CN116802208A - Treatment of parkinson's disease - Google Patents
Treatment of parkinson's disease Download PDFInfo
- Publication number
- CN116802208A CN116802208A CN202180072639.9A CN202180072639A CN116802208A CN 116802208 A CN116802208 A CN 116802208A CN 202180072639 A CN202180072639 A CN 202180072639A CN 116802208 A CN116802208 A CN 116802208A
- Authority
- CN
- China
- Prior art keywords
- subject
- disease
- parkinson
- ser
- weeks
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000018737 Parkinson disease Diseases 0.000 title claims abstract description 136
- 238000011282 treatment Methods 0.000 title claims description 85
- 238000000034 method Methods 0.000 claims abstract description 88
- 230000007423 decrease Effects 0.000 claims description 82
- 230000007659 motor function Effects 0.000 claims description 49
- 239000000902 placebo Substances 0.000 claims description 42
- 229940068196 placebo Drugs 0.000 claims description 42
- 102000010909 Monoamine Oxidase Human genes 0.000 claims description 30
- 108010062431 Monoamine oxidase Proteins 0.000 claims description 30
- 206010044565 Tremor Diseases 0.000 claims description 29
- 239000003112 inhibitor Substances 0.000 claims description 29
- 230000006872 improvement Effects 0.000 claims description 27
- 206010006100 Bradykinesia Diseases 0.000 claims description 25
- 208000006083 Hypokinesia Diseases 0.000 claims description 25
- 230000003727 cerebral blood flow Effects 0.000 claims description 21
- 230000008859 change Effects 0.000 claims description 21
- 230000033001 locomotion Effects 0.000 claims description 21
- 230000003920 cognitive function Effects 0.000 claims description 20
- 230000003211 malignant effect Effects 0.000 claims description 15
- 230000001965 increasing effect Effects 0.000 claims description 14
- 230000001149 cognitive effect Effects 0.000 claims description 13
- 229960003089 pramipexole Drugs 0.000 claims description 12
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 claims description 12
- 230000017531 blood circulation Effects 0.000 claims description 11
- 230000005750 disease progression Effects 0.000 claims description 11
- 230000005021 gait Effects 0.000 claims description 10
- 230000037396 body weight Effects 0.000 claims description 9
- 230000008921 facial expression Effects 0.000 claims description 9
- 210000002637 putamen Anatomy 0.000 claims description 9
- 230000037230 mobility Effects 0.000 claims description 7
- 241001112258 Moca Species 0.000 claims description 6
- 210000001905 globus pallidus Anatomy 0.000 claims description 6
- 238000002372 labelling Methods 0.000 claims description 6
- 210000000337 motor cortex Anatomy 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 3
- 230000000386 athletic effect Effects 0.000 claims description 2
- 230000006735 deficit Effects 0.000 claims description 2
- FSVJFNAIGNNGKK-UHFFFAOYSA-N 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one Chemical compound C1C(C2=CC=CC=C2CC2)N2C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-UHFFFAOYSA-N 0.000 claims 2
- 239000002899 monoamine oxidase inhibitor Substances 0.000 claims 2
- 229960002957 praziquantel Drugs 0.000 claims 2
- 239000000203 mixture Substances 0.000 description 77
- 238000009472 formulation Methods 0.000 description 63
- 208000024891 symptom Diseases 0.000 description 36
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 34
- 102000003802 alpha-Synuclein Human genes 0.000 description 32
- 108090000185 alpha-Synuclein Proteins 0.000 description 32
- 201000010099 disease Diseases 0.000 description 32
- 238000004458 analytical method Methods 0.000 description 17
- 230000000694 effects Effects 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 15
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 14
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 14
- 229920001213 Polysorbate 20 Polymers 0.000 description 12
- 150000001413 amino acids Chemical class 0.000 description 12
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 12
- 229940068977 polysorbate 20 Drugs 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 11
- 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 alpha,alpha-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
- 238000012360 testing method Methods 0.000 description 11
- MKJBPDLENBUHQU-CIUDSAMLSA-N Asn-Ser-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O MKJBPDLENBUHQU-CIUDSAMLSA-N 0.000 description 10
- 206010061818 Disease progression Diseases 0.000 description 10
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 10
- 238000011156 evaluation Methods 0.000 description 9
- 239000012931 lyophilized formulation Substances 0.000 description 9
- 102100028116 Amine oxidase [flavin-containing] B Human genes 0.000 description 8
- 101000768078 Homo sapiens Amine oxidase [flavin-containing] B Proteins 0.000 description 8
- 229930006000 Sucrose Natural products 0.000 description 8
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 8
- 230000005713 exacerbation Effects 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 238000005259 measurement Methods 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 239000005720 sucrose Substances 0.000 description 8
- 208000012661 Dyskinesia Diseases 0.000 description 7
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 7
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 7
- 206010071390 Resting tremor Diseases 0.000 description 7
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 7
- 208000032859 Synucleinopathies Diseases 0.000 description 7
- 210000004556 brain Anatomy 0.000 description 7
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 238000011985 exploratory data analysis Methods 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 229960004502 levodopa Drugs 0.000 description 7
- 230000004770 neurodegeneration Effects 0.000 description 7
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 6
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 6
- 229930195725 Mannitol Natural products 0.000 description 6
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 6
- MNYNCKZAEIAONY-XGEHTFHBSA-N Thr-Val-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O MNYNCKZAEIAONY-XGEHTFHBSA-N 0.000 description 6
- 239000007979 citrate buffer Substances 0.000 description 6
- 238000003745 diagnosis Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000000594 mannitol Substances 0.000 description 6
- 235000010355 mannitol Nutrition 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 229920005862 polyol Polymers 0.000 description 6
- 150000003077 polyols Chemical class 0.000 description 6
- 235000000346 sugar Nutrition 0.000 description 6
- 238000011269 treatment regimen Methods 0.000 description 6
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 5
- LMFXXZPPZDCPTA-ZKWXMUAHSA-N Ala-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N LMFXXZPPZDCPTA-ZKWXMUAHSA-N 0.000 description 5
- DYXOFPBJBAHWFY-JBDRJPRFSA-N Ala-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N DYXOFPBJBAHWFY-JBDRJPRFSA-N 0.000 description 5
- VKKYFICVTYKFIO-CIUDSAMLSA-N Arg-Ala-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N VKKYFICVTYKFIO-CIUDSAMLSA-N 0.000 description 5
- MNQMTYSEKZHIDF-GCJQMDKQSA-N Asp-Thr-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O MNQMTYSEKZHIDF-GCJQMDKQSA-N 0.000 description 5
- HTSSXFASOUSJQG-IHPCNDPISA-N Asp-Tyr-Trp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O HTSSXFASOUSJQG-IHPCNDPISA-N 0.000 description 5
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 5
- 102000006441 Dopamine Plasma Membrane Transport Proteins Human genes 0.000 description 5
- 108010044266 Dopamine Plasma Membrane Transport Proteins Proteins 0.000 description 5
- OYTPNWYZORARHL-XHNCKOQMSA-N Gln-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N OYTPNWYZORARHL-XHNCKOQMSA-N 0.000 description 5
- FQCILXROGNOZON-YUMQZZPRSA-N Gln-Pro-Gly Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O FQCILXROGNOZON-YUMQZZPRSA-N 0.000 description 5
- YQPFCZVKMUVZIN-AUTRQRHGSA-N Glu-Val-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O YQPFCZVKMUVZIN-AUTRQRHGSA-N 0.000 description 5
- BYYNJRSNDARRBX-YFKPBYRVSA-N Gly-Gln-Gly Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O BYYNJRSNDARRBX-YFKPBYRVSA-N 0.000 description 5
- YWAQATDNEKZFFK-BYPYZUCNSA-N Gly-Gly-Ser Chemical compound NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O YWAQATDNEKZFFK-BYPYZUCNSA-N 0.000 description 5
- MIIVFRCYJABHTQ-ONGXEEELSA-N Gly-Leu-Val Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O MIIVFRCYJABHTQ-ONGXEEELSA-N 0.000 description 5
- PDUHNKAFQXQNLH-ZETCQYMHSA-N Gly-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)NCC(O)=O PDUHNKAFQXQNLH-ZETCQYMHSA-N 0.000 description 5
- OMOZPGCHVWOXHN-BQBZGAKWSA-N Gly-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)CN OMOZPGCHVWOXHN-BQBZGAKWSA-N 0.000 description 5
- WNZOCXUOGVYYBJ-CDMKHQONSA-N Gly-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CN)O WNZOCXUOGVYYBJ-CDMKHQONSA-N 0.000 description 5
- PMGDADKJMCOXHX-UHFFFAOYSA-N L-Arginyl-L-glutamin-acetat Natural products NC(=N)NCCCC(N)C(=O)NC(CCC(N)=O)C(O)=O PMGDADKJMCOXHX-UHFFFAOYSA-N 0.000 description 5
- AXZGZMGRBDQTEY-SRVKXCTJSA-N Leu-Gln-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O AXZGZMGRBDQTEY-SRVKXCTJSA-N 0.000 description 5
- FEHQLKKBVJHSEC-SZMVWBNQSA-N Leu-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 FEHQLKKBVJHSEC-SZMVWBNQSA-N 0.000 description 5
- KIZIOFNVSOSKJI-CIUDSAMLSA-N Leu-Ser-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N KIZIOFNVSOSKJI-CIUDSAMLSA-N 0.000 description 5
- AIMGJYMCTAABEN-GVXVVHGQSA-N Leu-Val-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIMGJYMCTAABEN-GVXVVHGQSA-N 0.000 description 5
- GQZMPWBZQALKJO-UWVGGRQHSA-N Lys-Gly-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O GQZMPWBZQALKJO-UWVGGRQHSA-N 0.000 description 5
- SBQDRNOLGSYHQA-YUMQZZPRSA-N Lys-Ser-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SBQDRNOLGSYHQA-YUMQZZPRSA-N 0.000 description 5
- 108010079364 N-glycylalanine Proteins 0.000 description 5
- YMIZSYUAZJSOFL-SRVKXCTJSA-N Phe-Ser-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O YMIZSYUAZJSOFL-SRVKXCTJSA-N 0.000 description 5
- FGWUALWGCZJQDJ-URLPEUOOSA-N Phe-Thr-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FGWUALWGCZJQDJ-URLPEUOOSA-N 0.000 description 5
- CJZTUKSFZUSNCC-FXQIFTODSA-N Pro-Asp-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]1CCCN1 CJZTUKSFZUSNCC-FXQIFTODSA-N 0.000 description 5
- QEDMOZUJTGEIBF-FXQIFTODSA-N Ser-Arg-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O QEDMOZUJTGEIBF-FXQIFTODSA-N 0.000 description 5
- QYSFWUIXDFJUDW-DCAQKATOSA-N Ser-Leu-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYSFWUIXDFJUDW-DCAQKATOSA-N 0.000 description 5
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 5
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 5
- YOPQYBJJNSIQGZ-JNPHEJMOSA-N Thr-Tyr-Tyr Chemical compound C([C@H](NC(=O)[C@@H](N)[C@H](O)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 YOPQYBJJNSIQGZ-JNPHEJMOSA-N 0.000 description 5
- MBLJBGZWLHTJBH-SZMVWBNQSA-N Trp-Val-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 MBLJBGZWLHTJBH-SZMVWBNQSA-N 0.000 description 5
- OWFGFHQMSBTKLX-UFYCRDLUSA-N Val-Tyr-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N OWFGFHQMSBTKLX-UFYCRDLUSA-N 0.000 description 5
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 5
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 5
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 5
- 108010008355 arginyl-glutamine Proteins 0.000 description 5
- 229960002303 citric acid monohydrate Drugs 0.000 description 5
- 208000010877 cognitive disease Diseases 0.000 description 5
- 238000004108 freeze drying Methods 0.000 description 5
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 5
- 108010015792 glycyllysine Proteins 0.000 description 5
- 108010037850 glycylvaline Proteins 0.000 description 5
- 238000003384 imaging method Methods 0.000 description 5
- 208000015122 neurodegenerative disease Diseases 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 5
- 108010070643 prolylglutamic acid Proteins 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 238000002603 single-photon emission computed tomography Methods 0.000 description 5
- 239000001509 sodium citrate Substances 0.000 description 5
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 5
- 108010038745 tryptophylglycine Proteins 0.000 description 5
- BTRULDJUUVGRNE-DCAQKATOSA-N Ala-Pro-Lys Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O BTRULDJUUVGRNE-DCAQKATOSA-N 0.000 description 4
- ARHJJAAWNWOACN-FXQIFTODSA-N Ala-Ser-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O ARHJJAAWNWOACN-FXQIFTODSA-N 0.000 description 4
- CREYEAPXISDKSB-FQPOAREZSA-N Ala-Thr-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CREYEAPXISDKSB-FQPOAREZSA-N 0.000 description 4
- XYBJLTKSGFBLCS-QXEWZRGKSA-N Asp-Arg-Val Chemical compound NC(N)=NCCC[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC(O)=O XYBJLTKSGFBLCS-QXEWZRGKSA-N 0.000 description 4
- QNFRBNZGVVKBNJ-PEFMBERDSA-N Asp-Ile-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)O)N QNFRBNZGVVKBNJ-PEFMBERDSA-N 0.000 description 4
- NIXHTNJAGGFBAW-CIUDSAMLSA-N Cys-Lys-Ser Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CS)N NIXHTNJAGGFBAW-CIUDSAMLSA-N 0.000 description 4
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-N 0.000 description 4
- NVTPVQLIZCOJFK-FOHZUACHSA-N Gly-Thr-Asp Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O NVTPVQLIZCOJFK-FOHZUACHSA-N 0.000 description 4
- JRYQSFOFUFXPTB-RWRJDSDZSA-N Ile-Gln-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N JRYQSFOFUFXPTB-RWRJDSDZSA-N 0.000 description 4
- PXKACEXYLPBMAD-JBDRJPRFSA-N Ile-Ser-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PXKACEXYLPBMAD-JBDRJPRFSA-N 0.000 description 4
- HXWALXSAVBLTPK-NUTKFTJISA-N Leu-Ala-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(C)C)N HXWALXSAVBLTPK-NUTKFTJISA-N 0.000 description 4
- CQGSYZCULZMEDE-SRVKXCTJSA-N Leu-Gln-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(O)=O CQGSYZCULZMEDE-SRVKXCTJSA-N 0.000 description 4
- CQGSYZCULZMEDE-UHFFFAOYSA-N Leu-Gln-Pro Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)N1CCCC1C(O)=O CQGSYZCULZMEDE-UHFFFAOYSA-N 0.000 description 4
- FAELBUXXFQLUAX-AJNGGQMLSA-N Leu-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C FAELBUXXFQLUAX-AJNGGQMLSA-N 0.000 description 4
- VUBIPAHVHMZHCM-KKUMJFAQSA-N Leu-Tyr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CC1=CC=C(O)C=C1 VUBIPAHVHMZHCM-KKUMJFAQSA-N 0.000 description 4
- PXHCFKXNSBJSTQ-KKUMJFAQSA-N Lys-Asn-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCCN)N)O PXHCFKXNSBJSTQ-KKUMJFAQSA-N 0.000 description 4
- SKRGVGLIRUGANF-AVGNSLFASA-N Lys-Leu-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SKRGVGLIRUGANF-AVGNSLFASA-N 0.000 description 4
- PDIDTSZKKFEDMB-UWVGGRQHSA-N Lys-Pro-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O PDIDTSZKKFEDMB-UWVGGRQHSA-N 0.000 description 4
- SPSSJSICDYYTQN-HJGDQZAQSA-N Met-Thr-Gln Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O SPSSJSICDYYTQN-HJGDQZAQSA-N 0.000 description 4
- BPCLGWHVPVTTFM-QWRGUYRKSA-N Phe-Ser-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)NCC(O)=O BPCLGWHVPVTTFM-QWRGUYRKSA-N 0.000 description 4
- KLYYKKGCPOGDPE-OEAJRASXSA-N Phe-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O KLYYKKGCPOGDPE-OEAJRASXSA-N 0.000 description 4
- GOMUXSCOIWIJFP-GUBZILKMSA-N Pro-Ser-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GOMUXSCOIWIJFP-GUBZILKMSA-N 0.000 description 4
- BCKYYTVFBXHPOG-ACZMJKKPSA-N Ser-Asn-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CO)N BCKYYTVFBXHPOG-ACZMJKKPSA-N 0.000 description 4
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 4
- YIUWWXVTYLANCJ-NAKRPEOUSA-N Ser-Ile-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O YIUWWXVTYLANCJ-NAKRPEOUSA-N 0.000 description 4
- AZWNCEBQZXELEZ-FXQIFTODSA-N Ser-Pro-Ser Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O AZWNCEBQZXELEZ-FXQIFTODSA-N 0.000 description 4
- 102000019355 Synuclein Human genes 0.000 description 4
- 108050006783 Synuclein Proteins 0.000 description 4
- GXUWHVZYDAHFSV-FLBSBUHZSA-N Thr-Ile-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GXUWHVZYDAHFSV-FLBSBUHZSA-N 0.000 description 4
- BIBYEFRASCNLAA-CDMKHQONSA-N Thr-Phe-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 BIBYEFRASCNLAA-CDMKHQONSA-N 0.000 description 4
- QOIKZODVIPOPDD-AVGNSLFASA-N Tyr-Cys-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(O)=O QOIKZODVIPOPDD-AVGNSLFASA-N 0.000 description 4
- BIWVVOHTKDLRMP-ULQDDVLXSA-N Tyr-Pro-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O BIWVVOHTKDLRMP-ULQDDVLXSA-N 0.000 description 4
- ZYVAAYAOTVJBSS-GMVOTWDCSA-N Tyr-Trp-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C)C(O)=O ZYVAAYAOTVJBSS-GMVOTWDCSA-N 0.000 description 4
- AGDDLOQMXUQPDY-BZSNNMDCSA-N Tyr-Tyr-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O AGDDLOQMXUQPDY-BZSNNMDCSA-N 0.000 description 4
- 108010081404 acein-2 Proteins 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- 238000004220 aggregation Methods 0.000 description 4
- 108010062796 arginyllysine Proteins 0.000 description 4
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 229940052760 dopamine agonists Drugs 0.000 description 4
- 230000003291 dopaminomimetic effect Effects 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 230000007170 pathology Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 4
- 230000000069 prophylactic effect Effects 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- 108010035534 tyrosyl-leucyl-alanine Proteins 0.000 description 4
- 108010003137 tyrosyltyrosine Proteins 0.000 description 4
- JBGSZRYCXBPWGX-BQBZGAKWSA-N Ala-Arg-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](N)C)CCCN=C(N)N JBGSZRYCXBPWGX-BQBZGAKWSA-N 0.000 description 3
- SLKLLQWZQHXYSV-CIUDSAMLSA-N Asn-Ala-Lys Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O SLKLLQWZQHXYSV-CIUDSAMLSA-N 0.000 description 3
- VPPXTHJNTYDNFJ-CIUDSAMLSA-N Asp-Ala-Lys Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)O)N VPPXTHJNTYDNFJ-CIUDSAMLSA-N 0.000 description 3
- 206010003840 Autonomic nervous system imbalance Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 241000880493 Leptailurus serval Species 0.000 description 3
- IILUKIJNFMUBNF-IHRRRGAJSA-N Phe-Gln-Gln Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O IILUKIJNFMUBNF-IHRRRGAJSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 3
- 108010092854 aspartyllysine Proteins 0.000 description 3
- 210000004899 c-terminal region Anatomy 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000011194 good manufacturing practice Methods 0.000 description 3
- 230000001024 immunotherapeutic effect Effects 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 238000012423 maintenance Methods 0.000 description 3
- 208000027061 mild cognitive impairment Diseases 0.000 description 3
- 230000001537 neural effect Effects 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 230000004224 protection Effects 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 239000008223 sterile water Substances 0.000 description 3
- 239000008362 succinate buffer Substances 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 230000002459 sustained effect Effects 0.000 description 3
- 230000000946 synaptic effect Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 108010031491 threonyl-lysyl-glutamic acid Proteins 0.000 description 3
- 238000004448 titration Methods 0.000 description 3
- 208000019901 Anxiety disease Diseases 0.000 description 2
- 206010051290 Central nervous system lesion Diseases 0.000 description 2
- JVSBYEDSSRZQGV-GUBZILKMSA-N Glu-Asp-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CCC(O)=O JVSBYEDSSRZQGV-GUBZILKMSA-N 0.000 description 2
- PAQUJCSYVIBPLC-AVGNSLFASA-N Glu-Asp-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 PAQUJCSYVIBPLC-AVGNSLFASA-N 0.000 description 2
- 208000004547 Hallucinations Diseases 0.000 description 2
- 101000834898 Homo sapiens Alpha-synuclein Proteins 0.000 description 2
- 201000002832 Lewy body dementia Diseases 0.000 description 2
- WSXTWLJHTLRFLW-SRVKXCTJSA-N Lys-Ala-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O WSXTWLJHTLRFLW-SRVKXCTJSA-N 0.000 description 2
- YKBSXQFZWFXFIB-VOAKCMCISA-N Lys-Thr-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCCN)C(O)=O YKBSXQFZWFXFIB-VOAKCMCISA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 208000016285 Movement disease Diseases 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 2
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- DLRVVLDZNNYCBX-UHFFFAOYSA-N Polydextrose Polymers OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(O)O1 DLRVVLDZNNYCBX-UHFFFAOYSA-N 0.000 description 2
- PRKWBYCXBBSLSK-GUBZILKMSA-N Pro-Ser-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O PRKWBYCXBBSLSK-GUBZILKMSA-N 0.000 description 2
- HQTKVSCNCDLXSX-BQBZGAKWSA-N Ser-Arg-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O HQTKVSCNCDLXSX-BQBZGAKWSA-N 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 108010087924 alanylproline Proteins 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 2
- 239000004067 bulking agent Substances 0.000 description 2
- -1 but not limited to Substances 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 230000019771 cognition Effects 0.000 description 2
- 230000007278 cognition impairment Effects 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000001815 facial effect Effects 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 108010089804 glycyl-threonine Proteins 0.000 description 2
- 230000003862 health status Effects 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- 230000035800 maturation Effects 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 238000013105 post hoc analysis Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 229960003946 selegiline Drugs 0.000 description 2
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 2
- 208000019116 sleep disease Diseases 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000002636 symptomatic treatment Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 241000220479 Acacia Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- YLTKNGYYPIWKHZ-ACZMJKKPSA-N Ala-Ala-Glu Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCC(O)=O YLTKNGYYPIWKHZ-ACZMJKKPSA-N 0.000 description 1
- CXRCVCURMBFFOL-FXQIFTODSA-N Ala-Ala-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O CXRCVCURMBFFOL-FXQIFTODSA-N 0.000 description 1
- JBVSSSZFNTXJDX-YTLHQDLWSA-N Ala-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](C)N JBVSSSZFNTXJDX-YTLHQDLWSA-N 0.000 description 1
- WCBVQNZTOKJWJS-ACZMJKKPSA-N Ala-Cys-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(O)=O WCBVQNZTOKJWJS-ACZMJKKPSA-N 0.000 description 1
- FUSPCLTUKXQREV-ACZMJKKPSA-N Ala-Glu-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O FUSPCLTUKXQREV-ACZMJKKPSA-N 0.000 description 1
- BLIMFWGRQKRCGT-YUMQZZPRSA-N Ala-Gly-Lys Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN BLIMFWGRQKRCGT-YUMQZZPRSA-N 0.000 description 1
- MEFILNJXAVSUTO-JXUBOQSCSA-N Ala-Leu-Thr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MEFILNJXAVSUTO-JXUBOQSCSA-N 0.000 description 1
- MDNAVFBZPROEHO-UHFFFAOYSA-N Ala-Lys-Val Natural products CC(C)C(C(O)=O)NC(=O)C(NC(=O)C(C)N)CCCCN MDNAVFBZPROEHO-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- HPKSHFSEXICTLI-CIUDSAMLSA-N Arg-Glu-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O HPKSHFSEXICTLI-CIUDSAMLSA-N 0.000 description 1
- BVLIJXXSXBUGEC-SRVKXCTJSA-N Asn-Asn-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BVLIJXXSXBUGEC-SRVKXCTJSA-N 0.000 description 1
- ULRPXVNMIIYDDJ-ACZMJKKPSA-N Asn-Glu-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)N)N ULRPXVNMIIYDDJ-ACZMJKKPSA-N 0.000 description 1
- BZMWJLLUAKSIMH-FXQIFTODSA-N Asn-Glu-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O BZMWJLLUAKSIMH-FXQIFTODSA-N 0.000 description 1
- OLVIPTLKNSAYRJ-YUMQZZPRSA-N Asn-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N OLVIPTLKNSAYRJ-YUMQZZPRSA-N 0.000 description 1
- QUAWOKPCAKCHQL-SRVKXCTJSA-N Asn-His-Lys Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N QUAWOKPCAKCHQL-SRVKXCTJSA-N 0.000 description 1
- WQLJRNRLHWJIRW-KKUMJFAQSA-N Asn-His-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CC(=O)N)N)O WQLJRNRLHWJIRW-KKUMJFAQSA-N 0.000 description 1
- RCFGLXMZDYNRSC-CIUDSAMLSA-N Asn-Lys-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O RCFGLXMZDYNRSC-CIUDSAMLSA-N 0.000 description 1
- JWQWPRCDYWNVNM-ACZMJKKPSA-N Asn-Ser-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)N)N JWQWPRCDYWNVNM-ACZMJKKPSA-N 0.000 description 1
- ZAESWDKAMDVHLL-RCOVLWMOSA-N Asn-Val-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O ZAESWDKAMDVHLL-RCOVLWMOSA-N 0.000 description 1
- KBQOUDLMWYWXNP-YDHLFZDLSA-N Asn-Val-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CC(=O)N)N KBQOUDLMWYWXNP-YDHLFZDLSA-N 0.000 description 1
- YNQIDCRRTWGHJD-ZLUOBGJFSA-N Asp-Asn-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(O)=O YNQIDCRRTWGHJD-ZLUOBGJFSA-N 0.000 description 1
- WSGVTKZFVJSJOG-RCOVLWMOSA-N Asp-Gly-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O WSGVTKZFVJSJOG-RCOVLWMOSA-N 0.000 description 1
- KTTCQQNRRLCIBC-GHCJXIJMSA-N Asp-Ile-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O KTTCQQNRRLCIBC-GHCJXIJMSA-N 0.000 description 1
- KESWRFKUZRUTAH-FXQIFTODSA-N Asp-Pro-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O KESWRFKUZRUTAH-FXQIFTODSA-N 0.000 description 1
- AHWRSSLYSGLBGD-CIUDSAMLSA-N Asp-Pro-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O AHWRSSLYSGLBGD-CIUDSAMLSA-N 0.000 description 1
- VNXQRBXEQXLERQ-CIUDSAMLSA-N Asp-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)N VNXQRBXEQXLERQ-CIUDSAMLSA-N 0.000 description 1
- YUELDQUPTAYEGM-XIRDDKMYSA-N Asp-Trp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CC(=O)O)N YUELDQUPTAYEGM-XIRDDKMYSA-N 0.000 description 1
- KNDCWFXCFKSEBM-AVGNSLFASA-N Asp-Tyr-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O KNDCWFXCFKSEBM-AVGNSLFASA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 102100040999 Catechol O-methyltransferase Human genes 0.000 description 1
- 108020002739 Catechol O-methyltransferase Proteins 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- NDUSUIGBMZCOIL-ZKWXMUAHSA-N Cys-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CS)N NDUSUIGBMZCOIL-ZKWXMUAHSA-N 0.000 description 1
- SMEYEQDCCBHTEF-FXQIFTODSA-N Cys-Pro-Ala Chemical compound [H]N[C@@H](CS)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O SMEYEQDCCBHTEF-FXQIFTODSA-N 0.000 description 1
- KSMSFCBQBQPFAD-GUBZILKMSA-N Cys-Pro-Pro Chemical compound SC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 KSMSFCBQBQPFAD-GUBZILKMSA-N 0.000 description 1
- ALTQTAKGRFLRLR-GUBZILKMSA-N Cys-Val-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N ALTQTAKGRFLRLR-GUBZILKMSA-N 0.000 description 1
- 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 1
- 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 1
- 206010012289 Dementia Diseases 0.000 description 1
- 206010067889 Dementia with Lewy bodies Diseases 0.000 description 1
- 241000255925 Diptera Species 0.000 description 1
- 208000007590 Disorders of Excessive Somnolence Diseases 0.000 description 1
- 208000026331 Disruptive, Impulse Control, and Conduct disease Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 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 1
- NVEASDQHBRZPSU-BQBZGAKWSA-N Gln-Gln-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O NVEASDQHBRZPSU-BQBZGAKWSA-N 0.000 description 1
- KCJJFESQRXGTGC-BQBZGAKWSA-N Gln-Glu-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O KCJJFESQRXGTGC-BQBZGAKWSA-N 0.000 description 1
- FGYPOQPQTUNESW-IUCAKERBSA-N Gln-Gly-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)N FGYPOQPQTUNESW-IUCAKERBSA-N 0.000 description 1
- ORYMMTRPKVTGSJ-XVKPBYJWSA-N Gln-Gly-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCC(N)=O ORYMMTRPKVTGSJ-XVKPBYJWSA-N 0.000 description 1
- HMIXCETWRYDVMO-GUBZILKMSA-N Gln-Pro-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O HMIXCETWRYDVMO-GUBZILKMSA-N 0.000 description 1
- OSCLNNWLKKIQJM-WDSKDSINSA-N Gln-Ser-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O OSCLNNWLKKIQJM-WDSKDSINSA-N 0.000 description 1
- ITYRYNUZHPNCIK-GUBZILKMSA-N Glu-Ala-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O ITYRYNUZHPNCIK-GUBZILKMSA-N 0.000 description 1
- PVBBEKPHARMPHX-DCAQKATOSA-N Glu-Gln-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCC(O)=O PVBBEKPHARMPHX-DCAQKATOSA-N 0.000 description 1
- HTTSBEBKVNEDFE-AUTRQRHGSA-N Glu-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)O)N HTTSBEBKVNEDFE-AUTRQRHGSA-N 0.000 description 1
- HNVFSTLPVJWIDV-CIUDSAMLSA-N Glu-Glu-Gln Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HNVFSTLPVJWIDV-CIUDSAMLSA-N 0.000 description 1
- HILMIYALTUQTRC-XVKPBYJWSA-N Glu-Gly-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O HILMIYALTUQTRC-XVKPBYJWSA-N 0.000 description 1
- YGLCLCMAYUYZSG-AVGNSLFASA-N Glu-Lys-His Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 YGLCLCMAYUYZSG-AVGNSLFASA-N 0.000 description 1
- YHOJJFFTSMWVGR-HJGDQZAQSA-N Glu-Met-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YHOJJFFTSMWVGR-HJGDQZAQSA-N 0.000 description 1
- AAJHGGDRKHYSDH-GUBZILKMSA-N Glu-Pro-Gln Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O AAJHGGDRKHYSDH-GUBZILKMSA-N 0.000 description 1
- BFEZQZKEPRKKHV-SRVKXCTJSA-N Glu-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCCCN)C(=O)O BFEZQZKEPRKKHV-SRVKXCTJSA-N 0.000 description 1
- NNQDRRUXFJYCCJ-NHCYSSNCSA-N Glu-Pro-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O NNQDRRUXFJYCCJ-NHCYSSNCSA-N 0.000 description 1
- ALMBZBOCGSVSAI-ACZMJKKPSA-N Glu-Ser-Asn Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)O)N ALMBZBOCGSVSAI-ACZMJKKPSA-N 0.000 description 1
- DMYACXMQUABZIQ-NRPADANISA-N Glu-Ser-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O DMYACXMQUABZIQ-NRPADANISA-N 0.000 description 1
- MFYLRRCYBBJYPI-JYJNAYRXSA-N Glu-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O MFYLRRCYBBJYPI-JYJNAYRXSA-N 0.000 description 1
- ZALGPUWUVHOGAE-GVXVVHGQSA-N Glu-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZALGPUWUVHOGAE-GVXVVHGQSA-N 0.000 description 1
- WGYHAAXZWPEBDQ-IFFSRLJSSA-N Glu-Val-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGYHAAXZWPEBDQ-IFFSRLJSSA-N 0.000 description 1
- UGVQELHRNUDMAA-BYPYZUCNSA-N Gly-Ala-Gly Chemical compound [NH3+]CC(=O)N[C@@H](C)C(=O)NCC([O-])=O UGVQELHRNUDMAA-BYPYZUCNSA-N 0.000 description 1
- QXPRJQPCFXMCIY-NKWVEPMBSA-N Gly-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN QXPRJQPCFXMCIY-NKWVEPMBSA-N 0.000 description 1
- JRDYDYXZKFNNRQ-XPUUQOCRSA-N Gly-Ala-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN JRDYDYXZKFNNRQ-XPUUQOCRSA-N 0.000 description 1
- BIRKKBCSAIHDDF-WDSKDSINSA-N Gly-Glu-Cys Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(O)=O BIRKKBCSAIHDDF-WDSKDSINSA-N 0.000 description 1
- NNCSJUBVFBDDLC-YUMQZZPRSA-N Gly-Leu-Ser Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O NNCSJUBVFBDDLC-YUMQZZPRSA-N 0.000 description 1
- AFWYPMDMDYCKMD-KBPBESRZSA-N Gly-Leu-Tyr Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 AFWYPMDMDYCKMD-KBPBESRZSA-N 0.000 description 1
- VDCRBJACQKOSMS-JSGCOSHPSA-N Gly-Phe-Val Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O VDCRBJACQKOSMS-JSGCOSHPSA-N 0.000 description 1
- JSLVAHYTAJJEQH-QWRGUYRKSA-N Gly-Ser-Phe Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 JSLVAHYTAJJEQH-QWRGUYRKSA-N 0.000 description 1
- CQMFNTVQVLQRLT-JHEQGTHGSA-N Gly-Thr-Gln Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O CQMFNTVQVLQRLT-JHEQGTHGSA-N 0.000 description 1
- NWOSHVVPKDQKKT-RYUDHWBXSA-N Gly-Tyr-Gln Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O NWOSHVVPKDQKKT-RYUDHWBXSA-N 0.000 description 1
- BAYQNCWLXIDLHX-ONGXEEELSA-N Gly-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)CN BAYQNCWLXIDLHX-ONGXEEELSA-N 0.000 description 1
- 206010019075 Hallucination, visual Diseases 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- ALPXXNRQBMRCPZ-MEYUZBJRSA-N His-Thr-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ALPXXNRQBMRCPZ-MEYUZBJRSA-N 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- QQFSKBMCAKWHLG-UHFFFAOYSA-N Ile-Phe-Pro-Pro Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(NC(=O)C(N)C(C)CC)CC1=CC=CC=C1 QQFSKBMCAKWHLG-UHFFFAOYSA-N 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 208000030990 Impulse-control disease Diseases 0.000 description 1
- 108010065920 Insulin Lispro Proteins 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- LHSGPCFBGJHPCY-UHFFFAOYSA-N L-leucine-L-tyrosine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 LHSGPCFBGJHPCY-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- PVMPDMIKUVNOBD-CIUDSAMLSA-N Leu-Asp-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O PVMPDMIKUVNOBD-CIUDSAMLSA-N 0.000 description 1
- GPICTNQYKHHHTH-GUBZILKMSA-N Leu-Gln-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GPICTNQYKHHHTH-GUBZILKMSA-N 0.000 description 1
- HFBCHNRFRYLZNV-GUBZILKMSA-N Leu-Glu-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O HFBCHNRFRYLZNV-GUBZILKMSA-N 0.000 description 1
- QJUWBDPGGYVRHY-YUMQZZPRSA-N Leu-Gly-Cys Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N QJUWBDPGGYVRHY-YUMQZZPRSA-N 0.000 description 1
- VWHGTYCRDRBSFI-ZETCQYMHSA-N Leu-Gly-Gly Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)NCC(O)=O VWHGTYCRDRBSFI-ZETCQYMHSA-N 0.000 description 1
- APFJUBGRZGMQFF-QWRGUYRKSA-N Leu-Gly-Lys Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN APFJUBGRZGMQFF-QWRGUYRKSA-N 0.000 description 1
- BKTXKJMNTSMJDQ-AVGNSLFASA-N Leu-His-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N BKTXKJMNTSMJDQ-AVGNSLFASA-N 0.000 description 1
- IAJFFZORSWOZPQ-SRVKXCTJSA-N Leu-Leu-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O IAJFFZORSWOZPQ-SRVKXCTJSA-N 0.000 description 1
- AUNMOHYWTAPQLA-XUXIUFHCSA-N Leu-Met-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O AUNMOHYWTAPQLA-XUXIUFHCSA-N 0.000 description 1
- UHNQRAFSEBGZFZ-YESZJQIVSA-N Leu-Phe-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N UHNQRAFSEBGZFZ-YESZJQIVSA-N 0.000 description 1
- WMIOEVKKYIMVKI-DCAQKATOSA-N Leu-Pro-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O WMIOEVKKYIMVKI-DCAQKATOSA-N 0.000 description 1
- DPURXCQCHSQPAN-AVGNSLFASA-N Leu-Pro-Pro Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 DPURXCQCHSQPAN-AVGNSLFASA-N 0.000 description 1
- SBANPBVRHYIMRR-GARJFASQSA-N Leu-Ser-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N SBANPBVRHYIMRR-GARJFASQSA-N 0.000 description 1
- SBANPBVRHYIMRR-UHFFFAOYSA-N Leu-Ser-Pro Natural products CC(C)CC(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O SBANPBVRHYIMRR-UHFFFAOYSA-N 0.000 description 1
- AIQWYVFNBNNOLU-RHYQMDGZSA-N Leu-Thr-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O AIQWYVFNBNNOLU-RHYQMDGZSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 208000009829 Lewy Body Disease Diseases 0.000 description 1
- MPGHETGWWWUHPY-CIUDSAMLSA-N Lys-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN MPGHETGWWWUHPY-CIUDSAMLSA-N 0.000 description 1
- SWWCDAGDQHTKIE-RHYQMDGZSA-N Lys-Arg-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SWWCDAGDQHTKIE-RHYQMDGZSA-N 0.000 description 1
- NTSPQIONFJUMJV-AVGNSLFASA-N Lys-Arg-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O NTSPQIONFJUMJV-AVGNSLFASA-N 0.000 description 1
- YKIRNDPUWONXQN-GUBZILKMSA-N Lys-Asn-Gln Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N YKIRNDPUWONXQN-GUBZILKMSA-N 0.000 description 1
- HIIZIQUUHIXUJY-GUBZILKMSA-N Lys-Asp-Gln Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HIIZIQUUHIXUJY-GUBZILKMSA-N 0.000 description 1
- KWUKZRFFKPLUPE-HJGDQZAQSA-N Lys-Asp-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KWUKZRFFKPLUPE-HJGDQZAQSA-N 0.000 description 1
- GCMWRRQAKQXDED-IUCAKERBSA-N Lys-Glu-Gly Chemical compound [NH3+]CCCC[C@H]([NH3+])C(=O)N[C@@H](CCC([O-])=O)C(=O)NCC([O-])=O GCMWRRQAKQXDED-IUCAKERBSA-N 0.000 description 1
- PBLLTSKBTAHDNA-KBPBESRZSA-N Lys-Gly-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PBLLTSKBTAHDNA-KBPBESRZSA-N 0.000 description 1
- ODTZHNZPINULEU-KKUMJFAQSA-N Lys-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N ODTZHNZPINULEU-KKUMJFAQSA-N 0.000 description 1
- AFLBTVGQCQLOFJ-AVGNSLFASA-N Lys-Pro-Arg Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O AFLBTVGQCQLOFJ-AVGNSLFASA-N 0.000 description 1
- WQDKIVRHTQYJSN-DCAQKATOSA-N Lys-Ser-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N WQDKIVRHTQYJSN-DCAQKATOSA-N 0.000 description 1
- MIFFFXHMAHFACR-KATARQTJSA-N Lys-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCCN MIFFFXHMAHFACR-KATARQTJSA-N 0.000 description 1
- IEVXCWPVBYCJRZ-IXOXFDKPSA-N Lys-Thr-His Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 IEVXCWPVBYCJRZ-IXOXFDKPSA-N 0.000 description 1
- DLCAXBGXGOVUCD-PPCPHDFISA-N Lys-Thr-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DLCAXBGXGOVUCD-PPCPHDFISA-N 0.000 description 1
- CAVRAQIDHUPECU-UVOCVTCTSA-N Lys-Thr-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAVRAQIDHUPECU-UVOCVTCTSA-N 0.000 description 1
- QLFAPXUXEBAWEK-NHCYSSNCSA-N Lys-Val-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O QLFAPXUXEBAWEK-NHCYSSNCSA-N 0.000 description 1
- XABXVVSWUVCZST-GVXVVHGQSA-N Lys-Val-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN XABXVVSWUVCZST-GVXVVHGQSA-N 0.000 description 1
- GILLQRYAWOMHED-DCAQKATOSA-N Lys-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN GILLQRYAWOMHED-DCAQKATOSA-N 0.000 description 1
- HMZPYMSEAALNAE-ULQDDVLXSA-N Lys-Val-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O HMZPYMSEAALNAE-ULQDDVLXSA-N 0.000 description 1
- FVKRQMQQFGBXHV-QXEWZRGKSA-N Met-Asp-Val Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O FVKRQMQQFGBXHV-QXEWZRGKSA-N 0.000 description 1
- BJPQKNHZHUCQNQ-SRVKXCTJSA-N Met-Pro-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCSC)N BJPQKNHZHUCQNQ-SRVKXCTJSA-N 0.000 description 1
- 208000001089 Multiple system atrophy Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010031127 Orthostatic hypotension Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- HXSUFWQYLPKEHF-IHRRRGAJSA-N Phe-Asn-Arg Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N HXSUFWQYLPKEHF-IHRRRGAJSA-N 0.000 description 1
- FUAIIFPQELBNJF-ULQDDVLXSA-N Phe-Met-Lys Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N FUAIIFPQELBNJF-ULQDDVLXSA-N 0.000 description 1
- JDMKQHSHKJHAHR-UHFFFAOYSA-N Phe-Phe-Leu-Tyr Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=CC=C1 JDMKQHSHKJHAHR-UHFFFAOYSA-N 0.000 description 1
- WWPAHTZOWURIMR-ULQDDVLXSA-N Phe-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 WWPAHTZOWURIMR-ULQDDVLXSA-N 0.000 description 1
- SJRQWEDYTKYHHL-SLFFLAALSA-N Phe-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC3=CC=CC=C3)N)C(=O)O SJRQWEDYTKYHHL-SLFFLAALSA-N 0.000 description 1
- 229920001100 Polydextrose Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- OOLOTUZJUBOMAX-GUBZILKMSA-N Pro-Ala-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O OOLOTUZJUBOMAX-GUBZILKMSA-N 0.000 description 1
- LHALYDBUDCWMDY-CIUDSAMLSA-N Pro-Glu-Ala Chemical compound C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1)C(O)=O LHALYDBUDCWMDY-CIUDSAMLSA-N 0.000 description 1
- NXEYSLRNNPWCRN-SRVKXCTJSA-N Pro-Glu-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O NXEYSLRNNPWCRN-SRVKXCTJSA-N 0.000 description 1
- KWMUAKQOVYCQJQ-ZPFDUUQYSA-N Pro-Ile-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@@H]1CCCN1 KWMUAKQOVYCQJQ-ZPFDUUQYSA-N 0.000 description 1
- ULWBBFKQBDNGOY-RWMBFGLXSA-N Pro-Lys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCCCN)C(=O)N2CCC[C@@H]2C(=O)O ULWBBFKQBDNGOY-RWMBFGLXSA-N 0.000 description 1
- KBUAPZAZPWNYSW-SRVKXCTJSA-N Pro-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 KBUAPZAZPWNYSW-SRVKXCTJSA-N 0.000 description 1
- OWQXAJQZLWHPBH-FXQIFTODSA-N Pro-Ser-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O OWQXAJQZLWHPBH-FXQIFTODSA-N 0.000 description 1
- MKGIILKDUGDRRO-FXQIFTODSA-N Pro-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 MKGIILKDUGDRRO-FXQIFTODSA-N 0.000 description 1
- 208000037048 Prodromal Symptoms Diseases 0.000 description 1
- UEJYSALTSUZXFV-SRVKXCTJSA-N Rigin Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O UEJYSALTSUZXFV-SRVKXCTJSA-N 0.000 description 1
- YQHZVYJAGWMHES-ZLUOBGJFSA-N Ser-Ala-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YQHZVYJAGWMHES-ZLUOBGJFSA-N 0.000 description 1
- YUSRGTQIPCJNHQ-CIUDSAMLSA-N Ser-Arg-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O YUSRGTQIPCJNHQ-CIUDSAMLSA-N 0.000 description 1
- OYEDZGNMSBZCIM-XGEHTFHBSA-N Ser-Arg-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OYEDZGNMSBZCIM-XGEHTFHBSA-N 0.000 description 1
- KNCJWSPMTFFJII-ZLUOBGJFSA-N Ser-Cys-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(O)=O)C(O)=O KNCJWSPMTFFJII-ZLUOBGJFSA-N 0.000 description 1
- MOVJSUIKUNCVMG-ZLUOBGJFSA-N Ser-Cys-Ser Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O)N)O MOVJSUIKUNCVMG-ZLUOBGJFSA-N 0.000 description 1
- UOLGINIHBRIECN-FXQIFTODSA-N Ser-Glu-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O UOLGINIHBRIECN-FXQIFTODSA-N 0.000 description 1
- XXXAXOWMBOKTRN-XPUUQOCRSA-N Ser-Gly-Val Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O XXXAXOWMBOKTRN-XPUUQOCRSA-N 0.000 description 1
- HMRAQFJFTOLDKW-GUBZILKMSA-N Ser-His-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O HMRAQFJFTOLDKW-GUBZILKMSA-N 0.000 description 1
- SFTZTYBXIXLRGQ-JBDRJPRFSA-N Ser-Ile-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O SFTZTYBXIXLRGQ-JBDRJPRFSA-N 0.000 description 1
- XUDRHBPSPAPDJP-SRVKXCTJSA-N Ser-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CO XUDRHBPSPAPDJP-SRVKXCTJSA-N 0.000 description 1
- LRZLZIUXQBIWTB-KATARQTJSA-N Ser-Lys-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LRZLZIUXQBIWTB-KATARQTJSA-N 0.000 description 1
- CKDXFSPMIDSMGV-GUBZILKMSA-N Ser-Pro-Val Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O CKDXFSPMIDSMGV-GUBZILKMSA-N 0.000 description 1
- XQJCEKXQUJQNNK-ZLUOBGJFSA-N Ser-Ser-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O XQJCEKXQUJQNNK-ZLUOBGJFSA-N 0.000 description 1
- NADLKBTYNKUJEP-KATARQTJSA-N Ser-Thr-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O NADLKBTYNKUJEP-KATARQTJSA-N 0.000 description 1
- ZKOKTQPHFMRSJP-YJRXYDGGSA-N Ser-Thr-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZKOKTQPHFMRSJP-YJRXYDGGSA-N 0.000 description 1
- HNDMFDBQXYZSRM-IHRRRGAJSA-N Ser-Val-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HNDMFDBQXYZSRM-IHRRRGAJSA-N 0.000 description 1
- HSWXBJCBYSWBPT-GUBZILKMSA-N Ser-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)C(O)=O HSWXBJCBYSWBPT-GUBZILKMSA-N 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- IGROJMCBGRFRGI-YTLHQDLWSA-N Thr-Ala-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O IGROJMCBGRFRGI-YTLHQDLWSA-N 0.000 description 1
- DWYAUVCQDTZIJI-VZFHVOOUSA-N Thr-Ala-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O DWYAUVCQDTZIJI-VZFHVOOUSA-N 0.000 description 1
- ASJDFGOPDCVXTG-KATARQTJSA-N Thr-Cys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O ASJDFGOPDCVXTG-KATARQTJSA-N 0.000 description 1
- LAFLAXHTDVNVEL-WDCWCFNPSA-N Thr-Gln-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N)O LAFLAXHTDVNVEL-WDCWCFNPSA-N 0.000 description 1
- GKWNLDNXMMLRMC-GLLZPBPUSA-N Thr-Glu-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O GKWNLDNXMMLRMC-GLLZPBPUSA-N 0.000 description 1
- YOOAQCZYZHGUAZ-KATARQTJSA-N Thr-Leu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YOOAQCZYZHGUAZ-KATARQTJSA-N 0.000 description 1
- SCSVNSNWUTYSFO-WDCWCFNPSA-N Thr-Lys-Glu Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O SCSVNSNWUTYSFO-WDCWCFNPSA-N 0.000 description 1
- JLNMFGCJODTXDH-WEDXCCLWSA-N Thr-Lys-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O JLNMFGCJODTXDH-WEDXCCLWSA-N 0.000 description 1
- XSEPSRUDSPHMPX-KATARQTJSA-N Thr-Lys-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O XSEPSRUDSPHMPX-KATARQTJSA-N 0.000 description 1
- BEZTUFWTPVOROW-KJEVXHAQSA-N Thr-Tyr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O BEZTUFWTPVOROW-KJEVXHAQSA-N 0.000 description 1
- RPECVQBNONKZAT-WZLNRYEVSA-N Thr-Tyr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H]([C@@H](C)O)N RPECVQBNONKZAT-WZLNRYEVSA-N 0.000 description 1
- FYBFTPLPAXZBOY-KKHAAJSZSA-N Thr-Val-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O FYBFTPLPAXZBOY-KKHAAJSZSA-N 0.000 description 1
- KPMIQCXJDVKWKO-IFFSRLJSSA-N Thr-Val-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O KPMIQCXJDVKWKO-IFFSRLJSSA-N 0.000 description 1
- QNXZCKMXHPULME-ZNSHCXBVSA-N Thr-Val-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O QNXZCKMXHPULME-ZNSHCXBVSA-N 0.000 description 1
- UKINEYBQXPMOJO-UBHSHLNASA-N Trp-Asn-Ser Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N UKINEYBQXPMOJO-UBHSHLNASA-N 0.000 description 1
- NLWCSMOXNKBRLC-WDSOQIARSA-N Trp-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O NLWCSMOXNKBRLC-WDSOQIARSA-N 0.000 description 1
- SSSDKJMQMZTMJP-BVSLBCMMSA-N Trp-Tyr-Val Chemical compound C([C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CC=C(O)C=C1 SSSDKJMQMZTMJP-BVSLBCMMSA-N 0.000 description 1
- SCCKSNREWHMKOJ-SRVKXCTJSA-N Tyr-Asn-Ser Chemical compound N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O SCCKSNREWHMKOJ-SRVKXCTJSA-N 0.000 description 1
- QUILOGWWLXMSAT-IHRRRGAJSA-N Tyr-Gln-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QUILOGWWLXMSAT-IHRRRGAJSA-N 0.000 description 1
- FMOSEWZYZPMJAL-KKUMJFAQSA-N Tyr-Glu-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N FMOSEWZYZPMJAL-KKUMJFAQSA-N 0.000 description 1
- WURLIFOWSMBUAR-SLFFLAALSA-N Tyr-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CC3=CC=C(C=C3)O)N)C(=O)O WURLIFOWSMBUAR-SLFFLAALSA-N 0.000 description 1
- YYLHVUCSTXXKBS-IHRRRGAJSA-N Tyr-Pro-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YYLHVUCSTXXKBS-IHRRRGAJSA-N 0.000 description 1
- NWEGIYMHTZXVBP-JSGCOSHPSA-N Tyr-Val-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O NWEGIYMHTZXVBP-JSGCOSHPSA-N 0.000 description 1
- IZFVRRYRMQFVGX-NRPADANISA-N Val-Ala-Gln Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N IZFVRRYRMQFVGX-NRPADANISA-N 0.000 description 1
- YFOCMOVJBQDBCE-NRPADANISA-N Val-Ala-Glu Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N YFOCMOVJBQDBCE-NRPADANISA-N 0.000 description 1
- SLLKXDSRVAOREO-KZVJFYERSA-N Val-Ala-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)N)O SLLKXDSRVAOREO-KZVJFYERSA-N 0.000 description 1
- SCBITHMBEJNRHC-LSJOCFKGSA-N Val-Asp-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)O)N SCBITHMBEJNRHC-LSJOCFKGSA-N 0.000 description 1
- RKIGNDAHUOOIMJ-BQFCYCMXSA-N Val-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 RKIGNDAHUOOIMJ-BQFCYCMXSA-N 0.000 description 1
- PTFPUAXGIKTVNN-ONGXEEELSA-N Val-His-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)NCC(=O)O)N PTFPUAXGIKTVNN-ONGXEEELSA-N 0.000 description 1
- KTEZUXISLQTDDQ-NHCYSSNCSA-N Val-Lys-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)O)C(=O)O)N KTEZUXISLQTDDQ-NHCYSSNCSA-N 0.000 description 1
- SBJCTAZFSZXWSR-AVGNSLFASA-N Val-Met-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N SBJCTAZFSZXWSR-AVGNSLFASA-N 0.000 description 1
- VHIZXDZMTDVFGX-DCAQKATOSA-N Val-Ser-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N VHIZXDZMTDVFGX-DCAQKATOSA-N 0.000 description 1
- CEKSLIVSNNGOKH-KZVJFYERSA-N Val-Thr-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](C(C)C)N)O CEKSLIVSNNGOKH-KZVJFYERSA-N 0.000 description 1
- YQYFYUSYEDNLSD-YEPSODPASA-N Val-Thr-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O YQYFYUSYEDNLSD-YEPSODPASA-N 0.000 description 1
- TVGWMCTYUFBXAP-QTKMDUPCSA-N Val-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N)O TVGWMCTYUFBXAP-QTKMDUPCSA-N 0.000 description 1
- BGTDGENDNWGMDQ-KJEVXHAQSA-N Val-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N)O BGTDGENDNWGMDQ-KJEVXHAQSA-N 0.000 description 1
- ZHWZDZFWBXWPDW-GUBZILKMSA-N Val-Val-Cys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(O)=O ZHWZDZFWBXWPDW-GUBZILKMSA-N 0.000 description 1
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 1
- 102100038968 WAP four-disulfide core domain protein 1 Human genes 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 210000005221 acidic domain Anatomy 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- 230000006933 amyloid-beta aggregation Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 1
- 108010068265 aspartyltyrosine Proteins 0.000 description 1
- 230000002567 autonomic effect Effects 0.000 description 1
- 210000003403 autonomic nervous system Anatomy 0.000 description 1
- 210000000467 autonomic pathway Anatomy 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229960004205 carbidopa Drugs 0.000 description 1
- TZFNLOMSOLWIDK-JTQLQIEISA-N carbidopa (anhydrous) Chemical compound NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 TZFNLOMSOLWIDK-JTQLQIEISA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 230000007370 cognitive improvement Effects 0.000 description 1
- 230000003931 cognitive performance Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- GPLRAVKSCUXZTP-UHFFFAOYSA-N diglycerol Chemical compound OCC(O)COCC(O)CO GPLRAVKSCUXZTP-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229960003337 entacapone Drugs 0.000 description 1
- JRURYQJSLYLRLN-BJMVGYQFSA-N entacapone Chemical compound CCN(CC)C(=O)C(\C#N)=C\C1=CC(O)=C(O)C([N+]([O-])=O)=C1 JRURYQJSLYLRLN-BJMVGYQFSA-N 0.000 description 1
- OFKDAAIKGIBASY-VFGNJEKYSA-N ergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2C(C3=CC=CC4=NC=C([C]34)C2)=C1)C)C1=CC=CC=C1 OFKDAAIKGIBASY-VFGNJEKYSA-N 0.000 description 1
- 229960004943 ergotamine Drugs 0.000 description 1
- XCGSFFUVFURLIX-UHFFFAOYSA-N ergotaminine Natural products C1=C(C=2C=CC=C3NC=C(C=23)C2)C2N(C)CC1C(=O)NC(C(N12)=O)(C)OC1(O)C1CCCN1C(=O)C2CC1=CC=CC=C1 XCGSFFUVFURLIX-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 231100000573 exposure to toxins Toxicity 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 1
- 108010027668 glycyl-alanyl-valine Proteins 0.000 description 1
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 1
- 108010074027 glycyl-seryl-phenylalanine Proteins 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 210000003000 inclusion body Anatomy 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000025563 intercellular transport Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000003447 ipsilateral effect Effects 0.000 description 1
- 108010027338 isoleucylcysteine Proteins 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 1
- 108010012058 leucyltyrosine Proteins 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 108010009298 lysylglutamic acid Proteins 0.000 description 1
- 108010064235 lysylglycine Proteins 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000000626 neurodegenerative effect Effects 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 229940052740 other dopaminergic agent in atc Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 1
- 108010051242 phenylalanylserine Proteins 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 description 1
- 239000001259 polydextrose Substances 0.000 description 1
- 235000013856 polydextrose Nutrition 0.000 description 1
- 229940035035 polydextrose Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000001144 postural effect Effects 0.000 description 1
- 210000000063 presynaptic terminal Anatomy 0.000 description 1
- 230000009862 primary prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 108010077112 prolyl-proline Proteins 0.000 description 1
- 108010031719 prolyl-serine Proteins 0.000 description 1
- 230000036385 rapid eye movement (rem) sleep Effects 0.000 description 1
- 208000019969 rapid eye movement sleep disease Diseases 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000009863 secondary prevention Effects 0.000 description 1
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 1
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 1
- 230000007958 sleep Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 108010061238 threonyl-glycine Proteins 0.000 description 1
- 229960004603 tolcapone Drugs 0.000 description 1
- MIQPIUSUKVNLNT-UHFFFAOYSA-N tolcapone Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC(O)=C(O)C([N+]([O-])=O)=C1 MIQPIUSUKVNLNT-UHFFFAOYSA-N 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 108010044292 tryptophyltyrosine Proteins 0.000 description 1
- 108010079202 tyrosyl-alanyl-cysteine Proteins 0.000 description 1
- 108010051110 tyrosyl-lysine Proteins 0.000 description 1
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 1
- 108010073969 valyllysine Proteins 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 108010000998 wheylin-2 peptide Proteins 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present application provides a method of treating, preventing or ameliorating parkinson's disease with plausimide.
Description
Cross reference to related applications
The disclosure of each of U.S. provisional application No. 63/076,913 to month 10 of 2020, U.S. provisional application No. 63/076,915 to month 10 of 2020, U.S. provisional application No. 63/076,916 to month 10 of 2020, and U.S. provisional application No. 63/158,191 to month 8 of 2021 is claimed.
Sequence listing
The computer readable form of the sequence listing is submitted by electronic delivery in conjunction with the present application and is incorporated herein by reference in its entirety. The Sequence Listing is contained in an ASCII text file created at 2021, 9, with a file name of "20-1293-wo_sequence-listing_st25.txt" and a size of 15kb.
Background
Parkinson's Disease (PD) is a slow, chronic, progressive neurodegenerative disease estimated to affect 7 million to 1 million people worldwide. In the united states, 725,000 people are estimated to be affected and more than 50,000 new cases are reported annually. While 5% to 10% of patients were diagnosed before age 50, PD is generally considered a disease targeted to the elderly, with one person out of every 100 persons over age 60 affected, and more common in men than in women.
Alpha-synuclein is a protein that is normally associated with synapses and is thought to play a role in neuroplasticity, learning and memory. Alpha-synuclein can aggregate to form insoluble fibrils in pathological conditions, and is a major component of the pathology that characterizes several neurodegenerative diseases, including parkinson's disease. Soluble oligomers of alpha-synuclein may be neurotoxic. The accumulation of alpha-synuclein with similar morphology and neural changes in species and animal models as diverse as humans, mice and flies suggests that this molecule contributes to the appearance of parkinson's disease. Antibodies directed against alpha-synuclein may be capable of reducing alpha-synuclein deposition and symptoms of parkinson's disease.
Current treatments for PD control early motor symptoms of the disease, mainly through the use of dopamine replacement therapy and dopamine receptor agonists. Treatment with levodopa and other dopaminergic agents temporarily addresses motor symptoms. However, this does not reverse, slow or stop the pathological process associated with the disease. As the disease progresses, these drugs become less effective in controlling symptoms.
Patients taking these drugs often experience side effects such as motor complications (e.g., response oscillations, motor taper phenomena (wearing off phenomena) and drug-induced motor difficulties), as well as nausea, daytime sleepiness, sleep onset, orthostatic hypotension, or impulse control disorders. Symptomatic treatment of non-motor symptoms of PD (e.g., sleep disorders, anxiety and depression) is also available. However, to date, there is no approved treatment that has been demonstrated to protect neurons or alter the course of disease. There is an urgent need for new therapies that target the underlying etiology of parkinson's disease and, unlike symptomatic therapies, slow its continued progression.
Disclosure of Invention
In one aspect, the invention provides a method for maintaining motor function or slowing motor function decline in a subject having or at risk of parkinson's disease comprising administering to the subject a praziquanzumab (prazizumab) regimen, wherein the maintenance comprises reducing progression of parkinson's disease, as indicated by a delay in progression time to at least 5 minutes of progression in MDS-UPDRS part III, and
the slowing down the descent includes at least one of:
(a) Slow the patient's decrease in MDS-UPDRS part III motor exam scores,
(b) Slowing down the decline in one or more of the following: speech, facial expression, stiffness, finger strokes, hand movements, hand pronation-supination movements, toe strokes, leg mobility, standing from chair, gait stiffness, posture stability, posture, hand tremor, stationary tremor amplitude, stationary tremor constancy, or Hoehn and Yahr staging; or (b)
(c) Improving bradykinesia;
wherein the pramipexole mab regimen comprises 1000 to 5000mg of pramipexole mab at intervals of 3 to 5 weeks.
Improvement over placebo after one year of treatment was at least 18%, 24%, 25%, 33%, 35% or 45%.
In another aspect, the invention provides a method for maintaining or increasing cerebral blood flow in a subject suffering from or at risk of parkinson's disease comprising administering to the subject a plasamab regimen comprising 1000 to 5000mg plasamab at 3 to 5 week intervals.
In some methods, cerebral blood flow in the putamen is maintained or increased.
In some methods, cerebral blood flow in the globus pallidus is maintained or increased.
In some methods, cerebral blood flow in the anterior motor cortex is maintained or increased.
In some methods, blood flow is assessed by changes in magnetic resonance-arterial spin labeling (MRI-ASL).
In yet another aspect, the invention provides a method for improving cognitive function in a subject suffering from or at risk of parkinson's disease comprising administering to the subject a plausiab regimen comprising 1000 to 5000mg plausiab at 3 to 5 week intervals.
In some methods, the subject does not have impairment of cognitive function.
In some methods, improvement in cognitive function is measured by Montreal cognitive assessment (Montreal Cognitive Assessment; moCA), and wherein the improvement is at least 0.2 on the MoCa scoring scale.
In another aspect, the invention provides a method for maintaining motor function or slowing motor function decline in a subject having or at risk of parkinson's disease, comprising administering to the subject a plasamab regimen, wherein the maintaining comprises reducing progression of parkinson's disease as indicated by a delay in progression time to at least 5 minutes of progression in MDS-UPDRS part III, and the slowing decline comprises at least one of:
(a) Slow down the decline in the patient's MDS-UPDRS part III motor exam score,
(b) Slowing down the decline in one or more of the following: speech, facial expression, stiffness, finger strokes, hand movements, hand pronation-supination movements, toe strokes, leg mobility, standing from chair, gait stiffness, posture stability, posture, hand tremor, stationary tremor amplitude, stationary tremor constancy, or Hoehn and Yahr staging; or (b)
(c) Improving bradykinesia;
wherein the pramipexole mab regimen comprises 1000 to 5000mg of pramipexole mab at intervals of 3 to 5 weeks.
In some methods, the subject has been diagnosed with mild exercise as a major subtype, diffuse malignant subtype, or moderate subtype of parkinson's disease, and in some methods, the subject has been diagnosed with diffuse malignant subtype of parkinson's disease.
In some methods, slowing the decrease in the motor check score of the patient after one year of treatment compared to placebo comprises an improvement of at least 4%, 17%, 18%, 24%, 25%, 33%, 35%, 39%, 45%, 52%, 63%, 64%, 68%, 71%, 74%, 76%, or 109%.
In some methods, the plausizumab is administered intravenously.
In some methods, the method further comprises administering to the subject an MAO-B inhibitor.
In some methods, the subject is untreated, diagnosed with PD in the last two years, or previously treated with a MAO-B inhibitor.
In some methods, the subject has a body weight of greater than 65kg and is administered a dose of 4500mg of plausiab once every 4 weeks.
In some methods, the subject has a body weight of less than 65kg and is administered a dose of 3500mg of pramipexole mab once every 4 weeks.
In some methods, the subject is administered a 1500mg dose of antibody every 4 weeks.
In some methods, the subject receives plausimide once every 4 weeks for at least 52 weeks.
In some methods, the subject is male.
In another aspect, the invention provides a method of treating a subject suffering from or at risk of parkinson's disease, comprising administering to the subject a plasamab regimen, wherein the treatment comprises:
(a) Reduce parkinsonian progression as indicated by a delay in progression time to at least 5 points in MDS-UPDRS part III, or
(b) Slowing down the decline in athletic functionality includes at least one of:
(i) Slowing the patient's MDS-UPDRS part III motor test score down;
(ii) Slowing down the decline in one or more of the following: speech, facial expression, stiffness, finger strokes, hand movements, hand pronation-supination movements, toe strokes, leg mobility, standing from chair, gait stiffness, posture stability, posture, hand tremor, stationary tremor amplitude, stationary tremor constancy, or Hoehn and Yahr staging;
(iii) The action retardation is improved, and the action retardation is improved,
wherein the pramipexole mab regimen comprises 1000 to 5000mg of pramipexole mab at intervals of 3 to 5 weeks.
In some methods, the subject has been diagnosed with mild exercise as a major subtype, diffuse malignant subtype, or moderate subtype of parkinson's disease, and in some methods, the subject has been diagnosed with diffuse malignant subtype of parkinson's disease.
In some methods, slowing the decrease in the motor check score of the patient after one year of treatment compared to placebo comprises an improvement of at least 4%, 17%, 18%, 24%, 25%, 33%, 35%, 39%, 45%, 52%, 63%, 64%, 68%, 71%, 74%, 76%, or 109%.
In some methods, the plausizumab is administered intravenously.
In some methods, the method further comprises administering to the subject an MAO-B inhibitor.
In some methods, the subject is untreated, diagnosed with PD in the last two years, or previously treated with a MAO-B inhibitor.
In some methods, the subject has a body weight of greater than 65kg and is administered a dose of 4500mg of plausiab once every 4 weeks.
In some methods, the subject has a body weight of less than 65kg and is administered a dose of 3500mg of pramipexole mab once every 4 weeks.
In some methods, the subject is administered a 1500mg dose of antibody every 4 weeks.
In some methods, the subject receives plausimide once every 4 weeks for at least 52 weeks.
In some methods, the subject is male.
Drawings
Figure 1 shows the change in total MDS-UPDRS scores (parts I, II and III) from baseline to week 52. Patients who begin symptomatic PD treatment contributed to the last visit before starting symptomatic PD treatment. The results showed that the change from baseline in MDS-UPDRS total score at week 52 (parts I, II and III) for each treatment versus placebo group did not meet (combined dose content: -14.0%, -1.30, 80% CI = (-3.18,0.58), low dose content: -21.5%, -2.02, 80% CI = (-4.21,0.18) and high dose content: -6.6%, -0.62, 80% CI = (-2.82,1.58)). Bar graphs represent 80% CI. MDS-UPDRS, the dyskinesia Association unifies the Parkinson's disease rating scale.
Figure 2 shows improvement in MoCA scores from baseline to week 52. MoCA (montreal cognitive assessment) is a 30 score scale and higher scores indicate better cognitive performance. On average, patients treated with plausimab were within cognitive standards at baseline. Patients treated with plausimab show an improvement in MoCA scores.
Figure 3 shows that CGI-I demonstrates that patient risk of exacerbation at week 52 is reduced. In the clinical global improvement impression (CGI-I), both dose levels showed constant signals contributing to plausimide.
Figure 4 shows that PGI-C demonstrates that patients have reduced risk of exacerbation at week 52. In the overall patient change impression (PGI-C), both dose levels showed constant signals that contributed to plausiab.
Fig. 5 shows an MRI-ASL (magnetic resonance-arterial spin labeling) analysis indicating blood flow changes in the brain. Red indicates higher blood flow and blue indicates lower blood flow. Patients with placebo had reduced blood flow at week 52 (see arrow) compared to baseline. Patients with plausizumab had increased blood flow at week 52 compared to baseline (see arrow). The images were from all subsets of individuals treated with plausimide (low/high dose), and the images were complexes of patients that were superimposed to produce an average image.
Figures 6A, 6B and 6C show, respectively, that patients with plausizumab had increased blood flow in the putamen, globus pallidus and anterior motor cortex at week 52 compared to baseline. Increased cerebral blood flow in the putamen indicates potential synaptic protection.
Fig. 7A shows the change in baseline to week 52 total MDS-UPDRS part III for on-site ratings, demonstrating a decrease in motor function (combined dose content: -25.0%, -1.44, 80% CI = (-2.83, -0.06), low dose content: -33.8%, -1.88, 80% CI = (-3.49, -0.27), and high dose content: -18.2%, -1.02, 80% CI = (-2.64,0.61)). * Patients who begin symptomatic PD treatment contributed to the last visit before starting symptomatic PD treatment. Bar graphs represent 80% CI.
Figure 7B shows the change in total MDS-UPDRS part III from baseline to week 52 for concentration ratings, demonstrating a decrease in motor function (combined dose content: -35.0%, -1.88, 80% CI = -3.31, -0.45); low dose content: -45.4%, -2.44, 80% ci= (-4.09, -0.78); high dose content: -24.7%, -1.33, 80% ci= (-2.99,0.34)). On the centralized rating assessment of MDS-UPDRS part III, plausimide reduced the decline in motor function by 35% compared to placebo after one year of treatment. * Patients who begin symptomatic PD treatment contributed to the last visit before starting symptomatic PD treatment. Bar graphs represent 80% CI.
Figure 8 shows the time reduction to deterioration of motor function as the delay progresses to a clinically significant decline. As demonstrated by on-site rating for the time to at least 5 minutes of progression in MDS-UPDRS part III, the comparison of placebo was within 52 weeks, with plausimab delayed to a clinically significant time of progression of locomotion in plausimab-treated patients (combined dose content: hr=0.82, 80% ci=0.64 to 0.99; low dose content: hr=0.77, 80% ci=0.63 to 0.96; and high dose content: hr=0.87, ci=0.70 to 1.07). * Wald CI/test. The combined dose analysis was a post hoc analysis. CI, confidence interval; MDS-UPDRS, the dyskinesia Association unifies the Parkinson's disease rating scale.
Figure 9 shows a decrease in bradykinesia progression from baseline to week 52 confirming the clinical decline in bradykinesia progression. Efficacy signals were observed in praziram mab treated patients at week 52 by on-site rating versus placebo on the change in bradykinesia from baseline (combined dose content: -27.0%, -0.75, 80% CI = (-1.62,0.11), low dose content: -38.3%, -1.07, 80% CI = (-2.07, -0.07), and high dose content: -15.7%, -0.44, 80% CI = (-1.45,0.56)). The combined dose analysis was a post hoc analysis. CI, confidence interval; MDS-UPDRS, the dyskinesia Association unifies the Parkinson's disease rating scale.
FIG. 10 shows that MAO-B inhibitor treatment and diffuse malignant sub-phenotype show faster disease progression on MDS-UPDRS part III. Patients who begin symptomatic PD treatment contributed to the last visit before starting symptomatic PD treatment. Bar graphs represent 80% CI. The evaluation was based on MMRM with the following covariates: MAOB inhibitor at baseline (yes/no), treatment, weeks, age <60 vs. 60, sex, daT-SPECT core to shell binding ratio (side most clinically affected in contralateral comparison), baseline MDS-UPDRS corresponding endpoint. The combined dose analysis is a predetermined exploratory analysis. 4500mg is used for not less than 65kg;3500mg for <65kg. CI, confidence interval; daT-SPECT, dopamine transporter imaging by single photon emission computed tomography; MAO-B, monoamine oxidase B; MDS-UPDRS, unified PD rating scale of dyskinesia association; MMRM, mixed influence model repeated measurement; PD, parkinson's disease.
Figures 11A, 11B and 11C show that in individuals with faster disease progression, the reduction in clinical decline by plausimide was more pronounced. Patients who begin symptomatic PD treatment contributed to the last visit before starting symptomatic PD treatment. Bar graphs represent 80% CI. The evaluation was based on MMRM with the following covariates: MAOB inhibitor at baseline (yes/no), treatment, weeks, age <60 vs. 60, sex, daT-SPECT core to shell binding ratio (side most clinically affected in contralateral comparison), baseline MDS-UPDRS corresponding endpoint. The combined dose analysis is a predetermined exploratory analysis. 4500mg is used for not less than 65kg;3500mg for <65kg. CI, confidence interval; daT-SPECT, dopamine transporter imaging by single photon emission computed tomography; MAO-B, monoamine oxidase B; MDS-UPDRS, unified PD rating scale of dyskinesia association; MMRM, mixed influence model repeated measurement; PD, parkinson's disease.
Figures 12A, 12B and 12C show that by concentrated ranking, a greater effect of plausiab was seen in individuals with faster disease progression.
Figures 13A, 13B and 13C show that slowing down clinical decline by plausimide is more pronounced in individuals who progress faster in digital exercise measurements. Patients who begin symptomatic PD treatment contributed to the last visit before starting symptomatic PD treatment. Bar graphs represent 80% CI. The evaluation was based on MMRM with the following covariates: MAOB inhibitor at baseline (yes/no), treatment, weeks, age <60 vs. 60, sex, daT-SPECT core to shell binding ratio (side most clinically affected in contralateral comparison), baseline MDS-UPDRS corresponding endpoint. The combined dose analysis is a predetermined exploratory analysis. 4500mg is used for not less than 65kg;3500mg for <65kg. CI, confidence interval; daT-SPECT, dopamine transporter imaging by single photon emission computed tomography; MAO-B, monoamine oxidase B; MDS-UPDRS, unified PD rating scale of dyskinesia association; MMRM, mixed influence model repeated measurement; PD, parkinson's disease.
Detailed Description
The present invention relates to the use of plausiab and other similar anti-alpha-synuclein humanized antibodies in the treatment, prevention and/or amelioration of parkinson's disease, including early stage parkinson's disease (e.g., to reduce disease progression).
In one aspect of the invention, plausizumab is used to improve, maintain or reduce the decline in motor function in individuals with parkinson's disease. In one aspect of the invention, one measure of motor function is the movement disorder association unified parkinson's disease rating scale (MDS-UPDRS) part III, clinical examination of motor function. In another aspect of the invention, MDS-UPDRS section III is a field rating assessment. In another aspect of the invention, MDS-UPDRS section III is a centralized rating assessment. Motor symptoms associated with parkinson's disease include bradykinesia (bradykinesia), tremors, speech changes, facial expression, stiffness, and gait. In one aspect of the invention, plausizumab is used to delay the time to clinically significant progression of movement to MDS-UPDRS part III.
In another aspect of the invention, plausizumab is used to maintain or improve cerebral blood flow as assessed by changes in magnetic resonance-arterial spin labeling (MRI-ASL). In one aspect of the invention, plausiab is used to demonstrate an improvement in cerebral blood flow in brain regions including the anterior motor cortex, globus pallidus and putamen (brain regions associated with loss of dopaminergic ends and the presence of alpha-synuclein pathology in parkinson's disease), which demonstrate an impact on underlying biology involved in disease progression.
In yet another aspect of the invention, plausizumab is used to maintain or improve cognitive function in a patient. In one aspect of the invention, the patient has normal cognitive function. Montreal cognitive assessment (MoCA) can be used as a tool to screen patients for the presence of mild cognitive impairment and are typically expressed in the normal range for the simple smart state test (MMSE).
In another aspect of the invention, plausiab is used to improve, maintain, or reduce the decline in motor function in individuals with parkinson's disease. In one aspect of the invention, one measure of motor function is the movement disorder association unified parkinson's disease rating scale (MDS-UPDRS) part III, clinical examination of motor function. In another aspect of the invention, MDS-UPDRS section III is a field rating assessment. In another aspect of the invention, MDS-UPDRS section III is a centralized rating assessment. Motor symptoms associated with parkinson's disease include bradykinesia (bradykinesia), tremors, speech changes, facial expression, stiffness, and gait. In one aspect of the invention, plausizumab is used to delay the time to clinically significant progression of movement to MDS-UPDRS part III.
Before other aspects of the invention are set forth, a number of terms are defined below. As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. For example, the term "compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.
Alpha-synuclein is a sufficiently highly conserved protein in neurons, particularly in the presynaptic terminal, and is thought to fold abnormally and aggregate to form a protein structure highly involved in the pathology of parkinson's disease. Aggregated alpha-synuclein proteins that form brain lesions are a hallmark of neurodegenerative synucleinopathies. Furthermore, aberrant folding and aggregation may often be accompanied by β -amyloid deposition in some neurodegenerative diseases, and α -synuclein and tau aggregates coexist in several neurodegenerative diseases, including parkinson's disease.
Natural human wild-type α -synuclein is a 140 amino acid peptide having the following amino acid sequence (GenBank accession number: P37840):
proteins have three recognized domains: covering the N-terminal repeat domain of amino acids 1 to 61; NAC (non-amyloid component) domain, between about amino acids 60 and 95; and a C-terminal acidic domain between about amino acids 98 and 140. Unless otherwise apparent from the context, references to α -synuclein or fragments thereof include the native human wild-type amino acid sequences indicated above and human allelic variants thereof, particularly those associated with parkinson's disease.
Unless otherwise apparent from the context, the term "about" encompasses insubstantial variations such as values within the standard measurement error margin (e.g., SEM) of the stated values. The designation of a range of values includes all integers within or defining the range and all sub-ranges defined by integers within the range. As used herein, statistical significance means that p.ltoreq.0.05. Unless otherwise apparent from the context, the term "about" encompasses values within the standard deviation of the mean of the stated values or +/-5% of the stated values, whichever is greater.
A composition or method that "comprises" or "comprises" one or more recited elements may include other elements not specifically recited. For example, a composition that "comprises" or "includes" a polypeptide sequence may contain the sequence alone or in combination with other sequences or components.
If an individual has at least one known risk factor (e.g., age, genetic, biochemical, family history, and contextual exposure), the individual is at increased risk of developing a disease, such that an individual having the risk factor is at a statistically significantly greater risk of developing a disease than a subject not having the risk factor.
The term "subject" or "patient" includes human and other mammalian subjects receiving prophylactic or therapeutic treatment, including untreated subjects. As used herein, the term "subject" or "patient" refers to any single subject in need of treatment, including other mammalian subjects, such as humans, cows, dogs, guinea pigs, rabbits, and the like. Also intended to be included as a subject are any subjects participating in a clinical study trial that do not show any clinical signs of disease, or subjects participating in an epidemic study, or subjects used as controls. In some aspects of the invention, the patient is a male patient, and in some aspects of the invention, the patient is a female patient.
The term "disease" refers to any abnormal condition that impairs physiological function. The term is used broadly to encompass any disorder, disease, abnormality, pathology, disease, condition, or syndrome that impairs physiological function, regardless of the nature of the etiology.
The term "symptom" refers to subjective signs of a disease as perceived by a subject, such as gait changes. "signs" or "signals" refer to objective signs of a disease as observed by a clinician or physician.
As used herein, the term "treating" refers to alleviating or ameliorating one or more symptoms, signs, signals, or effects associated with a disease, preventing, inhibiting, or delaying the onset of one or more symptoms or effects of a disease, reducing the severity or frequency of one or more symptoms or effects of a disease, and/or enhancing or tending toward a desired outcome as described herein. Treatment regimen refers to a combination of parameters characterizing the administration of an antibody of the invention, including any or all of dose, frequency of administration, route of administration, and total duration of administration.
As used herein, the term "preventing" refers to contacting (e.g., administering) a composition of the invention with a subject in the presence or absence of an alpha-synuclein pathology (primary prevention and secondary prevention) prior to the onset of the disease, thereby delaying the onset of clinical symptoms and/or alleviating symptoms of the disease after the onset of the disease, as compared to when the subject is not contacted with the peptide or immunotherapeutic composition, and does not refer to completely suppressing the onset of the disease. In some cases, a prophylactic effect may occur for a limited period of time after administration of the peptide or immunotherapeutic composition of the invention. In other cases, a prophylactic effect may occur for the duration of a treatment regimen comprising administration of a peptide or immunotherapeutic composition of the invention.
The term "decrease" as used herein refers to an increase in the measurement or evaluation of a decrease or inhibition of symptoms, signs, signals or effects associated with parkinson's disease. In other embodiments, the term "reducing" as used herein refers to reducing or inhibiting an increase in the amount of α -synuclein present in a subject or tissue of a subject, which encompasses reducing or inhibiting an increase (e.g., reducing the rate of increase) in the amount of α -synuclein present, accumulated, aggregated, or deposited in a subject or tissue of a subject. In certain embodiments, reducing or inhibiting an increase in the amount of α -synuclein present, accumulated, aggregated, or deposited in a subject (e.g., reducing the rate of increase) refers to the amount of α -synuclein present, accumulated, aggregated, or deposited in the Central Nervous System (CNS) of the subject. In certain embodiments, reducing or inhibiting an increase in the amount of α -synuclein present, accumulated, aggregated, or deposited in a subject (e.g., reducing the rate of increase) refers to the amount of α -synuclein present, accumulated, aggregated, or deposited in the periphery (e.g., peripheral circulatory system) of the subject. In certain embodiments, reducing or inhibiting an increase in the amount of α -synuclein present, accumulated, aggregated, or deposited in a subject (e.g., reducing the rate of increase) refers to the amount of α -synuclein present, accumulated, aggregated, or deposited in the brain of the subject. In some embodiments, the reduced α -synuclein is a pathologically-form of α -synuclein (e.g., fibular α -synuclein inclusion bodies, oligomeric or fibrous α -synuclein stacks, or pre-fibrillar intermediates of α -synuclein oligomers). In still other embodiments, the pathological indicators of neurodegenerative diseases and/or synucleinopathies are reduced.
As used herein, the terms "[ now ] field rating", "[ now ] field monitoring", and the like refer to an in-situ in-person assessment by an sponsor or representative at the site where a clinical study is conducted.
As used herein, the terms "centralized [ local ] rating", "centralized [ local ] monitoring", and the like refer to remote assessment by an sponsor or representative (e.g., clinical monitor, data manager, or statistical practitioner) at a location other than the site at which the clinical study is conducted.
As used herein, the term "subgroup analysis" and the like refers to repeating the study analysis (e.g., vision-standing hypotension, mild cognitive impairment, rapid eye movement sleep disorder (RBD), depression, anxiety, and unified parkinson's disease rating scale at baseline, part II and part III scores) after dividing the study population by one or more subgroup variables, the mixed early parkinson's disease population may be divided into subgroups comprising (1) mild exercise as the major subtype, (2) diffuse malignant subtype, or (3) moderate subtype. The objective of subgroup analysis is typically to evaluate whether the association of two variables differs depending on the third variable (e.g. parkinson's disease subtype).
Praziram mAb (PRX 002/RG7935/RO7046015/NEOD 002) is an immunoglobulin G1 class (IgG 1) humanized monoclonal antibody (mAb) derived from the murine parent antibody 9E4 (produced by the hybridoma given ATCC accession No. PTA-8221) and is directed against an epitope (amino acids 118-126) in the C-terminus of human alpha synuclein. Praziram mab binds to both soluble and insoluble forms of human alpha-synuclein in biochemical and biophysical experiments, and wherein the relative affinity/avidity to the aggregated form of alpha-synuclein is greater than the monomeric form of alpha-synuclein. In cell culture, plausimab effectively blocks intercellular transport of alpha synuclein. The plausimab comprises the heavy chain variable region of SEQ ID NO. 1 and the light chain variable region of SEQ ID NO. 4. Prasenapine mab comprises a heavy chain (SEQ ID NO:10, with or without a C-terminal lysine) and a light chain (SEQ ID NO: 9). Other exemplary humanized versions of the mouse 9E4 antibody include three exemplary humanized light chain maturation variable regions (SEQ ID NOS: 2, 3) and three exemplary humanized heavy chain maturation variable regions (SEQ ID NOS: 5, 6, 7). Exemplary light and heavy chain mature variable regions can be paired in any combination. See WO2019/064053, which is incorporated herein by reference in its entirety. As shown herein, plausiab is the first potential disease modifying anti-alpha-synuclein antibody that exhibits efficacy signals for multiple clinical endpoints in patients with early parkinson's disease.
Turning now to the various aspects of the invention, montreal cognitive assessment (MoCA) is a tool to screen patients for the presence of mild cognitive impairment and generally to be represented in the normal context with respect to the simple smart state test (MMSE). MoCA is a 30 score scale and higher scores indicate better cognitive efficacy. Typically, a MoCA score of at least 26 indicates no cognitive impairment.
Cerebral blood flow may be used to exhibit an improvement in cerebral blood flow as assessed by changes in magnetic resonance-arterial spin labeling (MRI-ASL). According to one aspect of the invention, the decrease in cerebral blood flow in a patient, the maintenance of cerebral blood flow in a patient, or the improvement of cerebral blood flow in a patient may be reduced by a therapeutic regimen of plausiab. In one aspect of the invention, blood flow in the anterior motor cortex, globus pallidus and/or putamen (brain region associated with loss of dopaminergic terminals and the presence of parkinsonian alpha-synuclein pathology) is improved, indicating an impact on underlying biology involved in disease progression.
According to one aspect of the invention, decline in cognitive function, maintenance of cognitive function, or improvement of cognitive function in a patient, including a patient in the normal range of cognition, can be reduced by a treatment regimen of plausizumab. In one aspect of the invention, cognitive function is assessed by MoCA assessment. For example, as measured by MoCA, praziram monoclonal antibody can improve cognitive function by 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.1, 5.2, 5.3, 5.4, 5.5.6, 5.7, 5.8, 5.6, 6, 6.1. 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12, 12.1, 12.2, 12.3, 12.5. 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12, 12.1, 12.2, 12.3, 12.4, 12.5, 24.5, 24.6, 24.7, 24.8, 24.9, 25, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30; or up to at least 0.1, at least 0.2, at least 0.3, at least 0.4, at least 0.5, at least 0.6, at least 0.7, at least 0.8, at least 0.9, at least 1, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2, at least 2.1, at least 2.2, at least 2.3, at least 2.4, at least 2.5, at least 2.6, at least 2.7, at least 2.8, at least 2.9, at least 3, at least 3.1, at least 3.2, at least 3.3 at least 3.4, at least 3.5, at least 3.6, at least 3.7, at least 3.8, at least 3.9, at least 4, at least 4.1, at least 4.2, at least 4.3, at least 4.4, at least 4.5, at least 4.6, at least 4.7, at least 4.8, at least 4.9, at least 5, at least 5.1, at least 5.2, at least 5.3, at least 5.4, at least 5.5, at least 5.6, at least 5.7, at least 5.8, at least 5.9, at least 6, at least 6.1, at least 6.2, at least 6.3, at least 6.4, at least 6.5 at least 6.6, at least 6.7, at least 6.8, at least 6.9, at least 7, at least 7.1, at least 7.2, at least 7.3, at least 7.4, at least 7.5, at least 7.6, at least 7.7, at least 7.8, at least 7.9, at least 8, at least 8.1, at least 8.2, at least 8.3, at least 8.4, at least 8.5, at least 8.6, at least 8.7, at least 8.8, at least 8.9, at least 9, at least 9.1, at least 9.2, at least 9.3, at least 9.4, at least 9.5, at least 9.6, at least 9.7, at least 9.8 at least 9.9, at least 10, at least 10.1, at least 10.2, at least 10.3, at least 10.4, at least 10.5, at least 10.6, at least 10.7, at least 10.8, at least 10.9, at least 11, at least 11.1, at least 11.2, at least 11.3, at least 11.4, at least 11.5, at least 11.6, at least 11.7, at least 11.8, at least 11.9, at least 12, at least 12.1, at least 12.2, at least 12.3, at least 12.4, at least 12.5, at least 12.6, at least 12.7, at least 12.8, at least, at least 12.9, at least 13, at least 13.1, at least 13.2, at least 13.3, at least 13.4, at least 13.5, at least 13.6, at least 13.7, at least 13.8, at least 13.9, at least 14, at least 14.1, at least 14.2, at least 14.3, at least 14.4, at least 14.5, at least 14.6, at least 14.7, at least 14.8, at least 14.9, at least 15, at least 15.1, at least 15.2, at least 15.3, at least 15.4, at least 15.5, at least 15.6, at least 15.7, at least 15.8, at least 15.9, at least 16, at least 16.1, at least at least 16.2, at least 16.3, at least 16.4, at least 16.5, at least 16.6, at least 16.7, at least 16.8, at least 16.9, at least 17, at least 17.1, at least 17.2, at least 17.3, at least 17.4, at least 17.5, at least 17.6, at least 17.7, at least 17.8, at least 17.9, at least 18, at least 18.1, at least 18.2, at least 18.3, at least 18.4, at least 18.5, at least 18.6, at least 18.7, at least 18.8, at least 18.9, at least 19, at least 19.1, at least 19.2, at least 19.3, at least at least 19.4, at least 19.5, at least 19.6, at least 19.7, at least 19.8, at least 19.9, at least 20, at least 20.1, at least 20.2, at least 20.3, at least 20.4, at least 20.5, at least 20.6, at least 20.7, at least 20.8, at least 20.9, at least 21, at least 21.1, at least 21.2, at least 21.3, at least 21.4, at least 21.5, at least 21.6, at least 21.7, at least 21.8, at least 21.9, at least 22, at least 22.1, at least 22.2, at least 22.3, at least 22.4, at least 22.5, at least at least 22.6, at least 22.7, at least 22.8, at least 22.9, at least 23, at least 23.1, at least 23.2, at least 23.3, at least 23.4, at least 23.5, at least 23.6, at least 23.7, at least 23.8, at least 23.9, at least 24, at least 24.1, at least 24.2, at least 24.3, at least 24.4, at least 24.5, at least 24.6, at least 24.7, at least 24.8, at least 24.9, at least 25, at least 25.1, at least 25.2, at least 25.3, at least 25.4, at least 25.5, at least 25.6, at least 25.7, at least, at least 25.8, at least 25.9, at least 26, at least 26.1, at least 26.2, at least 26.3, at least 26.4, at least 26.5, at least 26.6, at least 26.7, at least 26.8, at least 26.9, at least 27, at least 27.1, at least 27.2, at least 27.3, at least 27.4, at least 27.5, at least 27.6, at least 27.7, at least 27.8, at least 27.9, at least 28, at least 28.1, at least 28.2, at least 28.3, at least 28.4, at least 28.5, at least 28.6, at least 28.7, at least 28.8, at least 28.9, at least 29, at least 29.1, at least 29.2, at least 29.3, at least 29.4, at least 29.5, at least 29.6, at least 29.7, at least 29.8, or at least 29.9.
In another example, as measured by MoCA, praziram mab may improve cognitive function by 0.10%, 0.20%, 0.30%, 0.40%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, 1.00%, 1.10%, 1.20%, 1.30%, 1.40%, 1.50%, 1.60%, 1.70%, 1.80%, 1.90%, 2.00%, 2.10%, 2.20%, 2.30%, 2.40%, 2.50%, 2.60%, 2.70%, 2.80%, 2.90%, 3.00%, 3.10%, 3.20%, 3.30%, 3.40%, 3.50%, 3.60%, 3.70%, 3.80%, 3.90% >, 4.00%, 4.10%, 4.20%, 4.30%, 4.40%, 4.50%, 4.60%, 4.70%, 4.80%, 4.90%, 5.00%, 5.10%, 5.20%, 5.30%, 5.40%, 5.50%, 5.60%, 5.70%, 5.80%, 5.90%, 6.00%, 6.10%, 6.20%, 6.30%, 6.40%, 6.50%, 6.60%, 6.70%, 6.80%, 6.90%, 7.00%, 7.10%, 7.20%, 7.30%, 7.40%, 7.50%, 7.60%, 7.70%, 7.80%, 7.90%, 8.00%, 8.10%, 8.20% >. 4.00%, 4.10%, 4.20%, 4.30%, 4.40%, 4.50%, 4.60%, 4.70%, 4.80%, 4.90%, 5.00%, 5.10%, 5.20%, 5.30%, 5.40%, 5.50%, 5.60%, 5.70%, 5.80%, 5.90%, 6.00%, 6.10%, and 6.20%, 6.30%, 6.40%, 6.50%, 6.60%, 6.70%, 6.80%, 6.90%, 7.00%, 7.10%, 7.20%, 7.30%, 7.40%, 7.50%, 7.60%, 7.70%, 7.80%, 7.90%, 8.00%, 8.10%, 8.20%, and, 16.30%, 16.40%, 16.50%, 16.60%, 16.70%, 16.80%, 16.90%, 17.00%, 17.10%, 17.20%, 17.30%, 17.40%, 17.50%, 17.60%, 17.70%, 17.80%, 17.90%, 18.00%, 18.10%, 18.20%, 18.30%, 18.40%, 18.50%, 18.60%, 18.70%, 18.80%, 18.90%, 19.00%, 19.10%, 19.20%, 19.30%, 19.40%, 19.50%, 19.60%, 19.70%, 19.80%, 19.90%, and the like. 20.00%, 20.10%, 20.20%, 20.30%, 20.40%, 20.50%, 20.60%, 20.70%, 20.80%, 20.90%, 21.00%, 21.10%, 21.20%, 21.30%, 21.40%, 21.50%, 21.60%, 21.70%, 21.80%, 21.90%, 22.00%, 22.10%, 22.20%, 22.30%, 22.40%, 22.50%, 22.60%, 22.70%, 22.80%, 22.90%, 23.00%, 23.10%, 23.20%, 23.30%, 23.40%, 23.50%, and 23.60%, 23.70%, 23.80%, 23.90%, 24.00%, 24.10%, 24.20%, 24.30%, 24.40%, 24.50%, 24.60%, 24.70%, 24.80%, 24.90%, 25.00%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%; or up to at least 0.10%, at least 0.20%, at least 0.30%, at least 0.40%, at least 0.50%, at least 0.60%, at least 0.70%, at least 0.80%, at least 0.90%, at least 1.00%, at least 1.10%, at least 1.20%, at least 1.30%, at least 1.40%, at least 1.50%, at least 1.60%, at least 1.70%, at least 1.80%, at least 1.90%, at least 2.00%, at least 2.10%, at least 2.20%, at least 2.30%, at least 2.40%, at least 2.50%, at least 2.60%, at least 2.70%, at least 2.80%, at least 2.90%, at least 3.00%, at least 3.10%, at least 3.20%, at least 3.70%, at least 3.80%, at least 3.90%, at least 4.00%, at least 4.10%, at least 4.20%, at least 4.30%, at least 4.40%, at least 4.50%, at least 4.60%, at least 4.70%, at least 4.80%, at least 5.5%, at least 5.40%, at least 5.10%, at least 0.40%, at least 3.30%. At least 5.30%, at least 5.40%, at least 5.50%, at least 5.60%, at least 5.70%, at least 5.80%, at least 5.90%, at least 6.00%, at least 6.10%, at least 6.20%, at least 6.30%, at least 6.40%, at least 6.50%, at least 6.60%, at least 6.70%, at least 6.80%, at least 6.90%, at least 7.00%, at least 7.10%, at least 7.20%, at least 7.30%, at least 7.40%, at least 7.50%, at least 7.60%, at least 7.70%, at least 7.80%, at least 7.90%, at least 8.00%, at least 8.10%, at least 8.20%, at least 8.30%, at least 8.40%, at least 8.90%, at least 9.00%, at least 9.10%, at least 9.20%, at least 9.30%, at least 9.40%, at least 9.50%, at least 9.60%, at least 9.70%, at least 9.80%, at least 9.00%, at least 10.10%, at least 10.30% At least 10.40%, at least 10.50%, at least 10.60%, at least 10.70%, at least 10.80%, at least 10.90%, at least 11.00%, at least 11.10%, at least 11.20%, at least 11.30%, at least 11.40%, at least 11.50%, at least 11.60%, at least 11.70%, at least 11.80%, at least 11.90%, at least 12.00%, at least 12.10%, at least 12.20%, at least 12.30%, at least 12.40%, at least 12.50%, at least 12.60%, at least 12.70%, at least 12.80%, at least 12.90%, at least 13.00%, at least 13.10%, at least 13.20%, at least 13.30%, at least 13.40%, at least 13.50%, at least 13.80%, at least 13.90%, at least 14.00%, at least 14.10%, at least 14.20%, at least 14.30%, at least 14.40%, at least 14.50%, at least 14.60%, at least 14.70%, at least 14.80%, at least 14.90%, at least 15.00%, at least 15.15%, at least 15.15.15%, at least 15.15%, at least 15.40%, at least 15.50%. At least 15.60%, at least 15.70%, at least 15.80%, at least 15.90%, at least 16.00%, at least 16.10%, at least 16.20%, at least 16.30%, at least 16.40%, at least 16.50%, at least 16.60%, at least 16.70%, at least 16.80%, at least 16.90%, at least 17.00%, at least 17.10%, at least 17.20%, at least 17.30%, at least 17.40%, at least 17.50%, at least 17.60%, at least 17.70%, at least 17.80%, at least 17.90%, at least 18.00%, at least 18.10%, at least 18.20%, at least 18.30%, at least 18.40%, at least 18.50%, at least 18.60%, at least 18.70%, at least 18.80%, at least 18.90%, at least 19.00%, at least 19.10%, at least 19.20%, at least 19.40%, at least 19.50%, at least 19.60%, at least 19.70%, at least 19.80%, at least 19.90%, at least 20.00%, at least 20.10%, at least 20.20%, at least 20.40%, at least 37.30%, at least 50% At least 20.70%, at least 20.80%, at least 20.90%, at least 21.00%, at least 21.10%, at least 21.20%, at least 21.30%, at least 21.40%, at least 21.50%, at least 21.60%, at least 21.70%, at least 21.80%, at least 21.90%, at least 22.00%, at least 22.10%, at least 22.20%, at least 22.30%, at least 22.40%, at least 22.50%, at least 22.60%, at least 22.70%, at least 22.80%, at least 22.90%, at least 23.00%, at least 23.10%, at least 23.20%, at least 23.30%, at least 23.40%, at least 23.50%, at least 23.60%, at least 23.70%, at least 23.80%, at least 23.90%, at least 24.00%, at least 24.10%, at least 24.20%, at least 24.30%, at least 24.40%, at least 24.50%, at least 24.60%, at least 24.70%, at least 24.80%, at least 24.90%, at least 25.00%, at least 26%, at least 27%, at least 28%, at least 29%, at least 29.00%. At least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84% > At least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.
Without being bound by a particular theory, neutralization of toxic synuclein and reduction of neuroblastoma by plausiab may lead to improved synaptic protection and neuronal activity, which improves cognitive function. In addition, the neurodegeneration of the blue-spotted (LC) -norepinephrine network was slowed by treatment with plausimide; LC innervates neurovascular distribution and protective measures against toxic synuclein may improve cognitive function. Furthermore, protecting motor function by administration of plausimide may reduce the need for the patient to engage cortical areas for compensation, which releases Pi Zhineng force to support cognitive function.
In various aspects of the invention, the plausizumab regimen comprises about 1000 to 5000mg plausizumab at intervals of 3 to 5 weeks. In a particular aspect, the plausizumab regimen comprises about 1000, 2000, 3000, 4000, or 5000mg plausizumab administered at 3, 4, or 5 week intervals or as further described herein.
The clinical global improvement impression scale (CGI-S) is a measure of disease severity and is rated in a 7 component table, where the severity of disease (CGI-S) is measured using a response range of 1 (normal, no disease at all) to 7 (in the most severely ill patients). Clinical global improvement impression (CGI-I) is the clinician assessing the severity and progression of a disease, while patient global change impression (PGI-C) is intended to be a measure of the change in health status from the patient's perspective. The two clinical overall improvement impression scores (CGI-I/PGI-C) ranged from 1 (greatly improved) to 7 (greatly worsened). Progressors on CGI-I and PGI-C were classified as patients scored from 5 to 7 (i.e., rated as "minimal exacerbation", "significant exacerbation" or "significant exacerbation").
Without being bound by a particular theory, neutralization of toxic synuclein and reduction of neuroblastoma by plausiab may lead to improved synaptic protection and neuronal activity, which increases cerebral blood flow. In addition, the neurodegeneration of the blue-spotted (LC) -norepinephrine network was slowed by treatment with plausimide; LC innervates neurovascular distribution and protective measures against toxic synuclein may improve cerebrovascular regulation.
In one aspect of the invention, a method of improving blood flow comprises administering a plausiab regimen according to the invention. In various aspects of the invention, the plausizumab regimen comprises about 1000 to 5000mg plausizumab at intervals of 3 to 5 weeks. In a particular aspect, the plausizumab regimen comprises about 1000, 2000, 3000, 4000, or 5000mg plausizumab administered at 3, 4, or 5 week intervals or as further described herein.
In another aspect of the invention, MDS-UPDRS part III is a clinical examination of motor function that evaluates motor symptoms associated with Parkinson's disease. In one aspect, plausiab may be used to reduce a decrease in motor function in a subject having or at risk of parkinson's disease comprising administering a plausiab regimen to the subject. For example, plausimide can reduce the decrease in motor function by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% as measured by MDS-UPDRS part III; or up to at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 33%, at least 50% at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100%.
In another example, with respect to a concentrated rating assessment of MDS-UPDRS part III, plausizumab may reduce the decline in motor function by up to 35% compared to placebo after one year of treatment, and with respect to a field rating assessment of MDS-UPDRS part III, plausizumab may reduce the decline in motor function by up to 25% compared to placebo after one year of treatment. In addition, plausiab may be used to ameliorate one of the principal symptoms of parkinson's disease for bradykinesia, which is assessed as a component of the MDS-UPDRS part III clinical exercise test.
In one aspect, praziram antibody can be used to maintain motor function or delay the time to clinically significant worsening of motor progression in a subject suffering from or at risk of parkinson's disease comprising administering a praziram antibody regimen to the subject. The method may reduce the progression of parkinson's disease, for example by delaying it until a clinically significant progression of movement is worsened. For example, the decrease in disease progression may be by extending the time to at least 5 minutes of progression in MDS-UPDRS part III.
In various aspects of the invention, the plausizumab regimen comprises 1000 to 5000mg plausizumab at intervals of 3 to 5 weeks. In a particular aspect, the plausizumab regimen comprises about 1000, 2000, 3000, 4000, or 5000mg plausizumab administered at 3, 4, or 5 week intervals or as further described herein.
In another aspect of the invention, the methods may improve the MDS-UPDRS part III motor test score of the patient and/or improve one or more of the following: speech, facial expression, stiffness, finger strokes, hand movements, hand pronation-supination movements, toe strokes, leg mobility, standing from a chair, gait stiffness, posture stability, posture, physical retardation, hand tremor, resting tremor amplitude, resting tremor constancy, or Hoehn and Yahr staging. Still further, the methods of the invention can improve bradykinesia by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40% compared to placebo after one year of treatment. For example, the measurement of motor function may also be determined by a positive signal on motor function, as determined by a digital motor score comprising a composite score consisting of 80% bradykinesia features and 20% resting tremor features.
In another aspect of the invention, MDS-UPDRS part III is a clinical examination of motor function that evaluates motor symptoms associated with Parkinson's disease. In one aspect, plausiab may be used to reduce a decrease in motor function in a subject having or at risk of parkinson's disease comprising administering a plausiab regimen to the subject. For example, as measured by MDS-UPDRS part III, plausizumab may reduce the decrease in motor function by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, 138%, 139% or 140%; or up to at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least 130%, at least 131%, at least 132%, at least 133%, at least 134%, at least 135%, at least 136%, at least 137%, at least 138%, at least 139%, or at least 140%.
In another example, with respect to a concentrated rating assessment of MDS-UPDRS part III, plausizumab may reduce the decline in motor function by up to 35% compared to placebo after one year of treatment, and with respect to a field rating assessment of MDS-UPDRS part III, plausizumab may reduce the decline in motor function by up to 25% compared to placebo after one year of treatment. In addition, plausiab may be used to ameliorate one of the principal symptoms of parkinson's disease for bradykinesia, which is assessed as a component of the MDS-UPDRS part III clinical exercise test.
In one aspect, praziram antibody can be used to maintain motor function or delay the time to clinically significant worsening of motor progression in a subject suffering from or at risk of parkinson's disease comprising administering a praziram antibody regimen to the subject. The method may reduce the progression of parkinson's disease, for example by delaying it until a clinically significant progression of movement is worsened. For example, the decrease in disease progression may be by extending the time to at least 5 minutes of progression in MDS-UPDRS part III.
In various aspects of the invention, the plausizumab regimen comprises 1000 to 5000mg plausizumab at intervals of 3 to 5 weeks. In a particular aspect, the pramipexole mab regimen comprises about 1000, 2000, 3000, 4000, or 5000mg of pramipexole mab administered at 3, 4, or 5 week intervals.
In another aspect of the invention, the methods may improve the MDS-UPDRS part III motor test score of the patient and/or improve one or more of the following: speech, facial expression, stiffness, finger strokes, hand movements, hand pronation-supination movements, toe strokes, leg mobility, standing from a chair, gait stiffness, posture stability, posture, physical retardation, hand tremor, resting tremor amplitude, resting tremor constancy, or Hoehn and Yahr staging. Still further, the methods of the invention can improve bradykinesia by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40% compared to placebo after one year of treatment. For example, the measurement of motor function may also be determined by a positive signal on motor function, as determined by a digital motor score comprising a composite score consisting of 80% bradykinesia features and 20% resting tremor features.
Formulation preparation
The formulations (also referred to as pharmaceutical compositions) of the invention comprise an antibody, such as plausiab, a similar humanized 9E4 antibody or antigen binding fragment thereof, a buffer, and one or more excipients. The formulations may be prepared for storage in liquid form or in lyophilized form. When stored in lyophilized form, the formulation can be reconstituted by a liquid (e.g., sterile water) to the concentrations and characteristics depicted herein. While the lyophilized composition is said to be reconstitutable by the addition of water to produce a formulation of prescribed compositional concentration and pH, it means that the lyophilized formulation can be so reconstituted by the addition of water alone (i.e., no additional amounts of components are supplied or acid or base is added to change the pH). If the lyophilized formulation is reconstituted to the same volume as the formulation is pre-lyophilized, the concentration and characteristics of the pre-lyophilized liquid formulation may also be compatible with those described below. If the volumes are different, the concentration of the formulation should be adjusted proportionally. For example, if the reconstitution volume is one half of the pre-lyophilization volume, the concentration of the components in the pre-lyophilization formulation should be one half of the concentration in the reconstituted formulation.
The pharmaceutical compositions for parenteral administration are preferably sterile and substantially isotonic and manufactured under GMP conditions. The pharmaceutical composition may be provided in unit dosage form (i.e., a dose for a single administration). The pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries. The formulation depends on the route of administration selected. For injection, the plausiab may be formulated in the form of an aqueous solution, preferably in the form of a physiologically compatible buffer, such as Hank's solution, ringer's solution, or physiological saline or acetate buffer (to reduce discomfort at the injection site). The solution may contain a formulation such as a suspending, stabilizing and/or dispersing agent. Alternatively, the plausizumab may be in lyophilized form for reconstitution with a suitable vehicle, such as sterile pyrogen-free water, prior to use.
The pharmaceutically acceptable carrier composition may also include additives including, but not limited to, water, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium carboxymethyl cellulose, sodium polyacrylate, sodium alginate, water-soluble polydextrose, sodium carboxymethyl starch, pectin, methylcellulose, ethylcellulose, xanthan gum, acacia, casein, agar, polyethylene glycol, diglycerol, glycerol, propylene glycol, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol, lactose, and surfactants acceptable as pharmaceutical additives.
The formulations (also referred to as pharmaceutical compositions) of the present invention comprise an antibody (e.g., plausiab or another chimeric, facial-decorated or humanized version of murine 9E 4), a buffer, one or more sugars and/or polyols, and a surfactant, and have a pH in the range of about 5 to about 7.5. The formulations may be prepared for storage in liquid form or in lyophilized form. When stored in lyophilized form, the formulation can be reconstituted by a liquid (e.g., sterile water) to the concentrations and characteristics depicted herein. While the lyophilized composition is said to be reconstitutable by the addition of water to produce a formulation of prescribed compositional concentration and pH, it means that the lyophilized formulation can be so reconstituted by the addition of water alone (i.e., no additional amounts of components are supplied or acid or base is added to change the pH). If the lyophilized formulation is reconstituted to the same volume as the formulation is pre-lyophilized, the concentration and characteristics of the pre-lyophilized liquid formulation may also be compatible with those described below. If the volumes are different, the concentration of the formulation should be adjusted proportionally. For example, if the reconstitution volume is one half of the pre-lyophilization volume, the concentration of the components in the pre-lyophilization formulation should be one half of the concentration in the reconstituted formulation.
Some formulations include a bulking agent, which may or may not be the same as the sugar/polyol component. Typically, the formulation is sterile, e.g., as achieved by sterile filtration using a 0.2 μm or 0.22 μm filter. Some formulations have a bioburden of less than or equal to about 3CFU/30 mL. Some formulations contain less than or equal to about 0.1EU/mg bacterial endotoxin. The formulations of the present invention are also generally stabilized by undetectable amounts of fragmentation and/or aggregation as further defined below with respect to freezing and thawing. After rehydration of the lyophilized cake at 40 ℃ for at least three months, the other formulations are still stable. In some formulations, less than about 10% of the antibody is present in the formulation in aggregate. In some formulations, less than or equal to about 5% of the antibodies are present in the formulation in aggregate.
In some formulations, the antibody is present at a concentration in the range of about 5mg/mL to about 100 mg/mL. In some formulations, the antibody is present at a concentration in the range of about 5mg/mL to about 50 mg/mL. In some formulations, the antibody is present at a concentration in the range of about 25mg/mL to about 50 mg/mL. For example, the antibody may be present at a concentration of about 35 to 45mg/mL or about 40 mg/mL. The antibodies may be present in sterile liquid dosage forms ranging from about 50 milligrams per vial (mg/visual) to about 500 milligrams per vial or greater. The antibodies may be present in a lyophilized dosage form of about 40 mg/vial to about 500 mg/vial. For example, the antibody may be present in a sterile liquid or lyophilized dosage form of about 250 to 350 milligrams per vial or about 200 milligrams per vial.
The formulated antibody may be any of the antibodies described above, including any of the chimeric, facial, or humanized versions of antibody 9E4 described above.
Buffers are used in the disclosed formulations to achieve a pH suitable for antibodies, such as histidine, succinate and citrate buffers. Some formulations have a pH in the range of about 5.5 to about 7, for example a pH of 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0. Some formulations have a pH between about 5.5 and about 6.5. Some formulations have a pH of about 6.0 and others have a pH of about 6.5. In some formulations, the citrate buffer or succinate buffer is present at a concentration in the range of about 10mM to about 30mM, for example at a concentration of about 15 to 25mM or about 20 mM. Some citrate buffers include sodium citrate dehydrate and citric acid monohydrate at concentrations ranging from about 15mM to about 20mM and from about 2mM to about 6mM, respectively.
Suitable sugars and/or polyols for formulation include trehalose, sucrose, mannitol, or combinations thereof. The sugar/polyol acts as a bulking agent, lyoprotectant, and/or tonicity adjuster. For example, some formulations include trehalose present at a concentration ranging from about 220mM to about 260mM, sucrose present at a concentration ranging from about 220mM to about 260mM, or a mixture of sucrose present at a concentration ranging from about 20mM to about 40mM and mannitol present at a concentration ranging from about 200mM to about 220 mM. Some formulations include trehalose present at a concentration of about 230mM or 240 mM. Other formulations include sucrose present at a concentration of about 230mM or 240 mM. Other formulations include mixtures of sucrose present at a concentration of about 50mM and mannitol present at a concentration of about 200 mM. Another formulation includes a mixture of sucrose present at a concentration of about 28mM and mannitol present at a concentration of about 212 mM. Some such formulations are characterized by an osmolality in the range of about 250 to 400, 300 to 400, or 300 to 350mOsm/kg, such as 335 mOsm/kg.
The formulation may contain surfactants to reduce antibody aggregation and surface absorption. Suitable surfactants include polysorbate 20 (PS 20) present at a concentration in the range of about 0.005 wt.% to about 0.05 wt.%. PS20 prevents significant increases in aggregation or turbidity that would otherwise occur in the formulation of the 9E4 antibody. Polysorbate 20 may be present at a concentration in the range of about 0.01% to about 0.05%. For example, the concentration may be 0.005%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, or 0.05%. Alternatively, in some formulations, polysorbate 20 is present at a concentration of about 0.05g/L, 0.1g/L, 0.15g/L, 0.2g/L, 0.25g/L, 0.3g/L, 0.35g/L, 0.4g/L, 0.45g/L, or 0.5 g/L. Some formulations included polysorbate 20 at a concentration of 0.2g/L (i.e., 0.163 mmol/L).
Exemplary formulations (liquid, pre-lyophilized, or reconstituted after lyophilization) feature a pH in the range of about 5.5 to about 7 and include: (a) Chimeric, facial or humanized versions of plausin mab or antibody 9E4 or fragments thereof that compete specifically with 9E4 for binding to antigen at concentrations ranging from about 10mg/ml to about 50 mg/ml; (b) Citrate buffer or succinate buffer present at a concentration in the range of about 10mM to about 30 mM; (c) One or more sugars and polyols ("sugar/polyols") selected from the group consisting of trehalose present at a concentration ranging from about 220mM to about 260mM, sucrose present at a concentration ranging from about 220mM to about 260mM, and a mixture of sucrose present at a concentration ranging from about 20mM to about 40mM and mannitol present at a concentration ranging from about 200mM to about 220 mM; and (d) polysorbate 20 present at a concentration in the range of about 0.005% to about 0.05% by weight. For example, the formulation may include: (a) An antibody comprising a light chain having an amino acid sequence as set forth in SEQ ID No. 1, 2, 3 or 9 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID No. 4, 5, 6 or 10, with or without a C-terminal lysine and present at a concentration of about 40 mg/mL; (b) citrate buffer at a concentration of about 20 mM; (c) trehalose at a concentration of about 230 mM; (d) polysorbate 20 at a concentration of about 0.02%; and the pH is about 6.0.
Some lyophilized formulations include: (a) A humanized version of antibody 9E4 (e.g., plausiab) or an antigen binding fragment thereof; (b) citrate; (c) trehalose and polysorbate 20. The lyophilized formulation may comprise about 200mg of antibody. Some lyophilized formulations can be reconstituted by sterile water. Some lyophilized formulations include 100 to 300 or 150 to 250mg or 15 to 35 or 20 to 25mg sodium citrate dehydrate, 1.65 to 2.75 or 2 to 2.3mg citric acid monohydrate, 360 to 500 or 400 to 470mg trehalose dehydrate, 0.5 to 1.5mg or 0.75 to 1.25mg polysorbate 20. Exemplary lyophilized formulations include 200mg of the 9E4 antibody (e.g., humanized 9E4 antibody), 25mg sodium citrate dehydrate, 2.15mg citric acid monohydrate, 435mg trehalose dehydrate, and 1mg polysorbate 20. Another exemplary lyophilized formulation includes 200mg of the 9E4 antibody (e.g., humanized 9E4 antibody), 25mg sodium citrate dehydrate, 3.15mg citric acid monohydrate, 435mg trehalose dehydrate, and 1mg polysorbate 20. Such formulations may be reconstituted to a volume of about 5 ml. Other lyophilized formulations included the same components (e.g., 400mg antibody, 50mg sodium citrate, 4.3mg citric acid monohydrate, 870mg trehalose dehydrate, and 2mg polysorbate 20) in the same proportions as disclosed in this paragraph, but in different amounts.
The lyophilized formulation may be reconstituted to an antibody concentration of about 30 to 50 or 35 to 45mg/mL, such as about 40 mg/mL; (b) Citrate buffer present at a concentration of about 10 to 30 or 15 to 25mM, preferably about 20 mM; (c) Trehalose present at a concentration of about 160 to 330 or 200 to 260mM, such as about 230 mM; (d) Polysorbate 20 present at a concentration of about 0.1 to 0.3 or 0.15 to 0.25g/L, such as about 0.2g/L, and (e) a pH of about 5.5 to 6.5, such as about 6.0.
The liquid or reconstituted lyophilized formulation may be substantially isotonic, meaning an osmotic pressure of about 250 to 350mOsm/kg water. Some formulations have an osmolality of about 335mOsm/kg. Some formulations have an osmolality of 270 to 300mOsm/kg. The liquid or reconstituted lyophilized formulation may also be high osmotic pressure >350mOsm/kg water or low osmotic pressure (< 250mOsm/kg water).
In addition to those formulations described as components herein, any of the described formulations may be prepared without pharmaceutical excipients, carriers, or the like. If there are insignificant amounts of other components that do not affect the properties of the formulation, such a formulation may be described as consisting of, or consist essentially of, the listed components. The formulations may be made under Good Manufacturing Practice (GMP) approved by the FDA or approved for the preparation of medicaments for administration to humans.
Diagnostic guidelines for parkinson's disease
The methods of the invention are typically performed by a qualified health practitioner diagnosis on subjects suffering from parkinson's disease, or at high risk thereof compared to the general population as evidenced by genetic or biochemical markers, family history, or prodromal symptoms of the disease. Such individuals include any subject who has received a prior prescription for treatment or prevention of parkinson's disease. Diagnosis of parkinson's disease synucleinopathy may be based on accepted guidelines for potential or potential parkinson's disease, such as those guidelines of the DSM-V or DSM IV-TR, the dementia with lewy bodies (the Lewy Body dementia) association, the parkinson's disease association, and the like. However, diagnosis may also be based on the presence of any sign or symptom of parkinson's disease that allows the treating physician to conclude that the subject may have parkinson's disease. Exemplary criteria for diagnosing potential or possible PD are shown below.
● Group A: resting tremor, bradykinesia, stiff hardness, and asymmetric attacks.
● Group B features: implying an alternative diagnosis.
● In the first 3 years after onset of symptoms, the posture was significantly unstable.
● Rigidification phenomenon in the last 3 years.
● The first 3 years were drug independent hallucinations.
● Dementia before motor symptoms or in the first year
● Supranuclear gaze paralysis (except for limitation of upward gaze) or slowed vertical jump.
● Drug-independent severe symptomatic autonomic dysfunction.
Symptoms known to produce parkinson's disease and likely associated with symptoms of the subject, such as focal brain lesions or antipsychotic use, suitably located over the last 6 months, were recorded.
Criteria for possible diagnosis of parkinson's disease include the following: there are at least 2 of the 4 features in group a; at least 1 of these features is tremor or bradykinesia and there is no feature in group B; or symptoms have been present for less than 3 years so far and none of the characteristics in group B are present; and substantial and sustained responses to levodopa or dopamine agonists have been recorded, or the subject has not been adequately tested for a levodopa or dopamine agonist.
Criteria for possible diagnosis of parkinson's disease include the following: there are at least 3 or 4 features in group a, and no features in group B and substantial and sustained responses to levodopa or dopamine agonists have been recorded.
The methods of the invention may also be performed on a subject at risk of parkinson's disease. A subject at risk for parkinson's disease may have one or more risk factors for developing parkinson's disease. Risk factors for parkinson's disease may include: age (parkinson's disease usually begins in mid-life or late-life and increases in risk with age), gene/genetics (i.e., having a close relationship with parkinson's disease, increasing the risk of developing PD), sex (men are more likely to develop PD than women), head trauma (trauma to the head, neck or upper cervical vertebrae can increase the risk of developing PD in individuals), and exposure to toxins (e.g., continued exposure to herbicides and pesticides can slightly increase PD risk).
In recent years, parkinson's disease has been divided into three subtypes: mild exercise is predominant (MM), diffuse Malignancy (DM), and moderate. These divisions are based on experienced symptoms, in particular motor symptoms, cognitive disorders, rapid Eye Movement (REM) sleep disorders and autonomic nerve disorders (abnormalities of the autonomic nervous system that control non-autonomic body processes such as heart beat rate and sweating).
Treatment regimen
A therapeutically effective amount is a dose that achieves a desired clinical effect when provided within an effective period of time. The dosing regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered at set intervals (e.g., daily, weekly, monthly), or the doses may be proportionally reduced as indicated by the emergency state of the treatable condition.
In therapeutic applications, antibodies are administered to subjects diagnosed with PD in a regimen (dosage, frequency, and route of administration) known or suspected to be effective to ameliorate at least one sign or symptom of the disease, or at least to inhibit further exacerbation thereof. In prophylactic applications, antibodies are administered to subjects at increased risk of synucleinopathies but not yet having symptoms sufficient to be diagnosed with the disease, in a regimen known or suspected to be effective in inhibiting at least one sign or symptom of the disease or delaying the onset thereof.
An exemplary dosage range for the antibody is 1000 to 5000mg of the antibody against alpha-synuclein administered intravenously at 3 to 5 week intervals, such as every 4 weeks. In some embodiments, an exemplary dosage range of the antibody is 3 to 5 week intervals, such as 3000 to 5000mg of the antibody to alpha-synuclein administered intravenously every 4 weeks. In some subjects, the dose is 3500 to 4500mg every 3 to 5 weeks, such as every 4 weeks. The subjects may receive dosages that are the same or different from each other (e.g., depending on the weight of the subject). In some methods, the subject receives one of two fixed doses. For example, a subject weighing less than 65kg may receive 3500mg and a subject weighing greater than or equal to 65kg may receive 4500mg. In some methods, the dosage range of at least some subjects is in the range of 45 to 75mg/kg, e.g., 50 to 70mg/kg, 45mg/kg, 60mg/kg, or 65 mg/kg. Dosages are typically administered at intervals of 3 to 5 weeks, such as every 28 days or four weeks or every month, on multiple occasions. The subject may receive at least 6, 9, 12 or 18 doses at such intervals, or may be administered or the remaining life of the subject is sustained as symptoms of the condition persist. In some embodiments, an initial starting dose of 2000mg is administered followed by a range of greater than or equal to 2000mg but less than the intended target dose until the intended target dose is reached. For example, the subject may receive an initial dose of 2000mg followed by incremental titration to a 3500mg dose or 4500mg dose. Incremental titration may be performed with a single subsequent dose or stepwise increase in doses until a target dose or a dose within a target range is reached. For example, the subject may receive an initial dose of 2000mg followed by a subsequent dose of 3500 mg. Alternatively, the subject may receive an initial dose of 2000mg followed by one or more subsequent doses of greater than or equal to 2000mg but less than 3500mg and a subsequent dose of 3500 mg. Likewise, the subject may receive an initial dose of 2000mg followed by a subsequent dose of 4500mg. Alternatively, the subject may receive an initial dose of 2000mg followed by a subsequent dose of greater than or equal to 2000mg but less than 4500mg and a subsequent dose of 4500mg. In some embodiments, the subject receives a dose of 3000 to 5000mg of antibody intravenously every four weeks for at least 52 weeks. In subjects receiving a multi-dose regimen having a dose within a specified range, such as 3500mg to 5000mg, the subject may receive the same or different doses within the specified range at each administration. In some embodiments, the subject receives the same dose within the specified range at each administration.
In another exemplary regimen, the subject is administered a 1300 to 1700mg dose of antibody intravenously at 3 to 5 week intervals. An exemplary dose is 1500mg. The subject may receive a single fixed dose or two or more different doses within this range based on, for example, the subject's weight. Some subjects dosed in this range receive 18 to 25mg/kg of antibody, e.g. 20mg/kg. As in other methods, the interval may be 3 to 5 weeks, such as every 4 weeks or every month. The subject may receive at least 6, at least 9, at least 12, or at least 18 doses, or may be administered at such intervals as symptoms continue or for the remainder of the subject's life.
Any of the treatment regimens may be accompanied by monitoring the change in motor and/or cognitive deficit in the subject receiving the treatment. Preferably, such monitoring includes at least one of an assessment before and after initiation of treatment. Preferably, the monitoring indicates a decrease rate that decreases in response to the treatment, i.e. relative to a decrease in motor and/or cognitive deficit prior to initiation of the treatment, or at least relative to a previous decrease rate of the subject or a decrease rate of a control patient not receiving any immunotherapy. Changes in one or more of the subject's autonomic dysfunction, gastrointestinal autonomic dysfunction, visual hallucinations, or other signs and symptoms may also be monitored.
The regimen of the invention may be administered concurrently with another agent effective to treat or prevent the disease being treated. The other agent may be another immunotherapeutic agent described herein or other agents for treating parkinson's disease, including levodopa, benzaseride, carbidopa (cabidopa), dopamine agonists, non-ergotamine dopamine agonists, catechol-methyl ("COMT") inhibitors such as entacapone (entacopone) or tolcapone (tolcopone), monoamine oxidase ("MAO") inhibitors including MAO-b inhibitors such as rasagaline (rasagaline) or selegiline (selegiline), amantadine or anticholinergic agents may be used in combination with the present regimens. Some such other agents reduce one or more symptoms of the disease without affecting the causative agent.
Examples
Example 1 phase II clinical trial for plausimab
Subjects with parkinson's disease were subjected to phase II test against the alpha-synuclein antibody plausimab (PASADENA, clinical trial number NCT 03100149). The trial had two treatment groups and one control group. Subjects were randomized into groups at 1:1:1, where n=316. The initial phase of the trial was a 52 week double blind treatment. During the initial phase of the trial, the subject received no additional parkinson's disease treatment (including symptomatic treatment). Subjects in one treatment group received a fixed dose of 1500mg of antibody (low dose) intravenously every four weeks. Depending on body weight, subjects in the other treatment group received 3500mg or 4500mg antibody intravenously every four weeks (high dose), with subjects below 65kg receiving a low dose and subjects equal to or above 65kg receiving a high dose. Subjects in the second group received an initial dose of 2000mg and optionally additionally escalated titration doses at 2000mg or higher until a target dose of 3500mg or 4500mg was reached. The administration was continued for one year (52 weeks). The subsequent trial had an extended period in which subjects initially in the placebo group received one of the two treatment regimens from the initial phase and subjects from the initial phase treatment group continued to receive the same treatment as before. During the extended phase of the trial, the subject may have received systemic treatment with levodopa and the antibody subject being tested, but not other treatments for parkinson's disease.
Baseline characteristics of patients in phase ii trial
/>
/>
Praziram mab was found to be generally safe and well tolerated, with most adverse events reported as mild or moderate and similar in placebo and both treatment groups. Most reported Adverse Events (AEs) (92%) were mild (grade 1 to 2). One grade 4 AE was reported and was considered irrelevant to study drug. There were no 5-stage AEs (see table 2).
TABLE 2 overview of security data
/>
The object is:
the main objective was to evaluate the efficacy of plausiab versus placebo in participants with early PD (stages H & Y I and II) who were untreated or treated with MAO-B inhibitors from baseline as measured by the change in MDS UPDRS total score (sum of parts I, II and III) from baseline at week 52.
A secondary objective was the effect of plausiab versus placebo in participants with early PD (H & Y I and phase II) untreated or treated with MAO-B inhibitors from baseline at week 52 based on the following evaluation:
●MDS-UPDRS;
● Dopamine transporter imaging by single photon emission computed tomography (DaT-SPECT) in ipsilateral (clinically overt) putamen;
● A montreal cognitive assessment (MoCA) total score;
● Clinical global improvement impression (CGI-I);
● Patient global change impression (PGI-C);
● Schwab and England activities of daily living (SE-ADL) scores;
● Time to deterioration of motor or non-motor symptoms; and/or
● Time to start dopaminergic PD treatment (levodopa or dopamine agonist).
Example 2 patients with parkinson's disease treated with plausimab demonstrate improved cognitive function
The study did not meet the primary shift endpoint for the MDS-UPDRS total score (FIG. 1; -21.5% low dose: -2.02% CI-4.21, -0.18; -6.6% high dose: -0.62% CI-2.82, -1.58). However, unexpected efficacy signals were observed in changes in cognitive function relative to baseline. On the montreal cognitive assessment (MoCA) (screening assessment of cognitive function), constant signals that contributed to plausiab were shown at both dose levels. On average, patients treated with plausimab were in the cognitive normal range at baseline and plausimab treated patients showed an improvement in MoCA score (MoCA is a 30-score scale and higher scores indicate better cognitive efficacy). For example, fig. 2 shows an improvement on the MoCa score scale of at least 0.2.
ANCOVA analysis showed that the difference in the adjusted mean of the absolute change from baseline of MoCA total score at week 52 compared to placebo was 0.22 in the low dose group (80% CI: -0.09,0.54) and 0.44 in the high dose group (80% CI:0.13,0.75) (see table 3 below).
Table 3. Variation of moca.
Other analyses by CGI-I and PGI-C demonstrated a reduced risk of exacerbation. Both dose levels also showed constant signals contributing to plausimide on an assessment of clinical global improvement impression (CGI-I) and patient global change impression (PGI-C). Patients treated with plausimab showed reduced risk of exacerbations on both CGI-I and PGI-C (assessment of changes in measured health status by clinicians and patients, respectively). (FIGS. 3 and 4).
Example 3 patients with Parkinson's disease treated with plausimab demonstrate an improvement in cerebral blood flow
The study did not meet the primary shift endpoint for the MDS-UPDRS total score (FIG. 1; -21.5% low dose: -2.02% CI-4.21, -0.18; -6.6% high dose: -0.62% CI-2.82, -1.58). However, unexpected efficacy signals were observed in the change in cerebral blood flow from baseline to week 52. In the analysis of cerebral blood flow, patients treated with plausiab showed an improvement in cerebral blood flow in the putamen, a region of the brain associated with loss of dopaminergic ends and pathology of alpha-synuclein in the presence of parkinson's disease, as assessed by changes in magnetic resonance-arterial spin labeling (MRI-ASL) in a subset of patients, indicating an impact on underlying biology involving the disease (fig. 5).
Assessment of specific areas of the brain showed improved blood flow in the putamen, globus pallidus and anterior motor cortex (fig. 6A, 6B and 6C).
Example 4 patients with Parkinson's disease treated with plausimab demonstrate improvement in motor function
The study did not meet the primary shift endpoint for the MDS-UPDRS total score (FIG. 1; -21.5% low dose: -2.02% CI-4.21, -0.18; -6.6% high dose: -0.62% CI-2.82, -1.58). However, at 52 weeks compared to placebo, unexpected efficacy signals were observed on the change in MDS-UPDRS part III from baseline in praziram-mab treated patients. Among patients with early parkinson's disease, praziram mab-treated patients showed reduced decline in motor function and delayed time to clinically significant worsening of motor progression over placebo at one year.
Using MDS-UPDRS part III field rating, the patient exhibited a decrease in motor function (fig. 7A; combined dose content: -25.0%, -1.44, 80% CI = (-2.83, -0.06), low dose content: -33.8%, -1.88, 80% CI = (-3.49, -0.27), and high dose content: -18.2%, -1.02, 80% CI = (-2.64,0.61)).
Regarding the concentrated rating assessment of MDS-UPDRS part III (clinical examination of motor function), praziram also reduced the decline of motor function by up to 35% compared to placebo after one year of treatment (fig. 7B; combined dose content: -35.0%, -1.88, 80% CI = (-3.31, -0.45), low dose content: -45.4%, -2.44, 80% CI = (-4.09, -0.78), and high dose content: -24.7%, -1.33, 80% CI = (-2.99,0.34)).
Furthermore, plausimide treatment caused a decrease in disease progression in plausimide treated patients, as demonstrated by a delay in time to clinically significant worsening of motor progression on site rating assessment or at least 5 minutes of progression on MDS-UPDRS part III by comparison to placebo over one year, with a risk ratio of 0.82 (fig. 8).
Efficacy signals were observed in praziram mab treated patients at week 52 by on-site rating versus placebo on the change in bradykinesia from baseline (combined dose content: -27.0%, -0.75, 80% CI = (-1.62,0.11), low dose content: -38.3%, -1.07, 80% CI = (-2.07, -0.07), and high dose content: -15.7%, -0.44, 80% CI = (-1.45,0.56)) (fig. 9). Bradykinesia is one of the major symptoms of parkinson's disease and is assessed as a component of the MDS-UPDRS part III clinical exercise trial.
Example 5 patients with Parkinson's disease treated with plausimab demonstrate improvement in motor function
The study did not meet the primary shift endpoint for the MDS-UPDRS total score (FIG. 1; -21.5% low dose: -2.02% CI-4.21, -0.18; -6.6% high dose: -0.62% CI-2.82, -1.58; and Table 4). However, at 52 weeks compared to placebo, unexpected efficacy signals were observed on the change in MDS-UPDRS part III from baseline in praziram-mab treated patients. Among patients with early parkinson's disease, praziram mab-treated patients showed reduced decline in motor function and delayed time to clinically significant worsening of motor progression over placebo at one year.
Table 4.
Using MDS-UPDRS part III field rating, the patient exhibited a decrease in motor function (fig. 7A; combined dose content: -25.0%, -1.44, 80% CI = (-2.83, -0.06), low dose content: -33.8%, -1.88, 80% CI = (-3.49, -0.27), and high dose content: -18.2%, -1.02, 80% CI = (-2.64,0.61)).
Regarding the concentrated rating assessment of MDS-UPDRS part III (clinical examination of motor function), praziram also reduced the decline of motor function by up to 35% compared to placebo after one year of treatment (fig. 7B; combined dose content: -35.0%, -1.88, 80% CI = (-3.31, -0.45), low dose content: -45.4%, -2.44, 80% CI = (-4.09, -0.78), and high dose content: -24.7%, -1.33, 80% CI = (-2.99,0.34)).
Furthermore, plausimide treatment caused a decrease in disease progression in plausimide treated patients, as demonstrated by a delay in time to clinically significant worsening of motor progression on site rating assessment or at least 5 minutes of progression on MDS-UPDRS part III by comparison to placebo over one year, with a risk ratio of 0.82 (fig. 8).
Efficacy signals were observed in praziram mab treated patients at week 52 by on-site rating versus placebo on the change in bradykinesia from baseline (combined dose content: -27.0%, -0.75, 80% CI = (-1.62,0.11), low dose content: -38.3%, -1.07, 80% CI = (-2.07, -0.07), and high dose content: -15.7%, -0.44, 80% CI = (-1.45,0.56)) (fig. 9). Bradykinesia is one of the major symptoms of parkinson's disease and is assessed as a component of the MDS-UPDRS part III clinical exercise trial.
Sub-analyses were performed on the total population to distinguish the effect of plausimab treatment on different sub-phenotypes within the total population. For example, individuals in need of symptomatic therapy, such as MAO-B inhibitors, and those in diffuse malignant subtypes. It was observed that although the progression of motion of parkinson's disease in the untreated early population was generally slow (approximately 5 minutes per year on MDS-UPDRS part III; fig. 10, upper panel), the progression of motion of the more aggressive parkinsonian subtype within the total population was significantly faster. A subset of patients taking the MAOB inhibitor exhibited about 7 changes per year; fig. 10, middle panel) and diffuse malignant subtyping shows about 10 point changes per year; fig. 10, bottom view).
For fig. 10, patient contribution to symptomatic PD treatment is initiated until the last visit before symptomatic PD treatment is initiated. Bar graphs represent 80% CI. The evaluation was based on MMRM with the following covariates: MAOB inhibitor at baseline (yes/no), treatment, weeks, age <60 vs. 60, sex, daT-SPECT core to shell binding ratio (side most clinically affected in contralateral comparison), baseline MDS-UPDRS corresponding endpoint. The combined dose analysis is a predetermined exploratory analysis. 4500mg is used for not less than 65kg;3500mg for <65kg. CI is a confidence interval; daT-SPECT is dopamine transporter imaging by single photon emission computed tomography; MAO-B is monoamine oxidase B; MDS-UPDRS is a unified PD rating scale for the dyskinesia Association and MMRM is a mixed influence model repetition measure.
Likewise, patients in the combined total population exhibited 25% reduction in motor function over placebo over one year of treatment using MDS-UPDRS part III field ratings, as assessed in situ. The low dose effect appears to be more robust at 33.8% decrease, whereas the high dose shows 18.2% decrease (see fig. 11A; combined dose content: -25.0%, -1.44, 80% CI = (-2.83, -0.06), low dose content: -33.8%, -1.88, 80% CI = (-3.49, -0.27), and high dose content: -18.2%, -1.02, 80% CI = (-2.64,0.61)).
In the MAO-B inhibitor treated subgroup, a 39% reduction in motor function was observed over the course of the treatment over the year compared to placebo, as assessed in situ. The low dose effect appears to be more robust at a decrease of 71.1%; however, the high dose showed a decrease of 4% over the year (see fig. 11B; combined dose content: -39.0%, -2.66, 80% CI = (-4.87, -0.45), low dose content: -71.1%, -4.85, 80% CI = (-7.33, -2.37), high dose content: -4.0%, -0.28, 80% CI = (-2.82,2.25)).
In the diffuse malignant subgroup, as assessed on site, a reduction of 63.9% in motor function was observed over the course of one year of treatment compared to placebo. The low dose regimen and the high dose regimen were similarly performed, wherein at one year the low dose exhibited decrease was 68.3% and the high dose exhibited decrease was 63.2% (see fig. 11C: combined dose content: -63.9%, -7.86, 80% CI = (-12.9, -2.82), low dose content: -68.3%, -8.4, 80% CI = (-14.2, -2.59), high dose content: -63.2%, -7.77, 80% CI = (-13.4, -2.14)).
For fig. 11A-11C, patient contribution to symptomatic PD treatment is initiated until the last visit before symptomatic PD treatment is initiated. Bar graphs represent 80% CI. The evaluation was based on MMRM with the following covariates: MAOB inhibitor at baseline (yes/no), treatment, weeks, age <60 vs. 60, sex, daT-SPECT core to shell binding ratio (side most clinically affected in contralateral comparison), baseline MDS-UPDRS corresponding endpoint. The combined dose analysis is a predetermined exploratory analysis. 4500mg is used for not less than 65kg;3500mg for <65kg.
Patients in the combined total population exhibited a 35% decrease in motor function over treatment for one year compared to placebo using the rating of MDS-UPDRS part III centralized monitoring or assessment, as assessed centrally. The low dose effect appears to be more robust at a 45.4% decrease, whereas the high dose shows a 24.7% decrease (see fig. 12A; combined dose content: -35.0%, -1.88, 80% CI = (-3.31, -0.45), low dose content: -45.4%, -2.44, 80% CI = (-4.09, -0.78), and high dose content: -24.7%, -1.33, 80% CI = (-2.99,0.34)).
In the MAO-B inhibitor treated subgroup, a reduction in motor function of 52.1% was observed over the course of the treatment over the year compared to placebo, as assessed centrally. The low dose effect appears to be more robust at a decrease of 74.1%; however, the high dose exhibited a 17.3% decrease in the first year (see fig. 12B; combined dose content: -52.1%, -3.16, 80% CI = (-5.50, -0.82), low dose content: -74.1%, -4.49, 80% CI = (-7.08, -1.90), high dose content: -17.3%, -1.05, 80% CI = (-3.97,1.87)).
In the diffuse malignant subgroup, as assessed centrally, a 76.1% decrease in motor function was observed over the course of one year of treatment compared to placebo. The low dose effect appears to be more robust at a 108.7% decrease; however, the high dose showed a decrease of 70.5% over the year (see fig. 12C; combined dose content: -76.1%, -9.24, 80% CI = (-15.4, -3.07), low dose content: -108.7%, -13.2, 80% CI = (-21.2, -5.17), high dose content: -70.5%, -8.56, 80% CI = (-16.0, -1.10)).
For fig. 12A-12C, patient contribution to symptomatic PD treatment is initiated until the last visit before symptomatic PD treatment is initiated. Bar graphs represent 80% CI. The evaluation was based on MMRM with the following covariates: MAOB inhibitor at baseline (yes/no), treatment, weeks, age <60 vs. 60, sex, daT-SPECT core to shell binding ratio (side most clinically affected in contralateral comparison), baseline MDS-UPDRS corresponding endpoint. The combined dose analysis is a predetermined exploratory analysis. 4500mg is used for not less than 65kg;3500mg for <65kg.
The patient also completed daily exercise tests on the smart phone using the input surface (e.g., screen) and internal sensors to evaluate measures of bradykinesia, tremor/bradykinesia, tremor only, stiffness and postural instability and cognition. The results are combined to produce a "digital PASADENA motor score". Frequent testing enables modeling of the slope of the motor progress that reflects primarily the measure of bradykinesia. This mixed model demonstrated a decrease in motor progression (compared to placebo) as measured by the digital PASADENA motor score in both the low and high dose groups.
In the pooled total population, a 25.0% decrease in the PASADENA digital motor score was observed over the treatment period of one year compared to placebo. The low dose effect appears to be more robust at 30.3% decrease; however, the higher dose showed a 21.5% decrease in one year (see fig. 13A; combined dose content: -25.0%, -0.030, 80% CI = (-0.050, -0.010)), low dose content: -30.3%, -0.040, 80% CI = (-0.063, -0.017), high dose content: -21.5%, -0.029, 80% CI = (-0.052, -0.006)).
In the MAO-B inhibitor treated subgroup, a 26.0% decrease in PASADENA digital motor score was observed over the course of the treatment period compared to placebo. The low dose effect appears to be more robust at a 31.0% decrease in drop; however, the high dose showed a 20.9% decrease over the year (see fig. 13B; combined dose content: -26.0%, -0.032, 80% CI = (-0.062, -0.003), low dose content: -31.0%, -0.039, 80% CI = (-0.072, -0.049), high dose content: -20.9%, -0.026, 80% CI = (-. 0.060,0.008)).
In the diffuse malignant subgroup, a 35.7% decrease in the PASADENA digital motor score was observed over the treatment year compared to placebo. The low dose effect appears to be less robust at 25.2% decrease; however, the high dose showed a 46.2% decrease in one year (see fig. 13C; combined dose content: -35.7%, -0.055, 80% C = (-0.105, -0.005), low dose content: -25.2%, -0.039, 80% CI = (-0.094,0.017), high dose content: -46.2%, -0.071, 80% CI = (-0.126, -0.017)).
For fig. 13A-13C, patient contribution to symptomatic PD treatment is initiated until the last visit before symptomatic PD treatment is initiated. Bar graphs represent 80% CI. The evaluation was based on MMRM with the following covariates: MAOB inhibitor at baseline (yes/no), treatment, weeks, age <60 vs. 60, sex, daT-SPECT core to shell binding ratio (side most clinically affected in contralateral comparison), baseline MDS-UPDRS corresponding endpoint. The combined dose analysis is a predetermined exploratory analysis. 4500mg is used for not less than 65kg;3500mg for <65kg.
Sequence(s)
SEQ ID NO. 1 shows the Hu9E4VLv3 variable region.
SEQ ID NO. 2 shows the Hu9E4VLv1 variable region.
SEQ ID NO. 3 shows the Hu9E4VLv2 (NO back mutation) variable region.
SEQ ID NO. 4 is the Hu9E4VHv3 variable region.
SEQ ID NO. 5 is the Hu9E4VHv1 variable region.
SEQ ID NO. 6 is the Hu9E4VHv2 variable region.
SEQ ID NO. 7 shows the Hu9E4VHv4 (NO back mutation) variable region.
SEQ ID NO. 8 is the amino acid sequence of a natural human wild type alpha-synuclein.
SEQ ID NO. 9 is the amino acid sequence of the light chain of plausin monoclonal antibody
SEQ ID NO. 10 shows the amino acid sequence of the pramipexole Shan Kangchong chain
/>
Sequence listing
<110> Pr Luo Saina biosciences Co., ltd
Hoffmann-La Luoqi Co., Ltd.
<120> treatment of Parkinson's disease
<130> 20-1293-WO
<150> US 63/076,913
<151> 2020-09-10
<150> US 63/076,915
<151> 2020-09-10
<150> US 63/076,916
<151> 2020-09-10
<150> US 63/158,191
<151> 2021-03-08
<160> 10
<170> PatentIn version 3.5
<210> 1
<211> 113
<212> PRT
<213> artificial sequence
<220>
<223> Hu9E4VLv3 variable region
<400> 1
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ser Ile Gln Thr Leu Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys
35 40 45
Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Ile Arg Lys Ser Gly Val
50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Pro Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 2
<211> 113
<212> PRT
<213> artificial sequence
<220>
<223> Hu9E4VLv1 variable region
<400> 2
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ser Ile Gln Thr Leu Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys
35 40 45
Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Ile Arg Lys Ser Gly Val
50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 3
<211> 113
<212> PRT
<213> artificial sequence
<220>
<223> Hu9E4VLv2 (no back mutation) variable region
<400> 3
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ser Ile Gln Thr Leu Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
35 40 45
Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Ile Arg Lys Ser Gly Val
50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 4
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> Hu9E4VHv3 variable region
<400> 4
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Pro Asp Asn Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ala Gly Ile Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 5
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> Hu9E4VHv1 variable region
<400> 5
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Pro Asp Asn Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Gly Gly Ala Gly Ile Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 6
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> Hu9E4VHv2 variable region
<400> 6
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Pro Asp Asn Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Gly Gly Ala Gly Ile Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 7
<211> 116
<212> PRT
<213> artificial sequence
<220>
<223> Hu9E4VHv4 (no back mutation) variable region
<400> 7
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Pro Asp Asn Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ala Gly Ile Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 8
<211> 140
<212> PRT
<213> Chile person
<400> 8
Met Asp Val Phe Met Lys Gly Leu Ser Lys Ala Lys Glu Gly Val Val
1 5 10 15
Ala Ala Ala Glu Lys Thr Lys Gln Gly Val Ala Glu Ala Ala Gly Lys
20 25 30
Thr Lys Glu Gly Val Leu Tyr Val Gly Ser Lys Thr Lys Glu Gly Val
35 40 45
Val His Gly Val Ala Thr Val Ala Glu Lys Thr Lys Glu Gln Val Thr
50 55 60
Asn Val Gly Gly Ala Val Val Thr Gly Val Thr Ala Val Ala Gln Lys
65 70 75 80
Thr Val Glu Gly Ala Gly Ser Ile Ala Ala Ala Thr Gly Phe Val Lys
85 90 95
Lys Asp Gln Leu Gly Lys Asn Glu Glu Gly Ala Pro Gln Glu Gly Ile
100 105 110
Leu Glu Asp Met Pro Val Asp Pro Asp Asn Glu Ala Tyr Glu Met Pro
115 120 125
Ser Glu Glu Gly Tyr Gln Asp Tyr Glu Pro Glu Ala
130 135 140
<210> 9
<211> 220
<212> PRT
<213> artificial sequence
<220>
<223> plausin mab light chain
<400> 9
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ser Ile Gln Thr Leu Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys
35 40 45
Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Ile Arg Lys Ser Gly Val
50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Pro Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 10
<211> 446
<212> PRT
<213> artificial sequence
<220>
<223> plassen Shan Kangchong chain
<400> 10
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Gly Ser Thr Tyr Tyr Pro Asp Asn Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ala Gly Ile Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Claims (38)
1. A method for maintaining motor function or slowing motor function decline in a subject suffering from or at risk of Parkinson's disease comprising administering to the subject a praziquanab (Prasinizumab) regimen,
Wherein the maintaining comprises reducing parkinson's disease progression as indicated by a delay in progression time to at least 5 minutes of progression in MDS-UPDRS part III, and the slowing down the decline comprises at least one of:
(a) Slowing the patient's decrease in MDS-UPDRS part III motor exam score,
(b) Slowing down the decline in one or more of the following: speech, facial expression, stiffness, finger strokes, hand movements, hand pronation-supination movements, toe strokes, leg mobility, standing from chair, gait stiffness, posture stability, posture, hand tremor, stationary tremor amplitude, stationary tremor constancy, or Hoehn and Yahr staging;
(c) Improving bradykinesia;
wherein the plausizumab regimen comprises 1000 to 5000mg plausizumab at intervals of 3 to 5 weeks.
2. The method of claim 1, wherein said slowing the decrease in the motor check score of the patient after one year of treatment compared to placebo comprises an improvement of at least 4%, 17%, 18%, 24%, 25%, 33%, 35%, 39%, 45%, 52%, 63%, 64%, 68%, 71%, 74%, 76%, or 109%.
3. The method of claim 1, wherein said slowing the decrease in the motor check score of the patient after one year of treatment compared to placebo comprises an improvement of at least 18%, 24%, 25%, 33%, 35% or 45%.
4. The method of claim 1, wherein the subject has been diagnosed with mild exercise of parkinson's disease as the major subtype, diffuse malignant subtype, or moderate subtype.
5. The method of claim 1, wherein the subject has been diagnosed with a diffuse malignant subtype of parkinson's disease.
6. The method of any one of claims 1 to 5, further comprising administering to the subject a monoamine oxidase ("MAO") inhibitor.
7. The method of claim 6, wherein the MAO inhibitor is a MAO-B inhibitor.
8. The method of any one of claims 1 to 7, wherein the plausizumab is administered intravenously.
9. A method for maintaining or increasing cerebral blood flow in a subject suffering from or at risk of parkinson's disease, comprising administering to the subject a plausiab regimen comprising 1000 to 5000mg plausiab at intervals of 3 to 5 weeks.
10. The method of claim 9, wherein cerebral blood flow in the putamen is maintained or increased.
11. The method of claim 9, wherein cerebral blood flow in the globus pallidus is maintained or increased.
12. The method of claim 9, wherein cerebral blood flow in the anterior motor cortex is maintained or increased.
13. The method of any one of claims 9 to 12, wherein the blood flow is assessed by a change in magnetic resonance-arterial spin labeling (MRI-ASL).
14. The method of any one of claims 9 to 13, wherein the plausizumab is administered intravenously.
15. A method for improving cognitive function in a subject suffering from or at risk of parkinson's disease, comprising administering to the subject a plasamab regimen comprising 1000 to 5000mg plasamab at intervals of 3 to 5 weeks.
16. The method of claim 15, wherein the subject does not have impairment of cognitive function.
17. The method of claim 15, wherein the improvement in cognitive function is measured by a montreal cognitive assessment (Montreal Cognitive Assessment; moCA), and wherein the improvement is at least 0.2 on a MoCA scoring scale.
18. The method of any one of claims 15 to 17, wherein the plausizumab is administered intravenously.
19. The method of any one of claims 15 to 18, further comprising administering to the subject an MAO-B inhibitor.
20. The method of any one of claims 15 to 19, wherein the subject has not been treated, has been diagnosed with PD in the last two years, or has been previously treated with a MAO-B inhibitor.
21. The method of any one of claims 1 to 20, wherein the subject has a body weight of greater than 65kg and is administered a dose of 4500mg of plausiab once every 4 weeks.
22. The method of any one of claims 1 to 20, wherein the subject has a body weight of less than 65kg and is administered a dose of 3500mg of praziquantel once every 4 weeks.
23. The method of any one of claims 1 to 20, wherein a 1500mg dose of antibody is administered to the subject every 4 weeks.
24. The method of any one of claims 1 to 24, wherein the subject receives plausiab once every 4 weeks for at least 52 weeks.
25. The method of any one of claims 1 to 24, wherein the subject is male.
26. A method of treating a subject suffering from or at risk of Parkinson's disease comprising administering to the subject a pramipexole antibody regimen,
wherein the treatment comprises
(a) Reduce parkinsonian progression as indicated by a delay in progression time to at least 5 points in MDS-UPDRS part III, or
(b) Slowing down the decline of athletic functionality, including at least one of:
i. slowing the patient's decrease in MDS-UPDRS part III motor check score;
Slowing the decline in one or more of: speech, facial expression, stiffness, finger strokes, hand movements, hand pronation-supination movements, toe strokes, leg mobility, standing from chair, gait stiffness, posture stability, posture, hand tremor, stationary tremor amplitude, stationary tremor constancy, or Hoehn and Yahr staging;
improving the retardation of the action,
and is also provided with
Wherein the plausizumab regimen comprises 1000 to 5000mg plausizumab at intervals of 3 to 5 weeks.
27. The method of claim 26, wherein the subject has been diagnosed with mild exercise of parkinson's disease as the major subtype, diffuse malignant subtype, or moderate subtype.
28. The method of claim 27, wherein the subject has been diagnosed with a diffuse malignant subtype of parkinson's disease.
29. The method of any one of claims 26 to 28, wherein the slowing of the decrease in the motor check score of the patient after one year of treatment compared to placebo comprises an improvement of at least 4%, 17%, 18%, 24%, 25%, 33%, 35%, 39%, 45%, 52%, 63%, 64%, 68%, 71%, 74%, 76% or 109%.
30. The method of any one of claims 26 to 29, wherein the plausizumab is administered intravenously.
31. The method of any one of claims 26 to 30, further comprising administering to the subject a monoamine oxidase ("MAO") inhibitor.
32. The method of claim 31, wherein the MAO inhibitor is a MAO-B inhibitor.
33. The method of any one of claims 26 to 32, wherein the subject has not been treated, has been diagnosed with PD in the last two years, or has been previously treated with a MAO-B inhibitor.
34. The method of any one of claims 26 to 33, wherein the subject has a body weight of greater than 65kg and is administered a dose of 4500mg of plausiab once every 4 weeks.
35. The method of any one of claims 26 to 33, wherein the subject has a body weight of less than 65kg and is administered a dose of 3500mg of praziquantel once every 4 weeks.
36. The method of any one of claims 26 to 33, wherein a 1500mg dose of antibody is administered to the subject every 4 weeks.
37. The method of any one of claims 26 to 36, wherein the subject receives plausiab once every 4 weeks for at least 52 weeks.
38. The method of any one of claims 26 to 37, wherein the subject is male.
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US63/076,915 | 2020-09-10 | ||
US63/076,916 | 2020-09-10 | ||
US63/076,913 | 2020-09-10 | ||
US202163158191P | 2021-03-08 | 2021-03-08 | |
US63/158,191 | 2021-03-08 | ||
PCT/US2021/049785 WO2022056209A1 (en) | 2020-09-10 | 2021-09-10 | Treatment of parkinson's disease |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116802208A true CN116802208A (en) | 2023-09-22 |
Family
ID=88048394
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202180072639.9A Pending CN116802208A (en) | 2020-09-10 | 2021-09-10 | Treatment of parkinson's disease |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116802208A (en) |
-
2021
- 2021-09-10 CN CN202180072639.9A patent/CN116802208A/en active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1797109B1 (en) | Mixtures of polypeptides, compositions containing and processes for preparing same, and uses thereof | |
US20070059798A1 (en) | Polypeptides useful for molecular weight determinations | |
CN113316588A (en) | Compositions and methods for treating inflammasome-related diseases or disorders | |
WO2013165590A1 (en) | Methods for treating idiopathic pulmonary fibrosis | |
CN113660981A (en) | Treatment of skin lesions and itching in prurigo nodularis patients | |
WO2020097099A1 (en) | Methods of treating graves' ophthalmopathy using anti-fcrn antibodies | |
AU2021200093A1 (en) | Treatment and prevention of alzheimer's disease (ad) | |
JP6262661B2 (en) | A therapeutic agent for amyotrophic lateral sclerosis | |
TW201204360A (en) | Treatment of multiple sclerosis with MASITINIB | |
CN116802208A (en) | Treatment of parkinson's disease | |
CN118055767A (en) | Novel combined application | |
TW202323296A (en) | Combination therapies | |
JP2020530846A (en) | Method | |
TW202227131A (en) | Treatment of parkinson’s disease | |
CN114555117A (en) | anti-CD 20 antibody preparation and application of anti-CD 20 antibody in treatment of CD20 positive diseases | |
US20180326014A1 (en) | Pharmaceutical formulations for the treatment of diabetes | |
TW201945026A (en) | Antibodies binding ERFE and methods of use | |
TW201927332A (en) | Use of aFGF for preventing or treating diseases related to muscle wasting | |
EP4342485A1 (en) | Ngf for the treatment of spasticity | |
JP7155116B2 (en) | Pharmaceutical compositions and methods for treating female sexual dysfunction | |
WO2023240031A1 (en) | Compositions and methods for treating postural tachycardia syndrome | |
WO2022245816A1 (en) | Treatment of autoimmune inflammatory diseases with tnfrsf25-binding agents | |
WO2024052358A1 (en) | Methods of treating chronic inflammatory demyelinating polyneuropathy using anti-fcrn antibodies | |
CN115812079A (en) | Methods of treating thyroid eye disease and Graves' orbitopathy using interleukin-17 (IL-17) antagonists | |
WO2024052357A1 (en) | Methods of treating graves' disease using anti-fcrn antibodies |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |