EP4237454A1 - Traitement neurodégénératif - Google Patents
Traitement neurodégénératifInfo
- Publication number
- EP4237454A1 EP4237454A1 EP21806022.6A EP21806022A EP4237454A1 EP 4237454 A1 EP4237454 A1 EP 4237454A1 EP 21806022 A EP21806022 A EP 21806022A EP 4237454 A1 EP4237454 A1 EP 4237454A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- polysaccharide
- arabinofuranose
- repeating units
- mice
- app
- 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
- 238000011282 treatment Methods 0.000 title description 66
- 230000000626 neurodegenerative effect Effects 0.000 title description 2
- 229920001282 polysaccharide Polymers 0.000 claims abstract description 140
- 239000005017 polysaccharide Substances 0.000 claims abstract description 140
- 239000000203 mixture Substances 0.000 claims abstract description 52
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 49
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 42
- 150000004676 glycans Chemical class 0.000 claims abstract 18
- 241000196324 Embryophyta Species 0.000 claims description 64
- 208000024891 symptom Diseases 0.000 claims description 51
- 208000024827 Alzheimer disease Diseases 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 29
- 244000191761 Sida cordifolia Species 0.000 claims description 20
- 125000000328 arabinofuranosyl group Chemical group C1([C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 208000018737 Parkinson disease Diseases 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 13
- 241000134966 Malvales Species 0.000 claims description 11
- HMFHBZSHGGEWLO-MBMOQRBOSA-N alpha-D-arabinofuranose Chemical group OC[C@H]1O[C@H](O)[C@@H](O)[C@@H]1O HMFHBZSHGGEWLO-MBMOQRBOSA-N 0.000 claims description 10
- 208000023105 Huntington disease Diseases 0.000 claims description 9
- 208000026072 Motor neurone disease Diseases 0.000 claims description 7
- 206010012289 Dementia Diseases 0.000 claims description 6
- 201000011240 Frontotemporal dementia Diseases 0.000 claims description 6
- HMFHBZSHGGEWLO-HWQSCIPKSA-N L-arabinofuranose Chemical compound OC[C@@H]1OC(O)[C@H](O)[C@H]1O HMFHBZSHGGEWLO-HWQSCIPKSA-N 0.000 claims description 6
- 208000024777 Prion disease Diseases 0.000 claims description 6
- 208000035475 disorder Diseases 0.000 claims description 6
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 5
- 208000029560 autism spectrum disease Diseases 0.000 claims description 5
- 102000014461 Ataxins Human genes 0.000 claims description 4
- 108010078286 Ataxins Proteins 0.000 claims description 4
- 206010008025 Cerebellar ataxia Diseases 0.000 claims description 4
- 208000009829 Lewy Body Disease Diseases 0.000 claims description 4
- 201000002832 Lewy body dementia Diseases 0.000 claims description 4
- 208000009415 Spinocerebellar Ataxias Diseases 0.000 claims description 4
- 201000004562 autosomal dominant cerebellar ataxia Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 208000002320 spinal muscular atrophy Diseases 0.000 claims description 4
- 201000004810 Vascular dementia Diseases 0.000 claims description 3
- HMFHBZSHGGEWLO-QMKXCQHVSA-N alpha-L-arabinofuranose Chemical compound OC[C@@H]1O[C@@H](O)[C@H](O)[C@H]1O HMFHBZSHGGEWLO-QMKXCQHVSA-N 0.000 claims description 3
- 201000000980 schizophrenia Diseases 0.000 claims description 3
- 150000004804 polysaccharides Chemical class 0.000 description 123
- 241000699670 Mus sp. Species 0.000 description 97
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 44
- 239000011780 sodium chloride Substances 0.000 description 43
- 238000010175 APPswe/PSEN1dE9 Methods 0.000 description 30
- 210000003710 cerebral cortex Anatomy 0.000 description 28
- 210000001947 dentate gyrus Anatomy 0.000 description 23
- 230000000694 effects Effects 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- -1 fatty acid amines Chemical class 0.000 description 17
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 13
- 150000003839 salts Chemical class 0.000 description 13
- 210000004556 brain Anatomy 0.000 description 12
- 210000000274 microglia Anatomy 0.000 description 12
- 230000003959 neuroinflammation Effects 0.000 description 12
- 238000010149 post-hoc-test Methods 0.000 description 12
- 239000000523 sample Substances 0.000 description 12
- 241001547426 Malvastrum Species 0.000 description 11
- 230000015654 memory Effects 0.000 description 11
- 230000003542 behavioural effect Effects 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- 238000012549 training Methods 0.000 description 10
- 238000000540 analysis of variance Methods 0.000 description 9
- 230000006735 deficit Effects 0.000 description 9
- 235000013305 food Nutrition 0.000 description 9
- 230000006870 function Effects 0.000 description 9
- 239000000546 pharmaceutical excipient Substances 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- 230000006886 spatial memory Effects 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 210000001130 astrocyte Anatomy 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 230000001771 impaired effect Effects 0.000 description 8
- 230000004065 mitochondrial dysfunction Effects 0.000 description 8
- 230000036542 oxidative stress Effects 0.000 description 8
- 238000011002 quantification Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 208000019901 Anxiety disease Diseases 0.000 description 7
- 244000130592 Hibiscus syriacus Species 0.000 description 7
- 235000018081 Hibiscus syriacus Nutrition 0.000 description 7
- 238000000692 Student's t-test Methods 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 230000036506 anxiety Effects 0.000 description 7
- 235000014113 dietary fatty acids Nutrition 0.000 description 7
- 239000000194 fatty acid Substances 0.000 description 7
- 229930195729 fatty acid Natural products 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 102000004127 Cytokines Human genes 0.000 description 6
- 108090000695 Cytokines Proteins 0.000 description 6
- 102100039289 Glial fibrillary acidic protein Human genes 0.000 description 6
- 101710193519 Glial fibrillary acidic protein Proteins 0.000 description 6
- 235000013939 Malva Nutrition 0.000 description 6
- 240000000982 Malva neglecta Species 0.000 description 6
- 235000000060 Malva neglecta Nutrition 0.000 description 6
- 238000012347 Morris Water Maze Methods 0.000 description 6
- 241001528594 Sidalcea Species 0.000 description 6
- 102100040247 Tumor necrosis factor Human genes 0.000 description 6
- 230000001580 bacterial effect Effects 0.000 description 6
- 208000010877 cognitive disease Diseases 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 150000004665 fatty acids Chemical class 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 210000005046 glial fibrillary acidic protein Anatomy 0.000 description 6
- 238000007918 intramuscular administration Methods 0.000 description 6
- 238000011201 multiple comparisons test Methods 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 238000001543 one-way ANOVA Methods 0.000 description 6
- 238000007920 subcutaneous administration Methods 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- 230000000699 topical effect Effects 0.000 description 6
- 230000031836 visual learning Effects 0.000 description 6
- 208000037259 Amyloid Plaque Diseases 0.000 description 5
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 5
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 5
- 206010002942 Apathy Diseases 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 5
- 208000004547 Hallucinations Diseases 0.000 description 5
- 240000002129 Malva sylvestris Species 0.000 description 5
- 235000006770 Malva sylvestris Nutrition 0.000 description 5
- 241001339257 Sidalcea malviflora Species 0.000 description 5
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 5
- 239000007900 aqueous suspension Substances 0.000 description 5
- 230000006399 behavior Effects 0.000 description 5
- 235000013361 beverage Nutrition 0.000 description 5
- 239000007859 condensation product Substances 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 235000013355 food flavoring agent Nutrition 0.000 description 5
- 235000003599 food sweetener Nutrition 0.000 description 5
- 238000007912 intraperitoneal administration Methods 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 230000003137 locomotive effect Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 4
- UBKVUFQGVWHZIR-UHFFFAOYSA-N 8-oxoguanine Chemical compound O=C1NC(N)=NC2=NC(=O)N=C21 UBKVUFQGVWHZIR-UHFFFAOYSA-N 0.000 description 4
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- 108090001005 Interleukin-6 Proteins 0.000 description 4
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 4
- 241000881780 Lavatera Species 0.000 description 4
- 241000219071 Malvaceae Species 0.000 description 4
- 241001581235 Malvoideae Species 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 241000994699 Sphaeralcea Species 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 235000015872 dietary supplement Nutrition 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003925 fat Substances 0.000 description 4
- 235000019197 fats Nutrition 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000004006 olive oil Substances 0.000 description 4
- 235000008390 olive oil Nutrition 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 230000002685 pulmonary effect Effects 0.000 description 4
- 230000036362 sensorimotor function Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 230000009885 systemic effect Effects 0.000 description 4
- 238000012353 t test Methods 0.000 description 4
- 238000007492 two-way ANOVA Methods 0.000 description 4
- 230000000007 visual effect Effects 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 3
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 3
- 206010013142 Disinhibition Diseases 0.000 description 3
- 239000004150 EU approved colour Substances 0.000 description 3
- 239000001828 Gelatine Substances 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 3
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 3
- 229920000869 Homopolysaccharide Polymers 0.000 description 3
- 241000003809 Malva arborea Species 0.000 description 3
- 235000008650 Malva dendromorpha Nutrition 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 241000375739 Sphaeralcea coccinea Species 0.000 description 3
- 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 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 206010044565 Tremor Diseases 0.000 description 3
- 230000006933 amyloid-beta aggregation Effects 0.000 description 3
- 201000007201 aphasia Diseases 0.000 description 3
- AEMOLEFTQBMNLQ-UHFFFAOYSA-N beta-D-galactopyranuronic acid Natural products OC1OC(C(O)=O)C(O)C(O)C1O AEMOLEFTQBMNLQ-UHFFFAOYSA-N 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 238000007913 intrathecal administration Methods 0.000 description 3
- 230000013016 learning Effects 0.000 description 3
- 229940057995 liquid paraffin Drugs 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000000813 microbial effect Effects 0.000 description 3
- 238000001000 micrograph Methods 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 208000005264 motor neuron disease Diseases 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000000750 progressive effect Effects 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 210000000952 spleen Anatomy 0.000 description 3
- 230000003393 splenic effect Effects 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 235000011351 tree mallow Nutrition 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- 241000219144 Abutilon Species 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- 235000006491 Acacia senegal Nutrition 0.000 description 2
- 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 2
- 208000000044 Amnesia Diseases 0.000 description 2
- 208000007415 Anhedonia Diseases 0.000 description 2
- 235000003911 Arachis Nutrition 0.000 description 2
- 244000105624 Arachis hypogaea Species 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 206010003591 Ataxia Diseases 0.000 description 2
- 208000028698 Cognitive impairment Diseases 0.000 description 2
- 206010010774 Constipation Diseases 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 241000283073 Equus caballus Species 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102100025087 Insulin receptor substrate 1 Human genes 0.000 description 2
- 101710201824 Insulin receptor substrate 1 Proteins 0.000 description 2
- 125000003264 L-arabinofuranosyl group Chemical group [H]OC([H])([H])[C@]1([H])OC([H])(*)[C@]([H])(O[H])[C@@]1([H])O[H] 0.000 description 2
- 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 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 208000026139 Memory disease Diseases 0.000 description 2
- 208000016285 Movement disease Diseases 0.000 description 2
- 208000007101 Muscle Cramp Diseases 0.000 description 2
- 208000002740 Muscle Rigidity Diseases 0.000 description 2
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 2
- 208000011644 Neurologic Gait disease Diseases 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- 206010034719 Personality change Diseases 0.000 description 2
- 241000425347 Phyla <beetle> Species 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 208000005392 Spasm Diseases 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 108700012920 TNF Proteins 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 102000003802 alpha-Synuclein Human genes 0.000 description 2
- 108090000185 alpha-Synuclein Proteins 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 230000008335 axon cargo transport Effects 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 238000004891 communication Methods 0.000 description 2
- 230000016396 cytokine production Effects 0.000 description 2
- 235000013365 dairy product Nutrition 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000013872 defecation Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 235000021185 dessert Nutrition 0.000 description 2
- 230000001627 detrimental effect Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000000378 dietary effect Effects 0.000 description 2
- 208000002173 dizziness Diseases 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 230000003370 grooming effect Effects 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 230000004046 hyporesponsiveness Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000007786 learning performance Effects 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 210000004558 lewy body Anatomy 0.000 description 2
- 244000144972 livestock Species 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000007726 management method Methods 0.000 description 2
- 235000013310 margarine Nutrition 0.000 description 2
- 239000003264 margarine Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000006984 memory degeneration Effects 0.000 description 2
- 208000023060 memory loss Diseases 0.000 description 2
- 230000007334 memory performance Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000002025 microglial effect Effects 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 230000004973 motor coordination Effects 0.000 description 2
- 230000003962 neuroinflammatory response Effects 0.000 description 2
- 239000000820 nonprescription drug Substances 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 238000003305 oral gavage Methods 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 230000000384 rearing effect Effects 0.000 description 2
- 230000003252 repetitive effect Effects 0.000 description 2
- 230000001953 sensory effect Effects 0.000 description 2
- 208000019116 sleep disease Diseases 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 235000014347 soups Nutrition 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 230000001755 vocal effect Effects 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
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-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
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 208000000187 Abnormal Reflex Diseases 0.000 description 1
- 240000006995 Abutilon theophrasti Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 241000272814 Anser sp. Species 0.000 description 1
- 206010003472 Asocial behaviour Diseases 0.000 description 1
- 241000934828 Bixaceae Species 0.000 description 1
- 241001581196 Bombacoideae Species 0.000 description 1
- 206010006100 Bradykinesia Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 241001581215 Brownlowioideae Species 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 241001581231 Byttnerioideae Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- 206010008748 Chorea Diseases 0.000 description 1
- 241000984092 Cistaceae Species 0.000 description 1
- 241001573498 Compacta Species 0.000 description 1
- 206010010219 Compulsions Diseases 0.000 description 1
- 206010010947 Coordination abnormal Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 241000307150 Cytinaceae Species 0.000 description 1
- WQZGKKKJIJFFOK-SVZMEOIVSA-N D-(+)-Galactose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-DTEWXJGMSA-N D-Galacturonic acid Natural products O[C@@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-DTEWXJGMSA-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
- 125000003317 D-arabinofuranosyl group Chemical group [H]OC([H])([H])[C@@]1([H])OC([H])(*)[C@@]([H])(O[H])[C@]1([H])O[H] 0.000 description 1
- AEMOLEFTQBMNLQ-YMDCURPLSA-N D-galactopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-YMDCURPLSA-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
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- 206010012239 Delusion Diseases 0.000 description 1
- 208000031124 Dementia Alzheimer type Diseases 0.000 description 1
- 206010012374 Depressed mood Diseases 0.000 description 1
- 241000123611 Dipterocarpaceae Species 0.000 description 1
- 206010013496 Disturbance in attention Diseases 0.000 description 1
- 241001581224 Dombeyoideae Species 0.000 description 1
- 206010013642 Drooling Diseases 0.000 description 1
- 206010013887 Dysarthria Diseases 0.000 description 1
- 206010013952 Dysphonia Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 206010017577 Gait disturbance Diseases 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010018341 Gliosis Diseases 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 241001581230 Grewioideae Species 0.000 description 1
- 206010019070 Hallucination, auditory Diseases 0.000 description 1
- 206010019075 Hallucination, visual Diseases 0.000 description 1
- 241001581213 Helicteroideae Species 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 102000016252 Huntingtin Human genes 0.000 description 1
- 108050004784 Huntingtin Proteins 0.000 description 1
- 206010020710 Hyperphagia Diseases 0.000 description 1
- 208000006083 Hypokinesia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- SHZGCJCMOBCMKK-PQMKYFCFSA-N L-Fucose Natural products C[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O SHZGCJCMOBCMKK-PQMKYFCFSA-N 0.000 description 1
- SRBFZHDQGSBBOR-HWQSCIPKSA-N L-arabinopyranose Chemical compound O[C@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-HWQSCIPKSA-N 0.000 description 1
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- SHZGCJCMOBCMKK-JFNONXLTSA-N L-rhamnopyranose Chemical compound C[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O SHZGCJCMOBCMKK-JFNONXLTSA-N 0.000 description 1
- 208000030979 Language Development disease Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010050183 Macrocephaly Diseases 0.000 description 1
- 208000032443 Masked facies Diseases 0.000 description 1
- 208000005767 Megalencephaly Diseases 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-O Methylammonium ion Chemical compound [NH3+]C BAVYZALUXZFZLV-UHFFFAOYSA-O 0.000 description 1
- 241000736262 Microbiota Species 0.000 description 1
- 206010057333 Micrographia Diseases 0.000 description 1
- 241000307196 Muntingiaceae Species 0.000 description 1
- 208000010428 Muscle Weakness Diseases 0.000 description 1
- 206010028289 Muscle atrophy Diseases 0.000 description 1
- 206010028347 Muscle twitching Diseases 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- 206010028403 Mutism Diseases 0.000 description 1
- 208000002033 Myoclonus Diseases 0.000 description 1
- 241001115451 Neuradaceae Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010029897 Obsessive thoughts Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 235000019482 Palm oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 206010034701 Peroneal nerve palsy Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 206010036437 Posturing Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000029797 Prion Human genes 0.000 description 1
- 108091000054 Prion Proteins 0.000 description 1
- 108010002519 Prolactin Receptors Proteins 0.000 description 1
- 102100029000 Prolactin receptor Human genes 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 206010037180 Psychiatric symptoms Diseases 0.000 description 1
- 208000001431 Psychomotor Agitation Diseases 0.000 description 1
- 235000019484 Rapeseed oil Nutrition 0.000 description 1
- 206010071390 Resting tremor Diseases 0.000 description 1
- 206010038743 Restlessness Diseases 0.000 description 1
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 1
- 206010039424 Salivary hypersecretion Diseases 0.000 description 1
- 208000018642 Semantic dementia Diseases 0.000 description 1
- 208000008630 Sialorrhea Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 206010071299 Slow speech Diseases 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 241000934848 Sphaerosepalaceae Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 206010041954 Starvation Diseases 0.000 description 1
- 241001581218 Sterculioideae Species 0.000 description 1
- 206010042458 Suicidal ideation Diseases 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 208000005028 anomia Diseases 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 208000037875 astrocytosis Diseases 0.000 description 1
- 230000007341 astrogliosis Effects 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-O butylazanium Chemical compound CCCC[NH3+] HQABUPZFAYXKJW-UHFFFAOYSA-O 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 206010007776 catatonia Diseases 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000013351 cheese Nutrition 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 208000012601 choreatic disease Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000009194 climbing Effects 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- 238000005354 coacervation Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 238000002288 cocrystallisation Methods 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 230000006999 cognitive decline Effects 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 231100000868 delusion Toxicity 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-O diethylammonium Chemical compound CC[NH2+]CC HPNMFZURTQLUMO-UHFFFAOYSA-O 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 210000005064 dopaminergic neuron Anatomy 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 235000005686 eating Nutrition 0.000 description 1
- 235000006694 eating habits Nutrition 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-O ethylaminium Chemical compound CC[NH3+] QUSNBJAOOMFDIB-UHFFFAOYSA-O 0.000 description 1
- 230000003090 exacerbative effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 210000001652 frontal lobe Anatomy 0.000 description 1
- 230000005021 gait Effects 0.000 description 1
- 229960003980 galantamine Drugs 0.000 description 1
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229940084910 gliadel Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000004518 granules dosage form Substances 0.000 description 1
- 210000004884 grey matter Anatomy 0.000 description 1
- 244000005709 gut microbiome Species 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 201000010235 heart cancer Diseases 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 208000024348 heart neoplasm Diseases 0.000 description 1
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000035859 hyperreflexia Effects 0.000 description 1
- 206010020745 hyperreflexia Diseases 0.000 description 1
- 238000002991 immunohistochemical analysis Methods 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 208000016290 incoordination Diseases 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000008611 intercellular interaction Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000012263 liquid product Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 1
- 229960004640 memantine Drugs 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 230000006724 microglial activation Effects 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 230000004898 mitochondrial function Effects 0.000 description 1
- 230000007659 motor function Effects 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000020763 muscle atrophy Effects 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 235000020830 overeating Nutrition 0.000 description 1
- 125000005489 p-toluenesulfonic acid group Chemical class 0.000 description 1
- 239000002540 palm oil Substances 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000155 polyglutamine Polymers 0.000 description 1
- 108010040003 polyglutamine Proteins 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 230000001144 postural effect Effects 0.000 description 1
- 230000036544 posture Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 208000001282 primary progressive aphasia Diseases 0.000 description 1
- 235000014059 processed cheese Nutrition 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000009979 protective mechanism Effects 0.000 description 1
- 235000021251 pulses Nutrition 0.000 description 1
- 230000036385 rapid eye movement (rem) sleep Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000009754 rhamnogalacturonan I Substances 0.000 description 1
- 239000008914 rhamnogalacturonan II Substances 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- 238000010079 rubber tapping Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 208000022925 sleep disturbance Diseases 0.000 description 1
- 230000011273 social behavior Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 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
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000008137 solubility enhancer Substances 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000001148 spastic effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000000528 statistical test Methods 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 102000013498 tau Proteins Human genes 0.000 description 1
- 108010026424 tau Proteins Proteins 0.000 description 1
- 210000003478 temporal lobe Anatomy 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000012762 unpaired Student’s t-test Methods 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 210000003934 vacuole Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000028973 vesicle-mediated transport Effects 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0057—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Xylans, i.e. xylosaccharide, e.g. arabinoxylan, arabinofuronan, pentosans; (beta-1,3)(beta-1,4)-D-Xylans, e.g. rhodymenans; Hemicellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the invention relates to an isolated polysaccharide and a composition comprising the polysaccharide for use in treating a neurodegenerative disease or a medical condition, and a method of treatment using the isolated polysaccharide or the composition thereof.
- AD Alzheimer’s Disease
- AD Alzheimer’s Disease
- AD Alzheimer’s Disease
- AD is the most common cause of dementia and contributes to 60-70% of cases.
- AD is an incurable, neurodegenerative disease and its worldwide prevalence is expected to double every twenty years reaching well over 100 million by 2050. It is estimated that there will be approximately 14.8 million prevalent cases of AD in the US, Japan, and five major EU markets by 2034. Within the UK, there are approximately 850,000 sufferers which contribute an economic cost to society in the region of £23bn. This is greater than heart disease and cancer combined.
- Drug development for AD has proven to be very difficult. The high-profile failure of clinical trials in AD, which primarily focus on the amyloid cascade hypothesis, strengthens the case for developing drugs with an alternative mechanism of action.
- AD Alzheimer's disease
- cholinesterase inhibitors to alleviate some of the symptoms of the disease, but are not curative, or disease modifying, and only work in certain individuals for a relatively short period of time.
- NMDA N-methyl-D-aspartate receptor AD antagonist
- an isolated polysaccharide comprising “n” repeating units; or a composition comprising an isolated polysaccharide comprising “n” repeating units, wherein each of the “n” repeating units comprises a backbone of alpha-(1-5)- linked arabinofuranose residues, a first side chain of a single alpha-arabinofuranose residue (l-2)-linked to an arabinofuranose residue of the backbone, and a second side chain of a single alpha-arabinofuranose residue (l-3)-linked to the same arabinofuranose residue of the backbone, for use in treating, preventing or ameliorating a neurodegenerative disease and/or symptoms thereof in a subject, optionally wherein the composition is a pharmaceutical composition and a pharmaceutically acceptable carrier or such like, or an edible composition.
- a method of treating, preventing or ameliorating a neurodegenerative disease and/or symptoms thereof in a subject comprising administering to the subject an isolated polysaccharide referred to herein, a composition referred to herein, or a plant of the Malvales order or a part thereof.
- the polysaccharide referred to herein is non-toxic and does not induce anaphylaxis in animals or humans. More importantly, however, the polysaccharide is edible and capable of crossing the blood brain barrier after oral consumption. Therefore, it can be administered orally to treat neurodegenerative diseases.
- the method may comprise administering a therapeutically effective amount of the isolated polysaccharide, the composition or the plant to treat a neurodegenerative disease.
- a plant of the Malvales order for use in treating, preventing or ameliorating a neurodegenerative disease and/or symptoms thereof in a subject is provided.
- the polysaccharide of the invention may be isolated from a Malvales plant.
- the plant may be a Malvales plant or a part thereof.
- the polysaccharide may be isolated from a plant of the Malvales order.
- the Malvales order comprises the Bixaceae family, the Cistaceae family, the Cytinaceae family, the Dipterocarpaceae family, the Muntingiaceae family, the Neuradaceae family, the Sarcloaenaceae family, the Sphaerosepalaceae family, the Thymelaeceae family and the Malvaceae family.
- the plant is a member of the Malvaceae family.
- the family Malvaceae comprises the subfamilies Bombacoideae, Brownlowioideae, Bytnnerioideae, Byttnerioideae, Dombeyoideae, Grewioideae, Helicteroideae, Malvoideae, Sterculioideae and Tiliodeae.
- the plant is a Malvoideae.
- the Malvoideae comprises the tribes Malveae, Gossypieae, Hibisceae, Kydieae.
- the plant is from the Malveae tribe.
- the plant may be from the Sida genus or the Malva genus or the Malvastrum genus or the Sidalcea genus or the Abutilon genus or the Althea genus or the Sphaeralcea genus or the Lavatera genus.
- the plant of the Sida genus is Sida cordifolia (also referred to as ilima, flannel weed, bala, country mallow or heartleaf sida).
- the plant of the Malva genus is Malva sylvestris.
- the plant of the Malvastrum genus is Malvastrum lateritium.
- the plant of the Sidalcea genus is Sidalcea malviflora. Most preferably plant of the Abutilon genus is Abutilon theophrasti. Most preferably the plant of Althea genus is Althea officinalis . Most preferably the plant of Sphaeralcea genus is Sphaeralcea coccinea. Most preferably the plant of Lavatera genus is Lavatera arborea. Most preferably the plant is Sida cordifolia.
- the polysaccharide may be from a plant of the Sida genus (e.g. Sida cordifolia) or the Malva genus (e.g. Malva sylvestris) or the Malvastrum genus (e.g. Malvastrum lateritium) or the Sidalcea genus (e.g. Sidalcea malviflora) or the Althea genus (e.g. Althea officinalis), or the Sphaeralcea genus (e.g. Sphaeralcea coccinea), or the Lavatera genus (e.g. Lavatera arborea).
- Sida genus e.g. Sida cordifolia
- the Malva genus e.g. Malva sylvestris
- Malvastrum genus e.g. Malvastrum lateritium
- the Sidalcea genus e.g. Sidalcea malviflora
- the plant may be a plant of the Sida genus (e.g. Sida cordifolia) or the Malva genus (e.g. Malva sylvestris) or the Malvastrum genus (e.g. Malvastrum lateritium) or the Sidalcea genus (e.g. Sidalcea malviflora) or the Althea genus (e.g. Althea officinalis), or the Sphaeralcea genus (e.g. Sphaeralcea coccinea), or the Lavatera genus (e.g. Lavatera arborea).
- Sida genus e.g. Sida cordifolia
- the Malva genus e.g. Malva sylvestris
- Malvastrum genus e.g. Malvastrum lateritium
- the Sidalcea genus e.g. Sidalcea malviflora
- the polysaccharide is from Sida cordifolia.
- the plant is Sida cordifolia.
- the polysaccharide may be isolated from part of a plant of the Malvales order, such as the leaves, the flower, the stem and/or the roots of the plant.
- the plant may be part of the plant, such as the leaves, the flower, the stem and/or the roots of the plant.
- the part of the plant is the roots. Therefore, the polysaccharide may be isolated from the roots of a plant of the Malvales order.
- the polysaccharide may be from the roots of a Sida spp. (e.g. Sida cordifolia) or a Malva spp. (e.g.
- the plant may be the roots of a Sida spp. (e.g. Sida cordifolia) or a Malva spp. (e.g. Malva sylvestris) or a Malvastrum spp. (e.g. Malvastrum lateritium) or a Sidalcea spp. (e.g. Sidalcea malviflora).
- the plant may be the roots of a Sida spp. (e.g. Sida cordifolia) or a Malva spp. (e.g. Malva sylvestris) or a Malvastrum spp. (e.g. Malvastrum lateritium) or a Sidalcea spp. (e.g. Sidalcea malviflora).
- the polysaccharide is isolated from the roots of Sida cordifolia.
- the plant may be the roots of Sida cordifolia.
- the polysaccharide may be a homopolysaccharide or a heteropolysaccharide.
- the polysaccharide may be an arabinan polysaccharide.
- the polysaccharide may be an arabinan homopolysaccharide.
- the residues of the homopolysaccharide may be L- arabinofuranose residues or be D-arabinofuranose residues. Preferably the residues are L-arabinofuranose residues.
- Each repeating unit of the backbone of the polysaccharide referred to within the first aspect may further comprise 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more or 10 additional residues (glycosidic) linked to a terminal residue of the backbone.
- the additional residues of the backbone are alpha-(1-5)- linked arabinofuranose residues. More preferably the additional residues of the backbone are alpha-L-(1-5)-linked arabinofuranose residues.
- One or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more or nine or more of the additional alpha-(1-5)-linked arabinofuranose residues may or may not comprise any side chains.
- One or more of the additional alpha-(1-5)- linked arabinofuranose residues may comprise a side chain of a single alpha-(l-2)- linked arabinofuranose residue.
- One or more of the additional alpha-(1-5)-linked arabinofuranose residues may comprise a side chain of a single alpha-(l-3)-linked arabinofuranose residue.
- One, two or three of the additional alpha-(1-5)-linked arabinofuranose residues may comprise a side chain of a single alpha-(l-2)-linked arabinofuranose residue and a side chain of a single alpha-arabinofuranose residue (1- 3)-linked to the same additional arabinofuranose residue of the backbone.
- Each of the repeating units may independently be branched or unbranched. Thus, at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 100% of the repeating units may be branched. Thus, less than about 100%, about 90%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10% or about 5% of the repeating units may be branched.
- Each of the repeating units may be directly or indirectly linked to each other.
- each of the repeating units is directly linked to each other via a glycosidic bond, such as an alpha-(1-5) glycosidic bond or an alpha-L-(1-5) glycosidic bond.
- the first side chain and the second side chain of the polysaccharide according to the invention may be linked to the same arabinofuranose residue of the backbone.
- the repeating unit comprises or consists of Formula (I) (which may also be referred to herein as block “A”), defined herein as follows:
- the repeating units of the polysaccharide according to the invention may comprise or consist of blocks referred to herein as blocks “A”, “E” and “F”.
- Block A (Formula I) is an essential block of the polysaccharide according to the invention.
- the repeating units of the polysaccharide may further comprise block E and/or block F.
- Block E may be represented by Formula II, as follows:
- Block F may be represented by Formula III, as follows:
- Each block (i.e. block A, block E and block F) comprises a backbone.
- Each block may be linked by an alpha-(1-5)-glycosidic bond, specifically the backbone of each block.
- the repeating units may comprise Formula (I) linked to Formula (II) by an alpha-(1-5)-glycosidic bond.
- the repeating units may comprise Formula (I) linked to Formula (III) by an alpha-(1-5)-glycosidic bond.
- the repeating units may comprise Formula (II) linked to Formula (III) by an alpha-(1-5)-glycosidic bond.
- block A is about three, about four or about five times more abundant than block E and/or block F (if E or F is present) in the repeating unit of the polysaccharide.
- the ratio of A:E:F in the repeating units may be 3-5 : 1 : 1.
- Most preferably the ratio of A:E:F is 4: 1 : 1.
- block F is the least abundant block of A, E and F.
- block A is the most abundant block of A, E and F.
- Block F (if present in the repeating unit) may be about two, about three, about four, about five, about six, about seven or about less abundant than block A.
- Block F (if present) may be between about one and about two times less abundant than block A.
- the ratio of A:E:F in the repeating units may be about 2-8: 1-3: 1 or 3-7: 1-2: 1 or 4-6: 1- 2: 1.
- Most preferably the ratio of A:E:F is 4-6: 1-2: 1.
- repeating unit may comprise Formula (II), defined herein as follows:
- each star of Formula (IV) corresponds to an arabinofuranose, preferably an L-arabinofuranose, more preferably an alpha-arabinofuranose, most preferably an alpha-L-arabinofuranose.
- the repeating unit of the polysaccharide may be represented by any one of the combinations shown in Table 1, as follows: Each cell of Table 1 above represents an embodiment of a repeating unit of the polysaccharide according to the invention. Thus the repeating unit of the polysaccharide may be represented by any one of the 48 examples shown in Table 1.
- the polysaccharide may comprise “n” repeating units, e.g. “n” repeating units of Formula (I) or Formula (II) or any of the 48 examples shown in Table 1.
- n may be 2 or more, 3 or more, 4 or more, 5 or more 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 15 or more, 20 or more, 25 or more, 30 or more, 35 or more, or 40 or more, 50 or more, 100 or more, 200 or more, 300 or more, 500 or more, or 1000 or more, “n” may be about 5 to about 1000, about 10 to about 500, or about 15 to about 250, or about 15 to about 230, or about 15 to about 220. Preferably “n” is about 15 to about 220 or about 15 to about 230.
- the polysaccharide according to the invention may or may not be a rhamnogalacturonan, such as rhamnogalacturonan-I of rhamnogalacturonan-II.
- the polysaccharide or composition referred to herein may be administered several different routes, including, for example, oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route.
- the polysaccharide or composition referred to herein may be administered orally.
- the polysaccharide or composition referred to herein may be administered rectally.
- the polysaccharide or composition referred to herein may be administered nasally.
- the polysaccharide or composition referred to herein may be administered via the pulmonary route.
- the polysaccharide or composition referred to herein may be administered topically (e.g. buccally or sublingually).
- the polysaccharide or composition referred to herein may be administered transdermally.
- the polysaccharide or composition referred to herein may be administered intracisternally.
- the polysaccharide or composition referred to herein may be administered intraperitoneally.
- the polysaccharide or composition referred to herein may be administered via the vaginal.
- the polysaccharide or composition referred to herein may be administered parenterally (e.g. subcutaneously, intramuscularly, intrathecally, intravenously or intradermally).
- Preferably the polysaccharide or composition is administered orally.
- a polysaccharide or a composition referred to herein for use according to the invention may be used to treat, prevent and/or ameliorate a neurodegenerative disease and/or symptoms thereof.
- a neurodegenerative disease is any medical disease or medical condition that is caused by the death of neurons of the central nervous system (e.g. the brain) and/or the peripheral nervous system. The death of the neurons results in symptoms which may affect speech, movement, memory, intelligence and/or more.
- the neurodegenerative disease referred to herein may be a disease selected from the group comprising or consisting of Alzheimer’s disease (AD) and/or related dementias, such as vascular dementia, frontotemporal dementia and/or lewy body dementia; Parkinson’s disease (PD) and/or PD-related disorders; Huntington’s disease (HD); dementia; Motor neurone diseases (MND) (also referred to as amyotrophic lateral sclerosis (ALS)); Spinocerebellar ataxia (SCA); Spinal muscular atrophy (SMA); prion disease; autism spectrum disorders and/or the neurodegenerative process associated with autism spectrum disorders; depression; and schizophrenia.
- the neurodegenerative disease is Alzheimer’s disease or Parkinson’s disease.
- the neurodegenerative disease referred to herein may be one or more diseases selected from the group comprising or consisting of Alzheimer’s disease; ALS; and Huntington’s disease.
- polysaccharide comprising “n” repeating units of Formula (I), Formula (IV) or any of the 48 examples shown in Table 1, for use in treating, preventing and/or ameliorating a selection of one or more diseases from the group comprising/consisting of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, motor neuron disease, prion disease, and/or symptoms thereof in a subject.
- polysaccharide comprising “n” repeating units of Formula (I), Formula (IV) or any of the 48 examples shown in Table 1, for use in treating, preventing and/or ameliorating Alzheimer’s disease and/or symptoms thereof in a subject.
- polysaccharide comprising “n” repeating units of Formula (I), Formula (IV) or any of the 48 examples shown in Table 1, for use in treating, preventing and/or ameliorating Parkinson’s disease and/or symptoms thereof in a subject.
- polysaccharide comprising “n” repeating units of Formula (I), Formula (IV) or any of the 48 examples shown in Table 1, for use in treating, preventing and/or ameliorating Huntington’s disease and/or symptoms thereof in a subject.
- polysaccharide comprising “n” repeating units of Formula (I), Formula (IV) or any of the 48 examples shown in Table 1, for use in treating, preventing and/or ameliorating motor neuron disease and/or symptoms thereof in a subject.
- polysaccharide comprising “n” repeating units of Formula (I), Formula (IV) or any of the 48 examples shown in Table 1, for use in treating, preventing and/or ameliorating prion disease and/or symptoms thereof in a subject.
- the neuroinflammatory response is subjects with a neuroinflammatory disorder is hyporesponsive. This hyporesponsiveness is believed to have detrimental effects on the brain and contribute to the progression of neurodegenerative diseases.
- the polysaccharide according to the invention may be used to enhance neuroinflammation in a subject with a neurodegenerative disorder (see Example 7), the polysaccharide according to the invention may be used to treat a neurodegenerative disorder and/or the symptoms thereof.
- Symptoms of Alzheimer’s disease include chronic and progressive memory loss (recognition and spatial memory, visuo-spatial dysfunction), disorientation to time and place, impairments in social and occupational functioning (executive function difficulties), deficits in motor function and speech, nominal dysphasia, apathy, personality changes and behavioural and psychological disturbances.
- Pathological brain changes include beta amyloid plaques, neurofibrillary tangles, marked neuroinflammation and neurodegeneration. A selection of one or more of these symptoms may be treated by a polysaccharide according to the invention.
- Symptoms of Parkinson’s disease include cardinal features of resting tremor, rigidity, bradykinesia and postural instability. Other common symptoms include masked facies, hypophonia, hypokinetic dysarthria, micrographia, shuffling gait, stooped posture, fatigue, constipation, depression, anxiety, dementia.
- Pathological brain changes include loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and accumulation of Lewy bodies (cytoplasmic protein inclusions composed of alpha synuclein protein) as well as mitochondrial dysfunction, neuroinflammation and neurodegeneration. A selection of one or more of these symptoms may be treated by a polysaccharide referred to herein.
- Huntington's disease Symptoms of Huntington’s disease include chorea, incoordination, cognitive decline, personality changes, and psychiatric symptoms, culminating in immobility, mutism, and inanition. Other common symptoms include cognitive dysfunction, impaired social and occupational functioning, irritability and impulsivity, twitching or restlessness, loss of coordination, deficits in motor coordination, impaired concentration, disinhibition or unusually anxious behaviour, depression, obsessions and compulsions.
- Huntington's disease is caused by an expanded CAG repeat at the N-terminus of the gene that encodes the huntingtin protein, which generates an elongated polyglutamine tail that promotes aggregation.
- Aggregates interfere with normal cellular functions, such as mitochondrial function, transcriptional regulation, axonal and vesicular transport, apoptosis, proteasome function, and cell-cell interactions.
- a selection of one or more of these symptoms may be treated by a polysaccharide referred to herein.
- Symptoms of motor neuron disease may comprise upper extremity weakness, stiffness with poor coordination and balance, spastic, unsteady gait, painful muscle spasms, difficulties arising from chairs and climbing stairs, foot drop, progressive difficulties in maintaining posture, muscle atrophy, hyper reflexia, dysponea, coughing and choking on liquids and food, strained slow speech, propensity for falls, sialorrhoea and drooling, inappropriate emotional outbursts, cognitive impairment, features of frontotemporal dementia.
- Pathological mechanisms involved include protein misfolding, glutamate toxicity, oxidative stress, microglial activation, mitochondrial dysfunction, disrupted axonal transport, RNA metabolism dysregulation. A selection of one or more of these symptoms may be treated by a polysaccharide referred to herein.
- Symptoms of prion disease may comprise cognitive impairment, ataxia, myoclonus, parkisnsonism, agitation, depression and other psychiatric features, visual changes, insomnia, dysautomia, dizziness and non-specific or constitutional symptoms, sensory symptoms and movement disorders.
- Pathologically, prion diseases are characterized by presence of pathogenic prion proteins or PrPSc, vacuoles, neutron loss and astrogliosis. A selection of one or more of these symptoms may be treated by a polysaccharide referred to herein.
- Symptoms of Lewy body dementia may comprise cognitive fluctuations, visual hallucinations, auditory hallucinations, olfactory hallucinations, tactile hallucinations, movement disorders, parkinsonian symptoms (such as slowed movement, rigid muscles, tremor or shuffling when walking), rapid eye movement (REM) sleep behavioural disturbance, dizziness, poor regulation of body functions (dysregulated blood pressure, pulse, sweating and the digestive processes and constipation), cognitive dysfunction, confusion, poor attention, visual-spatial problems and memory loss, sleep disorders, fluctuating attention, drowsiness, disorganized speech, depression and apathy.
- lewy body dementia is characterized by the presence of lewy bodies, composed of alpha-synuclein protein. Mitochondrial dysfunction, neuroinflammation and neurodegeneration are also apparent. A selection of one or more of these symptoms may be treated by a polysaccharide referred to herein.
- Symptoms of frontotemporal dementia may comprise inappropriate social behaviour, loss of empathy, poor judgment, loss of inhibition, apathy, repetitive compulsive behaviour (such as tapping, clapping or smacking lips), altered eating habits (usually overeating or developing a preference for sweets and carbohydrates), eating inedible objects, speech and language problems (such as primary progressive aphasia, semantic dementia and progressive agrammatic (nonfluent) aphasia), movement-related problems (including tremor, rigidity, muscle spasms, poor coordination, difficulty swallowing, and muscle weakness).
- frontotemporal dementia is associated with focal degeneration of frontal and temporal lobes, associated with intra-neuronal and glial cell inclusions composed of tau protein or ubiquitin. Mitochondrial dysfunction, neuroinflammation and neurodegeneration are also apparent. A selection of one or more of these symptoms may be treated by a polysaccharide referred to herein.
- vascular dementia may comprise difficulties in problem solving, disinhibition, apathy, slowed processing of information, inability to maintain attention, frontal release reflexes, focal neurological signs, impaired balance and gait, cognitive dysfunction, particular difficulties in executive function, motor impairment.
- Pathologically damage is observed in both grey and white matter from vascular causes: smallvessel changes, infarction, ischaemia and haemorrhage. Mitochondrial dysfunction, neuroinflammation and neurodegeneration are also apparent. A selection of one or more of these symptoms may be treated by a polysaccharide referred to herein.
- Symptoms of Autism spectrum disorders include social communication and interaction impairments and restricted, repetitive, and stereotyped patterns of behaviors, interests, or activities, language delays or regression, verbal and non-verbal communication impairments, unusual posturing, motor stereotypes, sensory interests, macrocephaly. Mitochondrial dysfunction, neuroinflammation and neurodegeneration are also apparent. A selection of one or more of these symptoms may be treated by a polysaccharide referred to herein.
- Symptoms of depression include low mood, anhedonia, weight changes, sleep disturbance, libido changes, low energy, psychomotor problems, excessive guilt, poor concentration, and suicidal ideation. Mitochondrial dysfunction, neuroinflammation and neurodegeneration are also apparent. A selection of one or more of these symptoms may be treated by a polysaccharide referred to herein.
- Symptoms of schizophrenia include delusions, hallucinations, disorganised speech, disorganised/catatonic behaviour, asocial behavior, affective flattening, avolition, anhedonia, attention deficits, alogia, cognitive deficits, somatisation, depression, anxiety, motor coordination deficits. Mitochondrial dysfunction, neuroinflammation and neurodegeneration are also apparent. A selection of one or more of these symptoms may be treated by a polysaccharide referred to herein.
- a symptom may be treated and/or ameliorated so that it is equal to or better than that of the average of a population of “m” age- and/or gender-matched subjects without a neurodegenerative disease, or improved compared to the subject’s symptom before treatment with the plant or polysaccharide.
- Treatment of a symptom may be preventing its progression.
- a symptom may be treated by preventing or reversing its progression within a subject.
- an extract from a plant i.e. the roots of Sida cordifolia
- a polysaccharide of Formula (I) or any one of the 48 examples shown in Table 1 may be used to:
- treat/improve impaired memory in a subject with a neurodegenerative disease such as Alzheimer’s disease (e.g. treat/improve impaired memory (such as recognition memory, spatial learning and memory and/or reversal learning and memory) in a subject with a neurodegenerative disease, such as Alzheimer’s disease, compared to the average recognition memory, spatial learning and memory and/or reversal learning and memory performance of a population of “m” age- and/or gender matched subjects with the same neurodegenerative disease before treatment with the plant or polysaccharide, or compared to the subject’s recognition memory, spatial learning and memory and/or reversal learning and memory performance before treatment with the plant or polysaccharide);
- beta amyloid plaque load in the cortex of a subject with a neurodegenerative disease such as Alzheimer’s disease
- a neurodegenerative disease such as Alzheimer’s disease
- astrocytes in the cerebral cortex of a subject with a neurodegenerative disease such as Alzheimer’s disease
- a neurodegenerative disease such as Alzheimer’s disease
- a neurodegenerative disease such as Alzheimer’s disease
- a neurodegenerative disease such as Alzheimer’s disease
- reduce levels of microglia in the cerebral cortex of a subject with a neurodegenerative disease, such as Alzheimer’s disease e.g. reduce levels of microglia in the cerebral cortex of a subject with a neurodegenerative disease, such as Alzheimer’s disease, compared to the levels of microglia in the cerebral cortex of the subject before treatment with the plant or polysaccharide, or compared to the average levels of microglia in a population of “m” age- and/or gender matched plant polysaccharide treatment naive subjects with the same neurodegenerative disease
- m age- and/or gender matched plant polysaccharide treatment naive subjects with the same neurodegenerative disease
- oxidative stress in the cerebral cortex of a subject with a neurodegenerative disease such as Alzheimer’s disease
- a neurodegenerative disease such as Alzheimer’s disease
- reduce levels of oxidative stress in the cerebral cortex of a subject with a neurodegenerative disease, such as Alzheimer’s disease compared to the level of oxidative stress in the cerebral cortex of the subject before treatment with the plant or polysaccharide, or compared to the average levels of oxidative stress in a population of “m” age- and/or gender matched plant polysaccharide treatment naive subjects with the same neurodegenerative disease.
- “m” may be about 5 or more, about 10 or more, about 20 or more, about 30 or more, about 40 or more, about 50 or more, about 60 or more, about 70 or more, about 80 or more, about 90 or more, about 100 or more, about 110 or more, about 120 or more, about 130 or more, about 140 or more, or about 150 or more subjects.
- compositions according to the invention may further comprise a pharmaceutically acceptable salt or other form thereof.
- Pharmaceutical compositions according to the invention may comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and/or solubility enhancers.
- Pharmaceutical compositions according to the invention may comprise a pharmaceutically acceptable salt and optionally one or more pharmaceutically acceptable excipients.
- the pharmaceutical compositions can be formulated by techniques known in the art.
- compositions can be formulated as dosage forms for oral, parenteral, such as topical, transdermal, intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardial, nasal or aerosol administration.
- parenteral such as topical, transdermal, intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardial, nasal or aerosol administration.
- the pharmaceutical composition may be formulated as a dosage form for oral administration.
- salts are intended to indicate salts which are not harmful to a patient.
- Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
- Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
- suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p- aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like.
- compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, volume 66, issue 2.
- metal salts include lithium, sodium, potassium, magnesium salts and the like.
- ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
- composition according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
- Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
- solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
- liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
- the compounds of the invention may form solvates with water or common organic solvents. Such solvates are also encompassed within the scope of the present invention.
- composition may further comprise a buffer system, preservative(s), tonicity agent(s), chelating agent(s), stabilizers and surfactants, which is well known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 20th edition, 2000.
- the composition may also further comprise one or more therapeutic agents active against the same disease state.
- Methods to produce controlled release systems useful for compositions of the current invention include, but are not limited to, crystallization, condensation, cocrystallization, precipitation, co-precipitation, emulsification, dispersion, high pressure homogenisation, encapsulation, spray drying, microencapsulating, coacervation, phase separation, solvent evaporation to produce microspheres, extrusion and supercritical fluid processes.
- General reference is made to Handbook of Pharmaceutical Controlled Release (Wise, D. L., ed. Marcel Dekker, New York, 2000) and Drug and the Pharmaceutical Sciences vol. 99: Protein Composition and Delivery (MacNally, E.J., ed. Marcel Dekker, New York, 2000).
- Administration of pharmaceutical compositions according to the invention may be through several routes of administration, for example, oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route.
- routes of administration for example, oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route.
- routes of administration for example, oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route.
- topical use sprays, creams, ointments, jellies, gels, inhalants, dermal patches, implants, solutions of suspensions, etc., containing the compounds of the present invention are contemplated.
- topical applications shall include mouth washes and gargles.
- Compounds of the invention may be used in wafer technology, wafer technology, such as the biodegradable Gliadel polymer wafer, is useful for brain cancer chemotherapy.
- compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, troches, dragees, pills, lozenges, powders and granules and liquid dosage forms for oral administration include solutions, emulsions, aqueous or oily suspensions, syrups and elixirs, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient.
- compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
- Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically-acceptable excipients which are suitable for the manufacture of tablets.
- excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,356, 108; 4, 166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release.
- Formulations for oral use may also be presented as hard gelatine capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
- Aqueous suspensions may contain the active compounds in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyl-eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
- the aqueous suspensions may also contain one or more colouring agents, one or more flavouring agents,
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as a liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
- a dispersing or wetting agent e.g., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
- the pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions.
- the oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof.
- Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
- the emulsions may also contain sweetening and flavouring agents.
- Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavouring agent and a colouring agent.
- the pharmaceutical composition may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents described above.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
- Suitable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
- sterile, fixed oils are conveniently employed as a solvent or suspending medium.
- any bland fixed oil may be employed using synthetic mono- or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables.
- Parenteral administration may be performed by subcutaneous, intramuscular, intraperitoneal or intravenous injection by means of a syringe, optionally a pen-like syringe.
- parenteral administration can be performed by means of an infusion pump.
- a further option is a composition which may be a solution or suspension for the administration of the prolactin receptor antagonist in the form of a nasal or pulmonal spray.
- the pharmaceutical compositions containing the compound of the invention can also be adapted to transdermal administration, e.g. by needle-free injection or from a patch, optionally an iontophoretic patch, or transmucosal, e.g. buccal, administration.
- compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
- a medicament includes but is not limited to a composition, such as an composition (e.g. a pharmaceutical composition or an edible composition), a prescription drug, a non-prescription drug, an over the counter medicine, a dietary supplement, a dietary food, a clinical food, an edible product, a tablet, a capsule, a pill, and food products such as beverages or any other suitable food product, and any other composition which is commonly known to the skilled person.
- the medicament may be an injectable substance or an inhalable substance, such as a nasal spray.
- the polysaccharide may be added to an edible composition or pharmaceutical composition in a specific salt form.
- the edible composition according to the present invention may take any physical form. In particular, it may be a food product, a beverage, a dietary food product, or a clinical food product. It may also be a dietary supplement, in the form of a beverage, a tablet, a capsule, a liquid (e.g. a soup or a beverage, a spread, a dressing or a dessert) or any other suitable form for a dietary supplement.
- the edible composition may be in a liquid or a spreadable form, it may be a spoonable solid or soft-solid product, or it may be a food supplement.
- the edible composition is a liquid product.
- the edible composition may suitably take the form of e.g. a soup, a beverage, a spread, a dressing, a dessert, a bread.
- the term “spread” as used herein encompasses spreadable products such as margarine, light margarine, spreadable cheese based products, processed cheese, dairy spreads, and dairy- alternative spreads.
- Spreads as used herein may have a concentration of oil and/or fat of between about 5% and 85% by weight, preferably between 10% and 80% by weight, more preferred between 20% and 70% by weight.
- oil and/or fat are from vegetable origin (such as but not limited to sunflower oil, palm oil, rapeseed oil); oils and/or fats of nonvegetable origin may be included in the composition as well (such as but not limited to dairy fats, fish oil).
- vegetable origin such as but not limited to sunflower oil, palm oil, rapeseed oil
- oils and/or fats of nonvegetable origin may be included in the composition as well (such as but not limited to dairy fats, fish oil).
- aqueous composition is defined as a composition comprising at least 50% w/w water.
- aqueous solution is defined as a solution comprising at least 50% w/w water, and the term “aqueous suspension” is defined as a suspension comprising at least 50% w/w water.
- aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
- the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
- the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art. Depot injectable formulations are also contemplated as being within the scope of the present invention.
- the isolated polysaccharide, or the composition may be administered through several routes of administration, for example, oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route.
- routes of administration for example, oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route.
- routes of administration for example, oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route.
- the preferred route will depend on the general condition and age of the subject to be treated,
- each star of Formula (I) and Formula (II) corresponds to an arabinofuranose, preferably an L-arabinofuranose, more preferably an alpha-arabinofuranose, most preferably an alpha-L- arabinofuranose.
- average may be the arithmetic mean, the mode or the median. Preferably the average refers to the arithmetic mean.
- isolated can refer to a polysaccharide that is no longer in its natural environment.
- isolated can refer to a polysaccharide that has been separated from Malvaceae/Malvoideae/Malveae plant tissue and cells (such as Sida Cordifolia tissue and Sida Cordifolia cells).
- a “subject” may be a vertebrate, a mammal, a non-human animal or a domestic animal.
- polysaccharide, the adjuvant, the vaccine, the composition and the medicament according to the invention may be used to treat any mammal, for example livestock (e.g. a horse), pets, or maybe used in other veterinary applications.
- Livestock may be bovine, cow, cattle, sheep, horse, chicken, goat, pig, calf, deer, goose, turkey or rabbit.
- a domestic animal may be a dog or a cat.
- the subject is a mammal.
- Most preferably the mammal is a human being.
- An organism can refer to a subject.
- treatment means the management and care of a subject for the purpose of combating a condition, such as a disease or a disorder.
- the term is intended to include the full spectrum of treatments for a given condition from which the subject is suffering, including alleviating symptoms or complications, delaying the progression of the disease, disorder or condition, alleviating or relieving the symptoms and complications, and/or to cure or eliminating the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a subject for the purpose of combating the disease, condition, or disorder and includes the administration of the ligand to prevent the onset of the symptoms or complications.
- Figure 1 is a bar graph showing the effect of the PP on the locomotor function of APP/PS 1 mice.
- APP/PS 1 and wild-type mice were subjected to assessment in an open field task, which measured path length (A), speed (B) and linearity (C) as measures of locomotor function.
- Data represent mean ⁇ SEM for 10-12 mice.
- Figure 2 is a bar graph showing the effect of the PP on the anxiety levels of APP/PS 1 mice.
- APP/PS 1 and wild-type mice aged 7 months were subjected to assessment in an open field task, which measured rearing (A), grooming (B), defecation (C) and time spent in the centre of the arena (D) as measures of anxiety.
- Data represent mean ⁇ SEM for 10-12 mice.
- Figure 3 is a bar graph showing that impaired recognition memory in APP/PS 1 mice is restored by PP treatment. Twenty-four hours following exposure to the open field arena, a novel object recognition task (ORT) was conducted using the same arena. Recognition index, a measure of the percentage of time spent exploring either object, is illustrated in the acquisition phase (A) during exposure to two identical objects, and the test phase (B), in the presence of one familiar and one novel object. ***p ⁇ 0.001, multiple t-test s with Holm-Sidak’s multiple comparisons post-hoc test. Data represent mean ⁇ SEM for 10-12 mice.
- Figure 4 shows that spatial learning and memory are improved by PP treatment in APP/PS 1 mice.
- the acquisition training phase involved four training sessions per day over four consecutive days. Illustrated are escape latency (A), path length (B) and swim speed (C) for APP/PS 1 mice treated with saline or PP during acquisition training.
- a probe trial was conducted on the fifth day, 24 hours following the final training session as a measure of spatial memory. Time spent in the exact target area is shown (D), as is the proportion of time spent in each quadrant during the probe trial by saline-treated (E) and PP-treated (F) APP/PS 1 mice.
- FIG. 5 shows that reversal learning is improved by PP treatment in APP/PS 1 mice.
- Reversal water maze training began 24 hours following the Morris water maze probe trial and consisted of four consecutive days with four training sessions per day. Illustrated are escape latency (A), path length (B) and swim speed (C) for APP/PS 1 treated with saline or PP during reversal acquisition training.
- a probe trial was conducted on the fifth day, 24 hours following the final training session as a measure of reversal spatial memory. Time spent in the exact target area is shown (D), as is the proportion of time spent in each quadrant during the reversal probe trial by saline- treated (E) and PP-treated (F) APP/PS 1 mice.
- Figure 6 shows that sensorimotor function in APP/PS 1 mice is unaffected by PP treatment. Subsequent to the reversal water maze probe trial, sensorimotor function was assessed in saline-treated and PP-treated APP/PS 1 mice in 3 visual water maze trials. Illustrated are escape latency (A), path length (B) and swim speed (C). Data represent mean ⁇ SEM for 10-12 mice per group.
- Figure 7 shows that PP treatment reduces A ⁇ deposition in the brains of APP/PS 1 mice.
- Representative images (lOx magnification) are shown that depict the cerebral cortex (A) and dentate gyrus (D) of APP/PS 1 mice treated with saline and the cerebral cortex (B) and dentate gyrus (E) of PP-treated APP/PS 1 mice.
- Quantification of A ⁇ immunopositivity in the cortex (C) and dentate gyrus (F) of saline- and PP-treated APP/PS 1 mice is also shown.
- Figure 8 shows that PP treatment reduces levels of astrocytes in the cerebral cortex of APP/PS 1 mice.
- Representative images (lOx magnification) are shown that depict the cerebral cortex (A) and dentate gyrus (D) of APP/PS 1 mice treated with saline and the cerebral cortex (B) and dentate gyrus (E) of PP-treated APP/PS1 mice.
- Also illustrated are exemplary magnified images (20x magnification) of GFAP staining in the cortex of saline- (G) and PP- (H) treated APP/PS1 mice, as well as representative 40x images in the upper right corner (G, H).
- Figure 9 shows that PP treatment reduces levels of microglia in the cerebral cortex of APP/PS 1 mice.
- Representative images (lOx magnification) are shown that depict the cerebral cortex (A) and dentate gyrus (D) of APP/PS 1 mice treated with saline and the cerebral cortex (B) and dentate gyrus (E) of PP-treated APP/PS1 mice.
- Also illustrated are exemplary magnified images (20x) of Ibal staining in the cortex of saline- (G) and PP- (H) treated APP/PS1 mice, as well as representative 40x images in the upper right corner (G, H).
- Figure 10 shows that PP treatment reduces levels of oxidative stress in the cerebral cortex of APP/PS 1 mice.
- Representative images (lOx magnification) are shown that depict the cerebral cortex (A) and dentate gyrus (D) of APP/PS 1 mice treated with saline and the cerebral cortex (B) and dentate gyrus (E) of PP-treated APP/PS 1 mice.
- Also illustrated are exemplary magnified images (20x magnification) of Ibal staining in the cortex of saline- (G) and PP- (H) treated APP/PS 1 mice, as well as representative 40x images in the upper right comer (G, H).
- *p ⁇ 0.05, Student’s t-test Data represent mean ⁇ SEM for 6 per group.
- Figure 11 shows that PP treatment has no effect on levels of IRS-1 pSer 616 in the brains of APP/PS 1 mice.
- Representative images (lOx magnification) are shown that depict the cerebral cortex (A) and dentate gyrus (D) of APP/PS 1 mice treated with saline and the cerebral cortex (B) and dentate gyrus (E) of PP-treated APP/PS 1 mice.
- Also illustrated are exemplary magnified images (20x) of Ibal staining in the cortex of saline- (G) and PP- (H) treated APP/PS1 mice, as well as representative 40x images in the upper right corner (G, H). Data represent mean ⁇ SEM for 6 per group.
- Figure 12 is a bar graph showing that PP treatment has no effect on spleen weight in APP/PS 1 mice. Average weights of spleens from PP-treated APP/PS 1 mice are illustrated (A). Data represent mean ⁇ SEM for 6 per group.
- Figure 13 shows, at the phyla level, the effect of the effect of an isolated polysaccharide according to the invention on the faecal bacterial biodiversity of wildtype and APP/PS 1 mice.
- Figure 14 shows the effect of the effect of an isolated polysaccharide according to the invention on the faecal bacterial biodiversity of wild-type and APP/PS 1 mice at the phyla and species level.
- Figure 15 shows the plasma IL-27 concentration in APP and wild-type mice treated with saline and the polysaccharide (PP) according to the invention for 7 days.
- Figure 16 shows the plasma TNF alpha concentration in APP and wild-type mice treated with saline and the polysaccharide (PP) according to the invention for 7 days.
- Figure 17 shows that the polysaccharide potentiates cytokine response after an LPS challenge in APP/PS 1 mice.
- Figure 18 is a concentration-effect curve in SIM-A9 microglia treated with the polysaccharide according to the invention or LPS.
- the measured effect is NO production.
- Figure 19 shows the effect of the polysaccharide according to the invention on cytokine production by microglia.
- mice with a C57B1/6J background were bred with wild-type C57B1/6J females at the Biomedical and Behavioural Research Unit at Ulster University in Coleraine.
- Offspring were ear punched and positivity for the APP swe /PS1 ⁇ e9 transgene, or lack thereof was confirmed by polymerase chain reaction, using primers specific for the APP sequence of the APP/PS1 construct (Forward "GAATTCCGACATGACTCAGG”, Reverse: "GTTCTGCTGCATCTTGGACA”).
- mice Seven month-old APP/PS 1 mice were treated with saline (0.9% w/v) or a plant polysaccharide (PP) isolated from Sida cordifolia (300 mg/kg bw) once-daily by oral gavage for 3 weeks prior to commencement of a 12 day period of behavioural testing, during which time treatment was maintained. Mice in both groups were treated for a total of 33 days before sacrifice.
- saline 0.9% w/v
- PP plant polysaccharide isolated from Sida cordifolia
- mice were subjected to open field, novel object recognition, Morris water maze and reversal water maze behavioural tests to assess locomotor function, anxiety and cognition in 7 month-old APP/PS 1 mice treated with saline and PP.
- mice were sacrificed and their brains were harvested and processed for immunohistochemical analysis, as described in. In both groups, brain sections were stained with GFAP, Ibal, 8- oxoguanine and IRS-lpSer 616 and levels of immunopositivity were quantified.
- mice Seven month old APP/PS1 mice were administered either saline (0.9% w/v) or a plant polysaccharide (PP) (300 mg/kg bw) by oral gavage, once daily (at 15:00h) for 3 weeks prior to the commencement of a 12-day battery of behavioural tests, during which time, dosing was continued.
- saline 0.9% w/v
- PP plant polysaccharide
- Plant polysaccharide treatment reduces levels of astrocytes in the cerebral cortex of APP/PS1 mice
- Plant polysaccharide treatment reduces levels of microglia in the cerebral cortex of APP/PS1 mice
- Plant polysaccharide treatment has no effect on levels of IRS-1 pSer 616 in the brains of APP/PS1 mice
- Example 5 The effect of the polysaccharide on faecal bacterial diversity
- Figure 13 shows the % composition of faecal microbiota in mice at the baseline and after 7 days of treatment with the polysaccharide.
- Figure 14 is a summary of the data shown in Figure 13 and also a summary of data in which bacterial diversity was analysed at the species level (Alpha diversity was calculated using the Shannon index).
- Figures 13 and 14 clearly show that the polysaccharide according to the invention increases bacterial faecal diversity at the phylum level and species level in both wild-type and APP/PS 1 mice.
- the polysaccharide according to the invention can be used to treat neurodegenerative diseases and/or neuroinflammation by increasing microbial diversity in the gut.
- Example 6 The polysaccharide increases plasma levels of IL-27 in wild-type and APP/PS1 mice and reduces plasma TNF ⁇ levels in the same mice
- Isolated plant polysaccharide (300mg/kg) or saline vehicle control was orally administered to 8-month-old APP/PS 1 mice for 7 days.
- Cytokine levels of IL-27 were significantly increased in wild-type (p ⁇ 0.05) and APP/PS 1-polysaccharide-treated mice (p ⁇ 0.05) compared to their respective controls.
- circulating IL-27 concentration in APP/PS 1 polysaccharide-treated mice was significantly increased compared to wild-type saline animals (p ⁇ 0.05). *p ⁇ 0.05.
- TNF- ⁇ levels of were significantly reduced in wild-type PP-treated mice compared to saline-treated wild- types, and significantly reduced compared to saline (p ⁇ 0.05), but not PP-treated APP/PS1 animals. *p ⁇ 0.05 **p ⁇ 0.001.
- the PP may be used to treat Parkinson’s disease.
- Example 7 The polysaccharide potentiates cytokines responses to LPS challenge
- Neuroinflammation resulting from systemic infections has been shown to play an important role in neurodegenerative disease.
- LPS hypo-responsiveness has been associated with detrimental effects in brain, by inhibiting microglial protective properties thereby exacerbating neurodegenerative disease processes.
- systemic inflammation enhances the risk and progression of Alzheimer’s disease
- systemic infections are associated with a significant percentage of clinical relapses in multiple sclerosis
- systemic infections in PD enhance motor symptoms. The inventors therefore decided to investigate whether the polysaccharide according to the invention may has an effect on cytokine responses to intravenously administered LPS.
- Isolated plant polysaccharide (PP) 300mg/kg or saline vehicle control was orally administered to 8-month-old APP/PS 1 mice for 7 days.
- IL-10, MCP-1, IL-12p7, IL-6, GM-CSF TNF- ⁇ and I1-1 ⁇ responses were significantly enhanced compared to saline-treated APP/PS 1 mice (P ⁇ 0.05-P ⁇ 0.01).
- PP administration potentiated MCP-1, IL-6 and TNF- ⁇ compared to saline-treated WT littermates (p ⁇ 0.05-p ⁇ 0.01).
- Increases in IL-10, IL-27, IL-12P70, GM-CSF and I1-1 ⁇ were unique to APP/PS 1 levels after administration of PP were unique to the APP/PS 1 model.
- this data shows that treatment with polysaccharide leads to much greater LPS responsiveness in the APP/PS 1, and this represents a protective mechanism for the brain.
- the polysaccharide according to the invention can be used to potentiate neuroinflammatory responses and/or treat neurodegenerative disorders.
- Example 8 The effect of the polysaccharide on cytokine production by microglia
- the polysaccharide also causes microglia to produce NO in a concentration-dependent manner (see Figure 18).
- Microglia produce IL-6 and IL- 12 in a concentration-dependent manner in response to contact with the polysaccharide according to the invention but do not produce any detectable levels of TNFa (see Figure 19).
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Materials Engineering (AREA)
- Biotechnology (AREA)
- Polymers & Plastics (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Psychiatry (AREA)
- Alternative & Traditional Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
L'invention concerne un polysaccharide isolé et une composition comprenant le polysaccharide pour une utilisation dans le traitement d'une maladie neurodégénérative.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB2017251.6A GB202017251D0 (en) | 2020-10-30 | 2020-10-30 | Neurodegenerative treatment |
PCT/GB2021/052817 WO2022090734A1 (fr) | 2020-10-30 | 2021-10-29 | Traitement neurodégénératif |
Publications (1)
Publication Number | Publication Date |
---|---|
EP4237454A1 true EP4237454A1 (fr) | 2023-09-06 |
Family
ID=73776477
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP21806022.6A Pending EP4237454A1 (fr) | 2020-10-30 | 2021-10-29 | Traitement neurodégénératif |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP4237454A1 (fr) |
GB (1) | GB202017251D0 (fr) |
WO (1) | WO2022090734A1 (fr) |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4356A (en) | 1846-01-15 | A horace h | ||
US108A (en) | 1836-12-15 | Braving | ||
US4166452A (en) | 1976-05-03 | 1979-09-04 | Generales Constantine D J Jr | Apparatus for testing human responses to stimuli |
US4265874A (en) | 1980-04-25 | 1981-05-05 | Alza Corporation | Method of delivering drug with aid of effervescent activity generated in environment of use |
US20150368372A1 (en) * | 2014-06-24 | 2015-12-24 | The United States Of America, As Represented By The Secretary Of Agriculture | Cellulosic Arabinoxylan fiber (CAF) And Methods Of Preparing |
-
2020
- 2020-10-30 GB GBGB2017251.6A patent/GB202017251D0/en not_active Ceased
-
2021
- 2021-10-29 WO PCT/GB2021/052817 patent/WO2022090734A1/fr unknown
- 2021-10-29 EP EP21806022.6A patent/EP4237454A1/fr active Pending
Also Published As
Publication number | Publication date |
---|---|
GB202017251D0 (en) | 2020-12-16 |
WO2022090734A1 (fr) | 2022-05-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Simon et al. | Parkinson disease epidemiology, pathology, genetics, and pathophysiology | |
TWI583374B (zh) | 使用植物***素次***二酚(cbdv)來治療癲癇之用途 | |
US9895375B2 (en) | Compositions containing riboflavin and sesamin-class compounds | |
JP6529634B1 (ja) | アミロイドβ分解排出促進剤 | |
US20220000882A1 (en) | Method of treating dementia | |
KR101807953B1 (ko) | 고수 추출물을 유효성분으로 하는 치매 예방 또는 치료용 약학적 조성물 | |
JP7410025B2 (ja) | オートファジーの誘導のために高タンパク質を使用する組成物及び方法 | |
KR20200038408A (ko) | IF1 (ATPase inhibitory factor 1)을 유효성분으로 함유하는 근감소증의 예방 또는 치료용 약학 조성물 | |
CN111032027B (zh) | 使用烟酰胺核糖核苷治疗和预防运动神经元疾病 | |
KR20190009174A (ko) | 우르소데옥시콜산을 함유하는 염증성 질환 또는 척수 손상 예방 또는 치료용 조성물 | |
US20210137857A1 (en) | A composition for treatment or prevention of a neurodegenerative disease | |
JP2021169506A (ja) | リポ多糖を用いた脳機能改善剤、食品及び医薬品 | |
US20140030353A1 (en) | Composition for prevention or treatment of disease associated with production of autoantibody | |
WO2022090734A1 (fr) | Traitement neurodégénératif | |
ES2973249T3 (es) | Composición que comprende cepa de Agathobaculum sp. como ingrediente efectivo para la prevención, alivio o tratamiento del trastorno del espectro autista | |
CA3017307A1 (fr) | Polycomplexes de composes poly-lysine pour la prevention et/ou la lutte contre la sclerose laterale amyotrophique | |
JPWO2008056452A1 (ja) | 希少糖の筋萎縮性側索硬化症と関連した運動障害の発症または進行の遅延への利用 | |
AU2017336292B2 (en) | Omega 3 fatty acids and choline as neuroprotectant in patients with no dementia | |
JP2020516586A (ja) | 認知症ではない個体において、認知的加齢を軽減する組成物及び方法 | |
US20240082292A1 (en) | Neurodegenerative treatment | |
JP7106340B2 (ja) | 血液脳関門保護剤 | |
US20140271908A1 (en) | Dietary supplements and methods for preventing and treating migraines | |
EP3388061A1 (fr) | Acides gras omega 3, composes liberant no, vitamine b12 et choline comme neuroprotecteurs pour patients sans demence | |
WO2012035871A1 (fr) | Composition amplifiant la fonction cérébrale et méthode d'amplification de la fonction cérébrale | |
JP2009256282A (ja) | 抗als剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: UNKNOWN |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20230526 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) |