NZ611948B2 - Methods and drug products for treating alzheimer's disease - Google Patents
Methods and drug products for treating alzheimer's disease Download PDFInfo
- Publication number
- NZ611948B2 NZ611948B2 NZ611948A NZ61194812A NZ611948B2 NZ 611948 B2 NZ611948 B2 NZ 611948B2 NZ 611948 A NZ611948 A NZ 611948A NZ 61194812 A NZ61194812 A NZ 61194812A NZ 611948 B2 NZ611948 B2 NZ 611948B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- subject
- alzheimer
- risk
- pioglitazone
- age
- Prior art date
Links
- 206010001897 Alzheimer's disease Diseases 0.000 title claims description 226
- 239000000825 pharmaceutical preparation Substances 0.000 title description 27
- HYAFETHFCAUJAY-UHFFFAOYSA-N Pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims abstract description 196
- 229960005095 Pioglitazone Drugs 0.000 claims abstract description 186
- 206010057668 Cognitive disease Diseases 0.000 claims abstract description 87
- 230000001965 increased Effects 0.000 claims abstract description 63
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 36
- 239000012472 biological sample Substances 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims description 86
- 201000010099 disease Diseases 0.000 claims description 58
- 102100007877 APOE Human genes 0.000 claims description 40
- 101700025839 APOE Proteins 0.000 claims description 40
- 102100016156 TOMM40 Human genes 0.000 claims description 37
- 108050002989 TOMM40 Proteins 0.000 claims description 37
- 238000009472 formulation Methods 0.000 claims description 33
- 230000002068 genetic Effects 0.000 claims description 30
- 239000007788 liquid Substances 0.000 claims description 24
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 claims description 24
- 230000035533 AUC Effects 0.000 claims description 23
- 239000007787 solid Substances 0.000 claims description 21
- 239000003826 tablet Substances 0.000 claims description 20
- 239000002775 capsule Substances 0.000 claims description 19
- 241000229754 Iva xanthiifolia Species 0.000 claims description 13
- 230000019771 cognition Effects 0.000 claims description 13
- 230000002354 daily Effects 0.000 claims description 12
- 230000001073 episodic memory Effects 0.000 claims description 11
- 239000002773 nucleotide Substances 0.000 claims description 11
- 125000003729 nucleotide group Chemical group 0.000 claims description 11
- 239000002552 dosage form Substances 0.000 claims description 10
- 239000000843 powder Substances 0.000 claims description 9
- 239000007894 caplet Substances 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 230000000699 topical Effects 0.000 claims description 3
- 240000000800 Allium ursinum Species 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims 2
- 240000004119 Melissa officinalis Species 0.000 claims 1
- 235000010654 Melissa officinalis Nutrition 0.000 claims 1
- 239000006071 cream Substances 0.000 claims 1
- 239000000865 liniment Substances 0.000 claims 1
- 239000006210 lotion Substances 0.000 claims 1
- 210000004556 Brain Anatomy 0.000 description 85
- 238000002360 preparation method Methods 0.000 description 75
- 239000011780 sodium chloride Substances 0.000 description 66
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 61
- 150000003839 salts Chemical class 0.000 description 57
- 239000003814 drug Substances 0.000 description 44
- 229940079593 drugs Drugs 0.000 description 40
- 235000010980 cellulose Nutrition 0.000 description 37
- 229920002678 cellulose Polymers 0.000 description 37
- 239000001913 cellulose Substances 0.000 description 37
- 206010012289 Dementia Diseases 0.000 description 35
- -1 DNA e hair Chemical class 0.000 description 33
- 230000001149 cognitive Effects 0.000 description 31
- 230000000694 effects Effects 0.000 description 30
- 150000007524 organic acids Chemical class 0.000 description 29
- 239000000654 additive Substances 0.000 description 25
- 238000000034 method Methods 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 239000002245 particle Substances 0.000 description 23
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 21
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 21
- 229960004106 citric acid Drugs 0.000 description 21
- 235000010355 mannitol Nutrition 0.000 description 21
- 230000001537 neural Effects 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 238000003745 diagnosis Methods 0.000 description 19
- 239000000594 mannitol Substances 0.000 description 19
- 239000003981 vehicle Substances 0.000 description 19
- 229920002472 Starch Polymers 0.000 description 18
- 239000011247 coating layer Substances 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 241000700159 Rattus Species 0.000 description 17
- 238000005469 granulation Methods 0.000 description 17
- 230000003179 granulation Effects 0.000 description 17
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 17
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 17
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 17
- 229940031703 LOW SUBSTITUTED HYDROXYPROPYL CELLULOSE Drugs 0.000 description 16
- 229960004793 Sucrose Drugs 0.000 description 16
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 16
- 235000019441 ethanol Nutrition 0.000 description 16
- 239000006191 orally-disintegrating tablet Substances 0.000 description 16
- 235000019698 starch Nutrition 0.000 description 16
- 239000005720 sucrose Substances 0.000 description 16
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 15
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-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 15
- 150000001720 carbohydrates Chemical class 0.000 description 15
- 235000015165 citric acid Nutrition 0.000 description 15
- 239000008107 starch Substances 0.000 description 15
- 238000002599 functional magnetic resonance imaging Methods 0.000 description 14
- 238000001990 intravenous administration Methods 0.000 description 14
- 230000015654 memory Effects 0.000 description 14
- 230000002438 mitochondrial Effects 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 13
- 239000007884 disintegrant Substances 0.000 description 13
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 13
- 150000002500 ions Chemical class 0.000 description 13
- 238000002595 magnetic resonance imaging Methods 0.000 description 13
- 230000002829 reduced Effects 0.000 description 13
- 230000036912 Bioavailability Effects 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 12
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 12
- 230000027455 binding Effects 0.000 description 12
- 239000011230 binding agent Substances 0.000 description 12
- 230000035514 bioavailability Effects 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 12
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 12
- 229940068196 placebo Drugs 0.000 description 12
- 239000000902 placebo Substances 0.000 description 12
- 238000011160 research Methods 0.000 description 12
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 11
- HDTRYLNUVZCQOY-LIZSDCNHSA-N Trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 230000000996 additive Effects 0.000 description 11
- 239000011248 coating agent Substances 0.000 description 11
- 239000008187 granular material Substances 0.000 description 11
- 239000000523 sample Substances 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 235000012239 silicon dioxide Nutrition 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 210000004369 Blood Anatomy 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 230000002490 cerebral Effects 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 239000000454 talc Substances 0.000 description 10
- 229910052623 talc Inorganic materials 0.000 description 10
- 235000012222 talc Nutrition 0.000 description 10
- 210000001320 Hippocampus Anatomy 0.000 description 9
- 230000036740 Metabolism Effects 0.000 description 9
- RMAQACBXLXPBSY-UHFFFAOYSA-N Silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 210000004027 cells Anatomy 0.000 description 9
- 238000000576 coating method Methods 0.000 description 9
- 230000003247 decreasing Effects 0.000 description 9
- 238000005259 measurement Methods 0.000 description 9
- 230000004060 metabolic process Effects 0.000 description 9
- 230000035786 metabolism Effects 0.000 description 9
- 101700064277 nadA Proteins 0.000 description 9
- 238000005507 spraying Methods 0.000 description 9
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 8
- 229960001031 Glucose Drugs 0.000 description 8
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 230000032683 aging Effects 0.000 description 8
- 230000003920 cognitive function Effects 0.000 description 8
- 239000008103 glucose Substances 0.000 description 8
- 230000002503 metabolic Effects 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- 210000002569 neurons Anatomy 0.000 description 8
- 230000002265 prevention Effects 0.000 description 8
- 230000000284 resting Effects 0.000 description 8
- 239000006188 syrup Substances 0.000 description 8
- 235000020357 syrup Nutrition 0.000 description 8
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 8
- 102000013918 Apolipoproteins E Human genes 0.000 description 7
- 108010025628 Apolipoproteins E Proteins 0.000 description 7
- 229960002827 Pioglitazone hydrochloride Drugs 0.000 description 7
- 230000035493 absolute bioavailability Effects 0.000 description 7
- 239000000090 biomarker Substances 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 230000000875 corresponding Effects 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 7
- 230000036541 health Effects 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 230000003340 mental Effects 0.000 description 7
- 230000004898 mitochondrial function Effects 0.000 description 7
- 239000004570 mortar (masonry) Substances 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 230000004083 survival Effects 0.000 description 7
- YJISHJVIRFPGGN-UHFFFAOYSA-N 5-[5-[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxy-6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)O)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 YJISHJVIRFPGGN-UHFFFAOYSA-N 0.000 description 6
- 229910002012 Aerosil® Inorganic materials 0.000 description 6
- 229960004543 Anhydrous Citric Acid Drugs 0.000 description 6
- 210000000349 Chromosomes Anatomy 0.000 description 6
- IQFYYKKMVGJFEH-XLPZGREQSA-N DEOXYTHYMIDINE Chemical group O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 6
- 206010012601 Diabetes mellitus Diseases 0.000 description 6
- TYQCGQRIZGCHNB-JLAZNSOCSA-N L-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 6
- 210000002966 Serum Anatomy 0.000 description 6
- 208000001072 Type 2 Diabetes Mellitus Diseases 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- 239000003086 colorant Substances 0.000 description 6
- 238000000748 compression moulding Methods 0.000 description 6
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 6
- 230000001419 dependent Effects 0.000 description 6
- 230000014509 gene expression Effects 0.000 description 6
- 238000003384 imaging method Methods 0.000 description 6
- 238000003780 insertion Methods 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- 230000013016 learning Effects 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 229960001367 tartaric acid Drugs 0.000 description 6
- 235000002906 tartaric acid Nutrition 0.000 description 6
- 239000011975 tartaric acid Substances 0.000 description 6
- 230000001225 therapeutic Effects 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 230000001755 vocal Effects 0.000 description 6
- 206010003694 Atrophy Diseases 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- JEIPFZHSYJVQDO-UHFFFAOYSA-N Iron(III) oxide Chemical compound O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 5
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 5
- BJEPYKJPYRNKOW-UHFFFAOYSA-N Malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 5
- 210000003470 Mitochondria Anatomy 0.000 description 5
- 229920000881 Modified starch Polymers 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- 235000010323 ascorbic acid Nutrition 0.000 description 5
- 229960005070 ascorbic acid Drugs 0.000 description 5
- 239000011668 ascorbic acid Substances 0.000 description 5
- 230000006399 behavior Effects 0.000 description 5
- 230000003727 cerebral blood flow Effects 0.000 description 5
- 238000009826 distribution Methods 0.000 description 5
- 239000007888 film coating Substances 0.000 description 5
- 238000009501 film coating Methods 0.000 description 5
- 239000012458 free base Substances 0.000 description 5
- 230000001771 impaired Effects 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- GUBGYTABKSRVRQ-XLOQQCSPSA-N 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 5
- 239000010410 layer Substances 0.000 description 5
- 229940099690 malic acid Drugs 0.000 description 5
- 235000011090 malic acid Nutrition 0.000 description 5
- 239000001630 malic acid Substances 0.000 description 5
- 239000003550 marker Substances 0.000 description 5
- 230000004065 mitochondrial dysfunctions Effects 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 230000000750 progressive Effects 0.000 description 5
- 239000000892 thaumatin Substances 0.000 description 5
- 235000010436 thaumatin Nutrition 0.000 description 5
- 238000010176 18-FDG-positron emission tomography Methods 0.000 description 4
- 229960005069 Calcium Drugs 0.000 description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 206010021034 Hypometabolism Diseases 0.000 description 4
- GUBGYTABKSRVRQ-YOLKTULGSA-N Maltose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)O[C@H]1CO)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 GUBGYTABKSRVRQ-YOLKTULGSA-N 0.000 description 4
- 229920001850 Nucleic acid sequence Polymers 0.000 description 4
- 229940068968 Polysorbate 80 Drugs 0.000 description 4
- 239000004373 Pullulan Substances 0.000 description 4
- 229920001218 Pullulan Polymers 0.000 description 4
- 229940083542 Sodium Drugs 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 230000001058 adult Effects 0.000 description 4
- 230000003542 behavioural Effects 0.000 description 4
- 230000017531 blood circulation Effects 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 108010002255 deoxyhemoglobin Proteins 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000002592 echocardiography Methods 0.000 description 4
- 230000003203 everyday Effects 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 235000019634 flavors Nutrition 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 238000002610 neuroimaging Methods 0.000 description 4
- 230000003557 neuropsychological Effects 0.000 description 4
- 150000007523 nucleic acids Chemical class 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- 230000001575 pathological Effects 0.000 description 4
- 230000003285 pharmacodynamic Effects 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 4
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 4
- 229920000053 polysorbate 80 Polymers 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 235000019423 pullulan Nutrition 0.000 description 4
- 230000035489 relative bioavailability Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 239000003765 sweetening agent Substances 0.000 description 4
- 229960001456 Adenosine Triphosphate Drugs 0.000 description 3
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 3
- 210000001130 Astrocytes Anatomy 0.000 description 3
- 210000001218 Blood-Brain Barrier Anatomy 0.000 description 3
- 230000037242 Cmax Effects 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- 206010061818 Disease progression Diseases 0.000 description 3
- 229920003116 HPC-SSL Polymers 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 206010022489 Insulin resistance Diseases 0.000 description 3
- VQHSOMBJVWLPSR-WUJBLJFYSA-N Maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 3
- 230000036091 Metabolic activity Effects 0.000 description 3
- 210000000214 Mouth Anatomy 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 229940113115 POLYETHYLENE GLYCOL 200 Drugs 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 102000001708 Protein Isoforms Human genes 0.000 description 3
- 108010029485 Protein Isoforms Proteins 0.000 description 3
- 102100017448 SCN8A Human genes 0.000 description 3
- 101700046029 SCN8A Proteins 0.000 description 3
- 102100014449 TANC2 Human genes 0.000 description 3
- 101700006780 TANC2 Proteins 0.000 description 3
- 229940104230 Thymidine Drugs 0.000 description 3
- 229960001295 Tocopherol Drugs 0.000 description 3
- 210000002700 Urine Anatomy 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 231100000494 adverse effect Toxicity 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 230000003110 anti-inflammatory Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003125 aqueous solvent Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 229940099112 cornstarch Drugs 0.000 description 3
- DFWFIQKMSFGDCQ-UHFFFAOYSA-N deethylatrazine Chemical compound CC(C)NC1=NC(N)=NC(Cl)=N1 DFWFIQKMSFGDCQ-UHFFFAOYSA-N 0.000 description 3
- 230000003111 delayed Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000010410 dusting Methods 0.000 description 3
- 230000004064 dysfunction Effects 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 235000012907 honey Nutrition 0.000 description 3
- 230000001976 improved Effects 0.000 description 3
- 230000000977 initiatory Effects 0.000 description 3
- 229910000460 iron oxide Inorganic materials 0.000 description 3
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 230000005291 magnetic Effects 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 230000036651 mood Effects 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 238000006213 oxygenation reaction Methods 0.000 description 3
- 230000004796 pathophysiological change Effects 0.000 description 3
- 230000000275 pharmacokinetic Effects 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000000092 prognostic biomarker Substances 0.000 description 3
- 238000010298 pulverizing process Methods 0.000 description 3
- 230000001603 reducing Effects 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 230000001839 systemic circulation Effects 0.000 description 3
- 235000010384 tocopherol Nutrition 0.000 description 3
- 239000011732 tocopherol Substances 0.000 description 3
- 229930003799 tocopherols Natural products 0.000 description 3
- 230000003936 working memory Effects 0.000 description 3
- 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 2
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 230000002407 ATP formation Effects 0.000 description 2
- 229960000583 Acetic Acid Drugs 0.000 description 2
- 206010002556 Ankylosing spondylitis Diseases 0.000 description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N Aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 2
- 229960003438 Aspartame Drugs 0.000 description 2
- 108010011485 Aspartame Proteins 0.000 description 2
- 229960002747 Betacarotene Drugs 0.000 description 2
- 229960003563 Calcium Carbonate Drugs 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L Calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L Calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- RZEKVGVHFLEQIL-UHFFFAOYSA-N Celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 2
- 229960000913 Crospovidone Drugs 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- UNXHWFMMPAWVPI-QWWZWVQMSA-N D-Threitol Natural products OC[C@@H](O)[C@H](O)CO UNXHWFMMPAWVPI-QWWZWVQMSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 244000024675 Eruca sativa Species 0.000 description 2
- 235000014755 Eruca sativa Nutrition 0.000 description 2
- 239000004386 Erythritol Substances 0.000 description 2
- 229940009714 Erythritol Drugs 0.000 description 2
- UNXHWFMMPAWVPI-ZXZARUISSA-N Erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- BJHIKXHVCXFQLS-UYFOZJQFSA-N Fructose Natural products OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 102000003746 Insulin Receptor Human genes 0.000 description 2
- 108010001127 Insulin Receptor Proteins 0.000 description 2
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 2
- 210000000265 Leukocytes Anatomy 0.000 description 2
- 210000004185 Liver Anatomy 0.000 description 2
- OAIJSZIZWZSQBC-LWRKPGOESA-N Lycopene Natural products CC(C)=CCC\C(C)=C/C=C/C(/C)=C\C=C\C(\C)=C/C=C/C=C(/C)\C=C\C=C(\C)/C=C/C=C(/C)CCC=C(C)C OAIJSZIZWZSQBC-LWRKPGOESA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 206010027175 Memory impairment Diseases 0.000 description 2
- 108020004999 Messenger RNA Proteins 0.000 description 2
- 210000003205 Muscles Anatomy 0.000 description 2
- CMWTZPSULFXXJA-VIFPVBQESA-N Naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 2
- 210000002682 Neurofibrillary Tangles Anatomy 0.000 description 2
- 108010064719 Oxyhemoglobins Proteins 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 229940088417 PRECIPITATED CALCIUM CARBONATE Drugs 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N Perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 229920001451 Polypropylene glycol Polymers 0.000 description 2
- 210000002442 Prefrontal Cortex Anatomy 0.000 description 2
- 229940100486 RICE STARCH Drugs 0.000 description 2
- 210000002356 Skeleton Anatomy 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 229960005137 Succinic Acid Drugs 0.000 description 2
- OGIDPMRJRNCKJF-UHFFFAOYSA-N TiO Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 2
- 229940035295 Ting Drugs 0.000 description 2
- MWOOGOJBHIARFG-UHFFFAOYSA-N Vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 2
- 229940100445 WHEAT STARCH Drugs 0.000 description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N Xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- 229960002675 Xylitol Drugs 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating Effects 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 230000003078 antioxidant Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000002216 antistatic agent Substances 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000000605 aspartame Substances 0.000 description 2
- 235000010357 aspartame Nutrition 0.000 description 2
- OENHQHLEOONYIE-VYAWBVGESA-N beta-Carotene Natural products CC=1CCCC(C)(C)C=1\C=C\C(\C)=C/C=C/C(/C)=C\C=C\C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-VYAWBVGESA-N 0.000 description 2
- 235000013734 beta-carotene Nutrition 0.000 description 2
- 239000011648 beta-carotene Substances 0.000 description 2
- 230000037185 brain physiology Effects 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 230000004094 calcium homeostasis Effects 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 229960000590 celecoxib Drugs 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000001684 chronic Effects 0.000 description 2
- 238000003759 clinical diagnosis Methods 0.000 description 2
- 230000003930 cognitive ability Effects 0.000 description 2
- 230000003931 cognitive performance Effects 0.000 description 2
- 230000001010 compromised Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000001054 cortical Effects 0.000 description 2
- 230000003412 degenerative Effects 0.000 description 2
- 230000001809 detectable Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000003292 diminished Effects 0.000 description 2
- TXVRKNUZLYFDTJ-DDVLFWKVSA-L disodium;(5E)-6-oxo-5-[(4-sulfonatophenyl)hydrazinylidene]naphthalene-2-sulfonate Chemical compound [Na+].[Na+].C1=CC(S(=O)(=O)[O-])=CC=C1N\N=C\1C2=CC=C(S([O-])(=O)=O)C=C2C=CC/1=O TXVRKNUZLYFDTJ-DDVLFWKVSA-L 0.000 description 2
- 229940043264 dodecyl sulfate Drugs 0.000 description 2
- 230000002708 enhancing Effects 0.000 description 2
- 235000019414 erythritol Nutrition 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 230000000763 evoked Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000004153 glucose metabolism Effects 0.000 description 2
- 210000004884 grey matter Anatomy 0.000 description 2
- 230000000004 hemodynamic Effects 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 2
- 229960003943 hypromellose Drugs 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000009114 investigational therapy Methods 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 229960002725 isoflurane Drugs 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 230000000670 limiting Effects 0.000 description 2
- 229960003511 macrogol Drugs 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 229940098895 maleic acid Drugs 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 235000010449 maltitol Nutrition 0.000 description 2
- 239000000845 maltitol Substances 0.000 description 2
- 229940035436 maltitol Drugs 0.000 description 2
- 150000002692 maltoses Chemical class 0.000 description 2
- 229920002106 messenger RNA Polymers 0.000 description 2
- 230000037323 metabolic rate Effects 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 230000000051 modifying Effects 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 229960002009 naproxen Drugs 0.000 description 2
- 230000000926 neurological Effects 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 230000003000 nontoxic Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 229920001888 polyacrylic acid Polymers 0.000 description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 239000000583 progesterone congener Substances 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 102000034577 retinoid X receptors Human genes 0.000 description 2
- 108010038912 retinoid X receptors Proteins 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 2
- STFSJTPVIIDAQX-LTRPLHCISA-M sodium;(E)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O STFSJTPVIIDAQX-LTRPLHCISA-M 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 230000002739 subcortical Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- 235000011044 succinic acid Nutrition 0.000 description 2
- 238000009495 sugar coating Methods 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000002459 sustained Effects 0.000 description 2
- 230000000946 synaptic Effects 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 230000002123 temporal effect Effects 0.000 description 2
- 210000001519 tissues Anatomy 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 229910001929 titanium oxide Inorganic materials 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 102000003995 transcription factors Human genes 0.000 description 2
- 108090000464 transcription factors Proteins 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 210000004885 white matter Anatomy 0.000 description 2
- 230000005186 women's health Effects 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
- 235000010447 xylitol Nutrition 0.000 description 2
- 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 2
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- WSVLPVUVIUVCRA-RJMJUYIDSA-N (2R,3R,4S,5R,6S)-2-(hydroxymethyl)-6-[(2R,3S,4R,5R)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol;hydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-RJMJUYIDSA-N 0.000 description 1
- OSNSWKAZFASRNG-BMZZJELJSA-N (3R,4S,5S,6R)-6-(hydroxymethyl)oxane-2,3,4,5-tetrol;hydrate Chemical class O.OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O OSNSWKAZFASRNG-BMZZJELJSA-N 0.000 description 1
- 229920000160 (ribonucleotides)n+m Polymers 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N 2-methyl-2-propenoic acid methyl ester Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-M 3-cyclopentylpropanoate Chemical compound [O-]C(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-M 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- CWSZBVAUYPTXTG-UHFFFAOYSA-N 5-[6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxy-5-[4-hydroxy-3-(2-hydroxyethoxy)-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)OCCO)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 CWSZBVAUYPTXTG-UHFFFAOYSA-N 0.000 description 1
- PVXPPJIGRGXGCY-IPFGBZKGSA-N 6-O-α-D-glucopyranosyl-β-D-fructofuranose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@](O)(CO)O1 PVXPPJIGRGXGCY-IPFGBZKGSA-N 0.000 description 1
- ILYBMUDLGFMEMU-UHFFFAOYSA-N 7-$l^{1}-oxidanyl-2,3,4,5,6,7-hexaoxoheptan-1-olate Chemical compound [O]C(=O)C(=O)C(=O)C(=O)C(=O)C(=O)C[O-] ILYBMUDLGFMEMU-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229960004998 Acesulfame potassium Drugs 0.000 description 1
- WBZFUFAFFUEMEI-UHFFFAOYSA-N Acesulfame potassium Chemical compound [K+].CC1=CC(=O)NS(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-N 0.000 description 1
- 210000000577 Adipose Tissue Anatomy 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 1
- 229920001276 Ammonium polyphosphate Polymers 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010002855 Anxiety Diseases 0.000 description 1
- 206010057666 Anxiety disease Diseases 0.000 description 1
- 206010002942 Apathy Diseases 0.000 description 1
- 206010059512 Apoptosis Diseases 0.000 description 1
- 229940072107 Ascorbate Drugs 0.000 description 1
- 229940009098 Aspartate Drugs 0.000 description 1
- 229960005261 Aspartic Acid Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N Benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940050390 Benzoate Drugs 0.000 description 1
- 230000036868 Blood Concentration Effects 0.000 description 1
- 210000001772 Blood Platelets Anatomy 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000001183 Brain Injury Diseases 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N Butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L Calcium hydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- JHLNERQLKQQLRZ-UHFFFAOYSA-N Calcium silicate Chemical compound [Ca+2].[Ca+2].[O-][Si]([O-])([O-])[O-] JHLNERQLKQQLRZ-UHFFFAOYSA-N 0.000 description 1
- 108010018336 Calcium-50 Proteins 0.000 description 1
- DSSYKIVIOFKYAU-UHFFFAOYSA-N Camphor Chemical compound C1CC2(C)C(=O)CC1C2(C)C DSSYKIVIOFKYAU-UHFFFAOYSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000218236 Cannabis Species 0.000 description 1
- 229950008138 Carmellose Drugs 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 210000001638 Cerebellum Anatomy 0.000 description 1
- 210000003467 Cheek Anatomy 0.000 description 1
- 229920002676 Complementary DNA Polymers 0.000 description 1
- 229960001681 Croscarmellose Sodium Drugs 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 229940097362 Cyclodextrins Drugs 0.000 description 1
- 229960003067 Cystine Drugs 0.000 description 1
- 108010075031 Cytochromes c Proteins 0.000 description 1
- 210000000805 Cytoplasm Anatomy 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-α-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N DL-aspartic acid Chemical compound OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N DL-leucine Chemical compound CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 238000001712 DNA sequencing Methods 0.000 description 1
- 206010012218 Delirium Diseases 0.000 description 1
- 206010012271 Dementia Alzheimer's type Diseases 0.000 description 1
- 206010012374 Depressed mood Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 230000036947 Dissociation constant Effects 0.000 description 1
- 206010014599 Encephalitis Diseases 0.000 description 1
- 210000001353 Entorhinal Cortex Anatomy 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 229920003148 Eudragit® E polymer Polymers 0.000 description 1
- 229920003136 Eudragit® L polymer Polymers 0.000 description 1
- 229920003153 Eudragit® NE polymer Polymers 0.000 description 1
- 229920003152 Eudragit® RS polymer Polymers 0.000 description 1
- 229920003137 Eudragit® S polymer Polymers 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 229920000665 Exon Polymers 0.000 description 1
- 210000003608 Feces Anatomy 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 210000002683 Foot Anatomy 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 229960002989 Glutamic Acid Drugs 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N Glycerol 3-phosphate Chemical compound OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- QGWNDRXFNXRZMB-UUOKFMHZSA-N Guanosine diphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O QGWNDRXFNXRZMB-UUOKFMHZSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229940093915 Gynecological Organic acids Drugs 0.000 description 1
- 210000004209 Hair Anatomy 0.000 description 1
- 210000003128 Head Anatomy 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- 241000257303 Hymenoptera Species 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010020993 Hypoglycaemia Diseases 0.000 description 1
- 210000003016 Hypothalamus Anatomy 0.000 description 1
- 102100002729 IRS1 Human genes 0.000 description 1
- 101700048020 IRS1 Proteins 0.000 description 1
- 229920002459 Intron Polymers 0.000 description 1
- 108020004391 Introns Proteins 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine zwitterion Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 101700015817 LAT2 Proteins 0.000 description 1
- 229960004873 LEVOMENTHOL Drugs 0.000 description 1
- 229940001447 Lactate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N Lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- JCQLYHFGKNRPGE-FCVZTGTOSA-N Lactulose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 JCQLYHFGKNRPGE-FCVZTGTOSA-N 0.000 description 1
- 235000019501 Lemon oil Nutrition 0.000 description 1
- 229940037627 MAGNESIUM LAURYL SULFATE Drugs 0.000 description 1
- 101710032250 MICAL1 Proteins 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L Magnesium hydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 235000019596 Masking bitterness Nutrition 0.000 description 1
- 229940041616 Menthol Drugs 0.000 description 1
- 229940117841 Methacrylic Acid Copolymer Drugs 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920002393 Microsatellite Polymers 0.000 description 1
- 210000003097 Mucus Anatomy 0.000 description 1
- 101710032102 NFE2L1 Proteins 0.000 description 1
- 102100002277 NRF1 Human genes 0.000 description 1
- 101700072279 NRF1 Proteins 0.000 description 1
- 208000009668 Neurobehavioral Manifestations Diseases 0.000 description 1
- 206010053643 Neurodegenerative disease Diseases 0.000 description 1
- 108091005503 Nucleic proteins Proteins 0.000 description 1
- 229940116315 Oxalic Acid Drugs 0.000 description 1
- 108009000578 Oxidative Stress Proteins 0.000 description 1
- 108010016731 PPAR gamma Proteins 0.000 description 1
- 102100000077 PPARG Human genes 0.000 description 1
- 102100008812 PSEN1 Human genes 0.000 description 1
- 101710033350 PSEN1 Proteins 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N Pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 206010061536 Parkinson's disease Diseases 0.000 description 1
- 208000003715 Parkinsonian Disorders Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 229920004694 Pedigree® Polymers 0.000 description 1
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 1
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 1
- 206010034719 Personality change Diseases 0.000 description 1
- KJFMBFZCATUALV-UHFFFAOYSA-N Phenolphthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2C(=O)O1 KJFMBFZCATUALV-UHFFFAOYSA-N 0.000 description 1
- 229950010765 Pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N Pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 210000002381 Plasma Anatomy 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 229940069328 Povidone Drugs 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 206010061920 Psychotic disease Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 229960002477 Riboflavin Drugs 0.000 description 1
- AUNGANRZJHBGPY-OUCADQQQSA-N Riboflavin Natural products OC[C@@H](O)[C@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-OUCADQQQSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 241000109329 Rosa xanthina Species 0.000 description 1
- 235000004789 Rosa xanthina Nutrition 0.000 description 1
- 229960005055 SODIUM ASCORBATE Drugs 0.000 description 1
- 229910002038 SYLYSIA SY320 Inorganic materials 0.000 description 1
- 229940085605 Saccharin Sodium Drugs 0.000 description 1
- WINXNKPZLFISPD-UHFFFAOYSA-M Saccharin sodium Chemical compound [Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-M 0.000 description 1
- 210000003296 Saliva Anatomy 0.000 description 1
- 210000000582 Semen Anatomy 0.000 description 1
- 230000037165 Serum Concentration Effects 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 210000003491 Skin Anatomy 0.000 description 1
- 229940091252 Sodium supplements Drugs 0.000 description 1
- 210000003802 Sputum Anatomy 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L Sulphite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 210000001138 Tears Anatomy 0.000 description 1
- 210000001103 Thalamus Anatomy 0.000 description 1
- 230000035852 Tmax Effects 0.000 description 1
- 229940042585 Tocopherol Acetate Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium 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
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- 102100014673 UCP2 Human genes 0.000 description 1
- 101710009617 USP14 Proteins 0.000 description 1
- 108020003635 Untranslated Regions Proteins 0.000 description 1
- 229920000146 Untranslated region Polymers 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- RHKRCMGVQNYYCS-DAYGRLMNSA-N [(2R,3S,4S)-1-(7,8-dimethyl-2,4-dioxobenzo[g]pteridin-10-yl)-3,4,5-trihydroxypentan-2-yl] butanoate Chemical compound CCCC(=O)O[C@@H]([C@@H](O)[C@@H](O)CO)CN1C2=CC(C)=C(C)C=C2N=C2C1=NC(=O)NC2=O RHKRCMGVQNYYCS-DAYGRLMNSA-N 0.000 description 1
- ASCUXPQGEXGEMJ-GPLGTHOPSA-N [(2R,3S,4S,5R,6S)-3,4,5-triacetyloxy-6-[[(2R,3R,4S,5R,6R)-3,4,5-triacetyloxy-6-(4-methylanilino)oxan-2-yl]methoxy]oxan-2-yl]methyl acetate Chemical group CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](COC(=O)C)O[C@@H]1OC[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](NC=2C=CC(C)=CC=2)O1 ASCUXPQGEXGEMJ-GPLGTHOPSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 235000010358 acesulfame potassium Nutrition 0.000 description 1
- 239000000619 acesulfame-K Substances 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute Effects 0.000 description 1
- 231100000569 acute exposure Toxicity 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000172 allergic Effects 0.000 description 1
- 229960001452 alpha-Tocopherol Acetate Drugs 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 102000004965 antibodies Human genes 0.000 description 1
- 108090001123 antibodies Proteins 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000038129 antigens Human genes 0.000 description 1
- 108091007172 antigens Proteins 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 125000005228 aryl sulfonate group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000004429 atoms Chemical group 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 230000008335 axon cargo transport Effects 0.000 description 1
- 230000003376 axonal Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000037348 biosynthesis Effects 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 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
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-M camphorsulfonate anion Chemical compound C1CC2(CS([O-])(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-M 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M caproate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 125000004432 carbon atoms Chemical group C* 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 230000024881 catalytic activity Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000001413 cellular Effects 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 229960002303 citric acid monohydrate Drugs 0.000 description 1
- 230000003081 coactivator Effects 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000036992 cognitive tasks Effects 0.000 description 1
- 201000008790 communication disease Diseases 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000004567 concrete Substances 0.000 description 1
- 230000002596 correlated Effects 0.000 description 1
- 230000001808 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000000115 debilitative Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003001 depressive Effects 0.000 description 1
- 230000001627 detrimental Effects 0.000 description 1
- JAUGGEIKQIHSMF-UHFFFAOYSA-N dialuminum;dimagnesium;dioxido(oxo)silane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O JAUGGEIKQIHSMF-UHFFFAOYSA-N 0.000 description 1
- 230000005292 diamagnetic Effects 0.000 description 1
- CRVGKGJPQYZRPT-UHFFFAOYSA-N diethylamino acetate Chemical compound CCN(CC)OC(C)=O CRVGKGJPQYZRPT-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- KHLVKKOJDHCJMG-QDBORUFSSA-L disodium;(2E)-3-oxo-2-(3-oxo-5-sulfonato-1H-indol-2-ylidene)-1H-indole-5-sulfonate Chemical compound [Na+].[Na+].N/1C2=CC=C(S([O-])(=O)=O)C=C2C(=O)C\1=C1/NC2=CC=C(S(=O)(=O)[O-])C=C2C1=O KHLVKKOJDHCJMG-QDBORUFSSA-L 0.000 description 1
- TXVRKNUZLYFDTJ-KZYDBBBVSA-L disodium;(5Z)-6-oxo-5-[(4-sulfonatophenyl)hydrazinylidene]naphthalene-2-sulfonate Chemical compound [Na+].[Na+].C1=CC(S(=O)(=O)[O-])=CC=C1N\N=C/1C2=CC=C(S([O-])(=O)=O)C=C2C=CC\1=O TXVRKNUZLYFDTJ-KZYDBBBVSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-M dodecyl sulfate Chemical compound CCCCCCCCCCCCOS([O-])(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-M 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000002359 drug metabolite Substances 0.000 description 1
- 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 1
- 238000007823 electrophoretic assay Methods 0.000 description 1
- 230000002996 emotional Effects 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000001667 episodic Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- FSXVSUSRJXIJHB-UHFFFAOYSA-M ethyl prop-2-enoate;methyl 2-methylprop-2-enoate;trimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]azanium;chloride Chemical compound [Cl-].CCOC(=O)C=C.COC(=O)C(C)=C.CC(=C)C(=O)OCC[N+](C)(C)C FSXVSUSRJXIJHB-UHFFFAOYSA-M 0.000 description 1
- 230000002964 excitative Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 230000004634 feeding behavior Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- FVTCRASFADXXNN-SCRDCRAPSA-N flavin mononucleotide Chemical compound OP(=O)(O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O FVTCRASFADXXNN-SCRDCRAPSA-N 0.000 description 1
- 235000002864 food coloring agent Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000003045 fructo oligosaccharides Chemical class 0.000 description 1
- 229940107187 fructooligosaccharide Drugs 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000004676 glycans Polymers 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000009499 grossing Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 230000003451 hyperinsulinaemic Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 230000002218 hypoglycaemic Effects 0.000 description 1
- 210000003702 immature single positive T cell Anatomy 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 230000002757 inflammatory Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 230000003834 intracellular Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-M isethionate Chemical compound OCCS([O-])(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-M 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M isothiocyanate Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- 150000002597 lactoses Chemical class 0.000 description 1
- 229960000511 lactulose Drugs 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M laurate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000010501 lemon oil Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 238000001325 log-rank test Methods 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 229960004999 lycopene Drugs 0.000 description 1
- 235000012661 lycopene Nutrition 0.000 description 1
- 239000001751 lycopene Substances 0.000 description 1
- 230000001926 lymphatic Effects 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- VPBIQXABTCDMAU-UHFFFAOYSA-N magnesium;oxido(oxo)alumane Chemical compound [Mg+2].[O-][Al]=O.[O-][Al]=O VPBIQXABTCDMAU-UHFFFAOYSA-N 0.000 description 1
- 230000005389 magnetism Effects 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 1
- 230000000873 masking Effects 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000021121 meiosis Effects 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M methanoate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- IQSHMXAZFHORGY-UHFFFAOYSA-N methyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound COC(=O)C=C.CC(=C)C(O)=O IQSHMXAZFHORGY-UHFFFAOYSA-N 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 230000026326 mitochondrial transport Effects 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 230000004766 neurogenesis Effects 0.000 description 1
- 210000004255 neuroglia Anatomy 0.000 description 1
- 238000010855 neuropsychological testing Methods 0.000 description 1
- 230000003957 neurotransmitter release Effects 0.000 description 1
- 230000019818 neurotransmitter uptake Effects 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drugs Drugs 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 239000011022 opal Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 210000000056 organs Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 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
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000036284 oxygen consumption Effects 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M palmitate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 230000005298 paramagnetic Effects 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000035778 pathophysiological process Effects 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 230000002974 pharmacogenomic Effects 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 238000007781 pre-processing Methods 0.000 description 1
- 238000009597 pregnancy test Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000000861 pro-apoptotic Effects 0.000 description 1
- 230000002250 progressing Effects 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L propanedioate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
- 239000003368 psychostimulant agent Substances 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000003638 reducing agent Substances 0.000 description 1
- 230000029964 regulation of glucose metabolic process Effects 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000000717 retained Effects 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 229950001574 riboflavin phosphate Drugs 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 238000007480 sanger sequencing Methods 0.000 description 1
- 230000001624 sedative Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N silicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 238000000264 spin echo pulse sequence Methods 0.000 description 1
- 230000002269 spontaneous Effects 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000010965 sucrose esters of fatty acids Nutrition 0.000 description 1
- 239000001959 sucrose esters of fatty acids Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000003319 supportive Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000000472 traumatic Effects 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- VOBHRQFELWTZFS-AWLRYRRCSA-K trisodium;(4Z)-3-oxo-4-[(4-sulfonatonaphthalen-1-yl)hydrazinylidene]naphthalene-2,7-disulfonate Chemical compound [Na+].[Na+].[Na+].C1=CC=C2C(N/N=C3/C4=CC=C(C=C4C=C(C3=O)S(=O)(=O)[O-])S([O-])(=O)=O)=CC=C(S([O-])(=O)=O)C2=C1 VOBHRQFELWTZFS-AWLRYRRCSA-K 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-M undecanoate Chemical compound CCCCCCCCCCC([O-])=O ZDPHROOEEOARMN-UHFFFAOYSA-M 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical class CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 229940117960 vanillin Drugs 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61P25/28—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/118—Prognosis of disease development
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/172—Haplotypes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
- Y10T436/142222—Hetero-O [e.g., ascorbic acid, etc.]
- Y10T436/143333—Saccharide [e.g., DNA, etc.]
Abstract
Disclosed is the use of from 0.5 to 9 milligrams of pioglitazone in the manufacture of a pharmaceutical formulation for treating cognitive decline in a subject in need thereof. Also disclosed is the use of from 0.5 to 9 milligrams of pioglitazone in the manufacture of a pharmaceutical formulation for treating cognitive impairment of the Alzheimer's type in a subject. Further disclosed are methods of determining increased risk of developing cognitive impairment of the Alzheimer's type that can be treated with from 0.5 to 9 mg pioglitazone in a human subject at a predetermined age or age range, comprising: detecting from a biological sample of the subject the rs10524523 genotype of the subject, wherein each allele of the rs10524523 genotype is assigned as: (a) short (S, less than 19 T residues); (b) long (L, 19-29 residues); or (c) very long (VL, 30 or more residues); and determining from the rs10524523 genotype whether the subject is at increased risk in developing cognitive impairment of the Alzheimer's type at the predetermined age or age range, wherein: (1) age greater than about 62 and L,L or L,VL indicates increased risk; (2) age greater than about 62 and VL,VL does not indicate increased risk; (3) age greater than about 74 and S,L indicates increased risk; (4) age greater than about 77 and S,S indicates increased risk; and (5) age greater than about 76 and S,VL indicates increased risk. for treating cognitive impairment of the Alzheimer's type in a subject. Further disclosed are methods of determining increased risk of developing cognitive impairment of the Alzheimer's type that can be treated with from 0.5 to 9 mg pioglitazone in a human subject at a predetermined age or age range, comprising: detecting from a biological sample of the subject the rs10524523 genotype of the subject, wherein each allele of the rs10524523 genotype is assigned as: (a) short (S, less than 19 T residues); (b) long (L, 19-29 residues); or (c) very long (VL, 30 or more residues); and determining from the rs10524523 genotype whether the subject is at increased risk in developing cognitive impairment of the Alzheimer's type at the predetermined age or age range, wherein: (1) age greater than about 62 and L,L or L,VL indicates increased risk; (2) age greater than about 62 and VL,VL does not indicate increased risk; (3) age greater than about 74 and S,L indicates increased risk; (4) age greater than about 77 and S,S indicates increased risk; and (5) age greater than about 76 and S,VL indicates increased risk.
Description
/020606
Methods and Drug Products for Treating Alzheimer's Disease
Allen D. Roses and Rajneesh Taneja
Related Applications
This application claims the benefit under 35 U.S.C. § 119(e) of US.
Provisional Patent Application No. 61/431,370, filed January 10, 2011.
Field of the Invention
The t invention relates to a method and drug product for treating a
subject who is at risk to develop Alzheimer’s disease.
Background
Alzheimer’s e is a neurodegenerative disease and the most common
cause of dementia. This disease manifests as a gradual but progressive decline in
, thinking skills and behavior that is accelerated ve to normal aging
(Reitz et al. 2011 Nat Rev Neurol 7: 137-152). Eventually, patients are unable to
recognize familiar people or carry out the simplest task. Alzheimer’s disease is, at
this time, the sixth g cause of death in the United States (US).
There are two predominant forms of the disease: Familial Alzheimer's disease
is typically caused by dominant mutations in one of three genes (APP, PSEN1 or
IPSEN2). This form of the disease is a rare and devastating illness with onset
occurring in mid-life. The second and far more common form of the disease is
Sporadic or Late onset mer's disease (hereinafter "Alzheimer’s disease” or
"AD"). Onset of Alzheimer’s disease lly occurs after the age of 62 years.
As the world population and human ity increase, so do the numbers of
people affected by Alzheimer’s disease globally. The estimated worldwide costs of
dementia, of which Alzheimer’s disease accounts for up to 80% of cases, was
US$604 billion in 2010, which was greater than 1% of US GDP (Wimo and Prince
2010 World Alzheimer Report 2010: The Global Economic Impact of Dementia 1-93).
The cost of caring for Alzheimer patients in the US is expected to increase from
US$172 n in12010, to US$1.07 trillion in 2050 (Alzheimer's Association.
"Changing the tory of Alzheimer's Disease: A National Imperative (2010)").
At this time, the few drugs that are ed for treatment of this disease
provide some symptomatic relief, but this is typically of relatively short on, and
the therapies do not alter the course of disease progression (Alzheimer's
Association. "Changing the Trajectory 0f Alzheimer's Disease: A National Imperative
(2010)"). Therapies that delay the onset of the e, reduce the rate of disease
progression, or that can do both are urgently needed. Therapies that can achieve
either of these goals will reduce the number of individuals with disease, or reduce
the number of individuals with the more advanced and debilitating stages of disease
(Brookmeyer et al. 2007 Alzheimers Dement 3: 186-191). It is projected that if the
onset of Alzheimer's disease is delayed by 5 years due to availability of a
breakthrough therapy in 2015, 43% of the 13.5 million Americans ed to have
the condition in 2050 would not have the e, and there will be fewer people with
advanced e.
The principal risk factor for Alzheimer’s disease is age, and prevalence of the
disease increases with age (approximately 10% of individuals over 65 and
approximately 50% of individuals over 85). The incidence of the disease doubles
every 5 years after 65 years of age, with the diagnosis of about 1275 new cases per
year per 100,000 persons older than 65 years of age urth et al., 2010 NEJM
362:4). Both men and women are affected by Alzheimer's e, but women
generally represent a higher percentage of cases overall (roughly 60% to 40%),
possibly due to greater longevity. People suffering from Alzheimer's disease tend to
live approximately 3 to 9 years after diagnosis, on average.
The epsilon 4 allele of APOE has previously been associated with
increased risk of developing Alzheimer's disease. (Pericak-Vance et al. 1991 Am J
Hum Genet 48: 1034-1050; Martin et al. 2000 Am J Hum Genet 67: 383-394; US
Patent Nos. 6,027,896 and 5,716,828 to Roses et al.) The relationship is copy
number dependent zawa et al. 1994 Ann Neurol 36: 656-659). That is to
say, a carrier of two APOE4 alleles is more likely to develop late-onset Alzheimer's
disease (LOAD) than a carrier of only one APOE4 allele, and at an earlier age
(Corder et al. 1993 Science 261, 921-3).
Nevertheless, APOE4 alleles only account for roughly 50% of the inherited
risk of late onset Alzheimer’s disease. One explanation is that APOE4 is merely
serving as a ate marker for something in linkage disequilibrium nearby.
Alternatively, considering the recent discovery of a mechanistic role for APOE4 in
mitochondrial ty, the negative effects of APOE4 may be abrogated or
bated by another gene product that may be encoded nearby (Chang et al.
2005 Proc Natl Acad Sci U S A 102: 18694-18699).
The symptomsof Alzheimer’s disease are primarily marked by cognitive
deficits including memory impairment, language dysfunction, and visuospatial skills;
functional impairment that may span occupational and social issues (9.9., activities
of daily living); and behavioral ms including depression, y, aggression
and psychosis may also appear as the disease progresses in severity.
At this time, unambiguous sis of Alzheimer's disease requires clinical
gs of cognitive deficits consistent with AD and post-mortem identification of
brain pathologies consistent with AD. The term AD dementia is used to describe
dementia that is due to the pathophysiologies of Alzheimer’s disease. The term
"probable Alzheimer’s disease" is used in life when a subject demonstrates clinical
characteristics of Alzheimer’s e and when other possible biological causes of
ia (e.g. Parkinson’s disease or stroke) are excluded.
There are currently a variety of cepted methods fOr diagnosing probable
Alzheimer’s disease. Typically, these methods are used in combination. These
methods include determining an individual's ability to carry out daily activities and
identifying changes in behavior and personality. Dementia of the AD type is also
typically characterized by an ic presentation (memory deficit) or language,
Visuospatial or executive on deficits. Cognitive ability/impairment may be
determined by art-accepted methods, including, but not limited to, validated
instruments that assess global cognition (e.g., the Modified Mini Mental State
Examination (3MS-E)), and specific domains such as visual and verbal memory
(e.g.,the Brief Visuospatial Memory Test (Revised) R) and the Hopkins
Verbal Learning Test (Revised) (HVLT-R), respectively), language (e.g., the
Generative Verbal Fluency Test (GVFT)) and exchtive function and attention (e.g.,
the Digit Span Test (DST)). Dementia due to AD is also defined by insidious onset
and a history of worsening cognitive performance.
The ia for ‘probable Alzheimer’s disease’ were recently updated by a
National Institute of Aging-Alzheimer’s Association oup nn et al. 2011
Alzheimers Dement 7: 263-269). This workgroup recommended that, for people who
first exhibit the core al teristics of Alzheimer’s disease dementia,
evidence of biomarkers associated with the disease may enhance the certainty of
the diagnosis.
In view of the fact that more than 4.5 million people in the United States
alone suffer from Alzheimer’s disease (and this number will continue to grow as the
population ages), the cruel and unforgiving degenerative and debilitative nature of
Alzheimer’s disease as it develops, and the high costs associated with the care for
people suffering from Alzheimer’s disease, there is a real and ate need for
an effective medical therapy that can delay the onset of Alzheimer’s disease.
Brief Summary of the Invention
Provided herein are itions including low dose tazone, which
compositions are useful in ng mild cognitive impairment (e.g., cognitive
impairment of the Alzheimer's type). In some embodiments, treating includes
delaying the onset of mild cognitive impairment. In some embodiments, treating
includes delaying the onset of mild cognitive ment in a cognitively normal
subject. In some embodiments, the delaying includes delaying the onset of
ment in episodic memory.
In some ments, treating includes delaying the onset of mild cognitive
impairment in a human subject at increased risk of developing cognitive impairment
within the next 5-7 years, said risk based upon the subject's age, or based upon the
subject's age and TOMM40 rs10524523 genotype.
In some embodiments, low dose pioglitazone is administered in unit dosage
form, e.g., having from 0.5, 1, 1.5 or 2, to 6, 8, 10 or 12 rams of pioglitazone or
a pharmaceutically acceptable salt thereof.
Also provided is the use of low dose pioglitazone in the cture of a
pharmaceutical formulation for the treatment of mild cognitive impairment (e.g.,
cognitive impairment of the Alzheimer's type). In some embodiments, the
pharmaceutical formulation is a tablet. In some embodiments, the pharmaceutical
formulation is a capsule. In some embodiments, the pharmaceutical formulation is a
caplet. In some embodiments, the pharmaceutical formulation is a liquid. In some
embodiments, the pharmaceutical formulation is a solid or olid.
Also provided is a composition including low dose pioglitazone for use in the
treatment of ive decline.
Further provided are methods for treating mild cognitive impairment (e.g.,
cognitive impairment of the Alzheimer's type) in a human subject in need thereof,
sing stering to the subject low dose pioglitazone. In some
embodiments, the treating includes delaying the onset of mild ive impairment.
In some embodiments, treating es delaying the onset of mild cognitive
impairment in a cognitively normal subject. In some embodiments, the delaying
includes delaying the onset of impairment in episodic memory.
In some ments, the subject is at increased risk in developing cognitive
impairment of the Alzheimer's type within the next 5-7 years, said risk based upon
the subject's age, or based upon the subject's age and rs10524523 ('523) pe.
In some embodiments, the t is at least 50, 55, 60, 62, 68,'or 70 years
old.
In some embodiments, the subject is a Caucasian subject. In some
embodiments, the subject is a non-Caucasian subject.
In some embodiments, the subject does not have one or two APOE2 alleles.
In some embodiments, low dose pioglitazone is administered in unit dosage
form, e.g., having from 0.5, 1, 1.5 or 2, to 6, 8, 10 or 12 milligrams of tazone. In
some embodiments, the administering is once daily.
In some ments, pioglitazone is provided as or stered at a
dosage that es an AUC of from about 0.15 pg-h/mL to about 3.6 pg-h/mL. In
some embodiments, pioglitazone is provided as or administered at a dosage that
provides an AUC of from 0.12 pg-h/mL to 4.5 pg-h/mL. In some embodiments,
pioglitazone is provided as or administered at a dosage that provides an AUC of
from 0.12 pg-h/mL to 3.4 pg°h/mL.
Also provided are methods of treating cognitive decline in a human subject in
need thereof, including administering to said subject low dose pioglitazone.
Still further provided are methods of determining increased risk in developing
cognitive impairment of the Alzheimer's type in a human subject at a predetermined
age or age range, including:
detecting from a biological sample of said subject the '523 genotype of said
t, wherein each allele of '523 is assigned as:
(a) short (8, less than 19 T residues);
(b) long (L, 19-29 residues); or
(c) very long (VL, 30 or more residues); and
determining from said '523 pe whether said t is at increased risk
in developing cognitive impairment of the Alzheimer's type at said predetermined age
or age range, wherein:
(1) age r than about 62 and L,L or L,VL indicates increased risk;
(2) age greater than about 62 and VL,VL does not indicate increased risk;
(3) age greater than about 74 and S,L indicates sed risk;
(4) age greater than about 77 and 8,8 tes increased risk; and
(5) age greater than about 76 and S,VL indicates increased risk.
in some embodiments, the determining further includes detecting from a
biological Sample of said subject the APOE genotype of said subject, wherein the
presence of an APOE2 allele in said genotype indicates the subject is not at
increased risk.
Also ed are methods of determining whether to administer low dose
tazone to a human subject for treatment of cognitive impairment of the
Alzheimer's type, including:
detecting from a biological sample of said subject the '523 pe of the
subject, wherein each allele is assigned as:
(a) short (8, less than 19 T residues);
(b) long (L, 19-29 residues); or
(c) very long (VL, 30 or more residues); and
determining from said '523 genotype and from the age of said human subject
whether to administer low dose pioglitazone to said subject for treatment of cognitive
impairment of the Alzheimer's type, wherein:
(1) age greater than about 62 and L,L or L,VL indicates treatment;
(2) age greater than about 62 and VL,VL does not indicate treatment;
(3) age greater than about 74 and S,L indicates treatment;
(4) age greater than about 77 and 8,8 tes treatment; and
(5) age greater than about 76 and S,VL indicates treatment.
In some embodiments, the determining further includes detecting from a
biological sample of said subject the APOE genotype of said subject, wherein the
presence of an APOE2 allele in said genotype does not indicate treatment.
In some embodiments of any of the above methods or compositions, the
subject has normal cognition.
Still further provided are methods of delaying the onset of Alzheimer’s
disease, wherein the method comprises (a) detecting a variant to the TOMM40 gene
in a subject who is at-risk to develop mer’s disease, and (b) stering a
drug product that contains an effective low dose pioglitazone or pioglitazone salt to
the at-risk subject detected with the TOMM40 variant to delay the onset of
Alzheimer’s e. For example, the present invention plates (a) detecting
a variant of the TOMM40 gene, such as a long poly-T allele (greater than 19
Thymidine residues), in asubject who is at-risk to p Alzheimer’s disease, and
(b) stering an effective amount of low dose pioglitazone or pioglitazone salt
drug product 0 the at-risk subject detected with the long poly-T allele variant of the
TOMM40 gene, who may for example be in a normal cognitive stage, to delay the
onset of Alzheimer’s e.
Also provided are s of delaying the onset of one or more stages that
progress to Alzheimer’s disease, such as the mild cognitive impairment stage, the
amnestic mild cognitive impairment stage, the preclinical Alzheimer’s disease stage
and/or the prodromal Alzheimer’s disease stage, in a subject at—risk to develop
Alzheimer’s disease, wherein the method comprises: (a) detecting in a subject who
is at-risk to develop Alzheimer’s disease a variant to the TOMM40 gene, such as a
long poly-T allele er than 19 Thymidine residues); and (b) stering a drug
product that contains an effective amount of low dose tazone or pioglitazone
salt to the at—risk subject in whom the TOMM40 variant has be detected to delay the
onset of one or more of the stages that progress to Alzheimer’s disease, including
any ive impairment or other stage, to delay the onset of Alzheimer’s disease in
the k t. It should be understood that, in accordance with this method of
the present invention, the at-risk subject, at time of detection of the TOMM40 variant
and/or treatment, may be in a normal cognitive stage or in any one of the stages that
progress to Alzheimer's disease.
The above summary is not ed to be each disclosed embodiment
or every implementation of the present invention. The description that follows more
particularly exemplifies rative embodiments. In several places hout the
application, guidance is provided through lists of examples, which examples can be
used in various ations. In each instance, the recited list serves only as a
entative group and should not be interpreted as an exclusive list.
Brief Description of the Drawings
Figure 1 presents fMRl images of rat brain at multiple doses of PIO relative to
vehicle control. The top panel shows the group-averaged fMRl signal at baseline;
the bottom panel illustrates the group-averaged fMRI signal at treatment day 7. This
is shows that pioglitazone HCI at doses as low as 004 mg/kg/day induces
change in metabolism in deep subcortical structure of the rat brain.
Figure 2 ts a graph of the age at onset of cognitive impairment of the
Alzheimer type for each of the TOMM40 523 genotypes. The Y axis shows the
percent survival without cognitive impairment, while the X axis represents age. Data
obtained from the Duke Bryan ADRC cohort N=438 subjects, 106 diagnosed with
cognitive impairment, 332 cognitively normal. N for each genotype: L,L:23; L,VL:54;
S,L:72; S,S:100; S,VL:138; VL,VL:51.
Figure 3 presents the curve showing the age at onset of cognitive
impairment of the Alzheimer type for individuals possessing the S,L 523
genotype. The Y axis shows the percent survival without cognitive impairment,
while the X axis represents age. The curve shows a steep slope beginning at
age 74 (vertical line). Individuals ng the trial at or above age 74 who
possess the S,L 523 genotype are at high risk of developing cognitive
ment during the next 5 years. Data is obtained from the Duke Bryan
ADRC cohort, N=72 subjects, 23 diagnosed with cognitive impairment, 49
cognitively normal.
Figure 4 ts the curve showing the age at onset of cognitive
impairment of the Alzheimer's type for 523 L,L genotype. The Y axis shows the
IO percent survival without Cl, while the X axis represents age. Data obtained from
the Duke Bryan ADRC cohort N=23 subjects, 11 diagnosed with Cl, 12
cognitively normal.
Figure 5 presents the curve showing age at onset of cognitive
impairment of the Alzheimer's type for 523 L,VL genotype. The Y axis shows
the percent al without Cl, while the X axis represents age. Data obtained
from the Duke Bryan ADRC cohort N=54 ts, 24 diagnosed with Cl, 30
cognitively normal.
Figure 6 presents the curve showing age at onset of cognitive
impairment of the Alzheimer’s type for 523 S,L genotype. The Y axis shows the
percent survival without CI, while the X axis represents age. Data obtained from
the Duke Bryan ADRC cohort N=72 subjects, 23 diagnosed with Cl, 49
cognitively normal.
Figure 7 ts the curve showing age at onset of cognitive
ment of the Alzheimer’s type for 523 8,8 genotype. The Y axis shows the
percent survival without CI, while the X axis represents age. Data obtained from
the Duke Bryan ADRC cohort N=100 subjects, 20 diagnosed with Cl, 80
cognitively normal.
2012/020606
Figure 8 presents the curve showing age at onset of cognitive
impairment of the Alzheimer’s type for 523 S,VL genotype. The Y axis shows
the percent survival without Cl, while the X axis represents age. Data obtained
from the Duke Bryan ADRC cohort N=138 subjects, 22 diagnosed with Cl, 116
cognitively normal.
Figure 9 ts the curve showing age at onset of cognitive
impairment of the Alzheimer’s type for 523 VL,VL pe. The Y axis shows
the percent survival without Cl, while the X axis represents age. Data obtained
from the Duke Bryan ADRC cohort N=51 subjects, 6 diagnosed with Cl, 45
cognitively normal.
Detailed Description of the Invention
By way of illustrating and ing a more complete appreciation of the
present invention and many of the attendant advantages thereof, 'the following
detailed description and es are given concerning the novel methods and
compositions.
In one aspect, the present invention relates to a pharmaceutical composition,
Le, a drug product, comprising low dose pioglitazone or a pharmaceutically
acceptable salt thereof and a pharmaceutically able e for administration
to a subject, such as a human patient in need of treatment to delay the onset of or
» otherwise treat Alzheimer’s disease in such a patient. While the t invention
may be embodied in many different forms, several specific embodiments are
discussed herein with the understanding that the present disclosure is to be
considered only as an exemplification of the principles of the invention, and it is not
intended to limit the invention to the embodiments described or rated.
I. Definitions
As used in the description of the invention and the appended claims, the
singular forms a an" and "the" are used interchangeably and ed to
include the plural forms as well and fall within each meaning, unless the context
clearly tes otherwise. Also, as used herein, "and/or" refers to and
encompasses any and all le combinations of one or more of the listed
items, as well as the lack of combinations when reted in the alternative
("or").
As used herein, "at least one" is intended to mean "one or more" of the listed
elements.
Singular word forms are intended to include plural word forms and are
likewise used herein interchangeably where appropriate and fall within each
meaning, unless expressly stated otherwise.
Except where noted othenNise, capitalized and non—capitalized forms of all
terms fall within each meaning.
Unless vise indicated, it is to be understood that all numbers sing
quantities, ratios, and numerical properties of ingredients, reaction conditions, and so
forth used in the specification and claims are contemplated to be able to be modified
in all instances by the term "about".
All parts, percentages, ratios, etc. herein are by weight unless indicated
othenNise.
As used herein, "bioequivalence" or "bioequivalent", refers to low dose
pioglitazone formulations or drug products which are pharmaceutically equivalent,
and their bioavailabilities (rate and extent of absorption) after administration in the
same molar dosage or amount are similar to such a degree that their eutic
effects, as to safety and efficacy, are essentially the same. In other words,
bioequivalence or bioequivalent means the absence of a significant difference in the
rate and extent to which pioglitazone becomes available from such formulations at
the site of pioglitazone action when administered at the same molar dose under
similar conditions, e.g., the rate at which pioglitazone can leave such a ation
and the rate at which pioglitaZone can be absorbed and/or become available at the
site of action to affect Alzheimer's disease. In other words, there is a high degree of
similarity in the bioavailabilities of two pioglitazone pharmaceutical products (of the
same galenic form) from the same molar dose, that are unlikely to produce clinically
relevant differences in therapeutic effects, or adverse reactions, or both. The terms
"bioequivalence", as well as "pharmaceutical equivalence” and "therapeutic
equivalence" are also used herein as defined and/or used by (a) the United States
Food and Drug Administration (FDA), (b) the Code of Federal Regulations ("C.F.R."),
Title 21, (0) Health Canada, (d) European Medicines Agency (EMEA), and/or (e) the
Japanese Ministry of Health and Welfare. Thus, it should be understood that the
present ion contemplates low dose pioglitazone formulations or drug products
that may be bioequivalent to other low dose pioglitazone formulations or drug
products of the present ion. By way of example, a first low dose pioglitazone
formulation or drug product is bioequivalent to a second low dose tazone
formulation or drug product, in accordance with the t invention, when the
measurement of at least one pharmacokinetic parameter(s), such as a Cmax, Tmax,
AUC, etc., of the first low dose pioglitazone formulation or drug product varies by no
more than about 125%, when compared to the measurement of the same
pharmacokinetic parameter for the second low dose pioglitazone formulation or drug
product.
As used herein, "bioavailability" or "bioavailable" means generally the rate
and extent of absorption of pioglitazone into the systemic circulation and, more
specifically, the rate or ements intended to reflect the rate and extent to
which pioglitazone becomes ble at the site of action or is absorbed from a drug
product and becomes available at the site of action. In other words, and by way of
example, the extent and rate of pioglitazone absorption from a lower dosage strength
formulation of the present invention as reflected by a oncentration curve of
tazone in ic circulation.
By way of further example, bioavailability is a ement of the extent of
a therapeuticallyactive drug that reaches the systemic circulation and is available at
the site of action. It is expressed as the letter F.
With respect to absolute bioavailability, absolute bioavailability compares
the bioavailability (estimated as area under the curve, or AUC) of the active drug in
systemic circulation following non-intravenous administration (i.e., after oral, rectal,
transdermal, subcutaneous administration), with the bioavailability of the same drug
following intravenous administration. It is the fraction of the drug absorbed through
non-intravenous administration compared with the corresponding intravenous
administration of the same drug. The ison must be close normalized if
different doses are used; consequently, each AUC is corrected by dividing the
corresponding dose administered.
In order to determine absolute bioavailability of a drug, a pharmacokinetic
study must be done to obtain a plasma drug tration vs time plot for the drug
after both intravenous (IV) and non-intravenous administration. The absolute
bioavailability is the dose-corrected area under curve (AUC) non—intravenous divided
by‘AUC intravenous. For example, the formUIa for ating F for a drug
stered by the oral route (po) is given below.
[AUChm 3 dose”:
much... 4: dose,”
Therefore, a drug given by the intravenous route will have an absolute
bioavailability of 1* (F=1) while drugs given by other routes y have an absolute
bioavailability of less than one.
With respect to relative bioavailability, this measures the bioavailability
(estimated as area under the curve, or 'AUC) of a certain drug when compared with
another formulation of the same drug, usually an ished rd, or through
administration via a different route. When the standard ts of intravenously
administered drug, this is known as absolute bioavailability.
relative bioavaz’labilz‘ty =W
[AUG]3 * doseA
As used herein, the terms "pharmaceutical lence" or
"pharmaceutically equivalent" refer to low dose pioglitazone formulations or drug
products of the t invention that contain the same amount of pioglitazone, in
the same dosage forms, but not necessarily containing the same inactive
ingredients, for the same route of administration and meeting the same or
comparable compendial or other applicable standards of identity, strength, quality,
and purity, including potency and, where applicable, content uniformity and/or
stability. Thus, it should be understood that the present invention contemplates
' low dose pioglitazone formulations or drug products that may be
pharmaceutically lent to other low dose pioglitazone formulations or drug
products used in ance with the present invention.
As used herein, the terms "therapeutic equivalence or therapeutically
equivalent" mean those low dose tazone formulations or drug ts which
(a) will produce the same clinical effect and safety e when utilizing pioglitazone
drug product to delay onset of Alzheimer's disease in accordance with the present
invention and (b) are pharmaceutical equivalents, e.g., they contain pioglitazone in
' the same dosage form, they have the same route of administration; and they have
the same pioglitazone strength. In other words, therapeutic equivalence means that
a chemical equivalent of a lower dosage strength pioglitazone formulation of the
present invention (i.e., containing the same amount of pioglitazone in the same
dosage form when administered to the same individuals in the same dosage
regimen) will e essentially the same cy and toxicity.
imer’s disease", "Alzheimer disease", or "AD" as used herein is a
disease in which cognitive function is impaired gradually over time, and includes a
symptomatic pre-dementia phase with presentation of mild cognitive impairment
(MCI), and a dementia phase, where there is a significant impairment in social or
occupational functioning. See Albert et al. 2011 Alzheimer's & Dementia 7: 270-279;
n et al. 2011 Alzheimer's & Dementia 7: 263-269.
Though a number of biomarkers are reported to coincide with Alzheimer's
disease, none are recognized as validated or ied biomarkers for the diagnosis
or prognosis of Alzheimer's disease by the US Food and Drug Administration. From
a clinical standpoint, the hallmark feature that is consistently t and needed for
the diagnosis of Alzheimer's disease is cognitive impairment.
IO Indications of cognitive impairment may include, but are not limited to,
difficulty with mental functions such as language, memory (e.g., episodic),
perception, emotional behavior or personality, cognitive skills (e.g., ation,
abstract thinking, judgment). The determination may be obtained from the patient,
from an informant who knows the patient well, from a skilled clinician observing the
patient, or a combination f.
"Mild cognitive impairment" or "MCI" refers to a reduction in cognitive ability
that is greater than pated considering a person’s age or education in one or
more cognitive domains. The cognitive domains include memory, executive functions
(e.g., problem-solving, ng or reasoning), attention (e.g., simple and d
attention), visuospatial skill, and language (e.g., naming, fluency, expressive ,
comprehension). Symptoms of MCI may include difficulties identifying the right word
or name; difficulty remembering names when introduced to new ; noticeably
greater difficulty performing tasks in social or work settings; forgetting material that
one has just read; losing or misplacing a valuable object; increasing trouble with
planning or zing; difficulty mastering new skills; concentration deficits; and
increased anxiety. Mild cognitive impairment is a phase at which symptoms are
sufficient to meet the tly accepted criteria of MCI, but where symptoms do not
meet dementia diagnostic criteria. People with MCI, however, may remain
functionally intact and independent. If formal, standardized cognitive tests are
administered, people with MCI lly score 1 to 1.5 standard deviations below
the age and education-adjusted mean for their peers. It should be noted that not all
MCI leads to dementia, nor to Alzheimer’s disease.
"Cognitive Impairment of the Alzheimer's Type" or "CIAT" as used herein
refers to cognitive impairment tent with features wherein Alzheimer's is the
likely cause, and thus may be considered a subset of MCI. The ations,
"Cognitive ment of the Alzheimer’s Type", "Mild Cognitive Impairment due to
Alzheimer’s disease (MCI due to AD)" or "amnestic Mild ive Impairment
(aMCI)" refer to the symptomatic, pre-dementia phase of Alzheimer’s disease. CIAT
or MCI due to AD is determined following use of neuropsychological tests and
clinician assessment of the cognitive function of the individual. Typically, episodic
memory is impaired in person with MCI that progresses to AD . However,
there are atypical forms of MCI — MCI with nonamnestic presentation — that also .
progress to Alzheimer’s disease. Progressive decline in cognitive on provides
onal evidence that a person suffers MCI due to AD.
There are a number of neuropsychological ments, particularly those
that test episodic memory (i.e., the ability to learn and retain new information), that
are useful in diagnosing MCI due to AD, or those patients with MCI who are likely to
progress to AD within a few years. Tests of episodic memory may assess ate
and/or delayed recall, such as word-list learning tests. In addition, an alternative
etiology for the ive impairment, such as degenerative (e.g., Parkinsonism),
vascular events including microinfarcts, depressive, traumatic, medical
comorbidities, should be ruled out. A number of biomarkers have been proposed for
use in research and may also be useful in supporting the clinical diagnosis of MCI
due to AD by confirming the presence of pathologies tent with AD or to
r progression of the disease, if desired. See, e.g., Albert et al. 2011
Alzheimer's & Dementia 7: 270-279.
In accordance with the present invention, cognitive impairment may be
determined by any art—accepted method of cognitive assessment, including, but not
limited to, an assessment of global cognition (e.g., the Modified Mini Mental State
Examination )), and specific domains such as visual and verbal memory
(e.g.,the Brief Visuospatial Memory Test (Revised) (BVMT—R) and the Hopkins
Verbal Learning Test (Revised) (HVLT-R), respectively), language (e.g., the
Generative Verbal Fluency Test (GVFT)) and executive function and attention (e.g.,
the Digit Span Test (DST)).
Physiological changes may or may not also be detected. "Physiological
changes" means, for example, the occurrence of at least one of altered functional
connectivity, brain atrophy, decreased synaptic activity in the brain, increased
amyloid accumulation in the brain, decreased mitochondrial function or increased
mitochondrial dysfunction in the brain, neuronal formation of neurofibrillary tangles in
the brain, and a change ponding to any other symptom of Alzheimer’s e.
Physiological changes that can be indicative of Alzheimer’s disease include, but are
not limited to, hypometabolism in the brain, altered onal connectivity, increased
beta d in the brain and or CSF and tau and o—tau in the CSF.
As used herein, "onset" means the occurrence in a subject of clinical
symptoms associated or consistent with a diagnosis Alzheimer’s disease or a phase
that progresses to mer’s dementia, such as CIAT, as defined herein.
As used herein, "delay" in the onset or progression of a phase consistent with
mer's disease means an increase in time from a first time point to onset or
worsening of a phase consistent with Alzheimer’s disease, such as cognitive
ment of the Alzheimer type. For example, a delay in the onset of Alzheimer’s
disease means that the onset of Alzheimer’s disease, as defined herein, in a subject
at risk to develop Alzheimer’s disease is delayed from happening at its natural time
frame by at least six months, 1 year, 1 1/2 years, 2, years, 2 1/2 years, 3 years, 3 1/2
years, 4 years, 4 1/2 years, 5 years, 5 1/2 years, 6 years, 6 % years, 7 years, 7 ‘/2 years
or 8 years or more, and ably from 3 years to 8 years and more preferably for 5
years after a normal cognitive t has been determined to be at high risk to
develop Alzheimer's disease. By way of further example, a delay in the progression
of cognitive ment that may progress to Alzheimer's disease or a delay in the
progression of ia means that the rate of cognitive decline is slowed relative to
its natural time frame. These determinations are performed by using appropriate
statistical analysis.
A "first time point’ includes, for example, the initiation of low dose pioglitazone
treatment as taught herein.
In some embodiments, a delay in the onset of cognitive impairment consistent
with mer's e can be determined by, for example, performing any of the
cognitive assessments described herein or by meeting accepted diagnostic criteria
for cognitive impairment of the Alzheimer’s type. In addition to the assessment of
cognitive performance, changes in other biomarkers that are consistent with
Alzheimer’s e pathologies may also be measured, if desired, including the rate
of brain atrophy, for example measured by magnetic resonance imaging (MRI) or
IS measurement of the changes in functional connections between brain regions,
assessment of brain metabolism or neuronal ty, amyloid accumulation in the
brain, brain physiology as measured by MRI signal, ondrial function in
the brain, mitochondrial proliferation in the brain, diseased neurons, neurofibrillary
tangles in the brain, amyloid in the CSF and Tau or phospho-Tau in the CSF, etc.
"Diagnosis" or "prognosis" as used herein refer to the use of ation
(e.g., c information or data from other molecular tests, biological'or
chemical information from biological samples, signs and symptoms, physical
exam findings, cognitive mance results, etc.) to anticipate the most
likely outcomes, timeframes, and/or responses to a particular treatment for a given
e, disorder, or condition, based on comparisons with a plurality of
individuals sharing common nucleotide sequences, symptoms, signs, family
histories, or other data relevant to consideration of a patient's health , or
the confirmation of a subject’s affliction, e.g., with mild cognitive impairment (MCI)
(e.g., cognitive impairment of the Alzheimer's type).
2012/020606
"Biological sample," as used herein, refers to a material containing, for
example, a nucleic acid, protein or other biological or chemical al of
interest. Biological samples containing nucleic acid such as DNA e hair,
skin, cheek swab, and biological fluids such as blood, serum, , sputum,
lymphatic fluid, semen, vaginal mucus, feces, urine, spinal fluid, and the like.
Isolation of DNA from such samples is well known to those skilled in the art.
A "subject" according to some embodiments is an individual whose
genotype(s) or haplotype(s) are to be determined and recorded in conjunction
with the individual's condition (i.e., disease or disorder status) and/or response to
a candidate drug or treatment.
"Subject," as used herein, is preferably, but not arily limited to, a
human subject. The subject may be male or female and may be of any race or
ethnicity, including, but not limited to, Caucasian, African—American, African,
Asian, Hispanic, lndian, etc. The subject may be of any age, including newborn,
neonate,~infant, child, cent, adult, and ric. Subject as used herein may
also include an animal, particularly a mammal such as a canine, feline, bovine,
caprine, equine, ovine, porcine, rodent (e.g., a rat and mouse), a
rph, a primate (including non-human e), etc., that may be treated
in accordance with the methods of the present invention or screened for veterinary
medicine or pharmaceutical drug development purposes. A subject according to
some embodiments of the t invention e a patient, human or
otherwise, in need of therapeutic treatment to delay onset of Alzheimer's disease.
"Gene," as used herein, means a t of DNA that contains information
forthe regulated biosynthesis of an RNA product, including promoters, exons,
introns, and other untranslated regions that control expression.
A "genetic risk factor," as used herein, means a genetic marker that is
associated with increased susceptibility to a condition, disease, or disorder. It may
also refer to a genetic marker that is associated with a particular response to a
selected drug or treatment of interest. iated with" as used herein
means the occurrence together of two or more characteristics more often
than would be expected by chance alone. An example of associated with involves
a feature 'on the surface of white blood cells called HLA (HLA stands for human
leukocyte antigen). A particular HLA type, HLA type 8-27, is associated with an
sed risk for a number of diseases including ankylosing spondylitis.
Ankylosing spondylitis is 87 times more likely to occur in people with HLA B-27
than in the general population.
A "prognostic" marker may be used to predict the probable course of a
condition or disease, including, but not limited to, prediction of the le age of
onset of the condition or e, course and/or rate of progression of the
condition or disease, etc. It could include genotype and/or other variables,
including age of the subject.
A subject "at increased risk of developing a condition" due to a c risk
factor is one who is predisposed to the condition, has genetic susceptibility for the
condition, and/or is more likely to develop the condition than subjects in which
the genetic risk factor is absent. A subject "at increased risk" may also be a
subject who is susceptible to developing the disease at'an earlier age.
As used herein, a subject "at-riskof ping Alzheimer’s disease"
includes an individual that is more likely to develop Alzheimer's disease based on
one or more of: age; rs10524523 genotype; APOE genotype, etc.
"Polymorphism," as used herein, refers to the existence of two or
more different nucleotide sequences at a particular locus in the DNA of the
genome. Polymorphisms can serve as c markers and may also be
referred to as genetic variants. rphisms include nucleotide tutions,
insertions, deletions and microsatellites, and may, but need not, result in detectable
differences in gene expression or protein function. A polymorphic site is a nucleotide
position within a locus at which the nucleotide sequence varies from a nce
ce in at least one individual in a population.
A "deletion/insertion polymorphism" or "DIP," as used herein, is an
insertion of one or more nucleotides in one version of a sequence relative to
another. If it is known which of the s represent minor alleles, the term
"deletion" is used when the minor allele has a deletion of one or more nucleotides,
and the term "insertion" is used when the minor allele has an additional one or
’more nucleotides. The term "deletion/insertion polymorphism" is also used
when there are multiple forms or lengths and it is not apparent which is the
minor allele. For e, for the poly-T polymorphisms described herein,
multiple lengths of rphisms are observed.
"Haplotype," as used herein, refers to a genetic variant or combination of
variants carried on at least one chromosome in an individual. A ype often
includes le contiguous polymorphic loci. All parts of a haplotype, as
used herein, occur on the same copy of a chromosome or haploid DNA
molecule. Absent evidence to the contrary, a haplotype is presumed to
represent a combination of multiple loci that are likely to be transmitted together
during meiosis. Each human s a pair of ypes for any given genetic
locus, consisting of sequences inherited on the homologous chromosomes from
two parents. These haplotypes may be identical or may represent two different
genetic variants for the given locus. Haplotyping is a process for determining
one or more haplotypes in an individual. yping may include use of family
pedigrees, molecular techniques and/or statistical inference.
A "variant" or "genetic variant" as used herein, refers to a specific isoform
of a haplotype found in a population. the specific form differing from other forms
of the same haplotype in at least one, and frequently more than one, variant
sites or nucleotides within the region of interest in the gene. The sequences at
these variant sites that differ between different alleles of a gene are termed
"gene ce variants, s," or "variants." The term "alternative form"
refers to an allele that can be guished from other alleles by having at least
one, and frequently more than one, variant sites within the gene sequence.
nts" include isoforms having single nucleotide polymorphisms (SNPs) and
deletion/insertion polymorphisms (DlPs). Reference to the presence of a variant
means a particular t, i.e., particular nucleotides at particular rphic
sites, rather than just the presence of any variance in the gene.
"lsoform," as used herein, means a particular form of a gene, mRNA, cDNA
or the protein encoded thereby, distinguished from other forms by its particular
sequence and/or structure. For example, the ApoE 4 isoform of apolipoprotein E
as opposed to the ApoE 2 or ApoE 3 isoforms.
The term "genotype" in the context of this invention refers to the particular
allelic form of a gene, which can be defined by the particular nucleotide(s)
present in a nucleic acid sequence at a particular site(s). pe may also
indicate the pair of alleles present at one or more polymorphic loci. For diploid
organisms, such as humans, tWo haplotypes make up a genotype. Genotyping is
any process for determining a genotype of an individual, e.g., by nucleic acid
ication, DNA sequencing, antibody binding, or other chemical is
(e.g., to determine the length). The resulting genotype may be ed,
meaning that the sequences found are not known to be derived from one
parental chromosome or the other.
"Treat," "treating," or ment" as used herein refers to any type of
measure that imparts a benefit to a patient afflicted with or at risk for
developing a disease, including improvement in the condition of the patient
(e.g., in one or more symptoms), delay in the'onset or progression of the
disease, etc. Treatment may include any drug, drug product, method,
procedure, lifestyle change, or other ment introduced in attempt to effect
a change in a particular aspect of a t's health (i.e., directed to a
particular disease, disorder, or condition).
"Drug" or "drug substance," as used herein, refers to an active ingredient,
such as a chemical entity or biological entity, or combinations of chemical entities
and/or biological entities, suitable to be stered to a subject to (a) delay the
onset or progression of Alzheimer’s disease. In accordance with the present
invention, the drug or drug substance is pioglitazone or a pharmaceutically
acceptable salt thereof.
The term "drug t," as used , is synonymous with the terms
ine, medicament," "therapeutic intervention," or "pharmaceutical
product." Most preferably, a drug product is approved by a government
agency for use in accordance with the methods of the present invention. A
drug product, in accordance with the present invention, contains low dose
pioglitazone.
"Disease," "disorder," and tion" are commonly recognized in the art
and designate the presence of signs and/or symptoms in an individual or patient
that are generally recognized as abnormal and/or undesirable. Diseases or
conditions may be diagnosed and categorized based on pathological changes.
The disease or condition may be selected from the types of diseases listed in
standard texts, such as Harrison's ples of Internal Medicine, 1997, or
Robbins Pathologic Basis of Disease, 1998.
hondrial dysfunction," as used herein, means any detrimental
abnormalities of the mitochondria within a cell or cells. AD and stages that
advance to AD are presently known in the art to be associated with mitochondrial
ction. This mitochondrial dysfunction causes cell damage and death by '
compromising ATP production, ting calcium homeostasis and increasing
ive stress. Furthermore, ondrial damage can lead to apoptotic cell
death by causing the release of cytochrome c and other pro-apoptotic factors into
the cytoplasm (for review, see Wallace 1999 Science 283: 1482—1488; Schapira
2006 The Lancet 368: 70-82). Regarding a specific example found herein, and
not wishing to be bound by , the ApoE 3 and ApoE 4 isoforms are
hypothesized to cause mitochondrial ction through interactions with
TOMM40. Some TOMM40 Variants may act synergistically with ApoE 3 isoform to
accelerate mitochondrial decline. In addition, in some embodiments the ApoE 2
m is thought to be protective against mitochondrial dysfunction.
As used herein, the "short" TOMM40 rs10524523 allele has less than 19
thymidine (T) residues, and the "long" TOMM40 rs10524523 allele has 19 or greater
T residues. In some embodiments, the long allele may indicate a higher risk of onset
of late onset Alzheimer's disease within a set period of time (e.g., over a 5-7 year
period).
The rs10524523 ("523") allele, an intronic polyT tract in the TOMM40 gene, is
highly polymorphic with t to length (i.e., number of T residues), and variable
sizes are associated with age-of—onset butions of late-onset AD. Measurements
of the number of T residues at each of the 2 copies of the 523 polyT, 1 on each
chromosome, that are carried by each individual comprise the 523 genotype and can
be assessed by standard procedures, such as Sanger sequencing or electrophoretic
assay.
Categorical designations of each 523 polyT are ed according to
lymer length: Short (S, lymer length less than 19 T residues), Long
(L, length r than or equal to 19, but shorter than 30) and Very Long (VL, length
greater than 29 T residues). Six different 523 genotypes, using the categorical
designations, are thus possible: (S,S), (VL, VL), (S,L), (VL,L), , (L,L). See also
US. Patent Application Publication No. 2011/0166185 to Roses, which is
incorporated by reference herein.
APOE genotype is a well established risk factor for age of onset of AD. APOE
£4 alleles are strongly linked to the 523 long (L) allele and, therefore, individuals who
have the 523 L,L pe usually (e.g., 98% for Caucasian) possess the APOE
54/84 genotype. However, the 523 short (8) and 523 very long (VL) alleles can be
linked to either APOE 52 or APOE £3 alleles. APOE £2 alleles are associated with a
later age of onset of AD relative to people who carry the £3 allele (5-8 years later,
comparing APOE 52/53 individuals with APOE 53/53). Therefore, in some
embodiments, APOE may be included in the determination in order to assign all
people carrying the APOE 52 allele to the sk group at the appropriate age
range. The 523 genotype provides higher resolution for age of onset of cognitive
impairment for duals who carry the APOE 53 allele in APOE (5/3/53) and the
APOE (53/54) genotypes.
In some ments, a subject with two copies of the long TOMM40
4523 allele is at greater risk of developing AD as compared to a subject with
one copy of the long TOMM40 rs10524523 allele, or two copies of the short
TOMM40 rs10524523 . In some embodiments, a subject with one copy of the
long TOMM40 rs10524523 allele is at greater risk of developing AD as ed to
a subject with two copies of the short TOMM40 rs10524523 allele. Determination of
the risk of developing AD or the onset of a stage or symptom thereof based upon
TOMM40 genotype should be performed in ance with other risk factors such
as age, and may also include APOE status in some embodiments. In some
embodiments, a cognitively normal subject older than 62 years of age with two
copies of the very long TOMM40 rs10524523 allele is at decreased risk of
developing AD relative to a subject with one or two copies of the long allele of
rs10524523.
Detection of a c variant of TOMM40 may be performed as described in
WC 2010/019550‘or US 2011/0166185, each herein incorporated by reference in its
entirety.
As used herein, a "subject at risk of developing Alzheimer’s disease" means
one who is predisposed to mer’s e, has genetic susceptibility for
Alzheimer’s disease and/or is more likely to develop Alzheimer’s disease at a
predetermined age than subjects in which the genetic risk factor is absent.
As used herein, "increased risk" means likely to develop AD within a short
time, 9.9, 5-7 years from a time point of, for example, the initiation of treatment
according to some embodiments described herein, or the time of determination of a
WO 96873
predisposition to or symptom of Alzheimer’s disease (for example by analysis of any
one of brain atrophy, sed synaptic activity in the brain, increased amyloid
accumulation in the brain, decreased mitochondrial function in the brain, decreased
proliferation in the brain, diseased neurons, the formation of neurofibrillar tangles in
the brain, amyloid in the CSF and Tau and/or o-Tau in the CSF).
"Increased risk" may also mean an individual is likely to develop AD at a
younger age than a control subject, that is! that an individual with at least one copy of
the long r310524523 allele is at greater risk of developing AD at an earlier age than
an individual with no copies of the long rs10524523 allele according to some
embodiments.
The age at which a subject is deemed to be at increased risk of developing
AD may be determined by graphing one or more factors (e.g., TOMM4O 523
genotype) t age and determining the point at which the risk changes are
largest related to a change in age (see Figure 2). This point may be "about" a
particular age, meaning that the age may vary by 0.5, 1, 2, 3, 4 or 5 years from that
point, which variation may result from, e.g., further zation or higher data
resolution of the graphs upon receipt of onal data.
A method of "administration" useful according to the invention includes, but is
not limited to, administration by, for example, ingestion via the oral route, intranasal,
rectal, tion, topical or injection, such as intravenous, subcutaneous,
intramuscular, intraperitoneal, intracranial and spinal injection. onal methods of
administration are provided herein below in the section entitled "Dosage and
Administration."
As used herein, "diagnosing" or "identifying a patient or subject having
Alzheimer’s disease" refers to a process of determining if an individual is ted
with Alzheimer’s disease or a stage that progresses to Alzheimer’s disease, as
defined herein. A diagnosis of Alzheimer's disease may be based on, for example,
al Institute of Neurological and Communicative Disorders and Stroke-
Alzheimer’s Disease and Related Disorders Association criteria.
"Low dose pioglitazone" refers to pioglitazone or a pharmaceutically
acceptable salt thereof in an amount in the range of from 0.5 mg to 12 mg, such as
0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg,
3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5 mg, 5.25 mg,
.5 mg, 5.75 mg, 6 mg, 6.25 mg, 6.5 mg, 6.75 mg, 7 mg, 7.25 mg, 7.5 mg, 7.75 mg,
8 mg, 8.25 mg, 8.5 mg, 8.75 mg, 9 mg, 9.25 mg, 9.5 mg, 9.75 mg, 10 mg, 10.25 mg,
10.5 mg, 10.75 mg, 11 mg, 11.25 mg, 11.5 mg, 11.75 mg or 12 mg. Alternatively, in
some embodiments of the present invention, low dose pioglitazone means a low
dose amount of tazone or a pharmaceutically acceptable salt thereof that
provides a pioglitazone AUC in a subject in a range of frOm about 0.15 ug-h/mL to
about 3.6 ug-h/mL (i 25%). For e, low dose pioglitazone AUC may be in a
range of from 0.12, 0.37, or 1.12 to 3.4 or 4.5 pgoh/mL.
As used herein, "control subjec " means a t that has not been
diagnosed with Alzheimer’s disease and/or does not t any detectable
symptoms associated with Alzheimer’s disease. A "control subject" also means a
subject that is not at risk of developing Alzheimer’s disease, as defined herein.
As used herein, a "subject that is not at risk of developing Alzheimer’s
disease" means, for example, a subject that does not have a TOMM40 rs10524523
genotype that indicates, together with age and possibly other factors such as APOE
status, that the subject is not more likely than the general population or a fied
portion thereof to develop AD or a stage or symptom thereof.
As used herein, the term "pharmaceutically acceptable salt" refers to those
salts which are, within the scope of sound l judgment, suitable for use with
pioglitazone when in contact with the s of ts, e.g., animals, including
mammals, humans and lower animals without undue toxicity, tion, allergic
response and the like, and are commensurate with a reasonable benefit/risk ratio.
ceutically acceptable salts are well known in the art. For example, ’8. M.
Berge, et al. describes pharmaceutically acceptable salts in detail in J.
Pharmaceutical es, 66: 1—19 (1977). The salts can be prepared in situ during
the final isolation and purification of the compounds of the invention, or separately by
reacting the free base function with a suitable organic acid. es of
pharmaceutically acceptable include, but are not limited to, nontoxic acid addition
salts which are salts of an amino group formed with inorganic acids, such as
hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric
acid, or with organic acids, such as acetic acid, maleic acid, tartaric acid, citric acid,
succinic acid or malonic acid, or by using other methods used in the art such as ion
exchange. Other pharmaceutically acceptable salts include, but are not limited to,
adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,
borate, te, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,
digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, oate, hexanoate, hydroiodide, 2-
hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate,
maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,
phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate,
2O thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium, m, potassium,
» calcium, magnesium, and the like. Further pharmaceutically acceptable salts include,
when riate, nontoxic ammonium, quaternary ammonium, and amine cations
formed using counterions such as halide, hydroxide, carboxylate, e, phosphate,
nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
II. Alzheimer’s Disease
ms of Alzheimer’s Disease
Common symptoms of mer’s disease include, but are not limited to, memory ‘
loss, difficulty performing familiar tasks, problems with language, disorientation to
time and place, poor or sed judgment, problems with abstract thinking,
misplacing things, change in mood or behavior, changes in ality and loss of
initiative. These symptoms appear gradually over time and usually (but not always)
begin with episodic memory problems, followed by other cognitive ts that
adversely affect a person’s normal functioning (i.e., activities of daily living).
Behavioral/personality changes usually occur later in the e process, as a
person becomes more moderately and severely affected. Some examples of these
teristic symptoms are described below.
Memory loss
This includes forgetting recently learned information and is one of the most common
early signs of dementia. A person begins to forget more often and is unable to recall
the ation later. This includes forgetting names or appointments occasionally.
Difficulty performing familiar tasks
People with dementia often find it hard to plan or complete everyday tasks.
Individuals may lose track of the steps involved in preparing a meal, placing a
telephone call or playing a game. This includes occasionally forgetting why you
came into a room or what you planned to say.
Problems with language
People with Alzheimer’s disease often forget simple words or substitute l
words, making their speech or writing hard to understand. They may be unable to
find the toothbrush, for example, and instead ask for "the thing for my " This
includes forgetting names or tments occasionally.
Disorientation to time and place
People with Alzheimer’s disease can become lost in their own neighborhood, forget
where they are and how they got there, and not know how to get home. This
includes forgetting the day of the week or where you were going. In some patients,
confusion and sometimes accompanying agitation and behavioral issues manifest
more in the late afternoon or early evening, a symptom referred to as "sundowning."
2012/020606
Poor or decreased nt
Those with Alzheimer’s may dress inappropriately, wearing several layers on a warm
day or little clothing in the cold. They may show poorjudgment, like giving away
large sums of money to telemarketers. This includes making a onable or
debatable decision from time to time.
Problems with abstract thinking
Someone with Alzheimer’s disease may have unusual difficulty performing complex
mental tasks, like forgetting what numbers are for and how they should be used.
This includes finding it challenging to e a checkbook.
Misplacing things
A person with Alzheimer’s disease may put things in unusual places: an iron in the .
freezer a wristwatch in the sugar bowl. This includes misplacing keys or wallet
temporarily.
Change in mood or behavior
Someone with Alzheimer’s disease may. show rapid mood swings—from calm to
tears to anger—for no apparent reason. This includes occasionally feeling sad or
moody.
Changes in ality
Personalities of people with dementia can change dramatically. They may become
extremely confused, suspicious, fearful or dependent on a family member. People’s
personalities do change somewhat with age.
Loss of tive
A person with Alzheimer’s disease may become very passive, sitting in front of the
TV for hours, sleeping more than usual or not wanting to do usual activities. This
‘ es feeling weary of work or social obligations.
WO 96873
Diagnosis and Staging of Alzheimer’s Disease
The clinical diagnosis of Alzheimer’s disease is a process that lly involves a
variety of steps (including medical history, physical and mental status examinations,
and laboratory tests) and tools. Of the latter, since 1984, the diagnostic criteria
established by the National Institute of Neurological Disorders and Stroke
(NINDS)/Alzheimer’s Disease and related Disorders Association (ADRDA) have
been, along with the DSM-IV criteria, the primary rds used in clinical practice
and research. Both require the presence of memory dysfunction and cognitive
impairment, although while the DSM criteria stipulate that the latter adversely affects
normal functioning, the NINCDS/ADRDA criteria do not. A feature of both sets of
criteria is that they do not consider an antemortem diagnosis of AD as definitive,
since until recently there was no methodology to assess brain pathology for
characteristic AD features until after a patient's death. The NlNCDS/ADRDA criteria
therefore ered the rtem diagnosis to be either "possible" or "probable",
ing on the strength of the clinical evidence, including the ruling out of multiple
differential diagnoses.
Until recently, the deterioration of a t to Alzheimer’s disease has been
characterized by multiple clinical stages. The term "stage" is used herein in a general
sense to describe how a subject’s abilities change from normal on, e.g., normal
cognitive state, to Alzheimer’s e. It should be noted that stages are general
guides, symptoms can vary greatly in and/or between the stages, and that not every
subject will experience the same symptoms in a given stage or ss to
Alzheimer’s e at the same rate. For example, a seven-stage framework was
developed by Barry Reisberg, M.D., clinical director of the New York University
School of Medicine's stein Aging and Dementia Research Center, which
includes: Stage 1: No impairment; Stage 2: Very mild decline; Stage 3: Mild e;
Stage 4: Moderate decline; Stage 5: Moderately severe decline; Stage 6: Severe
decline; and Stage 7: Very severe decline. In the clinical research arena, AD has
been often defined somewhat loosely as "mild", ate", or "severe" based on
scores from psychometric instruments such as the Mini~Menta| State Examination,
where, for example, mild AD could be considered 18-26, moderate 11-17, and
severe anything 10 or below (on a 30-point scale where higher scores indicate
greater cognitive on).
In 2007, Dubois et al proposed that the ‘NlNCDS/ADRDA criteria for AD
diagnosis be revised to incorporate learnings from the growth in the field’s
understanding of the disease process and the development of new methods to
assess antemortem biomarkers of AD, including brain g (Dubois et al. 2007
Lancet Neurol 6: 6). In this proposal, even with the presence of supportive
features, the antemortem diagnosis is still considered "probable" AD, while a
IO "definite" AD diagnosis was reserved for histopathological confirmation or genetic
evidence (mutation on chromosome 1, 14, or 21).
In 2011, a workgroup representing the National Institute on Aging /
Alzheimer’s Association Research Roundtable proposed similar revisions to the
/ADRDA criteria and proposed criteria to establish a diagnosis of MCI and
MCI due to AD (Albert et al. 2011 mers Dement 7: 270—279; McKhann et al.
2011 Alzheimers Dement 7: 263-269). This workgroup updated criteria for all cause
dementia and dementia due to AD. The workgroup retained the designations of
probable AD dementia, possible AD dementia, and probable or possible AD
dementia with ce of the AD pathophysiological process. The first two
designations were intended for use in all clinical settings, whereas the last
designation was determined to be appropriate for research purposes. The workgroup
recognized that the Alzheimer’s disease ssion is a continuum and that
distinguishing between MCI and ia is a clinical assessment of whether there
is significant interference with daily activities.
"Preclinical AD" refers to a stage at which symptoms are sufficient to meet the
currently accepted criteria of Preclinical AD (see Dubois et al., supra). lly
speaking, nical AD is the long, presymptomatic phase during which time the
hysiological processes of AD are beginning. There may be very subtle
cognitive symptoms years before subjects meet the clinical criteria of MCI (Sperling
et al. 2011 Alzheimers Dement 7: 280-292).
"Prodromal AD" refers to a stage at which symptoms meet the currently
accepted criteria of Prodromal AD (see Dubois et al. supra). In accordance with the
present invention, prodromal AD is a symptomatic predementia stage that generally
includes MCI but not dementia, and is characterized by symptoms not yet severe
enough to meet full Alzheimer’s disease diagnostic criteria. The Prodromal AD stage
is also referred to herein as the progressive MCI stage. '
III. Pioglitazone
Pioglitazone is a thiazolidinedione agent having the following chemical
structure:
o_ 8%,,
Pioglitazone HCI is a potent agonist for peroxisome proliferator—activated
receptor gamma (PPARy). PPAR receptors are found in s such as adipose
, al muscle and liver.
While not wishing to be bound by theory, it is thought that the PPARy agonist
pioglitazone protects t or ameliorates at least some of the pathological
mechanisms involved in Alzheimer's disease (AD), such as the decrease in
metabolic activity seen in the preclinical stage.
The pathophysiological changes corresponding to the clinical manifestation of
AD may begin years, or even decades, before the first cognitive ms ,
developing slowly over a preclinical phase. In some embodiments, administration of
low dose tazone as taught herein may protect against or ameliorate these
changes, g to a delay in the onset cognitive impairment of the Alzheimer's
type.
In some embodiments, pioglitazone is administered in an amount effective to
protect or increase al mitochondrial function, or to expand the mitochondrial
reservoir, for ng, such as delaying or preventing, cognitive impairment (e.g.,
cognitive impairment of the Alzheimer's type). In some embodiments, treatment is
initiated before significant pathological damage has accrued and/or cognitive
impairment is detected or sed.
Mitochondrial dysfunction is thought to play a significant role in the cerebral
hypometabOlism observed in AD. Brain metabolic activity, primarily due to
mitochondrial activity, ses and non-pathological brain atroph‘y occurs during
healthy aging (Curiati et al. 2011 Am J Neuroradiol 32: 560-565), but metabolic
decline and atrophy occur at a significantly higher rate in prodromal and symptomatic
early onset (Familial) AD, in mild cognitive impairment (MCI), and in late onset
Alzheimer‘s disease n et al. 1996 N Engl J Med 334: 752-758; Mosconi et al.
2004 Psychiatry Research: Neuroimaging 130: 141-151; Mosconi et al. 2005 J
Neurol Neurosurg Psychiatry 76: 15-23; i et al. 2006 J Nucl Med 47: 1778-
, 1786; Chételat et al. 2008 Brain 131: 60—71; Mosconi et al. 2008 Annals of the New
York Academy of Sciences 1147: 180-195; Mosconi et al. 2009 Neurology 72: 513-
520; Mosconi et al. 2009 Eur J Nucl Med Mol Imaging 36: 811-822; Villain et al. 2010
Brain 133: 3301-3314). Mitochondrial enzyme activity has also been found to be
d in autopsied hippocampus of AD patients, and in platelets and fibroblasts,
relative to cognitively normal subjects (Mancuso et al. 2010 Adv Exp Med Biol 685:
34-44).
The hypothesis that perturbation of mitochondrial function is a very early
event in AD etiology, occurring possibly decades ahead of clinical symptoms, is well—
supported (Castellani et al. 2002 Journal of Neuroscience Research 70: 0;
Bubber et al. 2005 Annals of Neurology 57: 3; Beal 2007 Mitochondrial
Biology: New Perspectives 287: 183-192; sion 192-186; Liang et al. 2008
Physiological Genomics 33: 240-256; Liang et al. 2008 PNAS 105: 4441-4446; Jack
et al. 2009 Brain 132: 1355-1365; Moreira et al. 2010 Biochimica et Biophysica Acta
(BBA) - Molecular Basis of Disease 1802: 2-10; Swerdlow et al. 2010 J Alzheimers
Dis 20 Suppl 2: 8265—279; Cunnane et al. 2011 Nutrition 27: 3-20). There are
changes in expression, in multiple brain s, of genes ed in mitochondrial
function in young individuals who are at increased risk of developing AD due to
carriage of APOEs4 ero-Goldberg et al. 2011 Molecular Psychiatry 16: 836-
847), and relatively decreased metabolic activity has been measured, biochemically,
following death and with g techniques during life, in brains of cognitively
normal people who are determined to be at increased risk of developing late onset
AD because of family history of the disease or carriage of at least one APOEe4 allele
(Small et al. 1995 JAMA 273: 942-947; Reiman et al. 2005 PNAS 102: 8299—8302;
Mosconi et al. 2008 Annals of the New York Academy of Sciences 1147: 180-195;
Langbaum et al. 2010 Arch Neurol 67: 462-468; Mosconi et al. 2011 Journal of
mer's Disease).
The human brain consumes more energy per gram of tissue than any other
organ, accounting for approximately a fifth of the body’s total energy expenditures.
Glucose is the primary fuel for brain metabolism, with the majority of cellular energy
production occurring in mitochondria. Neuronal mitochondria generate adenosine
triphosphate (ATP) to power neurotransmitter release and uptake at es, to
maintain ion gradients, to power mitochondrial and axonal transport. Mitochondria
also regulate calcium homeostasis and apoptosis, while dysfunctional mitochondria
e increased levels of toxic reactive oxygen species (Mattson et al. 2008
Neuron 60: 748—766). Some studies suggest that neurons also utilize lactate
produced by the oxidation of glucose in adjacent astrocytes (Pancani et al. 2011 Cell
Calcium 50: 548-558). Lactate is ultimately reduced to te in neurons and then,
like e, feeds into the oxidative phosphorylation y in ondria to
produce ATP.
In some embodiments, changes in brain lic activity upon administering
may be measured to determine the optimal dosages and/or forms of administration
for pioglitazone. Brain metabolic ty may be measured using specialized
techniques known in the art, including functional Magnetic Resonance g
, the most common implementation being Blood Oxygen Level Dependent
(BOLD) fMRI, and [18F]-fluorodeoxyg|ucose-Positron Emission Tomography (FDG-
PET) (Jack et al. 2000 Neurology 55: 484-490; Whitwell et al. 2007 Brain 130: 1777-
1786). BOLD fMRI measures the ratio of deoxyhemoglobin to oxyhemoglobin; small
increases in regional neural activity result in increased regional demand for oxygen
delivery via the cerebral vasculature, resulting in an increased fMRI signal in the
area. Thus, BOLD provides an indirect, but sensitive, measure of neural activity. A
quantitative measure of glucose uptake, the cerebral metabolic rate of glucose
(CMRglu), may be calculated with FDG-PET.
e et al., reviewing a substantial body of literature on FDG—PET studies
of MCI and AD, concluded that the global cerebral lic rate of glucose (CMRg)’
is reduced by approximately 20 - 25 % in AD patients after correction for brain
atrophy (Cunnane et al., supra).The most consistent FDG-PET findings in AD are
reduced CMRglu in entorhinal cortex and hippocampus — two regions that are
earliest affected by AD — progressing to posterior cingulate , oparietal
areas, precuneus and ntal cortex as the disease advances (During et al._2011
Neurological es 32: 559-569; Filippi and Agosta 2011 Journal of Alzheimers
e 24: 455—474). Reduced cerebral glucose metabolism may also be apparent
before a diagnosis of AD, at very early stages of cognitive e, as well as in AD-
sensitive brain regions in MCI, with the magnitude and extent of hypometabolism
worsening as cognition declines li et al. 2008 Arch Neurol 65: 1231-1236;
Nishi et al. 2010 J Neuroimaging 20: 29-36; Chételat et al. 2008, .
A longitudinal study demonstrated that, for people who progressed from
normal cognition to a clinical sis of amnestic MCI, there was a correlation
between decline in cognition and reduction in metabolism in brain regions known to
be preferentially affected by AD. This decline in the AD-sensitive regions of the brain
was not evidenced in a similar group of people who maintained stable cognition over
the study (Caselli et al. 2008, supra; Chételat et al. 2008, supra). In addition, young
adult and middle-age individuals who are cognitively normal but at risk for AD (e.g.,
with family history of AD, a carrier of APOEE4, or individuals with presymptomatic
early-onset, familial AD), have reduced glucose metabolism in brain regions
sensitive to AD pathology relative to those t these risk factors (Small, et al.
1995, supra; Reiman et al. 1996, supra; Reiman et al. 2005, supra; Mosconi et al.
2006, supra; Langbaum et al. 2010, supra; Small et al. 2000 PNAS 97: 6037-6042;
Reiman et al. 2004 PNAS 101: 284-289). Thus, reduced metabolism in regions of
the brain affected by AD may be one of the earliest hysiological changes
and/or indicators of future disease in those at risk of developing the disease, and
may also be correlated with disease progression.
As known in the art, fMRl, using Blood Oxygen Level dependent (BOLD)
contrast, can be used to visualize and measure neuronal activity during tasks, e.g.,
cognitive tasks, and to visualize the resting state activity of the brain, including the
default mode network (DMN), which is a network of brain s that is active during
the awake resting state but vated during a task (Pihlajamaki and Sperling 2008
Future Neurology 3: 409-421; Huettel and Larry 2009 Encyclopedia of cience
273-281). Neuronal activity increases metabolism and regional demand for e
and oxygen, which stimulates blood flow to the active regions of the brain. This is the
hemodynamic response (the product of local cerebral blood flow, the cerebral
metabolic rate of oxygen and cerebral blood volume) that is visualized by BOLD
fMRl is a widely accepted indicator of neuronal activity and reflects energy
consumption (Pihlajamaki and Sperling 2008, supra; Wise and n 2010 Drug
Discovery Today 15: 973—980; Reitz et al. 2011 Nat Rev Neurol 7: 137-152).
BOLD fMRl reveals that task-evoked brain activity is compromised in those at
risk of AD, and further diminishes as AD progresses (Filippi and Agosta 2011,
supra). Some of the tasks used may challenge the higher order cognitive functions
that are compromised early in the e process, including episodic and working
memory. The BOLD fMRl signal s earliest in the medialtemporal lobe (MTL),
including the hippocampus, and connected neural networks that are ed for
encoding or retrieving es (Pihlajamaki and Sperling 2008, supra). Reduced
neural activity is also evident in the MTL, particularly in regions of the hippocampus,
of young and old cognitively normal individuals who are at sed risk of
developing AD (Pihlajamaki and Sperling 2008, supra; Filippi and Agosta 2011,
supra; Wu et al. 2009 J Cell Physiol 220: 58-71; Jones et al. 2011 Neurology 77:
1524—1531), and the magnitude of the BOLD fMRI signal in the posteromedial
cortical region is associated with verbal episodic memory performance in cognitively
normal older subjects, and is sed as subjects progress from cognitive ‘
impairment to AD ia (Pihlajamaki et al. 2010 mer Disease & Associated
Disorders 24: 28-36). In addition to changes in task-evoked brain activity in
preclinical, prodromal and AD dementia, fMRI and FDG-PET studies of the‘brain in
its resting state indicate that the functional connectivity between specific regions of
the brain are increasingly altered as MCI and AD ss (Reiman et al. 1996,
supra; Filippi and Agosta 2011, supra; Jin et al. 2012 Magnetic Resonance Imaging
: 48-61). MRI has proven to be a particularly useful method for measuring
functional connectivity in human brain and in brains of other s, e.g., the rat.
Biswal et al. recognized as early as 1995 that there was temporal correlation of low
frequency fluctuations of blood flow and oxygenation, measured by fMRI, in regions
of the brain that were functionally related (Biswal et al. 1995 Magn Reson Med 34:
537-541). These spatio-temporally coordinated ations occur even when the
brain is not engaged in a task, i.e., when the brain is at rest, and are thought to
reflect spontaneous neuronal activity or background brain ses (Damoiseaux
et al. 2011 iology of Aging ; Yamasaki et al. 2012 Neurology Research
International 2012). In AD, altered functional connectivity has been noted n
brain regions or systems required for higher-order cognitive processes, including in
the DMN and the systems involved in attention (Yamasaki et al. 2012, supra).
Decreased resting connectivity in the DMN in specific brain regions — e.g., between
the posterior ate cortex and temporal cortex or hippocampus and between the
subcortical region, the thalamus, and a number of cortical regions — has been
reported for AD and MCI patients (Wang et al. 2011 European Journal of Radiology).
By contrast, there is increased resting state functional connectivity in frontal regions
and n regions of the DMN and frontal parts of the brain in AD and MCI (Wang
2012/020606
et al. 2006 Neurolmage 31: 496-504; Zhang et al. 2009 Behav Brain Res 197: 103-
108).
Heretofore the ability to predict which people are more likely to develop these
pathophysiological changes, which may lead to cognitive impairment, and ultimately
Alzheimer’s ia, has not been feasible. The TOMM40 rs10524523 genotype
along with age and possibly other s are useful as a prognostic biomarker to
determine which subjects are at risk for ping cognitive impairment of the
Alzheimer’s type and provide the opportunity to intervene in the early phase of this
progressive and devastating disease.
PPARy is a ligand-activated, nuclear transcription factor that impinges on
many ys implicated in the etiology of AD (Landreth et al. 2008
herapeutics 5: 481—489). Its biological actions include the modulation of
inflammatory gene expression and the regulation of glucose and lipid metabolism,
both of which are abnormal in AD. PPARy also has direct effects on mitochondrial
function and ATP production. Many thought leaders in AD research believe that
mitochondrial dysfunction plays a significant role in the cerebral hypometabolism
ed in AD.
The PPARv receptor is activated by endogenous ligands and by a number of
pharmacological agents including drugs of the lidinedione (TZD) class.
Pioglitazone is marketed for the treatment of type 2 diabetes (ActosTM), and
treats the insulin resistance that is the hallmark by type 2 diabetes by increasing the
sensitivity of tissues, particularly the liver, muscle and adipose tissue, to the effects
of insulin (Olefsky 2000 The Journal of Clinical Investigation 106: 467-472). T2DM
and insulin resistance are risk factors for ping AD, and diabetic patients
carrying APOE£4 are at particular risk (Irie et al. 2008 Arch Neurol 65: 89-93;
aa et al. 2008 Neurology 71: 1065-1071; Bruehl et al. 2009 Journal of
al and Experimental Neuropsychology 32: 487—493). Brains from autopsied AD
patients have markedly lower levels of insulin, insulin receptor and IRS-1 mRNA than
WO 96873
control brains, consistent with an insulin resistance or diabetic ype leading
some to characterize AD as type 3 diabetes (Steen et al. 2005 J Alzheimers Dis 7:
63-80. Insulin receptors are found throughout the human brain, and are at
particularly high concentrations in the hypothalamus, cerebellum, and cortex, and
PPARy and its coactivator, retinoid X receptor (RXR), are also expressed in the
brain, including in the hippocampus and cortex (lnestrosa et al. 2005 Experimental
Cell Research 304: 91—104; Gofflot et al. 2007 Cell 131: 405-418; Morales—Garcia et
al. 2011 GLIA 59: 293-307). PPARy or is expressed in astrocytes and
neurons, and the level of the protein is reduced by ~40% in postmortem brain lysates
from AD patients.
Pioglitazone improves neuronal insulin ance (Liu et al. 2010 European
Journal of Pharmacology 629: 153-158), and concentrations as low as 1 nM
significantly reduce cell death due to glucose deprivation, possibly because
pioglitazone affords tion from hypoglycemia by increasing mitochondrial
t and/or modulating mitochondrial structure. The drug also increases
expression of NRF1, TFAM1 (transcription factors required for ondrial
biogenesis), and UCP-2 (required for mitochondrial remodeling) (Miglio et al. 2009
Neurochemistry International 55: 496-504).
Beneficial effects of pioglitazone have been reported in transgenic mouse
models of AD, and mouse and rat models of neurodegeneration or brain injury. The
reported beneficial effects upon treatment with pioglitazone include the reduction of
brain amyloid plaque burden in transgenic mouse models of AD,\imprOVed brain.
glucose utilization and cerebrovascular function, reduced brain inflammation,
decreased oxidative stress, improvement of pathology-related memory and learning
deficits, and increased neurogenesis in adult animals (Heneka et al. 2000 l of
Neuroscience 20: 6862~6867; Yan et al. 2003 Journal of Neuroscience 23': 7504—
7509; Heneka et al. 2005 Brain 128: 1442-1453; Pathan et al. 2006 Life Sci 79:
216; kakis et al. 2008 Journal of cience 28: 9287-9296; Kaur et
al. 2009 Fundamental '& Clinical Pharmacology 23: 6; Roberts et al._ 2009
Experimental Neurology 216: 0; Glatz et al. 2010 Journal of Hypertension 28:
1488-1497; Nicolakakis and Hamel 2011 J Cereb Blood Flow Metab 31: 1354-1370;
Morales-Garcia et al. 2011, supra; Zhang, Xu et al. 2011, supra). Pioglitazone also
ed cognition and hyperinsulinemia, and improved regional cerebral blood flow
in small placebo-controlled clinical trials of diabetic ts with AD or mild cognitive
ment (Hanyu et al. 2009 Journal of the American Geriatrics Society 57: 177-
179; Hanyu etal. 2010 J Am Geriatr Soc 58: 1000-1001; Sato et al. 2010
Neurobiology of Aging 32: 1626-1633 ).
The marketed 15 mg, 30 mg and 45'mg dosage of pioglitazone is appropriate
for dosing for type 2 diabetes and is safe and efficacious for the treatment of this
e. Diabetes-level doses of pioglitazone have been used in small clinical
studies of mer's disease (Hanyu et al. 2009 Journal of the American Geriatrics
y 57: 177-179; Hanyu et al. 2010 J Am Geriatr Soc 58: 1000-1001; Satoet al.
2010 Neurobiology of Aging 32: 1626-1633 ). In addition, in a recent clinical trial for
Alzheimer's treatment using a different thiazolidinedione —- rosiglitazone — the type 2
diabetes dosage of the drug was used (Risner et al. 2006 Pharmacogenomics
Journal 6: 246-254; Gold et al. 2010 Dementia and Geriatric Cognitive Disorders 30:
131-146).
However, it would be preferred to limit exposure to drug if the ed
pharmacodynamic effect and efficacy may be sufficiently achieved at a lower dose
for the intended patient population. In this manner, the frequency of rare or
uncommon adverse events may be further reduced, thereby improving the safety.
As taught herein, and as trated by the BOLD study results presented
in the Examples below, it has been surprisingly found that dosages icantly
lower than those used for the treatment of type II diabetes (i.e., low dose
pioglitazone) result in a change in brain metabolism and thus may be effective in the
treatment of Alzheimer's disease, ing the delay of onset of cognitive decline
(e.g., cognitive impairment of the Alzheimer type).
V. Formulations and Modes of Administration
The invention es for a number of drug product ations of low dose
pioglitazone useful according to the methods of the present invention, including but
not d to a low th (LS) formulation, an orally disintegrating tablet (ODT)
formulation, a liquid formulation, a suspension formulation, a nasal formulation, an
orally immediate, modified, controlled or extended release formulation, a transdermal
formulation a rectal formulation, a topical formulation or an injectable formulation.
(a) Low Strength (LS) Formulation
The invention provides for LS formulations of low dose pioglitazone, for
example as described in U.S.S.N. 12/452,587 and US. Patent ation No.
2010/0166853, herein incorporated by reference in its entirety). The coated
preparation of the present invention comprises a core comprising a pharmaceutically
acceptable organic acid with water solubility at 20°C of not less than 10 mg/mL and
pKa1 (a negative common logarithm of the first acid dissociation constant K31) at
°C of not more than 5, and a coating layer comprising pioglitazone or a salt
thereof.
The coated preparation of the present invention may be a single preparation
having a core and a coating layer, or a collection of preparations each having a core
and a g layer. In addition, the coated preparation of the present invention may
be a e produced by mixing a collection of preparations each having a core and
a coating layer with additives as ary and filling a capsule with the mixture.
Furthermore, the coated preparation of the present invention may be a tablet
or caplet produced by mixing a collection of preparations each having a core and a
coating layer with ves and ssion-molding the mixture.
The core of the coated preparation of the present invention may consist only
of a pharmaceutically acceptable organic acid with water solubility at 20°C of not less
than 10 mg/mL and pKa1 at 25°C of not more than 5. Alternatively, it may consist of a
composition of a ceutically acceptable organic acid with water solubility at
°C of not less than 10 mg/mL and pKa1 at 25°C of not more than 5 and, for
e, the below-mentioned additive and the like.
The organic acid contained in the core of the coated preparation of the
present ion is a pharmaceutically acceptable organic acid with water solubility
at 20°C of not less than 10 mg/mL and pKa1 at 25°C of not more than 5. The water
solubility at 20°C is preferably not less than 50 mg/mL, more preferably not less than
100 mg/mL. The water solubility at 20°C is preferably not more than 2000 mg/mL.
pKa1 at 25°C is preferably not more than 5, more preferably not more than 4. The
pKa1 is preferably not less than 1. Preferred is an c acid with water solubility at
°C of not less than 300 mg/mL and pKa1 at 25°C of not more than 4.
Specific examples of organic acid include one or more of citric acid, tartaric
acid, malic acid and ascorbic acid, and the like. The organic acid may be any of
hydrate and acidic salt. In addition, the organic acid is preferably in the form of a
crystal, since the mechanical strength and chemical stability of the core ning
the crystalline organic acid are not degraded during the tion step of the
preparation of the present invention, and in view of the acidity.
In the present specification, citric acid includes citric acid monohydrate and
anhydrous citric acid.
As the organic acid, citric acid, tartaric acid and malic acid are preferable, and
citric acid (particularly anhydrous citric acid) is more preferable as a ceutical
additive.
The'average particle size of the organic acid is generally 100-1500 um,
preferably 300-800 pm. The average particle size is measured, for example, using a
laser diffraction particle bution measurement tus (e.g., SYNPATEC
HELOS-RODOS particle distribution measurement apparatus).
While the average particle size of the core varies depending on the kind of
coated preparation of the present invention, it is generally 100-1500 um, preferably
300-800 pm.
The core of the coated preparation of the present invention can be covered
with a coating layer comprising pioglitazone or a salt thereof.
While the content of the organic acid in the core of the coated ation of
the present invention varies depending on the kind of organic acid and the like, it is
generally 20-95 parts by weight, ably 40-80 parts by weight, per 100 parts by
weight of the coated preparation.
With regard to pioglitazone or a salt thereof used for the coated preparation of
the present invention, examples of the salt of pioglitazone include pharmacologically
acceptable salts such as salts with inorganic acid, salts with organic acid, salts with
acidic amino acid and the like.
Preferable examples of the salts with inorganic acid include salts with
hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the
like.
Preferable examples Of the salts with organic acid e salts with formic
acid, acetic acid, oroacetic acid, c acid, oxalic acid, tartaric acid, maleic
acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic
acid, p-toluenesulfonic acid and the like.
Preferable examples of the salts with acidic amino acid include salts with
aspartic acid, glutamic acid and the like.
In addition, tazone may be any of anhydride or hydrates, and the
pioglitazone may be further labeled with an isotope (9.9., 3H, 14C, 35S, 125I) and the
like.
tazone or a pharmaceutically acceptable salt thereof is preferably
pioglitazone hydrochloride.
Pioglitazone or a ceutically acceptable salt thereof may be diluted with
a diluent and the like that are generally known in the art.
In the coated preparation of the present invention, the median particle size of
pioglitazone and a salt thereof to be used as a starting material is preferably 0.5 to
50 pm.
By adopting such a median size, a coated preparation of pioglitazone or a
ceutically acceptable salt thereof, which has superior dissolution, can be
obtained.
The above-mentioned preferable median size is applied to pioglitazone or a
pharmaceutically acceptable salt thereof used as the starting material. The starting
material may comprise a pulverized product obtained by pulverization during the
process of producing coated preparation, or a mixed pulverized product obtained by
pulverization together with an excipient (e.g., crystalline cellulose) or the like. The
median size of pioglitazone or a pharmaceutically acceptable salt thereof may
change beyond the above range during a production process of the coated
preparation of the present invention, or a preservation process of the coated
preparation after production, by coagulation of pioglitazone or salt thereof. The
pulverization is med using a preparation forming machine such as a mortar, a
jet mill, a hammer mill, a screen mill (P-3; Showa Kagaku Kikai sho Co., Ltd.)
or the like.
As used herein, the median size means a le size that divides into crude
les and fine particles by 50% based on the weight bution or number
distribution. The median size can be ed, for example, by laser diffraction-
WO 96873
particle size distribution ement apparatus (e.g., SYNPATEC HELOS-RODOS
particle distribution measurement apparatus).
The dispersibility of tazone or a pharmaceutically acceptable salt thereof
having the above-mentioned desired median size is preferably as defined by
les of not more than 0.1 pm are contained at not more than 10% of the total
amount, and particles of not less than 1000 um are contained at not more than 10%
of the total amount. The lower limit thereof is generally as defined by particles of not
more than 0.1 pm are contained at not less than 0.1% of the total amount, and
. particles of not less than 1000 pm are contained at not less than'0.1% of the total
amount.
While the t of pioglitazone or a pharmaceutically acceptable salt thereof
in the coated preparation of the present invention varies depending on the dosage
form, dose and the like of the coated preparation, it is generally 0.01-30 parts by
weight, preferably 0.5-25 parts by weight, further preferably 0.5-20 parts by weight,
per 100 parts by weight of the coated preparation.
In the coated preparation of the present invention, a weight ratio of
pioglitazone and the aforementioned pharmaceutically acceptable organic acid is
preferably 1:4-1:100, more preferably 114-120, more preferably 115-1110. The weight
of the pioglitazone means pioglitazone equivalent in a pharmaceutically acceptable
salt of pioglitazone.
In the coated preparation of the present ion, the amount of the coating
layer comprising tazone or a salt thereof to be used is generally 5-205 parts by
weight, preferably 10-100 parts by weight, more ably 20-90 parts by weight,
per 100 parts by weight of the core.
The coated preparation of the present invention preferably contains cellulose
or a cellulose tive in a coating layer. Of these, a cellulose derivative is
preferable.
The cellulose derivative is a cellulose wherein a part of the cellulose molecule
is substituted by other atoms or functional groups. Examples of the cellulose
derivative include low-substituted hydroxypropylcellulose (L-HPC),
hydroxypropylmethylcellulose, methylcellulose, hydroxypropylmethylcellulose
ate, hydroxypropylmethylcellulose acetate succinate and the like. Of these,
bstituted hydroxypropylcellulose is preferable. More preferred is low—
substituted ypropylcellulose having a hydroxypropoxyl group content of 5-16
wt % (e.g., LH-11, LH-21, LH-31, LH—22, LH-32, LH-20, LH-30, LH-33 (trade names,
ctured by Shin-Etsu Chemical Co., Ltd.) etc.) and the like.
The content of the cellulose or cellulose derivative in the g layer of the
coated preparation of the present invention is generally 0.5-70 parts by weight,
preferably about 2-about 50 parts by , more preferably about 2-about 30 parts
‘15 by weight, per 100 parts by weight of the coating layer.
Since cellulose or a cellulose derivative (preferably cellulose derivative) is
contained in the coating layer, the coated preparation of the present invention has a
construct constituting a coating layer, which comprises cellulose or a cellulose
derivative as a skeleton and is maintained in an aqueous solvent, wherein
pioglitazone or a pharmaceutically acceptable salt thereof is dissolved in an organic
acid (solutiOn) in the construct to afford an aqueous solution. As a result, the coated
preparation of the present invention can, as compared to conventional preparations,
remarkably se the maximum blood concentration and AUC of pioglitazone
after administration, and remarkably decrease inter-individual relative standard
deviation (RSD) in AUC.
In addition, since the coated ation of the t invention has a
construct tuting a coating layer, which comprises cellulose or a cellulose
'30 derivative as a skeleton and is maintained in an aqueous solvent, wherein
pioglitazone or a pharmaceutically acceptable salt thereof is dissolved in an organic
acid ion) in the construct to afford an aqueous solution, it can enhance
ilability as compared to conventional preparations. Specifically, the
bioavailability of the coated preparation of the present invention exceeds 75% when
the preparation is administered to dogs.
In the present ication, the bioavailability can be determined by, for
example, dividing AUC at the time of non-intravenous administration of a given
amount of pioglitazone by AUC at the time of intravenous administration of the same
amount of pioglitazone. For example, when the bioavailability of a low dose
pioglitazone immediate release drug product of the t invention is administered
orally is to be calculated, the formula may be as the following:
Bioavailability(%)=(AUC of oral administration/AUG of intravenous
administration)x100.
When pioglitazone is dissolved in the construct to afford an aqueous solution,
a similar effect as ed by the administration of solution can be ed, which
is expected to increase maximum blood tration, AUC and bioavailability.
Here, the aqueous solvent in the present specification includes water, KC|--
HCI buffer (e.g., KCl--HCl buffer at pH 2.0), Mcllvaine buffer (e.g., Mcllvaine buffer at
pH 2.2, pH 2.5 or pH 3.0) and the like. The construct constituting a coating layer,
which ses a cellulose derivative as a on and is maintained in an
aqueous t specifically means, for example, that the construct is t for not
less than 10 minutes preferably in KCl--HC| buffer (pH 2.0, 900 mL) under conditions
of Paddle Method (50 rpm), more preferably in Mcllvaine buffer (pH 2.2, 900 ml)
under conditions of Paddle Method (50 rpm), still more preferably in Mcllvaine buffer
(pH 2.5, 900 ml) under conditions of Paddle Method (50 rpm), particularly preferably
in Mcllvaine buffer (pH 3.0, 900 mL) under conditions of Paddle Method (50 rpm).
The Paddle Method in the present specification means measurement
according to the Japanese Pharmacopoeia 14th Edition, General Tests, Dissolution
Test Method 2, unless particularly indicated.
WO 96873
The coated preparation of the present invention may contain additives
conventionally used in the technical field of formulation of preparations. Examples of
the additive includeexcipient, disintegrant, binder, lubricant, colorant, pH regulator,
surfactant, stabilizer, ent, ner, flavor, glidant, antistatic agent, light
shielding agent, antioxidant, ng agent, chelating agent and the like. These
additives are used in an amount conventionally employed in the technical field of
formulation of preparations. In addition, these additives may be used in a mixture of
two or more kinds thereof in an appropriate ratio.
EXamples of the excipient include saccharides; lline cellulose; starches
such as corn starch, potato starch, wheat starch, rice starch, partly pregelatinized
starch, pregelatinized starch, porous starch, n, carboxymethyl starch and the
like; anhydrous calcium ate, precipitated calcium carbonate, calcium silicate,
powder cellulose, n, light anhydrous silicic acid, synthetic um silicate,
magnesium aluminometasilicate, magnesium oxide, calcium phosphate, calcium
carbonate, calcium sulfate.
Examples of saccharides include sugar, starch sugar, e, honey and
sugar alcohol. Two or more kinds of these saccharides may be used in a mixture in
an appropriate ratio.
Examples of sugar include sucrose, white soft sugar, glycosyl sucrose
[coupling sugar (trade name)], fructooligosaccharide and palatinose.
es of starch sugar include glucose, maltose, powdered starch syrup,
starch syrup, fructose and ose.
Examples of lactose include lactose, isomerized lactose (lactulose) and ‘
hydrogenated lactose (lactitol).
Examples of honey include various kinds of honey generally used for eating.
Examples of sugar l include sorbitol, mannitol (specifically, D-mannitol),
maltitol, hydrogenated glucose syrup, xylitol, reduced paratinose and erythritol.
The saccharides are preferably sugar alcohol, starch sugar and sucrose,
more preferably mannitol, trehalose and sucrose. Of these, mannitol and trehalose
are preferable. From the aspect of suppressing color change of the preparation
(specifically color change under vation conditions), in the coated preparation
of the present invention, the coating layer is preferably to contain mannitol or
trehalose.
When saccharides are used for the coated ation, the content thereof is
for example, 5-90 parts by weight, preferably 5-40 parts by weight, per 100 parts by
weight of the. coated preparation.
Particularly, when the coated preparation of the present invention contains
mannitol or trehalose, the content of mannitol or trehalose is preferably 5-40 parts by
, more preferably 5-30 parts by weight, per 100 parts by weight of the coated
preparation.
' Examples of
crystalline cellulose include CEOLUS KG801, KG802, PH101,
PH102, PH301, PH302, PH-FZO, RC—A591 NF (trade names, manufactured by Asahi
Kasei Chemicals Corporation), including one called microcrystalline cellulose.
es of egrants include carboxymethylcellulose, calcium
carboxymethylcellulose llose calcium), sodium carboxymethyl starch,
carmellose sodium, croscarmellose sodium, crospovidone [preferably, on CL,
CL-M, CL-F, CL-SF (trade name, BASF JAPAN LTD.); Polyplasdone XL, XL-10, INF-
(trade name, ISP JAPAN LTD.)], low-substituted hydroxypropylcellulose
[preferably low-substituted ypropylcellulose having a hydroxypropoxyl group
content of 5-16 wt %, such‘as LH-11, LH-21, LH-31, LH—22, LH-32, LH-20, LH-30,
2012/020606
LH-33 (trade name, manufactured by Shin—Etsu Chemical Co., Ltd.) etc],
hydroxypropyl starch, cornstarch and partly pregelatinized starch.
When a disintegrant is used for the coated preparation of the present
invention, the content of the disintegrant is, for example, 0.5-50 parts by ,
preferably 1-25 parts by , per 100 parts by weight of the coated preparation.
es of binders include hydroxypropylcellulose [preferably HPC-SSL, SL,
L (trade name, NIPPON SODA Co., LTD.)], hydroxypropyImethylcellulose, povidone
(polyvinylpyrrolidone), arabic gum powder, sucrose, gelatin, pullulan,
methylcellulose, crystalline cellulose, bstituted hydroxypropylcellulose
rably low-substituted ypropylcellulose having a hydroxypropoxyl group
t of 5-16 wt %, such as LH-11, LH-21, LH-31, LH-22, LH-32, LH-20, LH-30,
LH-33 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) etc.], macrogol,
dextran, polyvinyl alcohol and starch paste. Of these, hydroxypropylcellulose is
preferable.
When a binder is used for the coated preparation of the present ion, the
content of the binder is, for example, 0.01-50 parts by weight, preferably 0.1-10 parts
by weight, per 100 parts by weight of the coated preparation.
Examples of lubricants include stearic acid, magnesium stearate, calcium
stearate, talc, sucrose esters of fatty acids, sodium stearyl fumarate, waxes, DL-
leucine, sodium lauryl sulfate, magnesium lauryl sulfate, macrogol and light
anhydrous silicic acid (e.g., AEROSIL). Of these, magnesium stearate is preferable.
Examples of colorants include food colors such as Food Yellow No. 5 (Sunset
Yellow, same as Food yellow No. 6 in the US), Food Red No. 2, Food Blue No. 2
and the like, food lake colors, yellow ferric oxide (yellow iron oxide), diiron trioxide
(red iron oxide), avin, riboflavin organic acid ester (e.g., riboflavin butyrate),
riboflavin phosphate or alkali metal salt thereof or alkaline earth metal salt thereof,
phenolphthalein, um oxide, lycopene, beta-carotene.
Examples of the pH regulator include citrate, phosphate, carbonate, tartrate,
fumarate, e and amino acid salt.
es of the surfactant include sodium lauryl sulfate, polysorbate 80,
polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196)
polyoxypropylene (67) glycol and polyoxyethylene hydrogenated castor oil 60'.
‘ es of the stabilizer include sodium ascorbate, tocopherol, tetrasodium
edetate, nicotinamide, cyclodextrins; alkaline earth metal salts (e.g., calcium
carbonate, calcium hydroxide, ium carbonate, magnesium hydroxide,
magnesium te, magnesium aluminate) and butylhydroxyanisole.
es of the corrigent include ascorbic acid, (anhydrous) citric acid,
tartaric acid and malic acid.
Examples of the sweetener include aspartame, acesulfame potassium,
tin, saccharin sodium and dipotassium rhizinate. Of these, aspartame is
preferable.
Examples of the flavor include menthol, peppermint oil, lemon oil and vanillin.
Examples of the glidant include light anhydrous silicic acid and hydrated
silicon dioxide. Here, the light anhydrous silicic acid may be any containing hydrated
silicon dioxide (Si02 nHZO) (n is an integer) as a main component and, as concrete
examples thereof, Sylysia 320 (trade name, FUJI SlLYSlA CHEMICAL LTD.),
AEROSIL 200 (trade name, NIPPON AEROSIL CO., LTD.) and the like can be used.
Examples of the antistatic agent include talc and light anhydrous c acid.
Examples of the light ing agent include titanium oxide.
Examples of the antioxidant include dibutylhydroxytoluene (BHT), tocopherol,
tocopherol ester (e.g., tocopherol acetate), ascorbic acid or alkali metal salt thereof
or alkaline earth metal salt thereof, chopene, beta—carotene.
Examples of the reducing agent include cystine and cysteine.
Examples of the ing agent include EDTA or alkali metal salt thereof or
alkaline earth metal salt thereof.
The coated preparation of the present invention may have an intermediate
layer formed between the core and the coating layer comprising pioglitazone or a
salt thereof. Using such intermediate layer, an adverse effect (e.g., decomposition of
pioglitazone) of the organic acid in the core on pioglitazone‘or a salt thereof in the
coating layer can be ted, and the durability of the coated preparation can be
prolonged.
The dosage form of the coated preparation of the present ion is
generally a solid preparation. Examples of the solid preparation e tablet,
caplet, capsule, powder, granule and troche. Of these, e, capsule and tablet
are preferable. Semi-solid dosage forms, such as a gel containing the coated
preparation, and liquid preparations containing a solution of pioglitazone of the
appropriate dosage are also useable in ance with the present invention.
The shape of the solid preparation is not particularly limited, and may be any
of round, caplet, ut, oblong and the like.
The solid preparation may be coated with a g agent, [and may have a
mark and letters for identification and further a score line for partition.
Examples of the coating base include sugar coating base, aqueous film
g base, enteric film coating base, sustained-release film coating base and the
like.
As the sugar coating base, sucrose is used and one or more kinds ed
from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba
wax and the like may be used in ation.
Examples of the s film coating base include cellulose polymers such
as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose,
methylhydroxyethylcellulose and the like; synthetic polymers such as polyvinylacetal
diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade
name)], polyvinylpyrrolidone and the like; polysaccharides such'as pullulan and the
like; and the like.
Examples of the enteric film coating base include cellulose polymers such as
hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate
succinate, carboxymethylethylcellulose, cellulose acetate phthalate and the like;
acrylic acid polymers such as rylic acid copolymer L [Eudragit L (trade
name)], methacrylic acid copolymer LD [Eudragit L-3OD55 (trade name)], rylic
acid copolymer S [Eudragit S (trade name)] and the like; naturally occurring
substances such as shellac and the like; and the like.
Examples of the sustained-release film coating base include ose
polymers such as ethylcellulose, cellulose e and the like; acrylic acid polymers
such as aminoalkyl methacrylate mer RS [Eudragit RS (trade name)], ethyl
acrylate—methyl methacrylate copolymer suspension [Eudragit NE (trade name)] and
the like; and the like.
Two or more kinds of the above-mentioned coating bases may be used in a
mixture in an appropriate ratio. In addition, coating additives may also be used
during coating.
Examples of the coating ve include light shielding agents and/or
colorants such as titanium oxide, talc, ferric oxide and the like; plasticizers such as
polyethylene glycol, triethyl citrate, castor oil, rbates and the like; and the like.
The coated preparation of the present invention can be produced by using the
mentioned various additives according to a conventional method in the
technical field of formulation of preparations.
For example, the coated preparation of the present invention can be produced
by:
(1) mixing an organic acid with additives where necessary'to give a core
containing an organic acid,
(2) forming a coating layer comprising pioglitazone or a salt f on the
surface of the core by coating the core containing an organic acid with pioglitazone
or a salt f and additives where necessary, and
(3)'drying and sieving the obtained coated product as ary.
In addition, the coated ation of the present invention can also be
produced by mixing the coated product after drying and sieving with an additive as
necessary, and compression molding or filling the mixture in a capsule.
Here, the mixing (including granulation, drying, milling and the like) is
performed, for example, using a preparation forming e such as a V—type
mixer, a tumbler mixer, a high speed agitating granulator (FM-VG—10; POWREX
CORPORATION), an all-round kneader (Hata Tekkosho, Co., Ltd.), a fluidized-bed
dryer/granulator , FD-BS, FD-3SN; POWREX ATION), a box
vacuum dryer (Kusunoki Machinery Co., Ltd.), a screen mill (P-3; Showa Kagaku
Kikai Kosakusho Co., Ltd.), centrifugal fluidized-bed granulator (CF-mini, CF-260,
CF-360; Freund Corporation), dry granulator, spray drying granulator, rotating
fluidized-bed granulator (MP10; POWREX CORPORATION) and the like.
For coating, for example, a preparation ing machine such as a
centrifugal fluidized-bed granulator (CF-mini, CF-260, CF-360; Freund Corporation),
a rolling granulator (MP10; POWREX CORPORATION), a general fluidized-bed
coating tus, a wurster type coating apparatus and the like is used, and a
centrifugal fluidized-bed ator is preferably used.
The compression molding is performed, for example, by punching generally at
a pressure of 03—35 kN/cm2 using a single-punch tableting machine (KIKUSUI
SEISAKUSHO LTD.), a rotary tableting machine (KIKUSUI SEISAKUSHO LTD.),
Auto-graph (Shimadzu Corporation) and the like.
Examples of capsules which can be used for capsule filling include n
capsules, hydroxypropylmethylcellulose (HPMC) capsules, pullulan capsules and the
like (preferably, hydroxypropylmethylcellulose (HPMC) capsules) Licaps®, Vcaps®,
Coni-Snap® caps, Press-fit® caps and Xpress-fitT'V' caps.
The above-mentioned core containing c acid is coated by the following
method or a method analogous thereto:
1) a method including spraying pioglitazone or a salt thereof er with
additives as necessary (preferably, an excipient [preferably crystalline cellulose
(which may be omitted), saccharides (preferably mannitol, trehalose, e)], a
disintegrant (preferably L-HPC)) onto the core containing an organic acid, while
spraying a solution of a binder (preferably, hydroxypropylcellulose) in a solvent [e.g.,
one or more kinds selected from water, alcohol (e.g., methanol, ethanol, propanol,
isopropanol), acetone and itrile; preferably water or isopropanol] (the on
may be a dispersion);
2) a method including spraying a solution of a binder (preferably,
ypropylcellulose) containing pioglitazone or a salt thereof, and an additive as
necessary rably, excipient [preferably crystalline cellulose (which may be
omitted), saccharides (preferably, ol, trehalose, e)], a disintegrant
(preferably, L-HPC)) in a solvent [ 9.9., one or more kinds selected from water,
alcohol (e.g., methanol, ethanol, propanol, isopropanol), e, acetonitrile;
preferably water or isopropanol] (the solution may be sion) onto the core
containing c acid;
3) a method including spraying pioglitazone or a salt thereof together with an
additive as necessary (preferably, ent rably, crystalline cellulose (which
may be omitted), sacCharides (preferably, mannitol, trehalose, sucrose)], a
disintegrant (preferably, L—HPC), and a binder (preferably, hydroxypropylcellulose))
onto the core containing organic acid, while, e.g., methanol, ethanol, propanol,
isopropanol), acetone, acetonitrile; preferably water or isopropanol]; or
4) a method including spraying pioglitazone or a salt thereof together with
cellulose or a cellulose derivative [preferably, cellulose derivative (more preferably L—
HPC)], and an additive as necessary (preferably, ent [preferably lline
cellulose (which may be omitted), saccharides (preferably, mannitol, trehalose,
sucrose)] onto the core containing organic acid, while spraying a on of a binder
(preferably, hydroxypropylcellulose) in a solvent [6.9, one or more kinds selected
from water, alcohol (e.g., methanol, ethanol, propanol, panol), acetone and
acetonitrile; ably water or isopropanol] (the solution may be dispersion).
The core of the coated preparation of the present invention preferably
consists of at least one kind of organic acid selected from citric acid, tartaric acid,
malic acid and ascorbic acid rably citric acid cularly ous citric
acid)].
In addition, the coating layer comprising pioglitazone or a salt thereof in the
coated preparation of the present invention preferably consists of pioglitazone or a
salt thereof (preferably pioglitazone hydrochloride), an excipient rably
crystalline cellulose (which may be omitted), saccharides (preferably mannitol,
trehalose, sucrose; more preferably mannitol)], a disintegrant (preferably L-HPC) and
a binder (preferably hydroxypropylcellulose), or it is a coating layer consisting of
pioglitazone or a salt thereof (preferably pioglitazone hydrochloride), an excipient
[preferably crystalline cellulose (which may be omitted), saccharides (preferably
mannitol, trehalose, sucrose; more preferably mannitol)], cellulose or a cellulose
derivative rably a cellulose derivative, more preferably L-HPC) and a binder
(preferably ypropylcellulose).
(b) Oral/y disintegrating tablet (CDT) Formulation
The invention provides for an orally egrating tablet wherein the active
ingredient is pioglitazone or a pharmaceutically acceptable salt thereof (for example
as described in USSN 12/810,779, ponding to US 278390, incorporated
by reference in its entirety).
Using the production method of the present invention, an orally disintegrating
, which is y disintegrated in an oral , has desired appropriate
hardness, and is superior in the storage stability since it shows only a small
se in the hardness and a small increase in the tablet thickness even under
high temperature and/or high humidity conditions without any packages, can be
easily produced by simple steps. In addition, using the production method of the
present invention, tableting troubles during tableting, such as capping and binding to
a die inner wall and the like can be suppressed.
As used herein, an orally disintegrating tablet or ODT means a tablet that is
rapidly egrated by saliva in an oral cavity.
The orally disintegrating tablet of the present invention may se (a) one
or more saccharides or sugar alcohols selected from the group consisting of
mannitol (particularly, D-mannitol), lactose (particularly, lactose hydrate), xylitol,
sucrose, erythritol and glucose (to be also referred to as component (a) in the
present specification) and (b) low substituted hydroxypropylcellulose (to be also
referred to as component (b) in the present specification).
As component (a), mannitol and lactose are preferable.
2012/020606
The content of component (a) is preferably 50-95 wt %, more preferably 70-90
wt %, of the weight of the preparation. Component (a) can also be optionally
dissolved in water and the like as mentioned below and used as a binding solution
for ion granulation. The content of the above-mentioned component (a) also
includes the amount used as the binding solution. When used as the binding
solution, the amount thereof is preferably less than 10 wt %, more preferably about
2-5 wt %, of the content of the above-mentioned component (a).
The average particle size of the saccharides and sugar alcohols of component
(a) is preferably not more than 50 pm, more preferably 10—20 pm. When the average
particle size exceeds 50 pm, the disintegration time tends to be extended.
The average particle size of the saccharides and sugar alcohols of the above-
mentioned component (a) means their initial average particle size of the ng
materials before being subjected to the agitation granulation and means that they
have a particle size within the mentioned range, and the average particle size
may change during the subsequent production processes and storage of the
preparation.
The rides and sugar alcohols of component (a) having an average
le size within the mentioned range are commercially ble.
Alternatively, the commercially available products may be pulverized with a
conventional method to adjust the particle size and thereafter used.
In one embodiment, the average particle size in the present specification
shows a 50% accumulated le size in the particle size distribution ed
based on a dry method using an airflow-type disperser.
In the present invention, the low substituted hydroxypropylcellulose does not
require a particular limitation on the grade and the like, and a commercially available
2012/020606
product can be used. For example, low substituted hydroxypropylcellulose having a
ypropoxyl group content of about 7.0-12.9 wt % can be used.
The content of the low substituted hydroxypropylcellulose is preferably 3-20
wt %, more preferably 5-15 wt %, of the weight of the preparation.
The orally disintegrating tablet of the present invention preferably contains (0)
one or more saccharides or sugar alcohols selected from the group consisting of
powder hydrogenated maltose starch syrup, maltose, maltitol, sorbitol and ose
(to be also referred to as component (c) in the present specification). The presence
of component (c) further increases the tablet hardness.
As component (0), powder hydrogenated maltose starch syrup and e
are preferable.
The content of component (c) is preferably 0.1-5 wt %, more preferably 0.1-1
wt %, of the weight of the ation.
The orally disintegrating tablet of the present invention does not substantially
contain a starch disintegrant (e.g., corn starch, sodium carboxymethyl starch, rice
starch, wheat starch, pregelatinized starch, partly pregelatinized starch etc.).
Here, substantially free of in the t specification means absence of an
amount that ely influences the storage stability of ations. Specifically,
the content of the starch disintegrant is preferably not more than 5 wt %, more
preferably not more than 3 wt %, still more preferably not more than 1 wt %, of the
weight of the preparation.
The orally disintegrating tablet of the present invention preferably contains
thaumatin. The content of thaumatin is preferably 0.1-5 wt %, more preferably 0.1-1
wt %, of the weight of the preparation. Thaumatin is a sweetener generally added for
masking the bitterness of an active ingredient. In the present invention, the presence
of thaumatin provides s of improved moldability during tion and
ased hardness.
Besides the above—mentioned components, the orally disintegrating tablet of
the present invention may contain additives generally used for solid preparations.
The additive is, for example, excipient, disintegrant other than starch disintegrant,
binder, lubricant, fluidizer, corrigent, sweetening agent, coating agent, colorant,
flavor and the like. The content of these additives is not particularly limited and may
be appropriately selected from an amount tionally used in the pharmaceutical
field. The total amount of the additives except for components (a) and (b) (when
component (c) is contained, the total amount of the additives except for components
(a)—(c)) is preferably not more than 50 wt %, more preferably not more than 25 wt %,
of the weight of the preparation.
The orally disintegrating tablet of the present invention contains pioglitazone
as an active ingredient. The content of the active ingredient may be appropriately
ined based on the amount used for clinical application, and it is preferably not
more than 50 wt %, more preferably not more than 25 wt %, of the weight of the
preparation.
The orally disintegrating tablet of the present invention is characterized by.
production including steps of granulating a composition containing the above—
mentioned components (a) and (b) rably the mentioned components (a),
(b) and (c)) by an ion granulation , and compression-molding the
obtained granulation product. It is considered that since the granulation product
s spherical by agitation granulation, tableting troubles (particularly, binding to
die inner wall) in the subsequent compression-molding step are prevented in the
present invention.
The production method of the orally disintegrating tablet of the present
invention is explained in detail in the following.
2012/020606
1. Granulation Step
The above-mentioned components (a) and (b) (preferably the above-
mentioned components (a), (b) and (c)), an optional active ingredient and/or an
optional additive are mixed. The additive is, for e, excipients.(e.g., talc),
disintegrants other than starch disintegrants (e.g., crospovidone), sweetening
agents, colorants, s and the like. The active ingredient may be mixed with an
excipient (e.g., talc) first and then coated with a coating agent (e.g., aqueous
ethylcellulose dispersion, tine) for the purpose of masking bitterness and the
like.
The above-mentioned mixture is granulated by an ion granulation
method. The agitation granulation method is also generally referred to as a high-
speed agitation granulation method. Here, the (high-speed) agitation granulation
method is a method including adding dropwise or spraying a binder solution on a
mixed powder by rotating the main wings set on the bottom of a ating machine
to form large particles, and grinding the particles by a chopper on the side wall to
give granules desired particle size (Yoshihisa SAGAWA, Pharmaceutical Product
Preparation Technique, CMC Publishing CO., LTD., published in 2002, page 108).
The granulation by an agitation granulation method can be performed by
using what is called an agitation granulator (also referred to as a high-speed
agitation granulator) (e.g., high-speed mixer, LFS-GS-ZJ (manufactured by Fukae
Powtec); VERTICAL GRANULATOR actured by POWREX CORPORATION);
NEW SPEED R actured by OKADA SEIKO CO., LTD.) etc). The
rotation speed of the main wings and chopper is not particularly limited, and may be
appropriately selected from the range generally used at agitation granulation.
ically, a binding solution (e.g., water or, where necessary, other additives may
be blended) is added to the above-mentioned mixture in the agitation ator, and
the mixture is granulated. When thaumatin is added in the present invention, though
not particularly limited, it may be added to the binding solution.
2. Compression Molding Step
To the granulation product obtained in the granulation step is added an
optional active ingredient and/or an optional additive (e.g., fluidizers (e.g., light
ous silicic acid), ants (e.g., magnesium stearate, sodium stearyl
fumarate, calcium stearate), flavors), and the mixture is blended and ssion-
molded by a tableting machine and the like. The compression molding pressure
(tableting pressure) may be appropriately selectedfrom the range generally used at
tablet production. While the pressure is not particularly limited, it is preferably not
less than 200 kg.
The orally disintegrating tablet of the present invention produced as
mentioned above has desired appropriate hardness, is rapidly disintegrated in an
oral cavity, and shows superior storage stability, even though it can be easily
produced without cumbersome steps of humidification and drying after tableting and
a special facility of an external lubrication system.
The hardness of the orally disintegrating tablet of the t invention is
generally about 3-6 kg when the tablet has a diameter of 6-7 mm and a thickness of
about 3 mm. Here, the hardness of the tablet in the present specification is a value
measured by a Schleuniger tablet ss tester (Dr. Schleuniger Pharmatron AG).
While the disintegration time of the orally disintegrating tablet of the present
invention in an oral cavity varies depending on the form of ation, close and the
like, it is generally within 60 sec, preferably within 30 sec.
The orally disintegrating tablet of the present invention is not particularly
d as regards the size and form, and may be a scored tablet having a ge
line.
The orally egrating tablet of the present invention can be ed
without water.
VI. Uses
The methods of the invention are used to delay onset of Alzheimer’s disease
or a phase or stage indicative of or associated with pment of Alzheimer’s
disease in a patient at risk of developing Alzheimer’s disease. The ion also
provides for pharmaceuticals that can be used to delay onset of Alzheimer’s disease,
a symptom f, or a phase or stage indicative of or associated with development
of Alzheimer’s disease in a patient at risk of developing Alzheimer’s disease.
Unless othenNise defined, all technical and scientific terms used herein have
the same meaning as commonly understood by one of ordinary skill in the art to
which this invention belongs. gh methods and materials similar or lent
to those described herein can be used in the practice or testing of the present
invention, suitable methods and materials are described below. All publications,
patent applications, patents, and other nces mentioned herein are incorporated
by reference in their entirety. In case of conflict, the t specification, including
definitions, will l. In addition, the materials, methods, and examples are
illustrative only and not intended to be limiting.
EXAMPLES
Having now generally described the invention, the same will be more readily
understood through reference to the ing Examples which are provided by way
of ration, and are not intended to be limiting of the present invention, unless
specified.
The following examples are put forth for illustrative purposes only and are not
intended to limit the scope of what the inventors regard as their invention.
EXAMPLE 1
Low Dose tazone Granules 1
Pioglitazone HCI (228.1 g), mannitol (ROQUETTE, 335.8 g) and L-HPC (LH—
32 Shin-Etsu Chemical Co., Ltd., 115.0 g) are mixed to give a dusting powder.
ypropylcellulose (HPC-SSL, NIPPON SODA CO., LTD., 9.2 g) is dissolved in
purified water (194.6 g) to give a binding liquid. Anhydrous citric acid crystal
unzlauer, 1380 g) is fed into a centrifugal fluidized-bed granulator (CF-360,
Freund Corporation) and coated with the dusting powder while spraying the binding
liquid. The resulting granules are dried under reduced pressure at 40°C for 18 hr,
and sieves of 16 mesh and 42 mesh are used to give granules at the range of 16 -
42 mesh (aperture 0.355 - 1.00 mm). The granUles (7193.6 9) are mixed with talc
(Matsumurasangyo Co., Ltd., 3.2 g) and light anhydrous silicic acid (AEROSIL, ,
NIPPON AEROSIL, 3.2 g) in a tumbler mixer (60 L, Showa Kagaku Kikai Kosakusho
IO Co., Ltd.) to give pioglitazone hydrochloride granules having the following
composition per 450 mg.
anhydrous citric acid crystal 300 mg
Pioglitazone HCI 49.59 mg
mannitol 73.01 mg
L-HPC 25 mg
hydroxypropylcellulose 2 mg
talc 0.2 mg
light anhydrous silicic acid 0.2 mg
total 450 mg
The ing composition can be diluted in an appropriate excipient to give
the d dosage, including any of the dosages recited herein, for example, 0.5
mg, 1.5 mg, 4.5 mg and 9.0 mg. The desired dosages can then be formulated into
oral dosage forms, such as capsules, tablets or caplets.
EXAMPLE 2
Low Dose Pioglitazone es 2
Pioglitazone HCI (9.90 9), mannitol (ROQUETTE, 186.29) and L-HPC (LH—32
tsu Chemical Co., Ltd., 39.96 g) are mixed to give a dusting .
Hydroxypropylcellulose (HPC—SSL, NIPPON SODA CO., LTD., 12.00 g) is dissolved
in purified water (340.2 g) to give a g liquid. Anhydrous citric acid l
(Jungbunzlauer, 400.0 g) is fed into a centrifugal fluidized—bed granulator (CF-260,
Freund Corporation) and coated with the g powder while spraying the binding
liquid. The resulting granules are dried under reduced pressure at 40°C for 18 hrs,
and sieves of 16 mesh and 42 mesh are used to give es of pioglitazone
hydrochloride at the range of 16 - 42 mesh (aperture 0.355 - 1.00 mm) having the
following composition.
anhydrous citric acid crystal 53.33 mg
pioglitazone HCl 1.102 mg
mannitol 20.69 mg
L-HPC 4.44 mg
hydroxypropylcellulose 0.36 mg
total 79.92 mg
EXAMPLE 3
Low Dose Pioglitazone Capsules
The low dose pioglitazone granules 2 formulated in Example 2 (39.96 g) are
mixed with talc (Matsumurasangyo Co., Ltd., 0.02 g) and light anhydrous silicic acid
(AEROSIL, NIPPON AEROSIL, 0.02 g) in a glass bottle to give pioglitazone
hydrochloride es having the following composition per 80 mg. The pioglitazone
hydrochloride granules (80mg) are filled in No. 4 hypromellose capsules (Qualicaps
Co., Ltd.) to give capsules having the following composition.
Component amount added
granule obtained in e 2 79.92 mg
talc 0,04 mg
light anhydrous silicic acid 0,04 mg
No. 4 hypromellose capsule 1 capsule
EXAMPLE 3
Pioglitazone Liguid Formulation 1
A liquid formulation of pioglitazone is prepared using the materials as s.
Materials:
Citric Acid, Sigma, C1857, lot 089K005?
Distilled Water, Ice Mountain
HPMC, USP, Sigma, H-3785, lot 122K0149
Pioglitazone l-lCI, Takeda, lot 345
Polyethylene Glycol 200, Sigma, P3015, lot 098K0056
Polysorbate 80, NF, Spectrum, P0138, lot XV0879
Propylene Glycol, USP/FCC, Fisher, P355, lot 080676
Sucrose, USP, Sigma, 83929, lot 086K0022
Syrup NF, Spectrum, SY105, lot XP0703
Approximately 0.014969 of pioglitazone HCI is transferred into a 50-mL
graduated cylinder. 0.699 of polyethylene glycol 200 is added and mixed to wet the
solids. 1.51 g of propylene glycol is added and the resulting mixture is d and is
sonicated to mix and dissolve the . 1.48 g of polysorbate 80 is added and is
d to mix. 3 9 of citric acid is added and is swirled to mix. Some citric acid
solids remain undissolved. Approximately 10mL of distilled water is added and is
swirled to mix/dissolve the solids. The mixture is d to 50mL with distilled water
and is mixed well such that all solids are in solution to formulate a liquid having the
following pioglitazone concentration of about 15 mg/50 mL or 0.3 mg/mL.
In practicing the methods of the present invention, a ed low dose
tazone can be administered to a subject using the pioglitazone liquid of this
Example 4. For example, 5 mL or a teaspoonful will deliver a dose of about 1.5 mg
pioglitazone HCI, whereas as 15 mL or a tablespoonful will deliver a dose of about
4.5 mg of pioglitazone HCI. Two tablespoonfuls or about 30 mL of the pioglitazone
liquid of this Example 4 will deliver about 9 mg of pioglitazone HCI per dose.
EXAMPLE 5
Pioglitazone Liguid Formulation 2
A liquid formulation of pioglitazone is prepared using the materials as follows.
Materials:
Citric Acid, Sigma, C1857, lot 089K005?
Distilled Water, Ice Mountain
HPMC, USP, Sigma, H-3785, lot 122K0149
Pioglitazone HCI, Takeda, lot 345
Polyethylene Glycol 200, Sigma, P3015, lot 098K0056
Polysorbate 80, NF, Spectrum, P0138, lot XV0879
Propylene Glycol, C, , P355, lot 080676
Sucrose, USP, Sigma, $3929, lot 086K0022
Syrup NF, Spectrum, SY105, lot XPO703
Approximately 0.016139 of pioglitazone HCI is added to a 50-mL volumetric
flask. 1.0043 g of citric is acid is added. Approximately 25mL of distilled water is
added and the resulting mixture is swirled and is sonicated to wet the . The
mixture is diluted to volume, i.e., about 50 mL, with led water, is mixed well and
then is sonicated for 1 — 2 minutes such that all solids are in solution.
The liquid pioglitazone solution ofthis Example’5 will have the following
pioglitazone concentration of about 16.13 mg/50 mL or 0.326 mg/mL.
In practicing the methods of the present ion using the liquid pioglitazone
solution of this Example 5, a selected low dose pioglitazone can be administered to a
subject. For example, 5 mL or a teaspoonful will deliver a dose of about 1.63 mg
tazone HCI, whereas as 15 mL or a tablespoonful will deliver a dose of about
4.89 mg of pioglitazone HCI. Two tablespoonfuls or about 30 mL of the tazone
liquid of this Example 5 will deliver about 9.78 mg of pioglitazone HCI per dose.
2012/020606
EXAMPLE 6
Pioglitazone Suspension Formulation 1
A suspension formulation of pioglitazone is prepared as follows.
Preparation of Pioglitazone HCI Suspension A: Suspending Vehicle is Syrup
NF (density of Syrup NF is 1.30 g/mL).
0.025 g of Pioglitazone HCI Drug Substance is transferred into a glass mortar
and pestle. The Pioglitazone HCI is wetted with about 4 drops of the Suspending
Vehicle and mixed/ground for about 1 minute to form a smooth uniform paste. The
suspending vehicle is added until the total weight in the mortar and pestle is about
lg. The ing mixture is mixed/ground for 1 . More suspending vehicle is
added until the total weight is about 89. The resulting mixture is mixed for 1 minute.
More suspending vehicle is added until the total weight is about 489 and then mixed
for 1 minute. Suspending Vehicle is added until the total weight of the suspension is
130.04 9 and mixed for 1 minute. The mixture from the mortar is poured into a 402
reagent . The bottle is capped and the suspension is shaken by hand for about
1 minute.
The theoretical concentration of tazone HCI is determined;
.60mg/130.04 g = 0.1969 mg/g (as the HCI salt — not the free base)
.60mg/100mL = 0.2560mg/mL (as the HCI salt — not the free base)
In practicing the methods of the present ion using the liquid pioglitazone
sion 1 of this Example 6, a selected low dose pioglitazone can be
administered to a subject. For example, 5 mL or a teaspoonful will deliver a dose of
about 1.28 mg pioglitazone HCl, whereas as 15 mL or a tablespoonful will deliver a
dose of about 3.84 mg of tazone HCI. Two tablespoonfuls or about 30 mL of the
liquid pioglitazone suspension 1 of this Example 6 will deliver about 7.68 mg of
pioglitazone HCI per dose.
EXAMPLE 7
Pioglitazone Suspension Formulation 2
Preparation of Suspending Vehicle B: 0.6% HPMC + 10% Sucrose
0.6% HPMC Solution:
1000 mL of distilled water is transferred into a 2—L Erlenmeyer flask. The
water is heated to 60°C with constant stirring. 6 g of HPMC is d and is
dispersed uniformly into the heated water. Heating of the mixture is continued until it
just reaches boiling. The mixture is removed from the heat and is placed in an ice
bath with constant stirring. The mixture is stirred until it clarifies and cools to room
temperature.
ding e: (0.6% HPMC with 10% Sucrose):
809 of e is added to a 1000—mL glass bottle. 50 mL of distilled water is
added and the mixture is mixed by shaking such all of the solids are dissolved. 0.6%
HPMC Solution is added until the total weight is 800 g. The mixture is shaken to
dissolve the solids.
The density of the solution is 103.869/100mL.
Preparation of Pioglitazone HCI Suspension B: Suspending Vehicle is 0.6% HPMC
+10% Sucrose
0.025 g of Pioglitazone HCI Drug Substance is transferred into a glass mortar
and pestle. The Pioglitazone HCI is wetted with about 4 drops of the ding
Vehicle and is mixed/ground for about 1 minute to form a smooth uniform paste.
Suspending vehicle is added until the total weight in the mortar and pestle is about
19. The mixture is mixed/ground for 1 minute. Additional suspending e is
added until the total weight is about 89 and then mixed for 1 minute. onal
suspending vehicle is add until the total weight is about 209 and then is mixed for 1
minute.
Additional suspending vehicle is added until the total weight is about 40g — 50
g and then is mixed for 1 . Suspending Vehicle is added until the total weight
ofthe suspension is 103.31 g and is mixed for 1 minute. The mixture is poured from
the mortar into a 402 reagent bottle. The bottle is capped and the suspension is
shaken by hand for about 1 minute.
The theoretical concentration of pioglitazone HCI is determined;
26.44mg/103.31 g = 0.25593 mg/g (as the HCI salt — not the free base)
26.44mg/100mL = 0.2644mg/mL (as the HCI salt— not the free base)
In cing the methods of the present invention using the liquid pioglitazone
suspension 2 of this Example 7, a selected low dose pioglitazone can be
administered to a subject. For example, 5 mL or a teaspoonful will deliver a dose of
about 1.322 mg pioglitazone HCI, whereas as 15 mL or a tablespoonful will deliver a
dose of about 3.966 mg of pioglitazone HCI. Two tablespoonfuls or about 30 mL of
the liquid pioglitazone suspension 2 of this Example 7 will deliver about 7.932 mg of
pioglitazone'HCl per dose.
Heretofore there has not been an ability to predict which people are more
likely to develop pathophysiological changes of the kind described herein that lead to
ive impairment and ultimately Alzheimer’s dementia.‘The TOMM40
rs10524523 genotype along with age and possibly other factors tute a
prognostic biomarker to determine which subjects are at risk for developing cognitive
impairment of the mer’s type in the next 5-7 years, and thus provide the
opportunity for medical ention in the early phase of this progressive and
devastating disease. The clinical benefit of this intervention may be confirmed in a
clinical study of thegeneral form bed below. In addition, a prospective clinical
study of this nature Would provide sufficient data to determine the positive predictive
and negative predictive values of the prognostic biomarker, an understanding of
which is needed prior to introduction of the biomarker into clinical practice.
OPAL Study
rs10524523 (523) is a poly-T length polymorphism that occurs in
linkage disequilibrium (LD) with APOE genotypes, and is inherited together with the
APOE genotype on each strand in the LD region. Essentially a single intronic variant
of TOMM40 varies by poly-T length, with the longer forms of the variant ated
with approximately a 7 year difference in the age of onset compared to the r
forms. Based on the presenting age of the normal subject, a determination of 'High
risk' of onset of cognitive impairment and AD over the next 5-7 years, or 'Low risk' is
determined.
This study provides a novel genetically-based model for the identification of
subjects in large diverse community-based tions who are at higher risk of AD
onset within 5—7 years by combining clinical risk assessments based on the presence
of specific pes related to Alzheimer’s disease onset and clinical expression.
The study:
0 uses the TOMM4O rs10524523 (523) poly-T length polymorphisms in the
TOMM4O - APOE LD region, perhaps in conjunction with the APOE
genotype, for predicting the age of onset of ive impairment and
Alzheimer’s e. Specifically, to determine if a discrete Alzheimer’s
disease diagnostic test can separate subjects into 'High—risk' and 'Low—risk
'groups for Alzheimer’s disease; and
. uses a low dose PPARy Agonist daily for 60 months (5 years) versus
placebo in pre-symptomatic subjects who are at High risk as d by
their TOMM4O - APOE genotype of Alzheimer’s disease, to delay the
onset of Alzheimer’s disease related ia symptoms.
Cognitively normal ts n the ages of 62 — 87 are evaluated for
susceptibility to AD within the next 5-7 years and are tested for effects of
pioglitazone on onset of AD. The definition cognitively normal is calculated as
within 1.5 standard deviations (SD) of the population mean taking into account the
age of the subject and the level of education for the assessments listed below.
Scores below this cut off are ered cognitively impaired. The following
ive ments are used to assess cognitive function at enrollment and
throughout the course of the study.
The cognitive assessment scales are chosen to be ive to early deficits in
Alzheimer’s disease. These assessment scales are used in the ADAPT study (1),
which is a prevention study for Alzheimer’s disease using NSAID therapy carried out
in 2004. The Mini Mental examination (2MS-E) is used in the Women's Health
Initiative Study for hormone replacement therapy (2) for the prevention of AD. Thus,
the cognitive assessments include:
. Modified Mini Mental State ‘Examination (3MS-E)
. Brief Visuospatial Memory Test ed) (BVMT—R)
. Hopkins Verbal Learning Test (Revised) (HVLT - R)
o Rivermead Behavioural Memory Test (RBMT)
. Generative Verbal Fluency Test (GVFT)
. Digit Span Test (DST)
Enrollment into the study is based solely on the scores from these
assessments. For randomization into the study, the individuals in addition are
given a DNA test ting of APOE genotyping and measurement of the
523 poly-T repeat lengths to assess their risk status as 'High risk' or 'Low risk'
of developing cognitive impairment or AD over the next 5-7 years. The
following designs describe the study procedure
Study design assumptions
The end points are 1) change in a measure of cognition from baseline based
. on the scores from the neuropsychological assessments and 2) diagnosis of
Alzheimer’s disease in accordance with NINCDS-ADRDA ia (National Institute
of Neurological and icative Disorders and Stroke (NlNCDS) and
WO 96873
Alzheimer's Disease and Related Disorders Association (ADRDA). These are either
taken as two primary end points or a combined event end point.
Sample Size Calculations
The sample size calculation is ined for a log-rank test of time to
event data based on the above end points. It is assumed that the conversion
rate for the 'High risk' group will be 20% at the end of 5 years follow-up based
on data from previous prevention studies (3,4). A sample size of 374/group is
required to detect a 50% improvement in this conversion rate (i.e. from 20% to
10%) at the 5% level of significance and with 90% power. A drop out rate of
% for both o and treatment groups over the five year period is built into
this calculation. This sample size is not adjusted for multiple comparisons.
A further assumption is made that the 'Low risk' group has a conversion rate
of 10% based on incidence rates of Alzheimer’s disease. in the general population
(4). The sample size required to compare this group with the 'High risk' placebo
group is again 374/group with 90% power and a 5% significance level.
Study s
The diagnostic test defines which patients are at 'High risk' of conversion to
Alzheimer’s disease or cognitive impairment, (High risk) and which patients are at
'Low risk' of conversion (Low risk). The investigators are d to the s of the
diagnostic test and central ization is used to maintain this blind. The main
objectives for any design are:
to determine whether the diagnostic test can discriminate between 'High' and
'Low risk' subjects, and
to evaluate the effect of treatment on the conversion rate of 'High risk'
patients.
All subjects recruited for these studies will be cognitively normal as
defined previously.
Preferred study design
Treatment (n=374)
High risk —> Randomize
\Placebo (n=374‘)
Diagnostic
Low risk —--——-———————-————> Placebo (imam)
In this design, only the 'High risk' group is randomized to receive placebo
or treatment. This is a simple design that, for example, utilizes a total sample size
of 1122 subjects. This design allows two hypotheses to be investigated: the first
relates to the ability of the diagnostic to define the ’High' and 'Low risk' groups by
comparing the data from the placebo treated subjects; the second relates to
whether the treatment can e the conversation rate by comparing the data
from the treatment and placebo groups of the 'High risk' arm.
Alternative design 1
Treatment (n=374)
High-’nsk +-'—> Randomize
/ /\Placebo )
' /
Diagnostic
.\_ Treatment )
Low risk ——-—~> Randomize /\
Placebo (n=374)
In this design a fourth group is added to allow the effect of treatment to be
evaluated in the 'Low risk' group. This design may increase the total sample size
to 1496 patients.
This design may provide useful information if the 'Low risk' group has a
higher than expected conversion rate. However, there are potential concerns with
this design in terms of risk/benefit to the 'Low risk' group. ts in the 'Low
risk' group might be at risk of encing side effects with treatment with no
expected benefit to their conversion rate.
Alternative design 2
Treatment (n=374)
High risk -—-—> ize
\Placebo ($374.7),
Diagnostic
\ Low risk ——D- Udtreatedi«’('n‘=".374)
This design is the same as the preferred design except that the 'Low risk'
group remains untreated and serves as an observational group. This design will
be able to meet the objectives of the study but there are a number of potential
pitfalls:
o unable to blind the untreated arm so results of the diagnostic test will not
be blinded,
. possibly higher drop out rate in the ‘Low risk' group if subjects feel that
being observed but not 'treated' is without benefit.
. will not be comparing like with like which could be an issue if there is a
'placebo' effect (unlikely for time to event but possible for cognitive
testing).
The sample size calculations are based on detecting a difference of 10
percentage points between conversion rates at the end of 5 years. An increase in
s allows a signal to be detected earlier with a r ence. If it is
assumed that the conversion rate in the 'High risk' group is 5°/o/year then after three
years approximately 15%iof the subjects may have converted to Alzheimer’s disease
or show cognitive impairment. Assuming that ent can improve this rate by 50%
then the expected conversion rate in the treated group will be 7.5%. In order to
detect the difference with 90% power an the 5% significance, 559 subjects per group
will be required resulting in a total sample size for the preferred design of 1677. This
increase in subject numbers permits investigation of a family of age of onset curves
associated with each TOMM4O — APOE haplotype. An atory analysis is used
to investigate the effects of age by including age as a covariate in a Cox's
proportional hazards time to event analysis, which allows the igation of
covariates. A certain percentage of subjects are defined as having mild cognitive
impairment (MCI) based on the neuropsychological assessments at screening. The
study will only recruit those ts who are defined as cognitively normal based on
the neuropsychological assessments.
References
1) ADAPT Research Group: Cognitive Function Over Time in the
Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) Results
of a Randomized, Controlled Trial of Naproxen and Celecoxib: Archives
of Neurology, Vol 65 (No 7), July 2008
.2) Stephen R. Rapp; Mark A. Espeland; Sally A. Shumaker et al: Effect of
Estrogen Plus Progestin on Global Cognitive on in
Postmenopausal Women, The Women's Health Initiative Memory Study:
2003;289(20):2663-2672 JAMA
3) Curtis L. Meinert, John C. S. Breitner: Chronic disease long-term drug
prevention trials: Lessons from the Alzheimer's Disease Anti-
matory Prevention Trial (ADAPT): Alzheimer's & Dementia 4
(2008) 87-814
4) Stephen Salloway, Stephan Correia: Alzheimer e: Time to
improve its diagnosis and treatment: Cleveland Clinic Journal Of
ne Volume 76, Number 1 January 2009
) ADAPT Research Group: Cognitive Function Over Time in the
Alzheimer's Disease Anti-inflammatory tion Trial (ADAPT) Results
of a Randomized, Controlled Trial of Naproxen and Celecoxib: Archives
of ogy, Vol 65 (No 7), July 2008
6) Stephen R. Rapp; Mark A. Espeland; Sally A. Shumaker et al: Effect of
Estrogen Plus Progestin on Global ive Function in
Postmenopausal Women, The s Health Initiative Memory Study:
2003;289(20):2663-2672 JAMA
7) Curtis L. t, John C. S. Breitner: Chronic e long-term drug
prevention trials: Lessons from the Alzheimer's Disease Anti-
inflammatory Prevention Trial (ADAPT): Alzheimer's & Dementia 4
(2008) 87-814
8) Stephen Salloway, Stephan Correia: Alzheimer disease: Time to
improve its diagnosis and treatment: Cleveland Clinic Journal Of
Medicine Volume 76, Number 1 January 2009
EXAMPLE 9
BOLD Study
The invention es for the following exemplary dose finding analysis.
The invention provides for measuring pharmacodynamic changes in se
to different low doses of pioglitazone. The pharmacodynamic measure that is
relevant is a change in regional blood oxygenation coupled to neuronal activity as
measured by blood oxygen level dependent functional magnetic resonance g
(BOLD fMRl).
rotection and mitochondrial esis are among the phySiological
effects of lidinediones. In one embodiment, pioglitazone treatment of subjects
may se the metabolic capacity of active regions of the brain. This change in
metabolic capacity may be observable using BOLD fMRI.
BOLD fMRI is a widely used technology for non-invasive whole brain imaging. .
This technique measures a change in regional blood oxygenation coupled to
neuronal activity.
BOLD fMRl measures the relative change in the ratio of oxy-to
deoxyhemoglobin in the brain that occurs as a result of neuronal activity. As neurons
become active, there is a concomitant increase in cell metabolism, and blood flow
increases to regions of increased neuronal activity to meet these metabolic
demands. The result of this hemodynamic response is a measurable change in the
local ratio of oxy-to deoxyhemoglobin. Oxyhemoglobin is diamagnetic and
deoxyhemoglobin is paramagnetic and this difference in magnetism is detected by
BOLD fMRl.
BOLD signals reflect complex and incompletely understood changes in
cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral lic rate
of oxygen consumption (CMROZ) following neuronal activity. Candidate circuit
elements for triggering various kinds of BOLD s include excitatory neurons,
mixed neuronal populations, astroglia, and axonal tracts or fibres of passage
(described in detail in Lee et al., 2010 Nature 465: 788-792; etis 2008 Nature
453: 869-878; Logothetis et al. 2001 Nature 412: 150-157l; Raichle 2010 Cell 14:
180—190, each of which is incorporated herein by reference in its entirety).
The study will utilize healthy, cognitively normal, older subjects of the age of
interest, e.g., n 62 and 87. BOLD fMRl scanning will be performed using a
scanner optimized for high-resolution structural and functional brain imaging (for
example a of—the—art GE 3 Tesla scanner).
In one embodiment, the study is a double-blinded study using multiple
cohorts, with each cohort receiving a ent tazone dose. In r
embodiment, the study is of a serial design wherein the same cohort es
multiple different drug doses. The pharmacodynamic marker used to indicate
changes in neuronal activity as a result of exposure to pioglitazone is a change in
BOLD signal, especially in the dorsolateral prefrontal cortex and hippocampus which
are associated with the higher cognitive functions that are impaired in Alzheimer’s
disease.
Each participant will undergo MRI scanning on at least three occasions:
1. pre-dose (to obtain a baseline or control value for each subject);
2. soon after receipt of the first dose (either at 2 hours or the imate time of
Cmax) to measure the result of acute exposure to drug; and
3. following 7 days of drug re (when pioglitazone serum concentration should
each steady state and physiological effect of drug on mitochondrial function should
have occurred).
Pioglitazone will be given every day for 7 days.
45 mg of tazone (the marketed formulation for the treatment of type 2
diabetes) results in a Cmax of approximately 3 mM in serum (see Ghosh et al. 2007
Mol. Pharmacol 71: 1695-1702).
The test doses include:
a) 0.5 mg dose-approximately 33.3 nM serum and approximately 6.7 nM brain
b) 1.5 mg dose-approximately 100 nM serum and approximately 20 nM brain;
c) 4.5 mg pproximately 300 nM serum and approximately 50 nM brain;
d) 9 mg pproximately 600 nM serum and approximately 120 nM brain.
Magnetic Resonance Imaging Protocol Summary
General Participant Screening Procedure
Participants will be screened for ferrous metal implants that would preclude
scanning prior to selection. Participants will be instructed to fast and abstain from
o products and exercise for two hours prior to the scan session, and
_ caffeine,
refrain from drinking alcohol and taking non-essential medication for twelve hours
prior to scanning. Participants taking stimulant medications will be asked not to take
them for at least 24 hours with physician al. Two breath samples will be
obtained to measure alcohol levels . Urine samples will be obtained to test 'for 5 drug
metabolites (psychostimulants, cannabis, s and sedatives). Female
participants will be given a urine pregnancy test, which must be negative for the
participant to undergo scanning.
General Scanning Protocol
Subjects will be provided the opportunity to enter an MRI simulator to assess
their t level for participating in the MRI session. Participants will then be
instrumented for heart rate (photoplethysmograph) and blood pressure monitoring
and will be positioned in the r. Head nt will be minimized using a
combination of pillows and tape. After acquiring localizer scans, the protocols will be
presented in the following fixed order, with a total scan time of approximately 60
minutes.
Structural MRI. Measures of total and regional gray and white matter as well
as CSF will be collected using high tion MRI.
Technical s: T1-weighted images with 1 mm isometric voxels will be
acquired using the Array Spatial Sensitivity Encoding Techniques (ASSET) with fast
d gradient-recall (FSPGR). Image parameters will be optimized for contrast
between white matter, gray matter and CSF (TR/TE/flip angle=7.484 ms/2.984
, 256 mm FOV, 1 mm slice, 166 slices, 256x256 matrix, 1 Nex).
Perfusion MRI. Measures of total and regional resting cerebral blood flow will
be collected using Pulsed al Spin Labeling (PASL).
Technical s: Interleaved images with and without labeling will be
acquired using a gradient echo-planar imaging (EPI) sequence. Acquisition
parameters consist of the following: field of view (FOV) = 22 cm, matrix = 64 x 64,
repetition time (TR) = 3 sec, echo time (TE) = 17 msec, label time = 1.6 sec, delay
time = .8 sec, flip angle = 90°. The resting perfusion scanning protocol takes
approximately 6 minutes during which subjects will be instructed to lie still ad‘let their
minds go blank, but keep their eyes open and stay awake. Data corresponding to
fourteen slices (8 mm thickness with 2 mm gap) will be acquired in sequential order
from inferior to superior.
Functional MRI . Archival working and episodic memory stimulation
gms will be administered to measure patterns of neural activation, especially in
the dorsolateral prefrontal cortex and hippocampus, associated with higher cognitive
functions impaired in mer’s disease using blood oxygen level-dependent
(BOLD) fMRl.
Technical Details: A series of 34 interleaved axial functional slices will be
acquired for rain coverage (TR/TE/flip=2000/31/60; FOV= 240 mm; 3.75 x 3.75
x 3.8 mm voxels; interslice skip = 0) using an inverse-spiral pulse ce to
reduce susceptibility ct. High-resolution three-dimensional spin-echo co-planar
structural images will be acquired in 68 axial slices (TR/TE/flip=12.2/5.3/20, voxel
size: 1 x 1 x 1.9 mm, FOV = 240 mm, interslice skip = 0) for normalization and
subject averaging.
fMRl Stimulation Paradigms Working Memory; See Mattay et al., PNAS 2003
for details. Episodic Memory: See Bookheimer et al. New England Journal of
ne 2000 for details.
EXAMPLE 10
Rat BOLD Study
Low dose pioglitazone penetrates the blood brain barrier and induces
changes in brain physiology.
It was determined whether low doses of pioglitazone HCl penetrate the blood
brain barrier in ient concentrations to elicit functional or molecular changes in
the brain. BOLD fMRI was used to measure drug-related changes in resting state
functional connectivity across the whole brain.
Adult male Wistar rats (275 :t 25 g) were housed separately and maintained
on a 12-h light,12-h dark schedule. Food and water was provided ad libitum. Animals
were cared for in accordance with the guidelines published in the Guide for the Care
and Use of Laboratory Animals (National Institutes of Health Publications No. 85-23,
d 1985). Animal body weights were measured approximately 24 hours before
Day -3, and on Study Days 3 and 6.
Pioglitazone HCl (PIO) was ved in 0.5 mol/L citric acid (CA) to yield a
stock solution at a concentration of 0.32 mg/10 mL/kg. Other dosages were prepared
by appropriate dilution of the stock solution with 0.5 mol/L CA to yield dose volumes
of 10 mL/kg. Control rats received the vehicle at 10 mL/kg. Dose concentrations
were based on the weight of the test article as supplied (i.e., as the HCI salt), with
the dose adjusted to the most recent body weight of the animal. Daily closing with
PlO in solution was by oral gavage at approximately the same time every day.
Animals were anesthetized lightly with isoflurane immediately beforehand to facilitate
dosing.
All animals used in the g studies were ated to the MRI holding
device by being placed in it for 15-90 minutes daily for at least 7 days, as previously
described (Zhang et al. 2010 J Neurosci Methods 189: 186-196; Liang et al. 2011 J
Neurosci 31: 783).
After the acclimation period, animals were assigned to 1 of 7 treatment arms
d for mean body weights (see Table 1). Dosing occurred once daily, at
approximately the same time every day. All animals were imaged at Baseline (Study
Day -3), approximately 2.5 to 3 h after dosing with vehicle. Dosing began 3 days
later (Study Day 1). On this day, all animals were stered either vehicle (CA) or
PIO depending on their group ment. On Study Day 2, one vehicle group and
one group treated with PlO at 0.08 mg/kg/day (Acute Arm) were imaged
approximately 2.5 to 3 h after dosing. For all groups, dosing continued for seven
days total. On StudyDay 7, all rats were imaged approximately 2.5 to 3h after
administration of the final dose.
Table 1.Treatment Arms, Dail PIO Dose and Ima_in Time Points
Treatment Daily Dose Ima- in_ Time—Points
Arm (mg/kg) Study Day -3 Study Study
(N=5/group) Baseline Da 2 Da 7
o 008 —_—
Sub-chronic 0, 0. 04, 0. 08, No'1maging
0.16, 0.32
Extrapolation to the corresponding dosage in humans was achieved while
adjusting for the relative AUC for each. In humans, a dose of 7.5 mg is associated
with an AUC of 2.8 ug'h/mL. In rats, a dose of 0.50 mg/kg/day PIO HCI is associated
with an AUC of 7.11 ug-h/mL. s of these calculations are presented in Table 2.
Table 2.Rat and E uivalent Doses, Based on Extra olated Exosures
Human Dose (m_ total/da )
Parameter —-—
(mg/kg/day) -
Targeted
(ugh/mL)
Animal preparation activities related to imaging were initiated to insure that
the g itself occurred imately 2.5 to 3 h after dosing. The s were
prepared for positioning in the restraint under isoflurane anesthesia as previously
described (Zhang et al. 2010, supra).This procedure took approximately 10—15
minutes, by which time animals were usually fully conscious. Imaging was conducted
on awake animals.
All MR experiments were conducted using a 4.7T/40cm horizontal magnet
(Oxford, UK) aced with a BiospecBruker console (Bruker, y) and
equipped with a 20G/cm magnetic field gradient. A dual 1H radiofrequency (RF) coil
configuration (Insight Neurolmaging Systems, Worcester, MA) consisting of a
volume coil for exciting the water proton spins and a surface coil for receiving MRI
signal was used; the volume and surface coils were actively tuned and detuned to
prevent mutual coil ng. This dual-coil configuration allowed for sufficient RF
field homogeneity in the rat brain for RF transmission, while preserving the
age of higher signal-to-noise ratio (SNR) provided by the smaller reception
coil.
Anatomical images were acquired first using a multi—slice fast spin-echo
sequence (RARE) with the parameters: repetition time (TR) = 2125 ms; RARE factor
= 8; effective echo time (TE) = 50 ms; matrix size = 6; field of view (FOV) =
3.2><3.2 cm2; slice number = 18; slice thickness = 1 mm; n = 8. Based on the
geometry of anatomical images, multi-slice gradient—echo images covering the whole
brain were acquired using echo-planar imaging (EPI) with the parameters: TR = 1 5;
Flip Angle = 60 ; TE '= 30 ms; matrix size = 64xe4; FOV = 3.ZX3.2 cm2; slice
number = 18; slice thickness = 1 mm. Rats were at rest during image acquisition. 4
200 volumes were acquired for each run; 9 runs were ed for each rat.
Analysis of all fMRI data was conducted using Medical Image Visualization
and Analysis (MlVA), Statistical Parametric Mapping (SPM8) software (Wellcome
Department of Cognitive Neurology, London, UK) and Matlab (The Mathworks |nc.,
Natick, MA, USA). The data was initially corrected for motion hold of 0.25 mm).
Further pre-processing of the data included (a) slice scan time correction, (b) spatial
smoothing using a 3D Gaussian filter (1-mm FWHM) to account for small variations
in signal due to movement and vascular effects, and (c) voer—wise linear detrending
and high-pass filtering of frequencies (3 cycles per time course) to adjust for scanner
drift between runs. Structural and functional data of each animal was then
transformed to rd stereotaxic space embedded in MlVA to tate group
analysis of onal data.
Correlational functional connectivity analysis was used to analyze resting-
state functional connectivity. First, each animal was aligned and istered, based
on anatomical images, to a fully segmented rat brain atlas. The co-registration
procedure will provide the coordinates of each seed region of interest (ROI) in the
image space. After co-registration and alignment, fMRI time courses for individual
voxels in a seed ROI were obtained according to their corresponding coordinates. A
time course for each seed region was created by regionally averaging time courses
from all pixels inside the seed ROI. All ROI time courses were 0.002—0.08 Hz band-
pass filtered. After filtering, the Pearson cross-correlation (CC) coefficient between
ROI time courses was calculated and used to quantify the strength of functional
connectivity.
To evaluate the effects of PlO on functional connectivity across the whole
brain, we divided the whole rat brain into 57 ROls. The strength of functional
IO connectivity between each pair of ROls was evaluated using the cross-correlation
coefficient between the two ROI time courses. In total 57XS6/2=1596 functional
connections were assessed for each rsfMRl runs. This procedure was ed for
all 9 runs of each fMRl session and the connectivity strength of the corresponding
connection was then averaged across 9 runs. As a result, the connectivity strength of
15% connections was obtained for each rsfMRl scan session.
For each connection (i.e. a tion between each pair of ROls), repeated
measure ANOVA with the factors of imaging day, dosage and interaction were then
calculated. Statistical significance level was set at P<0.005, uncorrected.
To evaluate the effects of PIO on the dual neural circuitries, seed-based
correlational analysis was used (Zhang et al. 2010, . The CA1 of the
hippocampus was ed as the seed ROI. The spatial n of brain regions that
are functionally connected with the seed ROI was ated in a voxel-by-voxel'
manner. First, the regionally averaged time course of the seed ROI was obtained as
a reference. Cross-correlation coefficient between the time course of each voxel and
the reference time course was then ated. The correlation coefficient
represented the functional connectivity strength n this voxel and the seed. A
connectivity map for the seed ROI was created for each fMRl run and maps across
nine runs were then ed to create the tivity map for each scan session.
At last, a composite connectivity map was generated by averaging connectivity maps
across rats of the same group that were imaged on the same day in the protocol
(Zhang et al. 2010, supra).
Figure 1 provides an example of the fMRI data and demonstrates that even
the lowest doses of orally-administered, immediate release pioglitazone produce a
change in metabolism in the central region of the deep al structures of the
brain. This is consistent with an intracellular mitochondrial effect
Conclusions
1. Relative to vehicle control, there is evidence that PlO treatment at doses as
low as 0.04 mg/kg/day induces s in multiple brain regions in the rat.
This result indicates that se PIO, administered orally, penetrates the
blood brain barrier.
2. PlO, at doses as low as 0.08 mg/kg/day, induced functional changes as early
as 24 hours, which was the earliest time point assayed after initiation of
treatment.
As seen in Figure 1, there appears to be a diminished signal at the 0.32
mg/kg/day dosage based on the appearance of these data. However, further
testing will be done in order to confirm whether or not there is an actual
diminished effect at this dosage relative to the lower dosages, and not simply
reflecting intrinsic ical variability between the animal ts.
EXAMPLE 11
Exemplary Risk Determination
in order to identify ts having normal cognition who are at high risk
of developing cognitive impairment of the Alzheimer type (also termed
ampal type) in the next 5 years based on TOMM40 rs1054523 (523)
genotype, age, and possibly APOE genotype, age-of-onset data were studied
WO 96873
from a cohort of 438 ctively followed individuals from the Duke Bryan
ADRC Memory Health and Aging study.
Table 3 izes an exemplary risk categorization based on 523 and
APOE genotypes and age. Note that there appears to be a subset of VLNL,
APOE 53/53 subjects who succumb to the onset of Alzheimer’s disease
between the ages of 51 and 59. These subjects are not considered in Table 3,
which presents only the low risk subset of VLNL carriers who are cognitively
normal after age 62. An expanded risk categorization that includes the younger
_10 ‘high risk’ VLNL APOE 53/53 subjects is also contemplated.
Table 3. ary Age Thresholds That Define High Risk for 523 Genotypes
at Ages 62-83
523 or APOE Genotype Age defining high risk
523 L,L All high risk
523 L,VL All high risk
523 S,L 74
523 8,8 77
523 S,VL 76
523 VL,VL All low risk
. APOE 52/52 All low risk
APOE 52/53 All low risk
APOE 52/54 All low risk
An exemplary use of these assignments is straightfonlvard. Table 3 is
used to make assignments of individuals into the high- or low-risk groups (which
may be irrespective of ethnicity) as follows:
1) individuals with a 523 genotype of (L,L) or (L,VL) are assigned to the
high—risk group, '
2) duals with a 523 genotype of (VL,VL) (>62 years) or APOE
genotype of (52/52) or (52/53) are assigned to the low-risk group,
3) for individuals with a 523 genotype of (8,8), (S,VL) or (S,L), an
individual's current age is compared to the age in Table 2 to make the risk
assignment.
For each 523 genotype, the ponding age—of—onset curve for
cognitive impairment is examined to identify the age where the slope of the
curve indicates high risk of development of cognitive impairment in a 5-year
window. The steep portion of the curve follows a relatively flat ote and
has a characteristic time point (age) where a rapid increase in the proportion of
duals with cognitive impairment is observed’(see Figure 2 and Figure 3).
Figure 3 illustrates determination of an age used to distinguish high- and
low-risk classification for the (S,L) 523 genotype. The steep part of the curve
can be fied as starting at about age 74, which corresponds to the age
. associated with a level of 90% of individuals with this genotype not presenting
with cognitive impairment. Therefore, duals aged 74 or older may be
assigned to the high-risk group for the study, whereas individuals younger than
74 are assigned to the sk group. Exemplary age-of-onset curves for
cognitive impairment for the remaining 523 genotypes are provided in Figures
4-9, which are reflected in the ments in Table 2 ted above.
It should be understood that, while the graphs presented herein are
interpreted to give a specific age where the slope change occurs, these graphs
may be updated as additional data are collected to modify and/or ze the
age designations without departing from the l teachings of this method.
The disclosures of the patents, patent documents, articles, abstracts and
other publications cited herein are incorporated by reference herein in their
entireties as if each were individually incorporated. In case of conflict, the
present specification, including definitions, shall control. Various modifications
and alterations to this invention will become apparent to those skilled in the art
without departing from the scope and spirit of this invention. Illustrative
embodiments and examples are provided as examples only and are not
intended to limit the scope of the present invention. The scope of the invention
is d only by the claims set forth as follows.
Having described our invention,
Claims (73)
1. The use of from 0.5 to 9 milligrams of pioglitazone in the cture of a pharmaceutical formulation for treating cognitive impairment of the Alzheimer's type in a
2. The use of claim 1, wherein said treating comprises delaying the onset of cognitive impairment of the Alzheimer's type.
3. The use of claim 1, wherein said treating comprises delaying the onset of cognitive impairment of the Alzheimer's type in a human subject at increased risk of developing cognitive impairment of the mer's type withinthe next 5-7 years, said risk based upon the subject's age and rs10524523 genotype.
4. The use of claim 1, claim 2 or claim 3, wherein said pioglitazone is formulated in unit dosage form.
5. The use of claim 4, wherein said unit dosage form comprises from 0.5 to 6 milligrams of pioglitazone.
6. The use of claim 4 or claim 5, wherein said unit dosage form comprises from 0.5 to 1.5 milligrams of tazone.
7. The use of any one of claims 1 to 6, wherein said pharmaceutical formulation is a tablet.
8. The use of any one of claims 1 to 6, wherein said pharmaceutical formulation is a capsule.
9. The use of any one of claims 1 to 6, wherein said pharmaceutical ation is a caplet.
10. The use of any one of claims 1 to 6, wherein said pharmaceutical formulation is a liquid.
11. The use of any one of claims 1 to 6, wherein said pharmaceutical formulation is a semisolid.
12. The use of any one of claims 1 to 6, n said pharmaceutical formulation is a solid.
13. The use of any one of claims 1 to 4, wherein said pioglitazone is ated to provide an AUC of from about 0.15 µg•h/mL to about 3.6 µg•h/mL.
14. The use of from 0.5 to 9 milligrams of pioglitazone in the cture of a pharmaceutical formulation for treating cognitive decline in a subject in need thereof.
15. The use according to any one of claims 1 to 14, wherein said subject is at increased risk of developing ive impairment of the Alzheimer's type within the next 5-7 years, said risk based upon the subject's age.
16. The use of any one of claims 1 to 15, wherein said subject is at least 50 years old.
17. The use of any one of claims 1 to 15, wherein said subject is at least 55 years old.
18. The use of any one of claims 1 to 15, wherein said subject is at least 60 years old.
19. The use of any one of claims 1 to 15, wherein said subject is at least 62 years old.
20. The use of any one of claims 1 to 15, wherein said subject is at least 68 years old.
21. The use of any one of claims 1 to 15, n said subject is at least 70 years old.
22. The use of any one of claims 1 to 21, wherein said subject is a Caucasian subject.
23. The use of any one of claims 1 to 21, wherein said subject is a non-Caucasian subject.
24. The use of any one of claims 1 to 23, wherein one or two APOE2 alleles are absent in a subject.
25. The use of any one of claims 1 to 24, wherein the ceutical formulation is formulated for administration once daily.
26. The use of any one of claims 2 to 25, wherein said delaying comprises delaying the onset of impairment in episodic memory.
27. A method of determining sed risk of ping cognitive impairment of the Alzheimer's type that can be treated with from 0.5to 9 mg pioglitazone in a human subject at a ermined age or age range, comprising: detecting from a biological sample of said subject the rs10524523 genotype of said subject, wherein each allele of the rs10524523 genotype is assigned as: (a) short (S, less than 19 T residues); (b) long (L, 19-29 residues); or (c) very long (VL, 30 or more residues); and determining from said rs10524523 genotype whether said subject is at increased risk in developing ive impairment of the Alzheimer'stype at said predetermined age or age range, wherein: (1) age greater than about 62 and L,L or L,VL indicates increased risk; (2) age greater than about 62 and VL,VL does not indicate sed risk; (3) age greater than about 74 and S,L indicates increased risk; (4) age greater than about 77 and S,S tes increased risk; and (5) age greater than about 76 and S,VL indicates increased risk.
28. The method of claim 27, n said determining further comprises detecting from a biological sample of said subject the APOE genotype of said subject, wherein the presence of an APOE2 allele in said genotype indicates the subject is not at increased risk.
29. A method of ining whether to administer from 0.5 to 9 rams of pioglitazone to a human subject for treatment of cognitive impairment of the Alzheimer's type, comprising: detecting from a biological sample of said subject the rs10524523 genotype of the subject, wherein each allele is assigned as: (a) short (S, less than 19 T residues); (b) long (L, 19-29 residues); or (c) very long (VL, 30 or more residues); and determining from said rs10524523 genotype and from the age of said human subject whether to administer low dose pioglitazone to said subject for treatment of cognitive impairment of the Alzheimer's type, wherein: (1) age greater than about 62 and L,L or L,VL indicates treatment; (2) age greater than about 62 and VL,VL does not indicate treatment; (3) age r than about 74 and S,L indicates treatment; (4) age greater than about 77 and S,S tes treatment; and (5) age greater than about 76 and S,VL indicates treatment.
30. The method of claim 29, wherein said determining further ses detecting from a biological sample of said subject the APOE genotype of said t, wherein the presence of an APOE2 allele in said pe does not indicate treatment.
31. The method of claim 29 or claim 30, wherein said subject has normal cognition.
32. The use of from 0.5 to 9 milligrams of pioglitazone in the cture of a pharmaceutical formulation for delaying the onset of Alzheimer’s disease in a subject at risk of developing Alzheimer’s e, wherein said risk is determined based on the presence of at least one genetic t of the TOMM40 gene, wherein said genetic variant is an rs10524523 allele, and wherein the presence of said at least one genetic variant indicates a risk of developing Alzheimer’s disease.
33. The use of from 0.5 to 9 milligrams of pioglitazone in the manufacture of a pharmaceutical formulation for delaying the onset of mild cognitive impairment in a subject at risk for ping mild cognitive impairment, wherein said risk is determined based on the presence of at least one c variant of the TOMM40 gene, wherein said genetic variant is an rs10524523 allele, and wherein the presence of said at least one genetic variant indicates a risk of developing mild cognitive impairment.
34. The use of from 0.5 to 9 milligrams of tazone in the cture of a pharmaceutical formulation for delaying the onset of amnestic mild cognitive impairment in a subject at risk of ping Alzheimer’s disease, wherein said risk is determined based on the presence of at least one genetic variant of the TOMM40 gene, wherein said genetic variant is an 4523 allele, and wherein the presence of said at least one genetic variant indicates a risk of developing Alzheimer’s disease.
35. The use of from 0.5 to 9 milligrams of pioglitazone in the manufacture of a pharmaceutical formulation for of delaying the onset of preclinical Alzheimer’s disease in a subject at risk of developing Alzheimer’s disease, wherein said risk is determined based on the presence of at least one genetic t of the TOMM40 gene, n said genetic variant is an rs10524523 , and wherein the presence of said at least one genetic variant indicates a risk of developing mer’s disease.
36. The use of from 0.5 to 9 milligrams of tazone in the manufacture of a pharmaceutical formulation for delaying the onset of prodromal Alzheimer’s disease in a subject at risk of developing Alzheimer’s disease, wherein said risk is determined based on the presence of at least one genetic variant of the TOMM40 gene, wherein said genetic variant is an rs10524523 allele, and wherein the presence of said at least one genetic variant indicates a risk of developing Alzheimer’s disease.
37. The use of from 0.5 to 9 milligrams of pioglitazone in the manufacture of a pharmaceutical formulation for delaying the onset of physiological changes associated with Alzheimer’s disease in a subject at risk of developing Alzheimer’s disease, wherein said risk is ined based on the presence of at least one genetic variant of the TOMM40 gene, n said genetic variant is an rs10524523 allele, and wherein the presence of said at least one genetic variant indicates a risk of developing mer’s disease.
38. The use of any one of claims 32 to 37, wherein the ceutical formulation is formulated at a dosage of pioglitazone of 0.5 mg to 6 mg per day.
39. The use of any one of claims 32 to 37, wherein the pharmaceutical formulation es an AUC of from about 0.15 µg•h/mL to about 3.6 µg•h/mL.
40. The use according to any one of claims 32 to 37, wherein the pharmaceutical formulation is formulated as part of a daily treatment regimen.
41. The use according to any one of claims 32 to 40, n said pharmaceutical formulation is a tablet.
42. The use according to any one of claims 32 to 40, wherein said pharmaceutical formulation is a capsule.
43. The use ing to any one of claims 32 to 40, wherein said pharmaceutical formulation is a caplet.
44. The use according to any one of claims 32 to 40, wherein said pharmaceutical ation is a liquid.
45. The use according to any one of claims 34 to 42, wherein said pharmaceutical formulation is a semi-solid.
46. The use according to any one of claims 32 to 40, wherein said pharmaceutical ation is a solid.
47. The use of claim 41, wherein said tablet is an orally egrating tablet.
48. The use of claim 45, n said semi-solid pharmaceutical formulation is selected from a group of semi-solid pharmaceutical formulations consisting of a gel, cream, lotion, ointment, salve and balm.
49. The use of claim 44, wherein the liquid is formulated for oral administration.
50. The use of claim 44, wherein the liquid is formulated for injection.
51. The use of claim 44, wherein the liquid is formulated for intra-nasal administration.
52. The use of claim 45, wherein the semi-solid pharmaceutical formulation is formulated for intra-nasal administration.
53. The use of claim 45, wherein the semi-solid pharmaceutical formulation is formulated for topical administration.
54. The use of claim 46, n said pharmaceutical formulation is a powder.
55. The use of claim 46, wherein the solid pharmaceutical ation is formulated for topical administration.
56. The use according to any one of claims 32 to 55, wherein said subject has normal cognition.
57. The use of any one of claims 32 to 56, wherein the subject is younger than 60.
58. The use of any one of claims 32 to 56, wherein the subject is n the ages of 60 and
59. The use of any one of claims 32 to 58, wherein the subject has one copy of the long TOMM40 rs10524523 allele.
60. The use of any one of claims 32 to 58, wherein the subject has two copies of the long TOMM40 rs10524523 allele.
61. The use of any one of claims 32 to 60, wherein the subject has an increased risk of ping Alzheimer’s disease as compared to a control subject.
62. The use of claim 61, wherein the control subject carries at least one copy of the TOMM40 rs10524523 allele sing a poly-T repeat that is less than 19 nucleotides in length.
63. The use of claim 61, wherein the control subject does not have a copy of the TOMM40 rs10524523 allele sing a poly-T repeat that is greater than 19 nucleotides in length.
64. The use of any one of claims 32 to 63, wherein the pharmaceutical formulation is a bioequivalent formulation.
65. The use of any one of claims 32 to 63, wherein the pharmaceutical formulation is a pharmaceutically lent formulation.
66. The use of claims 32 to 63, wherein the pharmaceutical formulation is a therapeutically equivalent formulation.
67. The use according to any one of claims 32 to 66, wherein the pioglitazone is formulated in a unit dose.
68. The use of claim 67, wherein the unit dosage comprises from 0.5 to 6 mg of pioglitazone.
69. The use of claims 67 or 68, wherein the unit dosage comprises from 0.5 to 1.5 mg of pioglitazone.
70. The use of claim 3, wherein the determination of said risk based upon the subject’s age and rs10524523 genotype comprises: detecting from a biological sample of said subject the rs10524523 genotype of said t, wherein each allele of the rs10524523 genotype is assigned as: (a) short (S, less than 19 T es); (b) long (L, 19-29 residues); or (c) very long (VL, 30 or more residues); and determining from said rs10524523 genotype whether said subject is at increased risk in developing cognitive impairment of the Alzheimer'stype at said predetermined age or age range, wherein: (1) age greater than about 62 and L,L or L,VL indicates increased risk; (2) age r than about 62 and VL,VL does not indicate increased risk; (3) age r than about 74 and S,L indicates increased risk; (4) age greater than about 77 and S,S indicates increased risk; and (5) age greater than about 76 and S,VL indicates increased risk.
71. The use of claim 70, wherein said determining further comprises detecting from a biological sample of said t the APOE genotype of said subject, wherein the presence of an APOE2 allele in said genotype indicates the subject is not at increased risk.
72. The use according to any one of claims 1, 14, and 32 to 37, substantially as herein described with reference to any one of the examples and/or figures.
73. A method according to any one of claims 27 or 29, substantially as herein bed with reference to any one of the examples and/or figures.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161431370P | 2011-01-10 | 2011-01-10 | |
US61/431,370 | 2011-01-10 | ||
PCT/US2012/020606 WO2012096873A1 (en) | 2011-01-10 | 2012-01-09 | Methods and drug products for treating alzheimer's disease |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ611948A NZ611948A (en) | 2015-08-28 |
NZ611948B2 true NZ611948B2 (en) | 2015-12-01 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11179375B2 (en) | Methods and drug products for treating Alzheimer's disease | |
JP6037615B2 (en) | How to treat hepatic encephalopathy | |
JP2022009066A (en) | Methods for diagnosing and treating alzheimer's disease with s-equol | |
JP2017197554A (en) | Method and medicine for treating alzheimer disease | |
JP2019515004A (en) | Compounds that promote normal processing of APP | |
AU2013204550B2 (en) | Methods and drug products for treating alzheimer's disease | |
NZ611948B2 (en) | Methods and drug products for treating alzheimer's disease | |
EP1578420A4 (en) | Treatment of cognitive impairment using a selective dopamine d1 receptor agonist |