), c), and d) until the subject has a redox potential of at least about an absolute value of 10 mV more negative than the redox potential of the subject prior to treatment.
- The method of
Embodiment 1, wherein the subject having a glutathione redox potential disorder has a ratio of oxidized glutathione concentration to reduced glutathione concentration of about 2 or greater prior to administering the compound. - The method of any of Embodiments 1-3, wherein the step of measuring the concentration of reduced glutathione and the concentration of oxidized glutathione comprises an HPLC measurement.
- The method of any of Embodiments 1-4, wherein the step of measuring the concentration of reduced glutathione and the concentration of oxidized glutathione in the subject comprises measuring the concentration of reduced glutathione and the concentration of oxidized glutathione in the blood plasma, blood serum, whole blood, cerebrospinal fluid, semen, breast milk, umbilical cord blood, umbilical cord tissue, or skin biopsy of the subject.
- The method of any of Embodiments 1-4, wherein the step of measuring the concentration of reduced glutathione and the concentration of oxidized glutathione in the subject comprises measuring the concentration of reduced glutathione and the concentration of oxidized glutathione in the lymphocytes of the subject.
- The method of any of Embodiments 1-7, wherein step a) and step d) additionally comprise measuring the concentration of total glutathione in the subject, or calculating the concentration of total glutathione in the subject from the measured concentration of reduced glutathione and concentration of oxidized glutathione in the subject, and step a) additionally comprises administering a therapeutically effective amount of N-acetyl cysteine to the subject if the concentration of total glutathione in the subject is below about 30 nmol/mg cell protein, or if the concentration of total glutathione in the subject is below about 1 micromolar.
- The method of
Embodiment 7, wherein sufficient N-acetyl cysteine is administered to the subject to adjust the concentration of total glutathione in the subject above about 30 nmol/mg cell protein, or to adjust the concentration of total glutathione in the subject above about 1 micromolar. - The method of
Embodiment 7, wherein a dosage of about 50 mg to about 1000 mg N-acetyl cysteine is administered to the subject. - The method of any of Embodiments 1-9, wherein the compound administered to the subject that alters the concentration of reduced glutathione in the subject, the concentration of oxidized glutathione in the subject, or both the concentration of reduced glutathione and the concentration of oxidized glutathione in the subject is selected from the group consisting of pharmaceutically acceptable two-electron redox-active molecules having a reduction potential between about −350 millivolts and about +150 millivolts versus the standard hydrogen electrode.
- The method of any of Embodiments 1-9, wherein the compound administered to the subject that alters the concentration of reduced glutathione in the subject, the concentration of oxidized glutathione in the subject, or both the concentration of reduced glutathione and the concentration of oxidized glutathione in the subject is selected from the group consisting of pharmaceutically acceptable two-electron redox-active molecules having a reduction potential between about 20 millivolts more reductive than Coenzyme Q and about 250 millivolts more reductive than Coenzyme Q.
- The method of any of Embodiments 1-9, wherein the compound administered to the subject that alters the concentration of reduced glutathione in the subject, the concentration of oxidized glutathione in the subject, or both the concentration of reduced glutathione and the concentration of oxidized glutathione in the subject is selected from the group consisting of compounds of Formula I:
- where R is selected from:
- where the asterisk * indicates the attachment of R in Formula I; where R1, R2, and R3 are independently H or C1-C6 alkyl, m is an integer from 0 to 9 inclusive, and the bonds indicated by a dashed line can be either double or single bonds.
- The method of any of Embodiments 1-9, wherein the compound administered to the subject is selected from the group consisting of compounds of Formula I-ox or Formula I-red:
- where R1, R2, and R3 are independently H or C1-C6 alkyl; m is an integer from 0 to 9 inclusive; and the bonds indicated by a dashed line can be either double or single bonds.
- The method of
Embodiment 13, wherein the compound administered to the subject that alters the concentration of reduced glutathione in the subject, the concentration of oxidized glutathione in the subject, or both the concentration of reduced glutathione and the concentration of oxidized glutathione in the subject is selected from the group consisting of: alpha-tocotrienol quinone, beta-tocotrienol quinone, gamma-tocotrienol quinone, delta-tocotrienol quinone, alpha-tocopherol quinone, beta-tocopherol quinone, gamma-tocopherol quinone, and delta-tocopherol quinone, or any combination thereof. - The disclosures of all publications, patents, patent applications and published patent applications referred to herein by an identifying citation are hereby incorporated herein by reference in their entirety.
- Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.
Claims (15)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/426,130 US20150216820A1 (en) | 2012-09-07 | 2013-09-06 | Quinone derivatives for use in the modulation of redox status of individuals |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261698431P | 2012-09-07 | 2012-09-07 | |
US201361792797P | 2013-03-15 | 2013-03-15 | |
PCT/US2013/058568 WO2014039862A1 (en) | 2012-09-07 | 2013-09-06 | Quinone derivatives for use in the modulation of redox status of individuals |
US14/426,130 US20150216820A1 (en) | 2012-09-07 | 2013-09-06 | Quinone derivatives for use in the modulation of redox status of individuals |
Publications (1)
Publication Number | Publication Date |
---|---|
US20150216820A1 true US20150216820A1 (en) | 2015-08-06 |
Family
ID=49170942
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/426,130 Abandoned US20150216820A1 (en) | 2012-09-07 | 2013-09-06 | Quinone derivatives for use in the modulation of redox status of individuals |
US14/426,135 Expired - Fee Related US9629815B2 (en) | 2012-09-07 | 2013-09-06 | Benzoquinone derivatives for treating oxidative stress disorders |
US15/483,933 Abandoned US20170209393A1 (en) | 2012-09-07 | 2017-04-10 | Benzoquinone derivatives for treating oxidative stress disorders |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/426,135 Expired - Fee Related US9629815B2 (en) | 2012-09-07 | 2013-09-06 | Benzoquinone derivatives for treating oxidative stress disorders |
US15/483,933 Abandoned US20170209393A1 (en) | 2012-09-07 | 2017-04-10 | Benzoquinone derivatives for treating oxidative stress disorders |
Country Status (6)
Country | Link |
---|---|
US (3) | US20150216820A1 (en) |
EP (2) | EP2892515A1 (en) |
JP (2) | JP2015533794A (en) |
CA (2) | CA2883879A1 (en) |
HK (1) | HK1211872A1 (en) |
WO (2) | WO2014039917A1 (en) |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9278085B2 (en) | 2006-02-22 | 2016-03-08 | Edison Pharmaceuticals, Inc. | Side-chain variants of redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers |
US9447006B2 (en) | 2005-06-01 | 2016-09-20 | Edison Pharmaceuticals, Inc. | Redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers |
US9464016B2 (en) | 2011-06-14 | 2016-10-11 | Edison Pharmaceuticals, Inc. | Catechol derivatives for treatment of oxidative stress diseases |
US9486435B2 (en) | 2008-01-08 | 2016-11-08 | Edison Pharmaceuticals, Inc. | (Het)aryl-p-quinone derivatives for treatment of mitochondrial diseases |
US9567279B2 (en) | 2011-07-19 | 2017-02-14 | Edison Pharmaceuticals, Inc. | Methods for oxidation of alpha tocotrienol in the presence of non-alpha tocotrienols |
US9629815B2 (en) | 2012-09-07 | 2017-04-25 | Bioelectron Technology Corporation | Benzoquinone derivatives for treating oxidative stress disorders |
US9868711B2 (en) | 2013-03-15 | 2018-01-16 | Bioelectron Technology Corporation | Phenazine-3-one and phenothiazine-3-one derivatives for treatment of oxidative stress disorders |
WO2018129411A1 (en) | 2017-01-06 | 2018-07-12 | Bioelectron Technology Corporation | Aryl- and heteroaryl-resorufin derivatives for treatment of oxidative stress disorders and liver and kidney disorders |
US10071978B2 (en) | 2008-10-28 | 2018-09-11 | Bioelectron Technology Corporation | Process for the production of alpha-tocotrienol and derivatives |
US10105325B2 (en) | 2008-09-10 | 2018-10-23 | Bioelectron Technology Corporation | Treatment of pervasive developmental disorders with redox-active therapeutics |
US10167251B2 (en) | 2007-11-06 | 2019-01-01 | Bioelectron Technology Corporation | 4-(p-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases |
US10189830B2 (en) | 2013-03-15 | 2019-01-29 | Bioelectron Technology Corporation | Alkyl-heteroaryl substituted quinone derivatives for treatment of oxidative stress disorders |
US10195161B2 (en) | 2009-04-28 | 2019-02-05 | Bioelectron Technology Corporation | Treatment of leber's hereditary optic neuropathy and dominant optic atrophy with tocotrienol quinones |
US10251847B2 (en) | 2014-12-16 | 2019-04-09 | Bioelectron Technology Corporation | Polymorphic and amorphous forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide |
US10703701B2 (en) | 2015-12-17 | 2020-07-07 | Ptc Therapeutics, Inc. | Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders |
US10707531B1 (en) | 2016-09-27 | 2020-07-07 | New Dominion Enterprises Inc. | All-inorganic solvents for electrolytes |
US10738014B2 (en) | 2016-11-15 | 2020-08-11 | Ptc Therapeutics, Inc. | 2-substituted amino-naphth (1,2-d) imidazol-5-one compounds or pharmaceutically acceptable salts thereof |
US10745371B2 (en) | 2015-12-16 | 2020-08-18 | Ptc Therapeutics, Inc. | Methods for enriching alpha-tocotrienol from mixed tocol compositions |
US11174212B2 (en) | 2018-10-17 | 2021-11-16 | Ptc Therapeutics, Inc. | 2,3,5-trimelthyl-6-nonylcyclohexa-2,5-diene-1,4-dione for suppressing and treating alpha-synucleinopathies, tauopathies, and other disorders |
US11786486B2 (en) | 2021-07-08 | 2023-10-17 | Ptc Therapeutics, Inc. | Pharmaceutical compositions comprising 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2262508B1 (en) | 2008-03-05 | 2018-10-03 | BioElectron Technology Corporation | SUBSTITUTED-p-QUINONE DERIVATIVES FOR TREATMENT OF OXIDATIVE STRESS DISEASES |
US9670170B2 (en) | 2013-03-15 | 2017-06-06 | Bioelectron Technology Corporation | Resorufin derivatives for treatment of oxidative stress disorders |
US9296712B2 (en) | 2013-03-15 | 2016-03-29 | Edison Pharmaceuticals, Inc. | Resorufin derivatives for treatment of oxidative stress disorders |
CA2912871A1 (en) | 2013-05-31 | 2014-12-04 | Edison Pharmaceuticals, Inc. | Carboxylic acid derivatives for treatment of oxidative stress disorders |
WO2015183963A2 (en) * | 2014-05-28 | 2015-12-03 | Stealth Peptides International, Inc. | Therapeutic compositions including redox-active parabenzoquinones and uses thereof |
US11267777B2 (en) | 2015-11-19 | 2022-03-08 | Concert Pharmaceuticals, Inc. | Deuterated EPI-743 |
US20190029975A1 (en) * | 2016-01-12 | 2019-01-31 | Bioelectron Technology Corporation | Tocopherol and tocotrienol quinone derivatives for increasing thiosulfate levels or decreasing hydrogen sulfide levels |
EP3983385B1 (en) | 2019-06-13 | 2023-08-30 | PTC Therapeutics, Inc. | Naphthoquinone derivatives for treatment of oxidative stress disorders |
JP2022551270A (en) | 2019-10-04 | 2022-12-08 | ステルス バイオセラピューティクス インコーポレイテッド | Quinone, hydroquinone and naphthoquinone analogues for the treatment of mitochondrial diseases |
CA3176909A1 (en) | 2020-04-03 | 2021-10-07 | Stealth Biotherapeutics Inc. | Compositions and methods for the prevention and/or treatment of mitochondrial disease, including friedreich's ataxia |
CN116096361A (en) * | 2020-08-07 | 2023-05-09 | 大鹏药品工业株式会社 | Novel cyclic enone compound or salt thereof |
WO2023220365A1 (en) * | 2022-05-13 | 2023-11-16 | Virginia Tech Intellectual Properties, Inc. | Mitochondrial antioxidant treatment for cask-linked neurodevelopmental disorders |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011041452A2 (en) * | 2009-10-01 | 2011-04-07 | Ampere Life Sciences, Inc. | Mouse model for identifying compounds for the treatment of oxidative stress |
Family Cites Families (64)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5621021B2 (en) | 1973-12-19 | 1981-05-16 | ||
EP0015436B1 (en) | 1979-03-08 | 1982-02-03 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Process for the stereospecific preparation of compounds of the vitamin k1- and k2-series, as well as new starting materials for the process |
JPS5640651A (en) | 1979-09-12 | 1981-04-16 | Takeda Chem Ind Ltd | Quinone compound and its preparation |
JPS57109739A (en) * | 1980-12-27 | 1982-07-08 | Takeda Chem Ind Ltd | Quinone compound and its preparation |
US4393075A (en) | 1980-04-14 | 1983-07-12 | Takeda Chemical Industries, Ltd. | Quinone compounds and their use in suppressing the production of SRS-A in mammals |
DE3362008D1 (en) * | 1982-07-09 | 1986-03-13 | Takeda Chemical Industries Ltd | Quinone compounds, their production and use |
JPS5910541A (en) * | 1982-07-09 | 1984-01-20 | Takeda Chem Ind Ltd | Quinone compound |
JPS6143132A (en) * | 1984-08-06 | 1986-03-01 | Takeda Chem Ind Ltd | Quinone derivative, its preparation, and pharmaceutical composition containing same |
JPS62294636A (en) | 1986-05-21 | 1987-12-22 | Eisai Co Ltd | Production of 2-methyl-1,4-naphthoquinone |
IE904264A1 (en) | 1989-11-28 | 1991-06-05 | Nippon Catalytic Chem Ind | Process for preparation of 2-substituted-1,4-naphthoquinone |
JPH06312950A (en) | 1993-03-01 | 1994-11-08 | Eezai Kagaku Kk | Production of quinone derivative and intermediate |
US5318993A (en) | 1993-04-16 | 1994-06-07 | Bristol-Myers Squibb Company | Antihyperlipidemic benzoquinones |
EP0636598B1 (en) | 1993-07-26 | 1997-04-09 | Eisai Chemical Co., Ltd. | Preparation process of naphthoquinone derivatives and intermediates for the preparation thereof |
AU698313B2 (en) * | 1994-03-14 | 1998-10-29 | Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services, The | Use of lipoxygenase inhibitors as anti-cancer therapeutic and intervention agents |
US5637741A (en) | 1994-09-27 | 1997-06-10 | Kuraray Co., Ltd. | Process for producing 2-methyl-1,4-naphthoquinone |
KR0178456B1 (en) | 1996-04-25 | 1999-05-15 | 김흥기 | Process for producing 2-methyl-1,4-naphthoquinone(vitamin k3) |
US6133322A (en) * | 1998-10-29 | 2000-10-17 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Quinone derivatives for treating or preventing diseases associated with iron overload |
US7034054B2 (en) | 2000-12-15 | 2006-04-25 | Galileo Pharmaceuticals, Inc. | Methods for the prevention and treatment of cerebral ischemia using non-alpha tocopherols |
WO2002056823A2 (en) * | 2001-01-18 | 2002-07-25 | Arnold Hoffman | Redox therapy for tumors |
US6579994B2 (en) | 2001-03-29 | 2003-06-17 | Council Of Scientific And Industrial Research | Process for preparation of 2-Methyl-1,4-naphthoquinone |
GB0117326D0 (en) | 2001-07-16 | 2001-09-05 | Univ Aberdeen | Napthoquinone-type inhibitors of protein aggregation |
NZ513547A (en) | 2001-08-13 | 2002-09-27 | Antipodean Biotechnology Ltd | Synthesis of triphenylphosphonium quinols (e.g. mitoquinol) and/or quinones (e.g. mitoquinone) |
JP2003226639A (en) | 2002-01-31 | 2003-08-12 | Hisamitsu Pharmaceut Co Inc | Pharmaceutical composition containing vitamin k as nerve growth factor activity promotor and use of the composition |
EP1378753B1 (en) | 2002-07-01 | 2006-05-31 | Santhera Pharmaceuticals (Schweiz) GmbH | A screening method and compounds for treating Friedreich Ataxia |
AU2003287250B9 (en) * | 2002-10-30 | 2010-01-28 | Ptc Therapeutics, Inc. | Identifying therapeutic compounds based on their physical-chemical properties |
US20040087527A1 (en) | 2002-10-31 | 2004-05-06 | Day Brian J. | Methods for treatment of thiol-containing compound deficient conditions |
US7470798B2 (en) | 2003-09-19 | 2008-12-30 | Edison Pharmaceuticals, Inc. | 7,8-bicycloalkyl-chroman derivatives |
MX359292B (en) | 2005-06-01 | 2018-09-24 | Bioelectron Tech Corp | Redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomakers. |
US7432305B2 (en) | 2005-09-15 | 2008-10-07 | Edison Pharmaceuticals, Inc. | Tail variants of redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers |
RU2318500C2 (en) | 2005-10-18 | 2008-03-10 | Общество С Ограниченной Ответственностью "Митотехнология" | Method for on body by target delivery of biologically active substances in mitochondria, pharmaceutical composition for its realization and compound used for this aim |
CA2635280C (en) * | 2006-02-22 | 2017-12-12 | Edison Pharmaceuticals, Inc. | Side chain variants of redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers |
CN101139272A (en) | 2006-09-08 | 2008-03-12 | 南京莱因医药科技有限公司 | Method for synthesizing vitamin K2 |
CA2606658A1 (en) | 2006-10-13 | 2008-04-13 | Mike Tyers | Compositions and methods for treating neurological disorders or damage |
KR20080047957A (en) | 2006-11-27 | 2008-05-30 | 주식회사 엠디바이오알파 | Pharmaceutical composition for treatment and prevention of hypertension |
PL2220030T3 (en) | 2007-11-06 | 2016-07-29 | Bioelectron Tech Corp | 4- (p-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases |
WO2009089224A1 (en) | 2008-01-08 | 2009-07-16 | Edison Pharmaceuticals, Inc. | (HET) ARYL-p-QUINONE DERIVATIVES FOR TREATMENT OF MITOCHONDRIAL DISEASES |
EP2262508B1 (en) | 2008-03-05 | 2018-10-03 | BioElectron Technology Corporation | SUBSTITUTED-p-QUINONE DERIVATIVES FOR TREATMENT OF OXIDATIVE STRESS DISEASES |
JP2011513420A (en) | 2008-03-05 | 2011-04-28 | エジソン ファーマシューティカルズ, インコーポレイテッド | Treatment of auditory and balance dysfunction with redox active therapeutics |
WO2009158348A1 (en) | 2008-06-25 | 2009-12-30 | Edison Pharmaceuticals, Inc. | 2-heterocyclylaminoalkyl-(p-quinone) derivatives for treatment of oxidative stress diseases |
LT3827815T (en) | 2008-09-10 | 2023-10-10 | Ptc Therapeutics, Inc. | Treatment of pervasive developmental disorders with redox-active therapeutics |
EP2362726B1 (en) | 2008-10-14 | 2018-08-08 | Bioelectron Technology Corporation | Treatment of oxidative stress disorders including contrast nephropathy, radiation damage and disruptions in the function of red cells |
PT2963006T (en) | 2008-10-28 | 2018-12-14 | Bioelectron Tech Corp | Composition containing alpha-tocotrienol quinone,and intermediates thereof |
US20100273892A1 (en) | 2009-04-28 | 2010-10-28 | Miller Guy M | Formulations of tocotrienol quinones for the treatment of ophthalmic diseases |
MX336800B (en) | 2009-04-28 | 2016-02-02 | Edison Pharmaceuticals Inc | Treatment of leber's hereditary optic neuropathy and dominant optic atrophy with tocotrienol quinones. |
DK2470168T3 (en) * | 2009-08-26 | 2018-05-07 | Bioelectron Tech Corp | PROCEDURES FOR PREVENTION AND TREATMENT OF CEREBRAL ISCAM |
US20110172312A1 (en) | 2009-12-31 | 2011-07-14 | Miller Guy M | Treatment of leigh syndrome and leigh-like syndrome with tocotrienol quinones |
CN102884037A (en) * | 2010-03-09 | 2013-01-16 | 爱迪生制药有限公司 | Synthesis of alpha-tocopherolquinone derivatives, and methods of using the same |
JP5902673B2 (en) * | 2010-04-27 | 2016-04-13 | エジソン ファーマシューティカルズ, インコーポレイテッド | Formulation of quinones for the treatment of eye diseases |
US20140031432A1 (en) | 2010-08-06 | 2014-01-30 | Ampere Life Sciences, Inc. | Treatment of mitochondrial diseases with vitamin k |
EP2600857A4 (en) | 2010-08-06 | 2014-06-11 | Edison Pharmaceuticals Inc | Treatment of mitochondrial diseases with naphthoquinones |
HUE030595T2 (en) * | 2010-08-16 | 2017-05-29 | Santhera Pharmaceuticals (Schweiz) Ag | Benzoquinone derivatives for the treatment of mitchondrial eye diseases |
WO2012170773A1 (en) | 2011-06-08 | 2012-12-13 | Edison Pharmaceuticals, Inc. | Adjunctive therapy for the treatment of mitochondrial disorders with quinones and naphthoquinones |
EP2720689A4 (en) | 2011-06-14 | 2014-11-26 | Edison Pharmaceuticals Inc | Catechol derivatives for treatment of oxidative stress diseases |
JP6728520B2 (en) | 2011-07-06 | 2020-07-22 | ピーティーシー セラピューティクス, インコーポレイテッド | Treatment of methylmalonic aciduria, isovaleric aciduria, and other organic aciduria with tocotrienol quinone |
EP2734512B1 (en) | 2011-07-19 | 2019-11-20 | Bioelectron Technology Corporation | Methods for selective oxidation of alpha tocotrienol in the presence of non-alpha tocotrienols |
CN103841969A (en) * | 2011-08-04 | 2014-06-04 | 美国卫生和人力服务部 | Treatment and prevention of diseases mediated by microorganisms via drug-mediated manipulation of the eicosanoid balance |
JP5076021B1 (en) | 2011-11-17 | 2012-11-21 | 株式会社東芝 | Electronic device, electronic device control method, electronic device control program |
CA2883879A1 (en) | 2012-09-07 | 2014-03-13 | Edison Pharmaceuticals, Inc. | Quinone derivatives for use in the modulation of redox status of individuals |
US9670170B2 (en) | 2013-03-15 | 2017-06-06 | Bioelectron Technology Corporation | Resorufin derivatives for treatment of oxidative stress disorders |
US20140275045A1 (en) | 2013-03-15 | 2014-09-18 | Edison Pharmaceuticals, Inc. | Phenazine-3-one and phenothiazine-3-one derivatives for treatment of oxidative stress disorders |
EP2970158B1 (en) | 2013-03-15 | 2019-02-20 | BioElectron Technology Corporation | Alkyl-heteroaryl substituted quinone derivatives for treatment of oxidative stress disorders |
US9296712B2 (en) | 2013-03-15 | 2016-03-29 | Edison Pharmaceuticals, Inc. | Resorufin derivatives for treatment of oxidative stress disorders |
US9868711B2 (en) | 2013-03-15 | 2018-01-16 | Bioelectron Technology Corporation | Phenazine-3-one and phenothiazine-3-one derivatives for treatment of oxidative stress disorders |
CA2912871A1 (en) | 2013-05-31 | 2014-12-04 | Edison Pharmaceuticals, Inc. | Carboxylic acid derivatives for treatment of oxidative stress disorders |
-
2013
- 2013-09-06 CA CA2883879A patent/CA2883879A1/en not_active Abandoned
- 2013-09-06 WO PCT/US2013/058637 patent/WO2014039917A1/en active Application Filing
- 2013-09-06 US US14/426,130 patent/US20150216820A1/en not_active Abandoned
- 2013-09-06 JP JP2015531266A patent/JP2015533794A/en not_active Ceased
- 2013-09-06 EP EP13762705.5A patent/EP2892515A1/en not_active Withdrawn
- 2013-09-06 CA CA2883882A patent/CA2883882A1/en not_active Abandoned
- 2013-09-06 WO PCT/US2013/058568 patent/WO2014039862A1/en active Application Filing
- 2013-09-06 JP JP2015531249A patent/JP6393684B2/en not_active Expired - Fee Related
- 2013-09-06 EP EP13765880.3A patent/EP2892516A1/en not_active Withdrawn
- 2013-09-06 US US14/426,135 patent/US9629815B2/en not_active Expired - Fee Related
-
2016
- 2016-01-04 HK HK16100029.7A patent/HK1211872A1/en unknown
-
2017
- 2017-04-10 US US15/483,933 patent/US20170209393A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011041452A2 (en) * | 2009-10-01 | 2011-04-07 | Ampere Life Sciences, Inc. | Mouse model for identifying compounds for the treatment of oxidative stress |
Non-Patent Citations (2)
Title |
---|
Moreira et al., Journal of Alzheimer's Disease, 2007, 195-206 * |
Owen et al., Methods in Molecular Biology, vol.648, 2010, pages 269-277 * |
Cited By (39)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9447006B2 (en) | 2005-06-01 | 2016-09-20 | Edison Pharmaceuticals, Inc. | Redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers |
US11021424B2 (en) | 2005-06-01 | 2021-06-01 | Ptc Therapeutics, Inc. | Redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers |
US9932286B2 (en) | 2006-02-22 | 2018-04-03 | Bioelectron Technology Corporation | Side-chain variants of redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers |
US9278085B2 (en) | 2006-02-22 | 2016-03-08 | Edison Pharmaceuticals, Inc. | Side-chain variants of redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers |
US10167251B2 (en) | 2007-11-06 | 2019-01-01 | Bioelectron Technology Corporation | 4-(p-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases |
US10968166B2 (en) | 2007-11-06 | 2021-04-06 | Ptc Therapeutics, Inc. | 4-(P-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases |
US11840497B2 (en) | 2007-11-06 | 2023-12-12 | Ptc Therapeutics, Inc. | 4-(p-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases |
US9486435B2 (en) | 2008-01-08 | 2016-11-08 | Edison Pharmaceuticals, Inc. | (Het)aryl-p-quinone derivatives for treatment of mitochondrial diseases |
US10736857B2 (en) | 2008-09-10 | 2020-08-11 | Ptc Therapeutics, Inc. | Treatment of pervasive developmental disorders with redox-active therapeutics |
US10105325B2 (en) | 2008-09-10 | 2018-10-23 | Bioelectron Technology Corporation | Treatment of pervasive developmental disorders with redox-active therapeutics |
US11312697B2 (en) | 2008-10-28 | 2022-04-26 | Ptc Therapeutics, Inc. | Process for the production of alpha-tocotrienol and derivatives |
US10071978B2 (en) | 2008-10-28 | 2018-09-11 | Bioelectron Technology Corporation | Process for the production of alpha-tocotrienol and derivatives |
US10195161B2 (en) | 2009-04-28 | 2019-02-05 | Bioelectron Technology Corporation | Treatment of leber's hereditary optic neuropathy and dominant optic atrophy with tocotrienol quinones |
US9464016B2 (en) | 2011-06-14 | 2016-10-11 | Edison Pharmaceuticals, Inc. | Catechol derivatives for treatment of oxidative stress diseases |
US9567279B2 (en) | 2011-07-19 | 2017-02-14 | Edison Pharmaceuticals, Inc. | Methods for oxidation of alpha tocotrienol in the presence of non-alpha tocotrienols |
US10202325B2 (en) | 2011-07-19 | 2019-02-12 | Bioelectron Technology Corporation | Methods for selective oxidation of alpha tocotrienol in the presence of non-alpha tocotrienols |
US10029971B2 (en) | 2011-07-19 | 2018-07-24 | Bioelectron Technology Corporation | Methods for selective oxidation of alpha tocotrienol in the presence of non-alpha tocotrienols |
US9629815B2 (en) | 2012-09-07 | 2017-04-25 | Bioelectron Technology Corporation | Benzoquinone derivatives for treating oxidative stress disorders |
US9868711B2 (en) | 2013-03-15 | 2018-01-16 | Bioelectron Technology Corporation | Phenazine-3-one and phenothiazine-3-one derivatives for treatment of oxidative stress disorders |
US10189830B2 (en) | 2013-03-15 | 2019-01-29 | Bioelectron Technology Corporation | Alkyl-heteroaryl substituted quinone derivatives for treatment of oxidative stress disorders |
US10251847B2 (en) | 2014-12-16 | 2019-04-09 | Bioelectron Technology Corporation | Polymorphic and amorphous forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide |
US11304914B2 (en) | 2014-12-16 | 2022-04-19 | Ptc Therapeutics, Inc. | Polymorphic and amorphous forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide |
US11938101B2 (en) | 2014-12-16 | 2024-03-26 | Ptc Therapeutics, Inc. | Polymorphic forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide |
US10751302B2 (en) | 2014-12-16 | 2020-08-25 | Ptc Therapeutics, Inc. | Polymorphic and amorphous forms of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide |
US10745371B2 (en) | 2015-12-16 | 2020-08-18 | Ptc Therapeutics, Inc. | Methods for enriching alpha-tocotrienol from mixed tocol compositions |
US11186559B2 (en) | 2015-12-16 | 2021-11-30 | Ptc Therapeutics, Inc. | Methods for enriching alpha-tocotrienol from mixed tocol compositions |
US11560364B2 (en) | 2015-12-16 | 2023-01-24 | Ptc Therapeutics, Inc. | Methods for enriching alpha-tocotrienol from mixed tocol compositions |
US10981855B2 (en) | 2015-12-17 | 2021-04-20 | Ptc Therapeutics, Inc. | Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders |
CN113024369A (en) * | 2015-12-17 | 2021-06-25 | Ptc医疗公司 | Compounds for the treatment of oxidative stress disorders |
US11680034B2 (en) | 2015-12-17 | 2023-06-20 | Ptc Therapeutics, Inc. | Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders |
US10703701B2 (en) | 2015-12-17 | 2020-07-07 | Ptc Therapeutics, Inc. | Fluoroalkyl, fluoroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders |
US10707531B1 (en) | 2016-09-27 | 2020-07-07 | New Dominion Enterprises Inc. | All-inorganic solvents for electrolytes |
US11390588B2 (en) | 2016-11-15 | 2022-07-19 | Ptc Therapeutics, Inc. | 2-substituted amino-naphth (1,2-d) imidazol-5-one compounds of pharmaceutically acceptable salts thereof |
US10738014B2 (en) | 2016-11-15 | 2020-08-11 | Ptc Therapeutics, Inc. | 2-substituted amino-naphth (1,2-d) imidazol-5-one compounds or pharmaceutically acceptable salts thereof |
WO2018129411A1 (en) | 2017-01-06 | 2018-07-12 | Bioelectron Technology Corporation | Aryl- and heteroaryl-resorufin derivatives for treatment of oxidative stress disorders and liver and kidney disorders |
US11667596B2 (en) | 2018-10-17 | 2023-06-06 | Ptc Therapeutics, Inc. | 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione for suppressing and treating alpha-synucleinopathies, tauopathies, and other disorders |
US11174212B2 (en) | 2018-10-17 | 2021-11-16 | Ptc Therapeutics, Inc. | 2,3,5-trimelthyl-6-nonylcyclohexa-2,5-diene-1,4-dione for suppressing and treating alpha-synucleinopathies, tauopathies, and other disorders |
US11746077B2 (en) | 2018-10-17 | 2023-09-05 | Ptc Therapeutics, Inc. | 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione for suppressing and treating alpha-synucleinopathies, tauopathies, and other disorders |
US11786486B2 (en) | 2021-07-08 | 2023-10-17 | Ptc Therapeutics, Inc. | Pharmaceutical compositions comprising 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione |
Also Published As
Publication number | Publication date |
---|---|
US20150218079A1 (en) | 2015-08-06 |
EP2892515A1 (en) | 2015-07-15 |
WO2014039917A1 (en) | 2014-03-13 |
CA2883879A1 (en) | 2014-03-13 |
US9629815B2 (en) | 2017-04-25 |
JP2015527400A (en) | 2015-09-17 |
US20170209393A1 (en) | 2017-07-27 |
HK1211872A1 (en) | 2016-06-03 |
CA2883882A1 (en) | 2014-03-13 |
EP2892516A1 (en) | 2015-07-15 |
WO2014039862A1 (en) | 2014-03-13 |
JP6393684B2 (en) | 2018-09-19 |
JP2015533794A (en) | 2015-11-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20150216820A1 (en) | Quinone derivatives for use in the modulation of redox status of individuals | |
US10736857B2 (en) | Treatment of pervasive developmental disorders with redox-active therapeutics | |
US20210145769A1 (en) | Treatment of methylmalonic aciduria, isovaleric aciduria, and other organic acidurias with tocotrienol quinones | |
US20220133648A1 (en) | Treatment of leigh syndrome and leigh-like syndrome with tocotrienol quinones | |
ES2823728T3 (en) | Tail variants of therapeutic agents with redox activity for the treatment of mitochondrial diseases and other conditions and the modulation of energy biomarkers | |
US20130116336A1 (en) | Treatment of ataxia telangiectasia | |
JP2014530821A (en) | Treatment of multiple sclerosis combining laquinimod and fingolimod | |
WO2013006736A1 (en) | Treatment of leigh syndrome and leigh-like syndrome, including complications of sucla2 mutations, with tocotrienol quinones | |
US20220265604A1 (en) | Treatment of mitochondrial diseases | |
US20240238238A1 (en) | Isotopically Modified Composition and Therapeutic Uses Thereof | |
US20190142893A1 (en) | Electron, Radical, or Reactive Oxygen Species-Scavenging Agent Based Therapy of Inborn Errors of Fatty Acid Oxidation and Oxidative Phosphorylation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: EDISON PHARMACEUTICALS, INC., CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MILLER, GUY M.;SHRADER, WILLIAM D.;KHEIFETS, VIKTORIA;REEL/FRAME:032068/0408 Effective date: 20140127 |
|
AS | Assignment |
Owner name: EDISON PHARMACEUTICALS, INC., CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MILLER, GUY M.;SHRADER, WILLIAM D.;KHEIFETS, VIKTORIA;REEL/FRAME:035872/0686 Effective date: 20140127 |
|
AS | Assignment |
Owner name: BIOELECTRON TECHNOLOGY CORPORATION, CALIFORNIA Free format text: CHANGE OF NAME;ASSIGNOR:EDISON PHARMACEUTICALS, INC.;REEL/FRAME:041660/0644 Effective date: 20170117 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |